Practical synthesis of a p38 MAP kinase inhibitor

Article abstract of DOI:10.1021/jo802186m

p38 MAP kinase inhibitors have attracted considerable interest as potential agents for the treatment of inflammatory diseases. Herein, we describe a concise and efficient synthesis of inhibitor 1 that is based on a phthalazine scaffold. Highlights of our approach include a practical synthesis of a 1,6-disubstituted phthalazine building block 24 as well as the one-pot formation of boronic acid 27. Significant synthetic work to understand the reactivity principles of the intermediates helped in selection of the final synthetic route. Subsequent optimization of the individual steps of the final sequence led to a practical synthesisof 1.

Full text of DOI:10.1021/jo802186m

Practical Synthesis of a p38 MAP Kinase Inhibitor
Michał Achmatowicz,* Oliver R. Thiel, Philip Wheeler, Charles Bernard, Jinkun Huang,
Robert D. Larsen, and Margaret M. Faul
Chemical Process Research and DeVelopment, Amgen Inc., One Amgen Center DriVe,
Thousand Oaks, California 91320-1799
michala@amgen.com
ReceiVed October 3, 2008
p38 MAP kinase inhibitors have attracted considerable interest as potential agents for the treatment of
inflammatory diseases. Herein, we describe a concise and efficient synthesis of inhibitor 1 that is based
on a phthalazine scaffold. Highlights of our approach include a practical synthesis of a 1,6-disubstituted
phthalazine building block 24 as well as the one-pot formation of boronic acid 27. Significant synthetic
work to understand the reactivity principles of the intermediates helped in selection of the final synthetic
route. Subsequent optimization of the individual steps of the final sequence led to a practical synthesis
of 1.
Introduction
p38 MAP kinase inhibitors has resulted in suitable phthalazine-
based candidates that were selected for further development.4
Herein, we describe process research and development toward
the phthalazine derivative 1 which has culminated in an efficient
and scalable synthesis of this drug candidate.
p38 mitogen-activated protein (MAP) kinases are intracellular
serine/threonine kinases that positively regulate the production
and action of several pro-inflammatory mediators, specifically
the release of tumor necrosis factor-R (TNF-R) and interleukin-1
(IL-1) in response to stress.1 These cytokines are involved in
autoimmune disease states like rheumatoid arthritis (RA),
Crohn’s disease (inflammatory bowel disease), and psoriasis.
Biological agents that sequester TNF-R show impressive clinical
efficacy in the treatment of these diseases.2 Small molecule
inhibitors of p38 MAP kinase have been shown to be efficacious
in clinical studies as alternatives for these biological agents.3
Our medicinal chemistry team’s work toward the discovery of
The original synthetic route to prepare 1 (Scheme 1)4 was
reasonably short and efficient. However, it required 4-bromo-
2-methylbenzonitrile (2), which was difficult to source, and other
expensive stoichiometric reagents such as AgNO3 and bis(pina-
colato)diboron. Moreover, the hydrative cyclization of 2-(di-
bromomethyl)benzonitrile 3 to hydroxyisoindolinone 4 proved
precarious, and the removal of the insoluble silver byproducts
(light-sensitive silver bromide, silver oxide, metallic silver)
during the reaction workup was problematic and deemed not
scalable. In order to address these issues, a number of silver-
free hydrative cyclization conditions to form 3 were briefly
* To whom correspondence should be addressed: Tel: 805-447-5774. Fax:
805-480-1346.
(1) (a) Chen, Z.; Gibson, T. B.; Robinson, F.; Silvestro, L.; Pearson, G.; Xu,
B.; Wright, A.; Vanderbilt, C.; Cobb, M. H. Chem. ReV. 2001, 101, 2449. (b)
Raingeaud, J.; Gupta, S.; Rogers, J. S.; Dickens, M.; Han, J.; Ulevitch, R. J.;
Davis, R. J. J. Biol. Chem. 1995, 270, 7420.
(2) Etanercept, infliximab, and adalimumab are TNF-R blockers currently
approved in the US and elsewhere for the treatment of various inflammatory
diseases.
(3) (a) Gaestal, M.; Mengel, A.; Bothe, U.; Asadullah, K. Curr. Med. Chem.
2007, 14, 2214. (b) Peifer, C.; Wagner, G.; Laufer, S. A. Curr. Top. Med. Chem.
2006, 6, 113. (c) Margutti, S.; Laufer, S. A. ChemMedChem 2007, 2, 1116.
