A practical synthesis of renin inhibitor MK-1597 (ACT-178882) via catalytic enantioselective hydrogenation and epimerization of piperidine intermediate

Article abstract of DOI:10.1021/jo102070e

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.

Full text of DOI:10.1021/jo102070e

pubs.acs.org/joc
A Practical Synthesis of Renin Inhibitor MK-1597 (ACT-178882)
via Catalytic Enantioselective Hydrogenation and Epimerization
of Piperidine Intermediate
,†
Carmela Molinaro,* Scott Shultz, Amelie Roy, Stephen Lau, Thao Trinh,
‡
†
†
†
ꢀ
Remy Angelaud, Paul D. O’Shea, Stefan Abele, Mark Cameron, Ed Corley,
†
†
§
‡
‡
ꢀ
Jacques-Alexis Funel,§ Dietrich Steinhuebel,‡ Mark Weisel,‡ and Shane Krska‡
†
ꢀ
Department of Process Research, Merck, 16711 Autoroute Transcanadienne, Kirkland, Quebec,
Canada H9H 3L1, ‡Department of Process Research, Merck, P.O. Box 2000, Rahway, New Jersey 07065,
United States, and Department of Process Research Chemistry, Actelion Pharmaceuticals Ltd.,
Gewerbestrasse 16, 4123 Allschwil, Switzerland
§
carmela_molinaro@merck.com
Received October 19, 2010
A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treat-
ment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall
yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asym-
metric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification se-
quence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.
Introduction
of the angiotensin converting enzyme (ACE) inhibitors2 and
angiotensin II receptor blockers (ARBs).3 Several antagonists
of the RAAS pathway have emerged as effective treatments for
hypertension.4 A collaboration between Actelion5 and our
discovery efforts at Merck1e identified MK-15976 as a potent,
selective inhibitor of the renin receptor and a promising lead in
The renin-angiotensin aldosterone system (RAAS),1 is
known to play a key role in the regulation of blood pressure
through several seminal studies culminating with the discovery
(1) (a) MacGregor, G. A.; Markandu, N. D.; Roulston, J. E.; Jones, J. C.;
Morton, J. J. Nature 1981, 291, 329. (b) Weber, M. A. Am. J. Hypertens.
1999, 12, 189S. (c) Weir, M. R.; Dzau, V. J. Am. J. Hypertens. 1999, 12, 205S.
(d) Brewster, U. C.; Perazella, M. A. Am. J. Med. 2004, 116, 263. (e) Chen, A.;
ꢀ
Bayly, C.; Bezenc-on, O.; Richard-Bildstein, S.; Dube, D.; Dube, L.; Gagne,
S.; Gallant, M.; Gaudreault, M.; Grimm, E.; Houle, R.; Lacombe, L.;
(2) (a) Patchett, A. A.; Cordes, E. H. Adv. Enzymol. Relat. Areas Mol.
Biol. 1985, 57, 1. (b) Fyhrquist, F. Drugs 1986, 32 (Suppl. 5), 33.
(3) (a) Ruilope, L. M.; Rosei, E. A.; Bakris, G. L.; Mancia, G.; Poulter,
N. R.; Taddei, S.; Unger, T.; Volpe, M.; Waeber, B.; Zanna, F. Blood
Pressure 2005, 14, 196. (b) Oparil, S.; Yarows, S. A.; Patel, S.; Fang, H.;
Zhang, J.; Satlin, A. Lancet 2007, 370, 221.
ꢀ
ꢀ
ꢀ
Laliberte, S.; Levesque, J.-F.; Liu, S.; MacDonald, D.; Mackay, B.; Martin,
D.; McKay, D.; Powell, D.; Remen, L.; Soisson, S.; Toulmond, S. Bioorg.
ꢀ
ꢁ
Med. Chem. Lett. 2010, 20, 2204.
1062 J. Org. Chem. 2011, 76, 1062–1071
Published on Web 01/20/2011
DOI: 10.1021/jo102070e
r
2011 American Chemical Society

Molinaro et al.
JOCArticle
SCHEME 1. Retrosynthetic Approach to Renin Inhibitor MK-1597 (1)
SCHEME 2. Synthesis of Amine Side Chain 2a
the treatment of hypertension. In order to support the devel-
opment of this compound, we sought to develop a scalable syn-
thesis of MK-1597. We describe herein a practical, chroma-
tography-free, enantioselective synthesis of MK-1597 that has
been performed on multikilogram scale.
Our retrosynthetic analysis of MK-1597 is shown in
Scheme 1. We envisioned that MK-1597 could be assembled
by a coupling between piperidine carboxylic acid 3 and cyclo-
propylamine fragment 2. The two stereocenters of carboxylic
acid 3 could be installed via a catalytic asymmetric hydro-
genation of a tetrasubstituted ene-ester 4 followed by an
epimerization/saponification sequence. Ene-ester 4 in turn
can be prepared from commercially available ethyl 4-oxopi-
peridine-3-carboxylate (8), 2,5-dibromopyridine (9) and
p-cresol (7).
aConditions: (a) 1. iPrMgCl, THF, -30 °C, 80%; 2. DMF, 0 °C; 3. HCl,
80%. (b) NaH, MeOCH2PPh3, THF, 50 °C, 86%. (c) H2 (45 psi), Pd-
(OH)2/C, EtOAc, 96%. (d) 1. CDI, CH3CN; 2. cyclopropylamine, 30 °C,
Results/Discussion
86%. (e) NaBH4, BF3 THF, 36 °C, 99%.
3
exchange protocol8 followed by a DMF quench. Aldehyde
10 was subsequently reacted with NaH and MeOCH2PPh3 to
furnish a 1:1 mixture of E- and Z-vinyl methyl ethers 11.9 The
mixture of olefins was submitted to hydrogenation condi-
tions using Pearlman’s catalyst, providing carboxylic acid 12
in 96% yield and 94 A%.10,11 CDI-mediated coupling of car-
boxylic acid 12 with cyclopropylamine in CH3CN afforded
amide 13 in 86% yield. In order to meet the purity criteria for
amine 2 (>95 A%), a recrystallization of amide 13 using hot
iPAc/hexanes was performed resulting in an 83% recovery
and a purity upgrade from 95 A% to 98 A%. Finally, a large-
Preparation of Amine Side Chain 2. Amine 2 was prepared
in five steps from cheap and readily available 5-bromo-2-
chlorobenzoic acid (5) (Scheme 2). The synthesis started with
a Bouveault reaction.7 Thus, bromide 5 was converted to al-
dehyde 10 in 65% yield via Knochel’s magnesium-halogen
(4) (a) Kasani, A.; Subedi, R.; Stier, M.; Holsworth, D. D.; Maiti, S. N.
Heterocycles 2007, 73, 47. (b) Fisher, N. D. L.; Hollenberg, N. K. J. Am. Soc.
Nephrol. 2005, 16, 592. (c) Amin Zaman, M.; Oparil, S.; Calhoun, D. A. Nat.
Rev. Drug. Discovery 2002, 1, 621. (d) Rahuel, J.; Rasetti, V.; Maibaum, J.;
Rueger, H.; Goschke, R.; Cohen, N.-C.; Stutz, S.; Cumin, F.; Fuhrer, W.;
Wood, J. M.; Gruetter, M. G. Chem. Biol. 2000, 7, 493. (e) Wood, J. M.;
Stanton, J. L.; Hofbauer, K. G. J. Enzyme Inhib. 1987, 1, 169. (f) Rahuel, J.;
Priestle, J. P.; Gruetter, M. G. J. Struct. Biol. 1991, 107, 227.
scale BH3 THF reduction12 at36 °C afforded 4.54 kg of crude
3
ꢁ
(5) (a) Corminboeuf, O.; Bezenc-on, O.; Grisostomi, C.; Remen, L.;
Richard-Bildstein, S.; Bur, D.; Prade, L.; Hess, P.; Strickner, P.; Fischli,
amine 2 in 99% assay yield and 96 A%.
W.; Steiner, B.; Treiber, A. Bioorg. Med. Chem. Lett. 2010, 20, 6286. (b)
ꢁ
Bildstein, S.; Bur, D.; Prade, L.; Strickner, P.; Hess, P.; Fischli, W.; Steiner,
B.; Treiber, A. Bioorg. Med. Chem. Lett. 2010, 20, 6291.
(6) Also known as ACT-178882.
Corminboeuf, O.; Bezenc-on, O.; Remen, L.; Grisostomi, C.; Richard-
(9) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635. (b)
Coffman, D. D.; Marvel, C. S. J. Am. Chem. Soc. 1929, 51, 3496. (c) Wittig,
G.; Geissler, G. Ann. 1953, 580, 44. (d) Wittig, G.; Schollkopf, U. Chem. Ber.
1954, 97, 1318. (e) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654. (f)
Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Ber. 1958, 91, 61. (g) Horner,
L.; Hoffmann, H. M. R.; Wippel, H. G.; Klahre, G. Ber. 1959, 92, 2499. (h)
Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733.
(10) A% = HPLC area percent monitored at 220 nm.
(7) (a) Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306. (b) Bouveault, L.
Bull. Soc. Chim. Fr. 1904, 31, 13C22.
(8) (a) Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew.
Chem., Int. Ed. 1998, 37, 1701. (b) Abarbri, M.; Dehmel, F.; Knochel, P.
Tetrahedron Lett. 1999, 40, 7449. (c) Jensen, A. E.; Dohle, W.; Sapountzis, I.;
Lindsay, D. M.; Vu, V. A.; Knochel, P. Synthesis 2002, 4, 565. (d) Knochel,
P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.;
Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.
(11) Other Pt- and Rh-based metals were also tested; however, much
lower reactivities and/or purity profiles were observed.
(12) For the large-scale in situ preparation of BH3 THF see: Kanth,
3
J. V. B.; Brown, H. C. Inorg. Chem. 2000, 39, 1795 and references therein.
J. Org. Chem. Vol. 76, No. 4, 2011 1063

Molinaro et al.