(4) Herberich, B.; Cao, G.-Q.; Chakrabarti, P. P.; Falsey, J. R.; Pettus, L.;
Rzasa, R. M.; Reed, A. B.; Reichelt, A.; Sham, K.; Thaman, M.; Wurz, R. P.;
Xu, S.; Zhang, D.; Hsieh, F.; Lee, M. R.; Syed, R.; Li, V.; Grosfeld, D.; Plant,
M. H.; Henkle, B.; Sherman, L.; Middleton, S.; Wong, L. M.; Tasker, A. S.
J. Med. Chem. 2008, 51, 6271.
(5) A one-pot hydrolysis/cyclization attempt under the conditions (1-BuOH,
aq NaOH, 120 °C) developed for cyclizations of o-cyanobenzaldehydes (Sato,
R.; Ohmori, M.; Kaitani, F.; Kurosawa, A.; Senzaki, T.; Goto, T.; Saito, M.
Bull. Chem. Soc. Jpn. 1988, 61, 2481) led to a complex mixture of products.
10.1021/jo802186m CCC: $40.75
Published on Web 12/16/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 795–809 795

Achmatowicz et al.
SCHEME 1. Original Discovery Synthesis of a Lead Drug Candidate 1
investigated, largely without success.5 These findings combined
with the relatively high cost of 4-bromo-2-methylbenzonitrile
(2)6 led us to focus on the development of a more practical
synthesis of 1,6-difunctionalized phthalazines. Other issues that
needed to be addressed included the development of a practical
synthesis of the boronic acid building block as well as a more
controlled isolation and purification of 1. Strategically, it was
also desirable to avoid the use of palladium in the last step of
the synthetic sequence to reduce potential issues with removal
of trace metal contaminants. Toward this end, two synthetic
approaches for the synthesis of 1 were proposed (Scheme 2),
both of which relied on the synthesis of key building blocks 24
and 27. As will be discussed below, we found that the order of
bond construction was important for the successful synthesis
of 1. Initially, we investigated installation of the morpholine
substituent late in the synthesis (first-generation approach,
Scheme 2). This route presented difficulties detailed below that
prompted us to pursue a strategy similar to that demonstrated
in the discovery approach (cf. Scheme 1). Thus, we successfully
developed a sequence in which early morpholine installation
afforded 37, which was coupled with 27 followed by amidation
to yield 1 (second-generation approach, Scheme 2).
of a suitable para-substituted benzamide III7 using alkyllithium
or amide bases followed by reaction with a formyl donor
(Scheme 3).8,9 The main advantage of this approach is the
inherent regiospecificitysonly a single lithio-regioisomer II is
expected to form due to the symmetry of the amide III.
Furthermore, the amide functionality is one of the strongest
ortho-directing groups,10 and methodology for ortho-function-
alization of benzamides by directed ortho-lithiation is well
established.11 Compared to tertiary amides (e.g., diisopropyl-
benzamides), secondary amides such as III require an additional
1 equiv of the lithium base for the initial N-deprotonation, but
this initial deprotonation also protects them against attack of
the alkyllithium species.12
(7) A number of inexpensive para-substituted benzoic acids or para-
substituted benzoyl chlorides are readily available.
(8) (a) Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1183.
(b) Metallinos, C. Development of New Directed Metalation Groups for the (-)-
Sparteine-Mediated Synthesis of Ferrocenes with Planar Chirality. Ph.D Thesis,
Queen’s University, Kingston, Ontario, Canada, 2001.
(9) Epsztajn, J.; Brzezinski, J. Z.; Czech, K. Monatsh. Chem. 1993, 124,
549.
(10) Snieckus, V. Chem. ReV. 1990, 90, 879.
(11) Recent examples of ortho-functionalization of benzamides via a directed
ortho-lithiation approach: (a) Olivier, A.; Sperry, J.; Larsen, U. S.; Brimble,
M. A. Tetrahedron 2008, 64, 3912. (b) Khanolkar, A. D.; Lu, D.; Ibrahim, M.,
Jr.; Thakur, G. A., Jr.; Porreca, F.; Veerappan, V.; Tian, X.; George, C.; Parrish,
D. A.; Papahatjis, D. P.; Makriyannis, A. J. Med. Chem. 2007, 50, 6493. (c)
Clayden, J.; Hebditch, K. R.; Read, B.; Helliwell, M. Tetrahedron Lett. 2007,
48, 8550. (d) Uchiyama, M.; Naka, H.; Matsumoto, Y.; Ohwada, T. J. Am. Chem.
Soc. 2004, 126, 10526. (e) Cornella, I.; Kelly, T. R. J. Org. Chem. 2004, 69,
2191. (f) Martin, C.; Macintosh, N.; Lamb, N.; Fallis, A. G. Org. Lett. 2001, 3,
1021.
Results and Discussion
Development of a Phthalazine Building Block. Precursors
of a 6-substituted phthalazin-1-ol system such as hydroxyisoin-
dolinones I can be obtained by directed ortho-metalation (DoM)
(6) $153/25 g or $1200/mol (Aldrich catalog price).