JOCArticle
SCHEME 3. Synthesis of Hydrogenation Precursor 4aa
TABLE 1. Selected Microscale Asymmetric Hydrogenation Screening
Resultsa
mol % of metal
precursor
temperature HBF4 OEt2
3
conv.b
(%)
%
ee
aConditions: (a) NaOCl, CH3CN, 89%. (b) 1. Ethylene carbonate,
1-methylimidazole, DMAc 110 °C; 2. KOH, dibromopyridine, 77%. (c) Bis-
(pinacolato)diboron, PdCl2(dppf), KOAc, DMAc, 80 °C, 71%. (d) Pd-
(PPh3)4, Na2CO3, water, DME, 50 °C, 99%.
entry
(°C)
(equiv)
1
2
3
4
5
6
7c
15
50
0
30
29
37
65
91
99
98
98
98
99
99
2.7
2.7
2.7
2.7
2.7
2.7
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
0.09
0.37
0.64
0.9
0.9
Preparation of Hydrogenation Precursor 4a. Ene-ester 4a
was prepared in 49% yield and four steps starting from p-
cresol (7) (Scheme 3). Dichlorination of p-cresol (7) using
commercial bleach cleanly provided 14 in 89% yield. Alkyla-
tion of phenol 14 with ethylene carbonate followed by SNAr
reaction on dibromopyridine 9 provided pyridine bromide
15. Aryl boronate 16 was prepared using bis(pinacolato)-
diboron and a palladium catalyst (PdCl2(dppf)) in 71% yield.13
Finally, Suzuki coupling between the aryl boronate 16 and the
Boc-protected piperidine triflate 17a14 provided 99% yield of
the tetrasubstituted ene-ester 4a.
Asymmetric Hydrogenation. During the course of devel-
opment we screened the tetrasubstituted ene-ester 4a under
microscale hydrogenation conditions15 using H2 (500 psi), a
metal precursor and ligand (1: 1.05 ratio) in a solvent at 50 °C
for 18 h, as a first pass approach.16 Ru-, Ir-, and Rh-based
metal precursors were tested using over 384 combinations of
metal precursors, ligands, and solvents. While a few Rh cata-
lysts did give some level of enantioselectivity, it is notable
that Rh catalysts derived from representative ubiquitous
ligand families such as BINAP and DuPhos gave no conver-
sion.17 In general, the reactivity was very poor, and only a
small selection of conditions gave reasonable conversions.
During our screen, we were pleased to find that Ru metal pre-
87
96
84d
aReaction conditions: (COD)Ru(Me-allyl)2: SL-J212-1(1: 1.05), 500
psi H2, 18 h. bConversion is defined as the HPLC area % product/(start-
ing material þ product) observed at 210 nm. 1.89 kg scale. dIsolated
c
yield.
cursor (COD)Ru(Me-allyl)2 and Josiphos ligand SL-J212-1
gave >90% ee albeit in low yield 30% (Table 1, entry 1).
Further optimization revealed that a lower catalyst loading
with a concurrent lower reaction temperature resulted in an
increase in enantioselectivity from 91% ee to 99% ee while
maintaining the yield to ∼30% (entry 1 vs 2). At this stage we
believedthatthe pyridine moietywas likelya catalystinhibitor
and that the addition of a Brønsted acid might help. However,
the potential lability of the Boc group gave us concern with
that approach. Nevertheless, HBF4 OEt2 was found to pro-
3
vide a considerable boost in reactivity from 36 to 96% con-
version (entries 3-6 vs 2) while maintaining the enantioselec-
tivities at 98-99%ee. The use of 0.9 equiv of HBF4 OEt2
3
resulted in a reasonably robust procedure and after Darco
treatment18 on scale provided 2.3 kg of 6a in 84% isolated
yield and 99% ee (entry 7).
Epimerization/Saponification Sequence. A study of the epi-
merization of the ester carbon center of piperidine 6a is re-
ported in Table 2. We were surprised and pleased to find that
depending on the source of NaOEt tested (solid NaOEt in
EtOH, a commercially available solution of 21 wt % NaOEt/
EtOH in EtOH or 2 N NaOH in EtOH) different results were
obtained (entries 1-3). The best trans/cis ratio (14:1) of the
ester substrate 18 was obtained with the commercially avail-
able solution of 21 wt % NaOEt/EtOH (entry 2).19 A direct
epimerization/saponification using 5 equiv of 2 N NaOH in
(13) (a) Ishiyama, T.; Matsuda, N.; Miyaura, N. J. Org. Chem. 1995, 60,
7508. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(14) Petersen, M. D.; Boye, S. V.; Nielsen, E. H.; Willumsen, J.; Sinning,
S.; Wiborg, O.; Bols, M. Bioorg. Med. Chem. 2007, 15, 4159.
(15) For a description of the microscale screening conditions utilized in
this study see: Shultz, C. S.; Krska, S. Acc. Chem. Res. 2007, 40, 1320.
(16) Previous approaches to this class of intermediates include: (1)
racemic hydrogenation followed by HPLC chiral separation: (a) Patane,
M. A.; DiPardo, R. M.; Price, R. P.; Chang, R. S. L.; Ransom, R. W.;
O’Malley, S. S.; Di Salvo, J.; Bock, M. G. Bioorg. Med. Chem. Lett. 1998, 8,
2495. (b) Bachmann, S.; Scalone, M. Schnider, P. Process for the preparation
of enantiomerically enriched cyclic β-aryl or heteroaryl carboxylic acids.
U.S. Pat. Appl. 2007/0232653 A1, 2007; (2) resolution of the racemic carboxylic
acid: ref 16a; (3) asymmetric hydrogenation on the carboxylic acid: ref 16b.
(17) Other ligands tested: (S)-xyl-BINAP, (R,R)-Me-DuPhos, (R,R,S,S)-
Tangphos, W006-1, Catasium I, J004-1 and J212-1 (structures are available
in the Supporting Information)
(18) The Darco treatment is necessary to reduce the metal content in the
product. Before treatment the levels are >20000 ppm.
(19) Isolation of the product and resubjecting the esters to the same
epimerization conditions did not change the trans/cis ratio observed.
1064 J. Org. Chem. Vol. 76, No. 4, 2011

Molinaro et al.
JOCArticle
TABLE 2. Epimerization/Saponification Sequencea
entry
conditions
solid NaOEt, EtOH
18 trans/cis ratio
3 trans/cis ratio
yield (%)b
1
2
3
4
only cis
14:1
1:1
n.d.
n.d.
n.d.
n.d.
21 wt % NaOEt/EtOH, EtOH 70 °C
1 equiv 2 N NaOH, EtOH, 70 °C
5 equiv 2 N NaOH, EtOH, 70 °C
5 equiv 2 N NaOH, dioxane, 70 °C
1) 5 equiv 21 wt % NaOEt/EtOH, EtOH, 70 °C
2) 5 equiv 2 N NaOH
n.a.
n.a.
10:1
n.a.
5
no rx
6c
14:1
99:1
83
84
7d
1) 5 equiv 21 wt % NaOEt/EtOH, EtOH
2) 5 equiv 2 N NaOH
14:1
>120:1
aUnless otherwise stated, the reactions were run on 100-mg scale in 0.5 mL of solvent. bIsolated yield of 3. c40-g scale. d4.8-kg scale.
SCHEME 4. Alternative Synthesis of Carboxylic acid 3a
EtOH and dioxane was also tested (entries 4-5).20 A 10:1 ratio
of trans-/cis-carboxylic acid substrate 3 was obtained (entry 4).
Although promising, we knew that we would be unable to meet
final purity criteria for MK-1597 (>97 A%) with this ratio. A
purity upgrade after this stage would be difficult without a
flash chromatography since we were unable to reject the dia-
stereomer with subsequent crystallizations. Gratifyingly, a se-
quential epimerization with a solution of 21 wt % NaOEt/EtOH
followed by an in situ saponification with 5 equiv of 2 N NaOH
resulted in a 99:1 ratio of trans/cis of carboxylic acid 3 (entries 6).
Presumably, under these conditions, the trans-ester 17 converts
to the trans-carboxylic acid 3 faster than the cis-somer, and in
parallel, the cis ester 6 would still equilibrate to the thermo-
dynamically stable trans-isomer, providing a final trans/cis ratio
of 99:1 for the carboxylic acid 3. We were able to reproduce these
results on 4.8 kg scale of 6a providing 3.8 kg of carboxylic acid 3
in 84% yield, trans/cis ratio >120:1 and 98.9 A%.
Alternative Synthesis of Carboxylic Acid 3. Although the
asymmetric hydrogenation with a Boc protecting group was
viable on ∼2.5 kg scale, for even larger-scale campaigns a
more robust procedure was necessary to address the lability
of the Boc-substrates 4a and 6a under acidic conditions. We
subsequently tested the TFA ene-ester 4b because of its abi-
lity to tolerate the acidic hydrogenation reaction conditions
(Scheme 4). We were pleased to find that the (COD)Ru(Me-
allyl)2 catalyst provided 92% yield and 99% ee of 6b under
the same conditions. We have run preliminary experiments in
order to determine the mechanism by which the reduction
occurs. Substrate 4b was subjected to D2 under the same re-
action conditions. Analysis of the reaction at partial conver-
sion (∼35%) revealed that the major product had incorpo-
rated three deuterium atoms in the molecule. The unreacted
olefin 4b, however, showed no evidence of deuterium incor-
poration. These results suggest that a rearrangement step
may be involved in the process and is enantioselective.21
aConditions: (a) 1. Pd(dppf)Cl2, KHCO3, water, 2-MeTHF, 60 °C; 2.
4 N HCl, dioxane; 3. aqueous NaHCO3, 80%. (b) SL-J212-1, Ru(cod)-
(methallyl)2, HBF4 OEt2, 2-MeTHF, 1000psiH2, 23°C, 92%, 99%ee. (c)
3
1. 21 wt % NaOEt/EtOH; 2. water; 3. Boc2O; 4. 2 N NaOH, 70 °C, 88%.