(12) Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 6790.
796 J. Org. Chem. Vol. 74, No. 2, 2009

Practical Synthesis of a p38 MAP Kinase Inhibitor
SCHEME 2. Key Disconnections in the Retrosynthesis of 1
SCHEME 3. Directed ortho-Lithiation Approach to Precursors of 6-Substituted Phthalazin-1-ol
SCHEME 4. Preparation of N-tert-Butylbenzamides 12a-c
was similarly unreactive (2.5 equiv of LDA, THF/heptane/PhEt,
-75 °C, 1 h).13,14 Due to the inability of a lithium amide base
to generate the lithiated species II, more basic organolithium
reagents were investigated. Since p-bromobenzamide 12a was
expected to undergo a competitive halogen-lithium exchange15
and p-nitrobenzamide 12b was found to give multiple products
under DoM conditions (2.5 equiv of tBuLi, THF/pentane, -78
°C, 15 min), DoM studies on p-chlorobenzamide 12c were
carried out. Benzamide 12c was successfully ortho-lithiated
using excess tert-butyllithium (2.5 equiv of tBuLi, THF/pentane,
-78 °C, 1 h) followed by trapping with a formyl donor (DMF,
A series of N-tert-butylbenzamides (12a-c) were prepared
from commercially available benzoic acids (11a-c) in good
yields and excellent purity (>99% by HPLC) (Scheme 4).
Initial attempts to effect deprotonation of 12a using lithium
diisopropylamide (3 equiv of LDA, THF/heptane/PhEt, -50 °C
to rt) were unsuccessful. After quenching with iodine or N,N-
dimethylformamide to trap the lithiated species II, no iodinated
or formylated products were detected, and nearly 100% of
starting material was recovered. The more acidic analogue 12b
(13) These results confirm that kinetic basicity of LDA (as well as other
lithium dialkylamides, e.g., LTMP) is insufficient for the directed ortho-metalation
(DoM) reaction of aromatic carbocycles.14
(14) (a) Equilibrium pKa values in DMSO: Bordwell, F. G. Acc. Chem. Res.
1988, 21, 456, and references cited therein. (b) Equilibrium pKa values in water:
Smith, M. B.; March, J. AdVanced Organic Chemistry, 5th ed.; Wiley-
Interscience: New York, 2001; pp 329-331, and references cited therein.
(15) Narasimhan, N. S.; Sunder, N. M.; Ammanamanchi, R.; Bonde, B. D.
J. Am. Chem. Soc. 1990, 112, 4431.
J. Org. Chem. Vol. 74, No. 2, 2009 797

Achmatowicz et al.
t
SCHEME 5. ortho-Formylation Using BuLi Followed by DMF Quench
-70 to 0 °C, then aq NH4Cl) to afford hydroxyisoindolinone
16 in excellent yield (89-94%). Formation of 16 was ac-
allowed for an increase in the deprotonation temperature to -22
°C. An impurity 17a that was observed in minor amounts on a
small scale (1.4 mol %) became more prominent (>5 mol %)
upon scaleup (see below for further discussion).20 Use of less
basic methyllithium21 in place of n-butyllithium mitigated this
problem, led to clean formation of 14 (as judged by DMF-
quenched aliquots), and gave the most favorable 16/17a ratio
(e2.5 mol % of 17a) after sequential addition of DMF (2.0
equiv) and aq NH4Cl. Conversion of 12c to 16 could be
successfully performed at 0 °C without any significant side
reactions, thereby obviating cryogenic conditions. Importantly,
no significant increase in the impurity formation was observed
upon increase in reaction scale. Based on its improved selectivity
toward the formation of 16,22 thermal stability, and favorable
mechanical properties of the reaction mixtures,23 methyllithium
was selected for further development of this ortho-lithiation/
formylation process.
Considerable experimental effort was devoted to understand-
ing the origin of the undesired bis-formylated product 17a in
order to suppress its formation. Two scenarios that could account
for the impurity 17a are possible: (i) via lithium o,o-dilithioben-
zamidate 1524 (Scheme 5); (ii) via iterative lithiation/formylation
during DMF quench. Apart from a correlation of alkyllithium
strength and magnitude of 17a detected after DMF quench, no
1
companied by a small amount (4-9 mol % by H NMR) of a
structurally related impurity, which was identified as the bis-
formylated product 17a (Scheme 5).
In an attempt to simplify the synthesis of the phthalazine
precursor, 4-chlorobenzoic acid (11c) was submitted to the
t
lithiation/formylation conditions (2.5 equiv of BuLi, THF/
pentane, -78 °C, 15 min, then DMF -70 to -10 °C, then aq
NH4Cl) with the expectation that lithium carboxylate would act
as an ortho-directing group.16 The desired 5-chloro-3-hydroxy-
isobenzofuran-1(3H)-one (19) was not formed, and the reaction
provided (4-chlorophenyl)-tert-butylketone (18) via nucleophilic
attack of tert-butyllithium on lithium 4-chlorobenzoate.
In a typical experiment, the alkyllithium solution was added
to a precooled solution of 12c, giving the lithium amidate 13
as a homogeneous solution. During the addition of the remainder
of the alkyllithium solution, the reaction mixture gradually
became heterogeneous, presumably a result of decreasing
polarity of the reaction medium17 and concomitant formation
of lithiated species 14. Due to the large amount of precipitates
in the reaction, mechanical agitation was found to be necessary
in these experiments. A number of issues were identified in the
development of more scalable reaction conditions for the
synthesis of 16: the use of an undesirable lithiation reagent
(tBuLi), cryogenic temperatures (<-70 °C), and selectivity (16
versus 17a). A comparison of different lithium reagents (tBuLi
in pentane, nBuLi in hexanes, MeLi in diethoxymethane)
(2.0-2.5 equiv) was thus initiated.18,19 Use of n-butyllithium
(18) The molarity of the alkyllithium reagents was determined immediately
prior each experiment using the 1,10-phenanthroline/menthol method: Ho-Shen,
L.; Paquette, L. Synth. Commun. 1994, 24, 2503.
(19) For a more detailed summary of the experiments, see Table 1 in the
Supporting Information.
(20) The extended time required to add DMF on a larger scale was a major
factor contributing to increased amounts of 17a, while use of unnecessarily strong
n
base (tBuLi or BuLi versus MeLi) exacerbated the issue.
t
(16) (a) Nguyen, T.-H.; Chau, N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.;
Mortier, J. J. Org. Chem. 2007, 72, 3419. (b) Nguyem, T.-H.; Castanet, A.-S.;
Mortier, J. Org. Lett. 2006, 8, 765. (c) Yang, K.; Blackman, B.; Diederich, W.;
Flaherty, P. T.; Mossman, C. J.; Roy, S.; Ahn, Y. M.; Georg, G. I. J. Org. Chem.
2003, 68, 10030. (d) Palmer, B. D.; Boyd, M.; Denny, W. A. J. Org. Chem.
1990, 55, 438.
(17) At the end of alkyllithium addition, the reaction medium consists of at
2/3 v/v THF and 1/3 v/v alkyllithium solvent (pentane, hexanes, or di-
ethoxymethane).
(21) Approximate pKa of conjugate acids in water BuLi (53), nBuLi (50),
MeLi (48).14b
(22) Minimization of 17a was desirable as it could not be readily cleared
from 16.
(23) The ability to agitate reaction mixtures by the end of the lithiation period.
Reactions using n-butyllithium in hexanes or n-hexyllithium in hexanes tend to
give thick gelatinous mixtures.
(24) A similar o,o-dilithioamide was postulated by: Eaton, P. E.; Cunkle,
G. T.; Marchioro, G.; Martin, R. M. J. Am. Chem. Soc. 1987, 109, 948.
798 J. Org. Chem. Vol. 74, No. 2, 2009

Practical Synthesis of a p38 MAP Kinase Inhibitor
SCHEME 6. Mechanism of the Formation of 17a
SCHEME 7. Optimized ortho-Formylation of 12c
other evidence for the formation of 15 was found under all the
conditions examined. In order to discount a mechanism involv-
ing intermediacy of 15, addition of a large excess of base
(2.5-3.0 equiv) along with deaggregating agents (TMEDA or
HMPT) under varying reaction temperatures (-78 to 0 °C) was
used. These conditions did not decrease the resulting 16/17a
ratio, but instead we found that the amount of 17a was highly
dependent on the mode of the DMF quench. Normal quench
with 2-3 equiv of DMF always led to varying amounts of 17a
(e20%); however, no 17a was detected during inverse quench
of a reaction mixture aliquot into excess DMF in THF. On the
basis of this observation, a subsequent deprotonation during the
DMF quench to 16 seems likely (iterative lithiation/formylation
mechanism). Lithium dimethylamide (a byproduct of the reac-
tion of 14 with DMF) or residual methyllithium could be
responsible for the deprotonation of a fraction of one of the
short-lived intermediates (20 or 21), leading consequently to
17a. Considering that lithium amides are not sufficiently basic
to deprotonate arenessLDA failed to react with 12a or 12b
(vide supra)sit seems more plausible that residual methyllithium
is the culprit. In a set of control experiments, 16 was allowed
to react with MeLi (2 equiv), and this was followed by a DMF
quench. The product distribution was highly dependent on the
extent of the lithiation period. Two regioisomeric aldehydes 17a/
17b (1:3 by LC) were produced as a result of DMF quench
immediately after MeLi addition (<2 min with MeLi). On the
other hand, prolonged incubation (DMF quench 1.5 h after MeLi
addition) afforded aldehyde 17b cleanly. Both aldehydes readily
ring-expanded in the presence of hydrazine hydrate to give
phthalazines 23a and 23b, respectively. The lithiation experi-
ments clearly indicate that fast kinetic deprotonation leading to
22a25 was followed by a relatively slow equilibration to
thermodynamically favored 22b (Scheme 6). On the basis of
these results, formation of the undesired side product 17a using
the previously described ortho-lithiation/formylation protocol
can be explained as follows: In the presence of sufficient excess
of alkyllithium (g2 equiv), amide 12 undergoes conversion to
14 with some of the unreacted alkyllithium remaining. During
DMF quench, aryllithium 14 reacts with DMF to produce
transient species 20, that rapidly collapses to form 21. The
relative amount of 21 and DMF present in the reaction mix-
ture during the normal quench makes 21 statistically more
accessible to secondary reaction with any residual alkyllithium
leading to 22a. The kinetic nature of this process is consistent
(25) An aromatic ring in a related unsubstituted isoindolone was lithiated at
the position adjacent to the amide carbonyl (cf. ref 8b, pp 29 and 30).