Similar conditions were used to convert the TFA protected
piperidine 6b to carboxylic acid 3. Thus a one-pot in situ
TFA deprotection, Boc protection, epimerization and hy-
drolysis sequence allowed the preparation of 3.9 kg of 3 in
88% yield and >100:1 trans/cis ratio.
Amidation. A series of coupling conditions for carboxylic
acid 3 with amine fragment 2 have been explored (Table 3).
Although, HATU coupling was the highest yielding and
cleanest reaction to provide 19 (96% yield and 97.7 A%),
the cost of this reagent is prohibitive on scale. After a screen
(20) The rate of dissolution or solubility of different NaOEt sources in
ethanol may explain the different results observed.
(21) A full mechanism analysis is underway and will be reported in due
course.
J. Org. Chem. Vol. 76, No. 4, 2011 1065

Molinaro et al.
JOCArticle
TABLE 3. Amidation
heptane was added. The slurry was filtered and dried. MK-
1597 AcOH was isolated as a white crystalline salt (Ru = 5
ppm, Pd = < 1 ppm, 2.94 kg, 83% yield, 98.6 A%).
3
Conclusion
In conclusion, a practical large-scale chromatography free
synthesis of renin inhibitor MK-1597, a potential new treat-
ment for hypertension, was developed. The synthetic route
provided MK-1597, as its acetate salt, in 9 steps (isolated
intermediates) and 29% overall yield from commercially
available p-cresol (7). The key features of this sequence in-
clude a catalytic asymmetric hydrogenation of a tetrasub-
stituted ene-ester and a highly efficient epimerization/
saponification sequence of 4 which sets both stereocenters of
the molecule, and a short synthesis of amine fragment 2. This
approach was used to successfully produce 2.94 kg of MK-1597
acetate salt.
entry
coupling reagent
yield (%)
purity (A%)
1
2
3
4
5
6
7
oxalyl chloride
CDI
EDC-HCl, HOBt
HATU
MsCl, 1-methylimidazole
TsCl, 4-methylmorpholine
TsCl, 1-methylimidazole
50
0
nd
nd
65
97.7
nd
nd
86
85
96
21
70
94
Experimental Section
2-Chloro-5-formylbenzoic Acid (10). A 100-L reactor equip-
ped with an overhead stirrer, a nitrogen inlet, and a temperature
probe was charged with THF (15 L, predegassed by bubbling
nitrogen for 30 min) followed by 5-bromo-2-chlorobenzoic acid
(5) (5027.3 g, 21.35 mol). The solution was degassed by bubbling
nitrogen for 15 min then cooled to -30 °C. iPrMgCl (2.0 M/
THF, 27.8 L, 55.5 mol) was slowly added via an addition funnel.
The rate of addition was controlled such that for the first equi-
valent of iPrMgCl (10.7 L), the temperature stayed below 0 °C
and for the second equivalent it stayed below -20 °C. The slurry
was aged O/N from -20 °C to rt (>99% conversion). The reac-
tion mixture was cooled to 0 °C, and a solution of DMF (4.15 L,
53.4 mol) in THF (16 L) was slowly added with vigorous stirring.
The rate of addition was controlled in order to keep the tempera-
ture below 25 °C. The thick slurry was aged at 10-15 °C for 1 h at
which point 4 N HCl (23.5 L, 93.9 mol) was added slowly. The
reaction mixture was stirred at rt for 30 min until all solids
dissolved. The batch was transferred to a 150-L extractor, and
the two layers were cut. The organic layer was successively washed
with 10 wt %/wt aqueous LiCl, (15 L), 1 M Na2CO3 (32 L)
and 1 M Na2CO3 (21 L). The combined Na2CO3 layers were
washed with MTBE (25 L), cooled to 0 °C, and acidified with
6 N HCl (15.9 L). The resulting slurry was filtered through a
filter pot. The solid obtained was washed with water (32 L) and
heptane (40 L) and dried under vacuum with a flow of nitrogen
until KF analysis showed <5500 ppm of water. Aldehyde 10
was thus obtained as a white solid (3410 g, 92 wt %, 80% yield).
1H NMR (500 MHz, CDCl3) δ 10.05 (s, 1H), 8.51 (d, 1H, J = 1.9
SCHEME 5. End Game
Conditions: (a) 1. H3PO4, 70 °C, 95%. 2. D-tartaric acid, 90 °C, 90%.
3. NaOH, MTBE, 99%. (b) AcOH, MTBE, Heptane, 83%.
of coupling agents, we opted for a cheaper mixed anhydride
approach using TsCl/1-methylimidazole activation/amida-
tion. This reagent gave a similar yield (94%) to HATU, albeit
in a lower purity profile (86 A%). The low purity profile can
be further upgraded during the subsequent salt formations.
End Game. Completion of the synthesis for MK-1597 is
22
outlined in Scheme 5. H3PO4 was used to cleave the Boc
protecting group and provided 3.91 kg of MK-1597 in 93%
yield and 91.8 A%. Rejection of impurities was possible dur-
ing the work up through a pH swing with aqueous MsOH.
Thus, the organic layer was treated with aqueous MsOH,
which formed a water-soluble salt with MK-1597. This layer
was washed with MTBE to remove impurities and then basi-
fied with NaOH and re-extracted to recover MK-1597. This
process allowed us a slight increase in purity profile from
86 A% for the amidation to 91.8 A% for the Boc deprotec-
tion and a reduction of the metal content of the final com-
pound MK-1597 (Ru = from 17 to 11 ppm and Pd = from
56 to 2 ppm). At this stage the purity of MK-1597 was further
upgraded to 98.6 A% with a bis-D-tartrate salt formation/
Hz), 8.01 (dd, 1H, J = 8.2, 1.9 Hz), 7.69 (d, 1H, J = 8.2 Hz); 13
C
NMR (125 MHz, acetone-d6) δ 190.8, 165.3, 139.1, 135.5, 132.7,
132.6, 132.3, 131.7; IR 2922, 1701, 1665, 1286, 1244, 1199, 1049,
911, 832, 783 cm-1; HRMS (ESI) (m/z): [M þ H]þ calcd for
C8H6ClO3, 185.0000; found 184.9997.
2-Chloro-5-(2-methoxyvinyl)benzoic Acid, 1:1 E:Z Isomers
(11). A 100-L reactor equipped with an overhead stirrer, a re-
fluxed condenser, a nitrogen inlet, and a temperature probe was
charged with THF (20 L). NaH (60%, 745 g, 17.88 mol) was
added, and the suspension was cooled to 0 °C. A solution of
aldehyde 10 (3137 g, 16.25 mol) in THF (7 L) was added to the
suspension over the course of 1 h in order to control the gas
evolution and the exotherm (T e 20 °C). (Methoxymethyl)-
triphenylphosphonium chloride (7.45 kg, 21.1 mol) was added
at rt to the reaction mixture (phosphonium NOT soluble in THF).
It was then heated to 40-45 °C, and NaH 60% in oil (945 g, 23.63
mol) was added portion wise (∼10 portions) to control the exo-
therm and the gas evolution. The slurry was aged at 50 °C for 1 h
salt break. Finally, MK-1597 AcOH was identified as a crys-
3
talline and bioavailable form for development. Therefore,
MK-1597 was dissolved in MTBE and a solution of AcOH in
(22) Alternatively 10 equiv of TFA can be used with carefull monitoring
of the KF.
1066 J. Org. Chem. Vol. 76, No. 4, 2011

Molinaro et al.
JOCArticle
and turned dark orange (which is an indication that the reaction
is complete). The slurry was then cooled to rt and aged overnight.
NaOH (1 N, 16.5 L), MTBE (16.5 L), and half brine (16.5 L) were
added to the slurry, and the layers were cut. The organic layer was
washed with 1 M NaOH (16.5 L). The combined aqueous layer
was washed twice with IPAc (2 ꢀ 15 L), then cooled to 0 °C at
which point 6 N HCl (36 L) was slowly added until pH = 1. The
slurry was aged at 10 °C for 15 min then filtered through a filter pot,
and the solid was washed with water (60 L). The pale-yellow solid
thus obtained was dried under vacuum with a flow of nitrogen for
48-72 h, yielding 3099 g (86% yield) of a 1:1 mixture of E/Z iso-
mers (11). 1H NMR (500 MHz, CDCl3) δ8.16 (d, 1H, J = 2.2 Hz),
7.86 (d, 1H, J = 2.2 Hz), 7.70 (dd, 1H, J = 8.4, 2.2 Hz), 7.38 (d,
1H, J = 8.4 Hz), 7.37 (d, 1H, J = 8.3 Hz), 7.32 (dd, 1H, J = 8.4,
2.2 Hz), 7.10 (d, 1H, J = 13.0 Hz), 6.23 (d, 1H, J = 7.0 Hz), 5.78
(d, 1H, J = 13.0 Hz), 5.21 (d, 1H, J = 7.0 Hz), 3.82 (s, 3H), 3.71 (s,
3H); 13C NMR (125 MHz, acetone-d6) δ 166.4, 166.3, 150.8, 150.1,
136.2, 135.5, 131.9, 131.0, 130.9, 130.7, 130.6, 129.3, 128.6, 127.7,
103.2, 103.1, 60.6, 56.3; IR 2936, 2824, 2536, 1702, 1647, 1285,
1238, 1193, 1092, 1042, 918, 828 cm-1; HRMS (ESI) (m/z): [M þ
H]þ calcd for C10H10ClO3, 213.0313; found 213.0315.