J. Org. Chem. Vol. 74, No. 2, 2009 799

Achmatowicz et al.
SCHEME 8. 6-Chlorophthalazin-1-ol (24) via Ring Expansion of Hydroxyisoinolinone 16 Using Hydrazine
SCHEME 9. An Efficient Three-Step Process to 6-Chlorophthalazin-1-ol (24)
with absence of aldehyde 17b, as only 17a is found in crude or
isolated samples of 16.
expanded product 24 was isolated via direct filtration from the
reaction mixture in high yield (89%) due to its low solubility
in acetic acid and most organic solvents (<5 mg/mL). The
starting material impurity 17a was converted into N-acetylhy-
drazone 23a (Scheme 6) under the reaction conditions and was
efficiently rejected in the mother liquors.27
In summary, this work resulted in the development of an
efficient process for the preparation of the 6-chlorophthalazin-
1-ol (24) building block from commercially available 4-chlo-
robenzoyl chloride in a three-step sequence in an overall yield
of 73%, which could be carried out on multikilogram scale
(Scheme 9).
Development of 3-Borono-4-methylbenzoic Acid Build-
ing Block. The first-generation route to the N-cyclopropyl-4-
methylbenzamide tail piece 10 of drug candidate 1 was deemed
not economically viable due to the high cost of bis(pinacola-
to)diboron used in the palladium-catalyzed carbon-boron bond
formation step (Scheme 1). Substitution of the diboron reagent
with the less expensive pinocolborane following the literature
protocol (dioxane, Et3N, cat. Pd(dppf)Cl2)28 led to a sluggish
reaction with only 66% conversion to 10 along with formation
of the reduction product (5% of des-iodo-9).
Following the optimized ortho-formylation protocol, amide
12c in THF (8 vol) was deprotonated using ∼3 M MeLi in
diethoxymethane (2.05 equiv) at e-10 °C over g3 h, followed
by a normal quench with DMF (2.0 equiv) at -15 to -10 °C
and then a final neutralization using satd aq NH4Cl at e-5 °C
to afford hydroxyisoindolinone 16 (98.5% LC purity) in 85%
yield (Scheme 7). Under these conditions, formation of the
undesired product 17a was minimized (typically 0.7-0.9% 17a
by LC in crude reaction mixtures). Since the byproduct is
efficiently rejected in the next reaction step, there was no need
to implement the more complicated inverse quench procedure
for the scale-up of this reaction.
Hydroxyisoindolinone 16 readily reacted with a stoichiometric
amount of hydrazine hydrate (65 wt %, 1.05 equiv) in acetic
acid at elevated temperatures (>50 °C) to produce 6-chlo-
rophthalazin-1-ol (24). In order to minimize an accumulation
of hydrazine in the reaction mixture,26 hydrazine hydrate was
added dropwise to a slurry of 16 in acetic acid at 100 °C. No
starting material 16 was detected, and no intermediates were
observed upon completion of the addition of hydrazine hydrate
over 10 min, indicating that the reaction is at least as fast as
the addition. When the reaction was performed at lower
temperatures (,90 °C), the bis-hydrazone intermediate 25 was
observed at significant concentrations by LC/MS (Scheme 8).
Under optimized conditions, the reaction was conducted at
90-93 °C using 1.05 equiv of hydrazine hydrate. The ring-
We decided to pursue the preparation of the corresponding
arylboronic acid 27 (Scheme 2), which seemed more attractive
than pinacol ester 10 for a number of reasons: (i) the amide
(27) 2.5% of 17a by LC in the starting hydroxyindolinone 16 led to an
acceptable <0.5% of 23a by LC in isolated 6-chlorophthalazin-1-ol (24).
(28) Cameron, K. S.; Pincock, A. L.; Pincock, J. A.; Thompson, A. J. Org.
Chem. 2004, 69, 4954.
(26) Accumulation of hydrazine is a safety hazard on scale.
800 J. Org. Chem. Vol. 74, No. 2, 2009

Practical Synthesis of a p38 MAP Kinase Inhibitor
SCHEME 10. Lithium-Based Synthesis of Boronic Acid 27
SCHEME 11. Magnesium-Based Synthesis of Boronic Acid 27
bond can be constructed late in the sequence, i.e., after the
palladium-catalyzed cross-coupling, affording additional control
point and facilitating palladium removal,29 and (ii) arylboronic
acid 27 should be readily available from 3-iodo-4-methylbenzoic
acid (8) in a short sequence involving halogen-metal exchange
followed by quench with alkylborate30 and hydrolysis.
In order to circumvent a net reduction of the aryl iodide 8
during the iodine-lithium exchange, masking of the acidic
carboxylic function was necessary.31 This could be achieved
by formation of the anhydrous lithium carboxylate 2632 that
could be conveniently converted into crystalline boronic acid
27 in 50-70% yield using a one-pot protocol (1.1-1.2 equiv
pentane fraction deviated slightly upward from this ratio (e.g.,
due to lower than expected titer of commercial 1.7 M tBuLi in
pentane), the halogen-lithium exchange reaction was signifi-
cantly hindered. This gave rise to some reproducibility issues,35
such that an alternative alkylmagnesium-based sequence for the
synthesis of boronic acid 27 was sought.
n
of BuLi in hexanes, THF, -78 °C; then B(OMe)3, -78 to 0
°C; then aq HCl 0 °C to rt). Performing the reaction at less
cryogenic conditions (-50 °C) led to incomplete conversion
of 26 and extensive formation of multiple n-butylated side
products arising from both nucleophilic attack of BuLi on
carboxylate carbonyl and Wurtz-type reactions between inter-
mediate aryllithium and n-butyl iodide.
In our previous work, we found that the direct reaction of 8
with organolithiums had led to deiodination, due to the
comparable rates of deprotonation and iodine-lithium ex-
change.36 In stark contrast, treatment of 8 with 1 equiv of
isopropylmagnesium chloride at -50 °C lead to a relatively
clean deprotonation of the carboxylic acid that is accompanied
by less than 10% reduction to p-toluic acid (29). The addition
of a second equivalent of isopropylmagnesium chloride to this
mixture resulted in iodine-magnesium exchange.37 The aryl-
magnesium species thus formed was then quenched with
triisopropylborate, and then the resulting borate complexes were
hydrolyzed with aq hydrochloric acid. The resulting boronic
acid was isolated by crystallization from THF/heptane (67%).
The reduction to p-toluic acid (10%) and the formation of bis-
arylboronic acid (up to 15%) are two side reactions that explain
the relatively low yield of this sequence. Recrystallization from
THF/heptane was used to further upgrade the purity of this
compound. Overall, this one-pot protocol offers a clear advan-
tage over the two-step protocol involving intermediate isolation
of the lithium salt.38
Development of the First-Generation Suzuki Coupling.
The Suzuki reaction coupled a boronate ester and an aryl
bromide for construction of the key aryl-aryl bond. The
synthesis of the phthalazinol building block described above
allowed access to the corresponding aryl chloride, thereby
making this palladium-catalyzed coupling more challenging.
Initial conditions used to carry out the Suzuki coupling between
24 and 27 (1 mol % of Pd2(dba)3, 5 mol % of ligand, 5 equiv
n
Using tert-butyllithium (2.1 equiv) instead of n-butyllithium
(1.1 equiv) allowed for a clean iodine-lithium exchange at -50
to -55 °C with no butylated side products observed.33 However,
the amount of p-toluic acid formed under these conditions was
increased. We speculated that the generated aryllithium inter-
mediate competes with tert-butyllithium for tert-butyl iodide
and, indeed, found that this side reaction could be effectively
minimized by inverse addition of a precooled solution of lithium
3-iodo-4-methylbenzoate (26) in THF into a solution of tert-
butyllithium in pentane/THF34 keeping the internal temperature
at or below -50 °C. Thus generated, the aryllithium was
quenched with trimethyl borate (-50 to -5 °C) followed by
hydrolysis via addition of water (-5 °C to rt). Under these basic
aqueous conditions, the intermediate boronic ester was rapidly
hydrolyzed into the water-soluble lithium salt of 27. Aqueous
workup, followed by pH adjustment using aq HCl, led to crude
27, and then recrystallization from THF/hexanes afforded
boronic acid 27 in 65-85% overall yield (96.2-99.3% LC
purity) starting from aryl iodide 8 (Scheme 10). Significantly,
we found that the hydrocarbon content in the reaction mixture
must be kept relatively low (initially at most 0.9:1.0 v/v) for a
successful halogen-lithium exchange to occur and that if the
(29) Use of transition-metal catalysts in the final step of the synthetic sequence
can be complicated by issues related to removal of metal residues. For a reference,
see: Garrett, C. E.; Prasad, K. AdV. Synth. Catal. 2004, 346, 889.