2-Chloro-5-(2-methoxyethyl)benzoic Acid (12). A 5-gal carboy
container was charged with alkenes 11 (3080 g, 14.49 mol), and it
was dissolved with EtOAc (10 L). The resulting solution was
sucked into a 10-gal reactor, and the carboy was then rinsed with
fresh EtOAc (2 L). The rinsate was then added to the vessel as
well. This was repeated a second time. Twenty weight percent
Pd(OH)2/C (308 g, 10 wt %) was added to a flask containing
EtOAc (2 L), and this solution was next sucked into the reactor.
Fresh EtOAc (10.7 L) was added to the vessel. The batch was
precooled to 15 °C, and the agitation rate was set to 800 rpm at
the start of reaction. The reaction mixture was agitated under a
hydrogen pressure of 45 psi. After 18 h, the resulting batch was
dropped, and the reactor was rinsed with fresh EtOAc (15 L).
The batch was filtered on a pad of solka floc using an 18-in. filter
pot, and EtOAc (15 L) was used to rinse the pad. The desired
compound was kept as an EtOAc solution, and it was assayed:
2980 g (96% yield). 1H NMR (500 MHz, CDCl3) δ 7.88 (d, 1H,
J = 1.9 Hz), 7.41 (d, 1H, J = 8.2 Hz), 7.35 (dd, 1H, J = 8.2, 2.1
Hz), 3.63 (t, 2H, J = 6.6 Hz), 3.36 (s, 3H), 2.91 (t, 2H, J = 6.6
Hz); 13C NMR (125 MHz, acetone-d6) δ 166.7, 138.9, 133.3,
131.8, 130.6, 130.5, 130.4, 72.5, 57.7, 34.9; IR 2926, 2868, 2826,
2638, 2579, 1693, 1297, 1261, 1200, 1104, 1042, 657 cm-1; HRMS
(ESI) (m/z): [M þ H]þ calcd for C10H12ClO3, 215.0469; found
215.0468.
2-Chloro-N-cyclopropyl-5-(2-methoxyethyl)benzamide (13). The
carboxylic acid (12) solution in EtOAc (5780 g, 26.93 mol) (from
the hydrogenation vessel) was inline filtered with an activated
carbon cartridge and concentrated with the batch-concentrator
to a final volume of 48 L. The batch was cooled to 10 °C, and
CDI (5240 g, 32.31 mol) was added in 10 portions over 30 min.
The reaction mixture was aged at rt for 1.5 h. Cyclopropylamine
(2.83 L, 40.40 mol) was added via the dropping funnel fitted with
a piece of Nalgene tubing immersed in the reaction mixture. The
rate of addition was controlled such that the temperature did not
exceed 33.5 °C. The addition took 30 min. The batch was aged at
30 °C for 1.5 h then cooled to rt. The batch was transferred to a
150-L extractor and cooled to 15 °C. HCl (3 N, 36 L, 107.7 mol)
was added with stirring. The temperature was maintained be-
tween 20 and 25 °C. Fresh EtOAc (23.5 L) was added. The two
layers were cut, and the organic layer was successively washed
with 1 M Na2CO3 (36 L) followed by half-saturated brine (36 L).
HPLC assay of the EtOAc layer showed 5880 g (86% yield). The
crude batch was inline filtered in a visually clean 100-L reactor
and was subsequently batch-concentrated and solvent-switched
to IPAc. At this point, there was 2.5% left of EtOAc compare to
iPAc. Fresh IPAc (8 L) was added to the batch to make a solution
of final volume =23.2 L. The batch was heated to 70 °C until a
clear solution was obtained, then it was cooled to 65 °C at which
point hexanes (12 L) was slowly added over 1 h between 62.5 and
65 °C. The batch was further cooled to 60 °C and seeded with
seeds (17.5 g). The batch was slowly cooled to 55 °C over 45 min
then to rt and aged for 10 h at rt. The next morning, the mother
liquors were analyzed by HPLC and showed 808 g of amide lost
to the mother liquors (14%). The batch was filtered and rinsed
with 10% iPAc/hexanes (24 L) followed by hexanes (20 L). The
batch was dried on the filter pot under vacuum and a flow of
nitrogen for 24 h and yielded 4820 g (71% yield, 100 wt %) of 13
as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.53 (d, 1H, J =
2.1 Hz), 7.29 (d, 1H, J = 8.2 Hz), 7.22 (dd, 1H, J = 8.2, 2.2 Hz),
6.29 (br, 1H), 3.59 (t, 2H, J = 6.7 Hz), 3.33 (s, 3H), 2.92 (m, 1H),
2.86 (t, 2H, J = 6.7 Hz), 0.88 (m, 2H), 0.65 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 167.8, 138.2, 134.7, 131.5, 130.0, 129.7,
128.2, 72.6, 58.4, 35.1, 22.9, 6.5; IR 3258, 1642, 1531, 1317, 1121,
726 cm-1; HRMS (ESI) (m/z): [M þ H]þ calcd for C13H17ClNO2,
254.0942; found 254.0944.
N-[2-Chloro-5-(2-methoxyethyl)benzyl]cyclopropanamine (2).
A 100-L reactor equipped with an overhead stirrer, a nitrogen
inlet, a reflux condenser, and a temperature probe was charged
with THF (24 L) followed by amide 13 (4799 g, 18.20 mol). Once
all the amide was in solution, NaBH4 (2862 g, 75.66 mol) was
added in one portion at rt. BF3 THF (9.4 L, 85.12 mol) was
3
slowly added over 1.5 h such that the internal temperature never
exceeded 36 °C. The slurry was aged at 37 °C overnight (97%
conversion). The reaction mixture was cooled to 10 °C and
slowly transferred into a 150-L extractor containing cool (6 °C)
3 N HCl (28.4 L). The quench was performed over 4 h to control
the gas evolution and the exotherm. Vigorous stirring was also
maintained throughout the operation. The white precipitate was
filtered on a filter pot and washed with MTBE (24 L). The fil-
trate was transferred to a clean 150-L extractor, and more
MTBE (24 L) was added. The layers were cut, and the organic
layer was washed 3 ꢀ 2 N HCl (3 ꢀ 20 L). The combined
aqueous layer was washed with MTBE (20 L), cooled to 10 °C,
and basified with 50 wt/wt aqueous NaOH (20 L) until pH > 10.
The rate of addition of 50 wt/wt aqueous NaOH was such that
internal temperature was maintained below 26 °C. The batch
was extracted with 2 ꢀ MTBE (2 ꢀ 45 L), and the combined
organic layer was washed with water (20 L), dried over Na2SO4
(8 kg), filtered, and concentrated, yielding the desired amine 2:
6448 g (70.4 wt %, 95.85 A%, 99% yield). 1H NMR (500 MHz,
CDCl3) δ 7.27 (d, 1H, J = 8.2 Hz), 7.21 (d, 1H, J = 2.0 Hz), 7.06
(dd, 1H, J1 = 2.1 Hz, J2 = 8.1 Hz), 3.90 (s, 2H), 3.57 (t, 2H, J =
6.9 Hz), 3.34 (s, 3H), 2.84 (t, 2H, J = 6.9 Hz), 2.11 (m, 1H), 1.93
(br, 2H), 0.47-0.40 (m, 4H); 13C NMR (125 MHz, CDCl3) δ
137.7, 137.4, 131.4, 130.8, 129.2, 128.6, 73.1, 58.5, 51.1, 35.4,
29.7, 6.4; IR 3314, 3083, 2925, 2866, 2826, 1648, 1470, 1374,
1107, 1039, 1014, 811, 752 cm-1; HRMS (ESI) (m/z): [M þ H]þ
calcd for C13H19ClNO, 240.1150; found 240.1148.
2,6-Dichloro-4-methylphenol (14).23 A 400 L reactor equip-
ped with an overhead stirrer, a nitrogen inlet and an addition
funnel was charged with p-cresol (7) (8000 g, 74 mol) and ace-
tonitrile (40 L). The solution was cooled to 0 °C and 10% aq-
ueous sodium hypochlorite solution (127 kg, 169 mol) was
added over 2 h keeping the temperature <5 °C. On complete
addition the batch was allowed to warm to 18 °C and stirred
overnight when HPLC showed complete reaction. The batch
was cooled to 10 °C and MTBE (66 L) was charged followed by
solid sodium bisulfite (3850 g, 37 mol) in portions ensuring the
temperature does not exceed 18 °C. The batch was aged for 1 h
when starch iodide paper indicated no oxidant present. Con-
centrated hydrochloric acid (12.4 kg, 126 mol) was then added
(23) Gauvreau, D.; Huffman, M. A.; Hughes, G.; Itoh, T.; Yin, J.; Lau,
S.; O’Shea, P. Process for the preparation of diazabicyclo[3.3.1]nonane
derivatives. WO 2008/088690 A2, 2008.
J. Org. Chem. Vol. 76, No. 4, 2011 1067

Molinaro et al.
JOCArticle
while keeping the temperature <10 °C (pH of aqueous phase =
5-5.5). The batch was warmed to 15 °C, and the aqueous phase
was separated. The MTBE solution of 2,6-dichloro-4-methyl-
phenol 14 was assayed at 11.6 kg (89% yield) and carried for-
ward into the next step. H NMR (500 MHz, CDCl3) δ 7.30
(s, 1H,), 5.75 (s, 1H), 2.27 (s, 3H).
nitrogen inlet, a reflux condenser, and an addition funnel was
charged with pinacol borate 16 (3096 g, 7.30 mol), triflate 17 (2945
g, 7.3 mol), DME (11.7 L) and 2 M Na2CO3 (11.7 L). The solu-
tion was heated to 50 °C and was aged under N2 for 5 min. Solid
Pd(PPh3)4 (84 g, 0.073 mol) was charged, and the reaction mixture
was warmed to reflux temperature (83 °C). After 1 h a cloudy mix-
ture formed, and HPLC showed no triflate. The resultant was
batch-concentrated to remove DME. MTBE (7.3 L) and water
(7.3 L) were added, and the mixture was transferred to a 100-L ex-
tractor with heptane (14.6 L) and water (7.3 L). The reaction flask
was rinsed with MTBE (7.3 L), and the solution was combined
with that in the extractor. The aqueous layer was cut, and the org-
anic layer was washed twice with water (2 ꢀ 14.6 L). The organic
solution was filtered through a pad of silica gel (2.0 kg), and the
pad was rinsed with 1:1 MTBE/heptane (7.3 L). The concentration
of the filtrate under reduced pressure afforded compound 4a as a
light-brown oil (4000 g, 99%). 1H NMR (500 MHz, acetone-d6) δ
7.96 (d, 1H, J = 6 Hz), 7.57 (t, 1H, J = 7.5 Hz), 7.25 (d, 2H, J = 9
Hz), 6.79 (t, 1H, J = 8.5 Hz), 4.71 (s (br), 2H), 4.40 (s (br), 2H),
4.23 (s (br), 2H), 3.96 (s (br), 2H), 3.62 (s (br), 2H), 2.54 (s (br),
2H), 2.32(s(br), 3H), 1.48 (s, 9H), 0.96 (s(br), 3H);13CNMR (125
MHz, acetone-d6) δ 164.1, 162.8, 154.0, 149.1, 144.9, 142.7, 140.5,
137.9, 137.6, 136.0, 131.0, 129.5, 128.5, 125.9, 110.1, 109.5, 82.6,
80.2, 79.2, 71.9, 64.8, 64.6, 60.0, 59.3, 44.0, 40.4, 39.2, 32.4,
27.7, 27.3, 19.5, 13.6, 13.3; IR 2977, 2932, 1693, 1601, 1475,
1366, 1287, 1257, 1161, 1041, 893, 849, 797, 765 cm-1; HRMS
(ESI) (m/z): [M þ Na]þ calcd for C27H32Cl2N2O6Na, 575.1507;
found 575.1516.
(30S,40S)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)ethoxy]-30,40,50,
60-tetrahydro-20H-[3,40]bipyridinyl-10,30-dicarboxylic Acid 10-tert-
Butyl Ester 30-Ethyl Ester (6a). Catalyst Preparation. In a nitro-
gen-filled glovebox, (O2 < 10 ppm) SL-J212-1 (93.3 g, 0.179 mol)
was combined with (COD)Ru(Me-allyl)2 (54.3 g, 0.170 mol) in a
2-Lround-bottomflask followedby anhydrous, degassed CH2Cl2
(1.0 L). A red-brown catalyst solution was observed with some
solids persisting. The round-bottom flask was removed from the
glovebox and connected to a N2 manifold. The catalyst solution
was cooled to 0-5 °C, and HBF4*OEt2 (43.9 mL, 0.323 mol) was
added dropwise via syringe through the rubber stopper over 20-
30 min. After acid addition the catalyst solution was warmed to
room temperature and then returned to the nitrogen-filled glove-
box. The catalyst solution was transferred to a 2.0-L stainless steel
vessel followed by a CH2Cl2 rinse (250 mL). Additional CH2Cl2
(250 mL) was added to a 0.5-L stainless steel vessel, and the two
vessels were connected via a ball-valve.
Hydrogenation. Ene-ester 4a (30.3 wt %) in THF (6.23 kg,
3.42 mol) was drawn into an autoclave under partial vacuum
followed by THF rinse (3.5 L). Batch temperature was brought
to 0-5 °C. HBF4*OEt2 (422 mL, 3.08 mol) was added in five
portions while monitoring batch temperature (maintained <15 °C).
The autoclave was sealed and purged with N2 (3 ꢀ 40 psig). The
catalyst assembly was connected to the autoclave via flex tubing,
and under partial vacuum the catalyst solution was drawn into
the autoclave followed by the CH2Cl2 (250 mL) rinse. The
reactor was sealed and the headspace exchanged with H2 (3 ꢀ
800 psig). Agitation was begun, and the reaction temperature
was maintained at 15 °C for 20 h. The reaction was sampled after
20 h, and there was 0.2 A% ene-ester 4a remaining. The prod-
uct ee was observed to be 99%, and there was 3.5 A% de-Boc
(SM þ product) observed. The reaction was vented, and the
product solution (12.2 kg) was drummed into a chilled receiving
flask (0-5 °C). The autoclave was rinsed with IPAc (5.0 L). A
100-L cylindrical reaction vessel was charged with the cooled
hydrogenation stream (∼12.5 L total volume, 1.89 kg chiral
ester 6a), the iPAc flush (5.0 L), additional iPAc (21.0 L), and
cooled to 5 °C. The batch was washed with 7.5 wt % aqueous
NaHCO3 (11.4 L) and saturated aqueous NaCl (11.4 L), keeping
the temperature between 4 and 8 °C. The layers are dark on
1
5-Bromo-2-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]pyridine
(15). A 100-L reactor equipped with an overhead stirrer, a nitro-
gen inlet, a reflux condenser, and an addition funnel was charged
with ethylene carbonate (2200 g, 29.75 mol) and DMAc (16.7 L).
The solution was heated to reflux. A solution of the 2,6-dichloro-
4-methylphenol 14 (5000 g, 28.24 mol) and imidazole (190 g, 2.8
mol) in DMAc (7 L) was added over 15 min. The solution was
heated at reflux for 2 h and then cooled to 25-30 °C. Potassium
hydroxide (2220 g, 39.6 mol) was added and the mixture stirred for
30 min at rt. 2,5-Dibromopyridine (9) (6700 g, 28.28 mol) was
added and the mixture was heated to 80-90 °C and aged over-
night. The mixture was then allowed to cool slightly and water
(72 L) was added. The mixture was cooled to 20-25 °C and then
filtered. The cake was copiously washed with water (172 L) and
ethanol (72 L). The cake was dried under a nitrogen stream to
1
afford 8637 g (77%) of 15 as a pale-beige solid. H NMR (500
MHz, CDCl3) δ8.20 (s, 1H), 7.68 (d, 1H, J = 8.5 Hz), 7.11 (s, 2H),
6.75 (d, 1H, J = 9 Hz), 4.68 (apparent s (br), 2H), 4.37 (apparent s
(br), 2H); 2.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.2,
148.9, 147.3, 141.1, 135.5, 129.4, 128.8, 113.1, 111.9, 71.5, 65.2,
20.5; IR 2972, 2929, 2869, 1586, 1476, 1450, 1351, 1280, 1264,
1042, 932, 843, 824, 798, 676 cm-1; HRMS (ESI) (m/z): [M þ
Na]þ calcd for C14H12BrCl2NO2, 397.9321; found 397.9319.
2-[2-(2,6-Dichloro-4-methyl-phenoxy)ethoxy]-5-(4,4,5,5-tetra-
methyl-[1,3,2]dioxaborolan-2-yl)pyridine (16). A 400-L reactor
equipped with an overhead stirrer, a nitrogen inlet, and an addi-
tionfunnel was chargedwitharyl bromide15(12.37 kg, 32.8 mol),
pinacol diboron (10.0 kg, 39.4 mol), potassium acetate (9.66 kg,
98.4 mol), and DMAc (92.7 kg). The solution was degassed three
timeswithnitrogen/vacuum purges. The mixturewas theninerted
with subsurface nitrogen sparging for 15 min. PdCl2(dppf)-
CH2Cl2 (804 g, 0.984 mol) was added, and subsurface nitrogen
sparging continued for an additional 15 min. The batch was heat-
ed to 80-85 °C and aged for 20 h when HPLC showed complete
reaction. The reaction mixture was then allowed to cool to 20-
25 °C, and water (99 kg) and isopropyl acetate (87 kg) were
added. The mixture was stirred for 30 min and allowed to settle
overnight. The aqueous layer was cut, and then the organic layer
was washed with water (50 kg). The organic layer was then con-
centrated under reduced pressure at <40 °C to a volume of 25-
30 L. The concentrated iPAc solution was diluted with n-heptane
(20.5 kg), and the solution was passed through a pad of silica gel
(10 kg). The silica pad was washed through with 1:1 iPAc/n-hep-
tane (120 L). The filtrate and washes were concentrated under re-
duced pressure at <40 °C to ∼25-30 L. Isopropanol (50 kg)
was added and the solution concentrated again by distillation at
<40 °C to a volume of ∼30 L. Isopropanol (50 kg) was added,
and the resulting slurry stirred at 20 °C over the weekend. The
solid was collected by filtration, and the cake washed with iso-
propanol (20 kg) and dried in vacuo at 40 °C to afford 9.943 kg
(71% yield, 96.5 A%) of pinacoloborate ester 16 as an off-white
solid. 1H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 7.95 (d, 1H,
J = 8.5 Hz), 7.11 (s, 2H), 6.79 (d, 1H, J = 8 Hz), 4.75 (apparent s
(br), 2H), 4.38 (apparent s (br), 2H); 2.29 (s, 3H), 1.36 (s, 12H);
13C NMR (125 MHz, CDCl3) δ 165.4, 153.9, 149.0, 144.6, 135.3,
129.3, 128.8, 110.7, 83.8, 71.7, 64.8, 25.0, 24.8, 20.5; IR 2972,
2929, 2869, 1600, 1474, 1449, 1401, 1366, 1345, 1319, 1286, 1264,
1146, 1129, 1098, 1048, 1065 cm-1; HRMS (ESI) (m/z): [M þ
Na]þ calcd for C20H24BCl2NO4, 446.1071; found 446.1085.
6-[2-(2,6-Dichloro-4-methyl-phenoxy)ethoxy]-50,60-dihydro-20H-
[3,40]bipyridinyl-10,30-dicarboxylic Acid 10-tert-Butyl Ester 30-Ethyl
Ester (4a). A 75-L reactor equipped with an overhead stirrer, a
1068 J. Org. Chem. Vol. 76, No. 4, 2011

Molinaro et al.