(30) Sharp, M. J.; Snieckus, V. Tetrahedron Lett. 1985, 26, 5997.
(31) Halogen-lithium exchange occurs at competitive rates to deprotonation;
see: Narasimhan, N. S.; Sunder, N. M.; Ammanamanchi, R.; Bonde, B. D. J. Am.
Chem. Soc. 1990, 112, 4431.
(35) Likely due to impeded deaggregation of tBuLi and decreased solubility
of 26 in pentane-rich pentane/THF mixtures.
(36) (a) Only limited examples of in situ deprotonation of a carboxylic acid
followed by halogen-metal exchange with another reagent have been reported.
Deprotonation with dibutylmagnesium: Kato, S.; Nonoyama, N.; Tomimoto, K.;
Mase, T. Tetrahedron Lett. 2002, 43, 7315. (b) Deprotonation with methylmag-
nesium bromide: Kopp, F.; Wunderlich, S.; Knochel, P. Chem. Commun. 2007,
2075. (c) One isolated example of using nBuLi for both deprotonation and
halogen-metal exchange has been reported for a sterically hindered benzoic
acid. Wang, Q.; Qu, D.; Ren, J.; Chen, K.; Tian, H. Angew. Chem., Int. Ed.
2004, 43, 2661.
(37) For a comprehensive review about the preparation of organomagnesium
reagents, see: 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.
(38) Exploration of the scope of this method for the synthesis of other boronic
acid with free carboxylic acid groups is currently ongoing and will be reported
in due course.
(32) Two protocols could be used: (1) 8, LiOH (1.0 equiv), EtOH, followed
by solvent removal and oven drying, affording anhydrous solid lithium
carboxylate 26; (2) 8, LiOH (1.0 equiv), 3 Å molecular sieves, THF, followed
by filtration, affording anhydrous THF solution of lithium carboxylate 26.
(33) tert-Butyl iodide rapidly reacts with excess tert-butyllithium to form
isobutylene, isobutane, and lithium iodide.
t
(34) A freshly titrated commercial 1.7 M BuLi in pentane (2.1 equiv, 4.6
vol relative to 26) was diluted by addition into anhydrous THF (5.0-7.8 vol
t
per 26) resulting in ca. 0.64-0.81 M BuLi in pentane/THF (0.9:1.0 to 0.6:1.0
v/v).
J. Org. Chem. Vol. 74, No. 2, 2009 801

Achmatowicz et al.
SCHEME 12. Initial Suzuki Coupling Conditions Leading to 28
SCHEME 13. Optimized Suzuki Coupling of 24 and 27
SCHEME 14. Proposed Routes from 28 to Drug Candidate 1
of Cs2CO3, 1-BuOH, water, 100 °C) were found by screening
several ligands (N-heterocyclic carbene ligands, biphenyldialky-
lphosphines). Buchwald’s biphenyl ligands containing a dicy-
clohexylphosphino- (Cy2P-) moiety were found to be particularly
effective, and structurally the simplest competent monodentate
ligand, 2′-methyl(dicyclohexylphosphino)biphenyl (MePhos),
was selected for the initial development.39,40 Protodeboronation
of 27 leading to 29 was found to be a major side reaction
necessitating use of a significant excess (1.5 equiv) of the
boronic acid in order to reach complete conversion of the aryl
chloride 24. As a result, approximately 50 mol % of p-toluic
acid (29) (Scheme 12) was contained in the crude reaction
mixture.
The inability to clear the p-toluic acid side product (up to 10
mol % in the isolated product) combined with the large excess
of valuable boronic acid 27 required identification of Suzuki
coupling conditions which would eliminate or at least minimize
protodeboronation. The protodeboronation of 27 proceeds even
in the absence of palladium catalyst. The rate of this process
correlates with base strength in the following approximate order:
K2CO3 > K3PO4 > KOAc . alkylamines. Thus, using dicyclo-
hexylamine in the Suzuki coupling of 24 and 27 (1.1 equiv)
led to clean formation of 28 with significantly less p-toluic acid
(up to 10 mol %).41 Inferior results were obtained with
structurally related diisopropylamine (poor conversion/impurity
profile) or some other mild organic (TEA, poor conversion/
impurity profile) or inorganic bases (KOAc, 50% conversion).
t
(39) Respective Bu2P-analogues of these ligands were not effective.