JOCArticle
dark, but one can see the interface with a flashlight, and there is
gray solid at the interface.
late (5980 g, 28.8 mol) in MeTHF (48 L) was cooled to 3 °C under
nitrogen. Triethylamine (10.1 L, 72 mol) was charged, followed
by the addition of trifluoroacetic anhydride (4.2 L, 30.2 mol) over
60 min at 4-5 °C. The resulting slurry was aged at <5 °C for
another 10 min, and a sample was taken to confirm <0.8%
starting material by HPLC. HCl (2 N, 6 L) was poured, and the
mixture was transferred to a 100-L extractor. The reaction flask
was rinsed with 2 N HCl (30 L), and the solution was also
transferred to the extractor. The aqueous layer was cut, and the
organic layer was washed with water (36 L) and 10% KHCO3
(36L). After the washes, 38.7 kg oforganic solution was obtained.
By NMR it was pure enough for the next reaction. The bulky
organic solution was batch concentrated to get the TFA-
protected piperidinone as a yellow oil, and it was used for the
next reaction without further purification.
Triflation. The TFA-protected piperidinone was dissolved in
DCM (40 L), and triethylamine (6.0 L, 43 mol) was charged. The
mixture was cooled to -28 °C under nitrogen, triflic anhydride
(5.27 L, 31.4 mol) was added over 60 min at r10 °C. Resulting
solution was aged at r10 °C for another 10 min, and a sample
was taken to confirm <0.6% TFA-protected piperidinone by
HPLC. Water (11 L) was poured into the flask, and the mixture
was transferred to a 100-L extractor containing water (11 L).
The aqueous layer was cut, and the organic layer was washed
with 2 N HCl (22 L), water (22 L), 10% KHCO3 (22 L), and
water (22 L). The organic solution was concentrated by batch
concentration to about 30 L, and heptane (30 L) was charged.
The mixture was further concentrated to about 40 L (slurry was
generated, and the heavy slurry was filtered at 37 °C. The cake
was rinsed with heptane (11 L). After drying under a nitrogen
stream, 10.353 kg (91%, >99 A%) of product 17b was obtained
as light brown color solid. 1H NMR (600 MHz, DMSO-d6, 90 °C):
δ4.48 (s, 1 H); 4.28 (q, J=7.10Hz, 1H);3.85(t, J=5.86Hz, 1H);
3.02 (s, 1 H); 2.72 (s, 2 H); 1.29 (t, J = 7.09 Hz, 2 H); 13C NMR
(125 MHz, DMSO-d6) δ 161.95, 161.88, 155.16, 155.09, 154.9,
154.8, 154.6, 151.2, 150.1, 122.0, 119.8, 119.6, 119.5, 117.6, 116.9,
115.3, 115.3, 114.4, 62.2, 62.1, 43.6, 42.4, 41.9, 29.1, 27.8, 13.9, 13.9;
IR 1697, 1461, 1418, 1245, 1207, 1135, 1045, 902, 831, 758, 621
cm-1; HRMS (ESI) (m/z): [M þ H]þ calcd for C11H11F6NO6S,
400.0289; found 400.0292.
6-[2-(2,6-Dichloro-4-methyl-phenoxy)ethoxy]-10-(2,2,2-trifluoro-
acetyl)-10,20,50,60-tetrahydro-[3,40]bipyridinyl-30-carboxylic Acid
Ethyl Ester (4b). A 100-L vessel equipped with an overhead
stirrer, a nitrogen inlet, a reflux condenser, and an addition
funnel was charged with borane 16 (9500 g, 22.4 mol), triflate
17b (8500 g, 21.3 mol), Pd(dppf)Cl2 (313 g, 0.383 mol), KHCO3
(5300 g, 52.9 mol), 2-MeTHF (47.5 L), and water (14.3 L). The
reaction mixture was degassed with N2/vacuum purges and
then heated to 60 °C and aged for 1 h. The reaction mixture
was cooled to room temperature and transferred into the 180-L
extractor containing 5% NaH2PO4 (48 L). The bottom aqueous
layer was cut away, and hexanes (50 L) was added to the organic
layer. The organic layer was then washed with brine (30 L). The
remaining organic layer was then diluted with more hexanes
(38 L). The organic layer was collected and passed through a
10 kg silica gel plug in an 18” filter pot. The cake was washed with
1:1 2-MeTHF: hexanes (12 L). The filtrate was concentrated to a
volume of ca. 28 L and then diluted back to 48 L with 2-MeTHF.
The solution was then treated with slow addition of 4 N HCl in
dioxane (10 L) and allowed to stir overnight. The solids were then
filtered, washed with 1:1 2-MeTHF/hexanes, and dried under a
nitrogen sweep to give 11.2 kg (90% yield) of 4b HCl salt.
Salt Break. The solid was then charged into a 100-L cylin-
drical vessel containing 2-MeTHF (55 L), water (28 L), and
NaHCO3 (3.0 kg). The mixture was stirred for 30 min and then
allowed to settle. The aqueous layer was collected, and the
organic layer was treated with H2O (12 L) and NaCl (2.0 kg).
After stirring for 15 min the layers were allowed to settle and
Darco Treatment: (Two Hydrogenation Batches Combined).
The solution containing the chiral ester 6a was added to a 100-L
RB flask and treated with Darco KB-G (1.9 kg), aged for 2 h,
filtered through solka floc, and the cake was washed with iPAc
(5.0 L). The batchwas thenconcentrated to3.68kg of a 62.7 wt%
oil (2.3 kg assay, 84%yield, 99% ee). [R]D = -47.3 (c 1.2, EtOH);
1
(at rt mixture of rotamers) H NMR (500 MHz, acetone-d6) δ
8.08 (s, 1H), 7.65 (d, 1 H, J = 8.4 Hz), 7.25 (s, 2H), 6.73 (d, 1H,
J = 8.6 Hz), 4.67 (s, 2H), 4.43 (s (br), 1H), 4.38 (apparent s (br),
2H), 4.26 (s (br), 1H), 3.96 (m, 1H), 3.89 (s (br), 1H), 3.28 (s (br),
1H), 3.22 (s (br), 1H), 3.15 (s (br), 1H), 3.01 (s (br), 1H), 2.91 (s,
1H), 2.84 (s, 3H), 2.64 (s, 1H), 2.32 (s, 3H), 1.67 (d, 1H, J = 12.7
Hz), 1.45 (s, 10H), 1.09 (t, 3H, J = 7.2 Hz); 13C NMR (125 MHz,
acetone-d6) δ 171.4, 162.6, 149.1, 145.8, 138.4, 137.1, 131.5, 129.5,
128.5, 110.2, 78.6, 71.9, 64.6, 59.6, 45.3, 27.8, 19.6, 13.6; IR 2975,
2930, 1703, 1690, 1605, 1474, 1426, 1365, 1256, 1156, 1118, 1028,
1003, 798 cm-1; HRMS (ESI) (m/z): [M þ Na]þ calcd for
C27H34Cl2N2O6, 575.1686; found 575.1697.
Procedure 1 (from 6a): (30R,40S)-6-[2-(2,6-Dichloro-4-methyl-
phenoxy)ethoxy]-30,40,50,60-tetrahydro-20H-[3,40]bipyridinyl-10,30-
dicarboxylic Acid 10-tert-Butyl Ester (3). A 100-L vessel equipped
with an overhead stirrer, a vacuum inlet, and a temperature
probe was charged with the ester 6a solution in iPAc (8.63 mol).
The solution was concentrated under vacuum (10-30 mmHg,
30 °C) and solvent switched to ethanol (1H NMR indicated 18%
residual iPAc). The flask was then equipped with a nitrogen inlet
and a reflux condenser and charged with EtOH (25 L) and
NaOEt/EtOH 21 wt % (14 L, 43.2 mol) and heated at 70 °C
for 1 h. AtthistimeanHPLC assay showeda ∼14:1trans/cis ratio
of the ester and some hydrolysis to the carboxylic acid. NaOH
(2 N, 22 L, 44 mol) was then added, and the batch was heated to
70 °C for an additional hour. At this time an HPLC assay showed
nomore ester. Mostofthe ethanol was evaporated fromthe batch
before being transferred into a 150-L extractor. MTBE (40 L) was
added into the extractor, and the solution was cooled to 0 °C. HCl
(4 N 20 L) was then added at such a rate to maintain the internal
temperature below 20 °C. The pH was adjusted to ∼5 by adding
extra 2 N HCl (0.3 L) and 10% KH2PO4 (12 L). The two layers
were cut, and the organic layer was washed with more 10%
KH2PO4 (40 L) followed by half-saturated brine (20 L), dried
over Na2SO4 (3 kg) and inline-filtered (Carbon-cap 75 HD,
Whatman Inc.) into a 100-L vessel and concentrated under vacu-
um (10-30 mmHg, 30 °C) to a final volume of ∼20 L. The re-
sulting solution was stirred for 1 h at room temperature, and
hexanes (10 L) was added. The batch was seeded (34.53 g), and
more hexanes (20 L) was added. The slurry was aged at room
temperature overnight and for 2 h at 0 °C. Supernatant assay
showed 9.75 g/L. The slurry was filtered through a filter pot, and
the solid obtained was washed twice with 1:1 cold hexanes:MTBE
(0 °C, 2 ꢀ 10 L). The solid was dried overnight under vacuum and
nitrogen sweep to give acid 3 as a brown powder: 3810.4 g (84%
yield, 98.9 A%, 99 wt %, trans/cis ratio >120:1). [R]D = þ5.71 (c
0.80, EtOH); 1H NMR (500 MHz, acetone-d6) δ 10.8 (d, 1H, J =
2.5 Hz), 7.66 (dd, 1H, J = 8.5, 2.5 Hz), 7.25 (s, 2H), 6.74 (d, 1H,
J = 8.5 Hz), 4.66 (t, 2H, J = 5 Hz), 4.41 (s (br), 1H), 4.38 (t, 2H,
J = 5 Hz), 4.22 (s (br), 1H), 2.97 (td, 2H, J = 12, 3.5 Hz), 2.87 (s
(br), 1H), 2.72 (td, 2H, J = 12, 4 Hz), 2.31 (s, 3H), 1.79 (m, 1H),
1.68 (qd, 1H, J = 12.5, 4.5 Hz), 1.49 (s, 9H);13C NMR(125 MHz,
acetone-d6) δ 172.6, 162.5, 153.9, 149.1, 145.8, 137.9, 136.0, 131.9,
129.5, 128.5, 110.6, 79.1, 71.9, 64.5, 41.9, 27.7, 19.4; IR 1713,
1472, 1444, 1286, 1262, 1233, 1191, 1126, 1050, 935, 925, 849, 825
cm-1; HRMS (ESI) (m/z): [M þ H]þ calcd for C25H30Cl2N2O6,
525.1559; found 525.1557.
1-(2,2,2-Trifluoro-acetyl)-4-trifluoromethanesulfonyloxy-1,2,5,
6-tetrahydro-pyridine-3-carboxylic Acid Ethyl Ester (17b). TFA
Protection. The suspension of ethyl 4-oxopiperidine-3-carboxy-
J. Org. Chem. Vol. 76, No. 4, 2011 1069

Molinaro et al.
JOCArticle
then separated. The organic layer was dried over Na2SO4 and
then sucked into a batch concentrator through a 5 μm line filter
and concentrated to ∼10 L. The batch was then diluted back to
∼35 L with 2-MeTHF. The batch was then drummed off into
polyjugs to give 32.8 kg of a 28.4 wt % solution. (9.32 kg assay,
transferred to an extractor filled with IPAc (20 L) and 2 N HCl
(24.03 L, 48.1 mol). The layers were cut, and the aqueous layer
(should be acidic, pH < 4) was extracted with IPAc (20 L). The
combined organic layers were washed with half-saturated brine
(2 ꢀ 10 L), batch concentrated, and flushed with fresh IPAc
(20 L). Once the final volume was ∼16 L, the solution was warm-
ed to 70 °C while heptane (40 L) was added. The temperature
was cooled to ∼50 °C, additional heptane (40 L) was added, and
the solution was cooled to rt overnight. The solid was filtered,
washed with 5:1 heptane/IPAc (20 L) and flushed with N2 for
20 h. Product can be dried under vacuum/N2 flush at 70 °C to
bring water level at or below 3000 ppm. 3.9 kg trans-acid 3 was
isolated as a beige powder (88% yield, 95 wt %, 7.05 mol, trans/
cis ratio >100:1).
1
80% overall yield). H NMR (500 MHz, CDCl3) (at r.t. see
mixture of rotamers): δ 8.02 (s, 1H), 7.63 (d, 1H, J = 8.5 Hz),
7.26 (s, 2H), 6.82 (d, 1H, J = 8.5 Hz), 4.72 (t, 2H, J = 4 Hz), 4.53
(s, 1H), 4.50 (s, 1H), 4.41 (t, 2H, J = 4 Hz), 4.10-3.97 (m, 2H),
3.92 (t, 2H, J = 5.5 Hz), 2.76 (s, 1H), 2.71 (s, 1H), 2.32 (s, 3H),
2.07 (s, 1H), 1.02-0.94 (m, 3 H); 13C NMR (125 MHz, CDCl3) δ
165.4, 163.1, 154.7 (q, J = 35.4 Hz), 149.0, 144.9, 144.4, 143.2,
138.1, 136.0, 130.3, 129.5, 128.5, 124.2, 123.9, 116.7 (q, J =
277.5 Hz), 110.2, 71.8, 64.8, 60.4, 44.6, 43.3, 42.1, 39.9, 32.9,
31.6, 19.6, 13.3; IR 2982, 1692, 1600, 1474, 1376, 1287, 1258,
1199, 1175, 1133, 1046, 935, 792 cm-1; HRMS (ESI) (m/z): [M þ
Na]þ calcd for C24H23Cl2F3N2O5Na, 569.0828; found 569.0848.
Procedure 2 (from 6b): (30R,40S)-6-[2-(2,6-Dichloro-4-methyl-
phenoxy)ethoxy]-30,40,50,60-tetrahydro-20H-[3,40]bipyridinyl-10,30-
dicarboxylic Acid 10-tert-Butyl Ester (3). Catalyst Preparation.
In a nitrogen filled glovebox, (O2 < 10 ppm) SL-J212-1 (230.4 g,
0.441 mol) was combined with (COD)Ru(Me-allyl)2 (134.2 g,
0.42mol) in a 1 gallon blow can followed by anhydrous, degassed
CH2Cl2 (2.5 L).
Hydrogenation. Ene-ester (4b) 28.4 wt % in 2-MeTHF (32.4
kg, 16.8 mol) was drawn into an autoclave under partial vacuum
followed by 2-MeTHF rinse bringing the batch volume to 300 L.
HBF4*OEt2 (3.40 kg, 21.0 mol)) was added slowly while mon-
itoring the batch temperature (maintained <40 °C). The auto-
clave was sealed and purged with N2 (3 ꢀ 40 psig). The catalyst
solution was introduced into the autoclave. The reactor was
sealed, and then the pressure was tested to 1000 psig N2. The
reactor was then vented and pressurized with H2 to 1000 psig.
Agitation was begun and the reaction temperature maintained
at 23 °C for 43 h. The reaction was vented, and HPLC confirmed
<0.1 A% ene-ester 4b with an ee of >99%. Aqueous NaHCO3
(100.0 kg, 7.5 wt %) was added slowly to the hydrogenation
batch, while maintaining a batch temperature <30 °C. The aq-
ueous layer was confirmed to have pH ≈ 8. The aqueous layer was
cut away, and the organic layer was washed with water (150 L).
The organiclayer (282.6 kg) was assayed, andthe concentrationof
chiral ester was determined to be 3.0 wt % (8.48 kg, 15.44 mol).
The batch was then distilled toa final weight of 71.0kg. 2-MeTHF
(12.0 kg) was used to rinse the distillation vessel. Into a visually
clean and dry 160 L extractor, the ester 6b solution was added and
rinsed with small amount of fresh 2-MeTHF.
Darco Treatment. The solution was then treated with Darco
KB-G (4.3 kg) for 2 h., filtered over silica gel (4.3 kg)on bed of
solka floc and washed with 2-MeTHF (50 L). The solution was
line filtered using a whatman polycap 75 HD to a visually clean
and dry 100 L rbf equipped with a thermocouple, overhead
mechanical stirrer and attached to a batch concentrator and the
2-MeTHF was removed in vacuo. The material was flushed with
EtOH (25 L), concentrated and diluted to a final volume of 25 L.
(Assayed at 8.48 kg, 15.44 mol, 92% yield).
TFA Deprotection, Boc Protection, Epimerization and Hydro-
lysis Sequence. A 75-L vessel equipped with an overhead stirrer,
a nitrogen inlet, and a temperature probe was charged with cis-
ester 6b (4400 g, 8.01 mol) and EtOH (20 L). The solution was
cooled to 5 °C, and NaOEt/EtOH (21 wt %, 3.59 L, 9.61 mol)
was added over 15 min. The reaction mixture was allowed to
warm to ∼15 °C over 4 h. Water (173 mL, 9.61 mol) was added, and
the reaction mixture was stirred for 10 h and then cooled to 5 °C.
Boc2O (2098 g, 9.61 mol) was added portionwise as a neat melt
(GAS EVOLUTION!). The reaction mixture was aged for 30 min
while allowing to warm to rt. NaOH (2 M, 20.0 L, 40.0 mol) was
added over 15-20 min, and the reaction mixture was heated to
70 °C for 2 h. Once cooled to rt, the reaction mixture was
(30R,40S)-30-{[2-Chloro-5-(2-methoxy-ethyl)-benzyl]cyclopropyl-
carbamoyl}-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-30,40,50,
60-tetrahydro-20H-[3,40]bipyridinyl-10-carboxylic Acid tert-Butyl
Ester (19). A 100-L vessel equipped with an overhead stirrer, a
vacuum inlet, a nitrogen inlet, and a temperature probe was
charged with trans-acid 3 (3840 g, 6.94 mol), MeCN (8.00 L),
2-MeTHF (8.00 L), and tosyl chloride (1747 g, 9.16 mol). The
slurry was cooled to -20 °C, and 1-methylimidazole (1.942 L,
24.36 mol) was added over 15 min, dissolving the slurry and
warming the mixture to -10 °C. The reaction mixture was stirred
for 3 h while internal temperature was kept between -10 and
-5 °C. Amine 2 (2031 g, 8.47 mol) in MeCN (2 L) and 2-MeTHF
(2 L) was then added over 5 min, and the reaction was allowed to
warm to rt and stirred for 16 h under N2. An extractor was
charged with 2-MeTHF/MTBE (3:1) (20 L) and cooled to 15 °C,
and the reaction mixture was transferred into it. Water (20 L) was
added, and the layers were separated. The aqueous layer was ex-
tracted with 2-MeTHF/MTBE (3:1) (20 L). The combined orga-
nics were successively washed with 0.5 N NaOH (20 L), 0.5 N
HCl (20 L), and water (20 L). The organic layer was then treated
with 2.5 kg Darco KB-G for 1 h and filtered over solka floc, and
the pad was washed with 2-MeTHF/MTBE (3:1) (20 L) to give
4.87 kg (94% yield, 86 A%) of coupled product 19. [R]D = -0.96
(c 1.87, EtOH); 1H NMR (500 MHz, acetone-d6) δ 8.06 (s, 1H),
7.67 (d, 1H, J = 8.5 Hz), 7.25 (s, 2H), 7.22 (d, 1H, J = 8 Hz), 7.08
(d, 1H, J = 8 Hz), 6.73 (d, 1H, J = 8.5 Hz), 6.55 (s, 1H), 4.68 (t,
2H, J = 4 Hz), 4.57 (d (br), 1H, J = 15.5 Hz), 4.42 (d (br), 1H,
J = 15.5 Hz), 4.39 (t, 2H, J = 4 Hz), 4.29 (s (br), 2H), 3.64 (t, 1H,
J = 10 Hz), 3.48 (t, 2H, J = 6.5 Hz), 3.26 (s, 3H), 3.21-3.16 (m,
1H), 2.96 (s (br), 3H), 2.68 (apparent s (br), 2H), 2.62 (apparent s
(br), 1H), 2.31 (s, 3H), 1.80 (s (br), 2H), 1.51 (s, 9H), 1.46 (s, 1H),
1.20 (d, 1H, J = 8 Hz), 0.96 (s, (br), 1H), 0.84 (s (br), 2H), 0.57 (s
(br), 1H); 13C NMR (125 MHz, acetone-d6) δ 174.1, 162.4, 149.1,
146.1, 138.7, 138.2, 136.0, 135.3, 132.1, 129.5, 128.84, 128.81,
128.7, 128.5, 110.6, 79.0, 72.8, 71.8, 66.9, 64.6, 57.7, 47.5, 46.8,
41.8, 35.2, 32.0, 30.4, 29.9, 27.8, 21.2, 19.5, 13.6, 8.6; IR 2972, 2929,
2869, 1736, 1691, 1649, 1605, 1474, 1426, 1406, 1365, 1285, 1255,
1231, 1160, 1115, 1042, 984, 828, 798 cm-1; HRMS (ESI) (m/z):
[M - H]þ calcd for C38H45Cl3N3O6, 746.2530; found 746.2532.
(30R,40S)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)ethoxy]-10,20,30,
40,50,60-hexahydro-[3,40]bipyridinyl-30-carboxylic Acid [2-Chloro-
5-(2-methoxy-ethyl)benzyl]cyclopropylamide (MK-1597). A 50-L
vessel equipped with an overhead stirrer, a vacuum inlet, a nitro-
gen inlet, and a temperature probe was charged with compound 19
(4800 g, 6.42 mol) in solution in ∼10 L of 2-MeTHF and fresh
MTBE (10 L). Phosphoric acid (85 wt %, 5 L, 74 mol) was added
over 10 min, and the reaction mixture was heated to 60 °C for 16 h.
It was diluted with MTBE (10 L), cooled to 0 °C, and quenched
with 5 N NaOH (∼18 L) to reach pH >12. The layers were cut,
and the aqueous layer was back-extracted with MTBE (10 L).
The combined organic layers were washed with water (5 L) and
then extracted with 40% v/v aq MsOH (3 ꢀ 10 L). The combined
aqueous MsOH layers were washed with MTBE (5 L). Fresh
MTBE (20 L) was added, and the heterogeneous mixture was
1070 J. Org. Chem. Vol. 76, No. 4, 2011

Molinaro et al.
JOCArticle
cooled to 0 °C and basified with 10 N NaOH (∼19 L) to pH >12.
The layers were cut, and the aqueous layer was back-extracted
with MTBE (2 ꢀ 5 L). The combined organic layers were washed
with half-saturated brine (2 ꢀ 10 L), dried over Na2SO4, and
batch concentrated to give MK-1597 (1) (3.95 kg, 95% yield,
91.8 A%).
a vacuum inlet, a nitrogen inlet, an addition funnel, and a tem-
perature probe was charged with a solution of MK-1597 (3141 g,
4.85 mol) in MTBE, and fresh MTBE (20 L) was added (filtered
through an inline filter, Polycap 36 HD, 1 μm, Whatman Inc.). A
solution of AcOH (600 mL, 10.48 mol) in heptane (4 L) was
filtered through an inline filter (Polycap 36 HD, 1 μm, Whatman
Inc.) into the addition funnel. AcOH/heptane (500 mL) was
added before seeding (22.28 g). The slurry was aged at room
temperature for 30 min, and the rest of AcOH/heptane solution
(4.1 L) was added over 35 min. The slurry was aged at room
temperature for 3 h and at 0 °C for 30 min. The slurry was filtered
through a filter pot, and the solid obtained was washed with cold
(0 °C) 10% heptane in MTBE (3 ꢀ 3 L) and with cold (0 °C) 1:1
heptane/MTBE (10 L). The solid was dried under vacuum and
nitrogen sweep and filtered over a sieve to give the MK-1597
AcOH salt as a white powder: 2941.6 g (83% AY, 98.6 A%). Ru
content: 5 ppm, Pd content: <1 ppm. [R]D = þ20.3 (c 1.12,
EtOH); 1H NMR (500 MHz, acetone-d6) δ 8.06 (s, 1H), 7.69 (d,
1H, J = 8.5 Hz), 7.26 (s, 2H), 7.22 (d, 1H, J = 8 Hz), 7.07 (d, 1H,
J = 8 Hz), 6.74 (d, 1H, J = 8 Hz), 6.53 (s, 1H), 4.68 (t, 2H, J = 4
Hz), 4.52 (d, 1H, J = 16 Hz), 4.46 (d, 1H, J = 16 Hz), 4.39 (t, 2H,
J = 4 Hz), 3.81-3.77 (m, 1H), 3.47 (t, 2H, J = 6.5 Hz), 3.41 (d,
1H, J = 11.5 Hz), 3.25 (s, 3H), 3.21 (d, 1H, J = 15 Hz), 3.12 (t,
1H, J = 14 Hz), 2.79 (q, 2H, J = 17.5, 12.5 Hz), 2.75-2.59 (m,
3H), 2.32 (s, 3H), 1.95 (s, 3H), 1.95-1.90 (m, 1H), 1.81 (d, 1H,
J = 13.5 Hz), 0.89-0.81 (m, 2H), 0.75-0.70 (m, 1H), 0.48-0.44
(m, 1H); 13C NMR (125 MHz, acetone-d6) δ 175.3, 162.3, 149.0,
146.1, 138.7, 138.3, 136.0, 135.6, 129.6, 129.4, 128.7, 128.64,
128.60, 128.50, 110.4, 72.8, 71.8, 64.5, 57.6, 47.6, 47.2, 41.6,
35.2, 30.4, 19.4, 8.97, 7.91; IR 1636, 1602, 1472, 1408, 1266,
1114, 1034, 1011, 839, 648 cm-1; HRMS (ESI) (m/z): [M þ H]þ
calcd for C33H38Cl3N3O4, 646.2001; found 646.1996.
Bis-D-Tartrate Salt Formation and Salt Break. MK-1597
(3900 g, 6.03 mol) was dissolved in THF (30 L), then D-tartaric
acid (1809 g, 12.06 mol) was added, and the reaction mixture was
stirred at rt for 20 h. MTBE (45 L) was added over 1 h, and the
slurry was aged for 1 h. The solid was filtered through a filter
pot, washed with 1.5:1 MTBE/THF (35 L), and dried under
nitrogen sweep to give 5100 g of MK-1597 bis-D-tartrate salt
(90%). Into a visually clean and dry 160-L extractor was intro-
duced MTBE (16 L) and 1 M NaOH (20 L). MK-1597 bis-D-
tartrate salt (4.5 kg, 4.66 mol) was added, and the slurry was
vigorously stirred for 3 h to completely dissolve the salt. The
layers were cut, and the organic layer was washed with half-
saturated brine (2 ꢀ 10 L). The organic solution was assayed at
2.9 kg of MK-1597 and dried over Na2SO4 and MgSO4 to bring
the water level down to 5000 ppm. A sample was analyzed:
[R]D = þ14.4 (c 1.06, EtOH); 1H NMR (500 MHz, acetone-d6) δ
8.05 (d, 1H, J = 0.2 Hz), 7.67 (dd, 1H, J = 8.5, 2.5 Hz), 7.26 (s,
2H), 7.22 (d, 1H, J = 8 Hz), 7.07 (dd, 1H, J = 8.5, 2 Hz), 6.74 (d,
1H, J = 8.5 Hz), 6.53 (s, 1H), 4.68 (t, 2H, J = 4.5 Hz), 4.52 (d,
1H, J = 16 Hz), 4.46 (d, 1H, J = 16 Hz), 4.39 (t, 2H, J = 4.5 Hz),
3.65 (td, 1H, J = 11, 4 Hz), 3.47 (t, 2H, J = 6.5 Hz), 3.37 (dd,
1H, J = 12.5, 3.5 Hz), 3.16-3.07 (m, 2H), 2.76-2.63 (m, 5H),
2.32 (s, 3H), 2.07 (quint, 1H, J = 2 Hz), 1.84-1.73 (m, 3H),
0.89-0.79 (m, 2H), 0.72-0.67 (m, 1H), 0.48-0.43 (m, 1H); 13
C
NMR (125 MHz, acetone-d6) δ 175.3, 162.2, 149.0, 146.1, 138.7,
138.3, 136.0, 135.7, 133.2, 129.4, 128.7, 128.61, 128.56, 128.51,
110.4, 72.8, 71.8, 64.5, 57.6, 50.2, 48.3, 47.6, 46.8, 41.8, 35.2,
33.5, 30.3, 29.4, 27.0, 19.4, 9.06, 7.78; IR 3492, 3312, 2970, 2933,
Acknowledgment. We thank Dr. Wayne Mullett, Mr.
Ravi Sharma, Dr. Mirlinda Biba, Dr. Yong Liu, and Dr.
Peter Sajonz for analytical support (Merck).
1645, 1606, 1476, 1404, 1260, 1203, 1077, 1036, 797 cm-1
;
HRMS (ESI) (m/z): [M þ H]þ calcd for C33H38Cl3N3O4,
646.2001; found 646.1996.
(30R,40S)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)ethoxy]-10,20,30,
40,50,60-hexahydro-[3,40]bipyridinyl-30-carboxylic Acid [2-Chloro-
5-(2-methoxy-ethyl)benzyl]cyclopropylamide Acetate (MK-1597
AcOH Salt). A 100-L vessel equipped with an overhead stirrer,
Supporting Information Available: Experimental proce-
dures and spectroscopic data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 4, 2011 1071