(40) 2-Dicyclohexylphosphinobiphenyl ligands in Suzuki coupling reactions: (a)
Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722.
(b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 4685.
(41) A related recent application of dicyclohexylamine to minimize protode-
boronation in a Suzuki reaction: (a) Payack, J. F.; Vazquez, E.; Matty, L.; Kress,
M. H.; McNamara, J. J. Org. Chem. 2005, 70, 175.
802 J. Org. Chem. Vol. 74, No. 2, 2009

Practical Synthesis of a p38 MAP Kinase Inhibitor
FIGURE 1. Proposed structures of chlorination impurities MS 579 and MS 597 (Route A).
SCHEME 15. Preparation of 1 (Route A)
SCHEME 16. Unsuccessful Isolation of Hydrolytically Labile Chloro Acid 32 (Route B)
Use of an excess of dicyclohexylamine (4 equiv)42 was critical
for a smooth and fast coupling reaction. The reaction conditions
were subsequently optimized: 24, 27 (1.1 equiv), Pd2(dba)3 (0.50
mol %), MePhos (1.25 mol %), Cy2NH (4 equiv), 1-butanol/
water (4/1 v/v, 7.0 vol) at 80 °C. Complete conversion of 24
(<1% by LC) was typically observed after 17-20 h with most
or all of the residual 27 (initially 10 mol % excess) converted
into 29 (0.5-10 mol %). The crude product was extracted into
aqueous 5 N NaOH (6 equiv), washed with MTBE (2.5 vol),
and precipitated using aq HCl to afford 28 (86-91% isolated
yield) (Scheme 13). Modest rejection of p-toluic acid was
observed during workup and isolation, and it remained the major
impurity (up to 10 mol %). In addition, the product that was
isolated using this procedure was significantly colored and
contained relatively high levels of residual Pd (approximately
500 ppm).
reaction of 31 with morpholine afforded 1 in 80% yield after
chromatography (Scheme 15). Several attempts to improve assay
yields of 31 beyond the initially observed range by modifying
reaction parameters such as amount of POCl3, reaction solvent,
temperature, or inverse or normal quench failed. The overall
yield of this sequence was not satisfactory (20-32%), and
combined with the need for chromatographic purification of both
31 and the final product 1, it was deemed a nonpractical route.
Route B takes advantage of a selective hydrolysis of the more
reactive acid chloride in intermediate 30, thereby theoretically
allowing for an additional isolation and control point at the stage
of intermediate 32. However, in practice, isolation of the chloro
acid 32 was difficult. The material was sensitive to aqueous
acid43 or aqueous base,44 and the neutralized wet solid of 32
was found to rapidly degrade at room temperature (Scheme 16).
The same persistent impurities MS 579 and MS 597 were
obtained in the formation of 32 as were identified in route A
(Figure 1). For these reasons, a demonstration of the downstream
chemistry was not pursued.
Development of the First-Generation End-Game. Three
routes toward 1 starting from intermediate 28 can be envisaged
(Scheme 14):
Route C (Scheme 14), in which the order of steps is reversed
as compared to route A and B, was the final attempt to utilize
the hydroxy acid 28 for synthesis of 1. Thus, carbonyldiimi-
dazole promoted the formation of the cyclopropylamide 34 in
85-95% yield. The subsequent chlorodehydroxylation in di-
oxane or 1,2-dimethoxyethane produced the desired chloroamide
31 as a major product; however, dimeric side products MS 639
and MS 621 were also formed in substantial quantities (Scheme
17). Moreover, mixtures of 31 and these impurities were found
to be prone to further oligomerization. Transformation of the
Route A was conceptually and practically the earliest ap-
proach which was successfully used to prepare multiple lots of
1. It consists of two steps: (i) exhaustive chlorodehydroxylation
and acid chloride formation followed by a cyclopropylamine
quench to establish both cyclopropylamide and 1-chlorophthala-
zine functionality and (ii) aromatic nucleophilic substitution in
the phthalazine ring using morpholine to afford 1. Reaction of
28 with POCl3 leads to the formation of the desired acid
chloride/1-chlorophthalazine intermediate 30, but it is ac-
companied by dimeric species (Figure 1) and other largely
unidentified oligomeric side products. The presence of multiple
electrophilic and nucleophilic moieties in the intermediate makes
control over competitive reaction rates challenging.
(42) 3 equiv of Cy2NH was sufficient for a complete conversion at the expense
of extended reaction time.
(43) Rapid hydrolysis back to 28 and oligomerization to MS 579, MS 597,
and higher molecular weight products.
(44) Typically, 1-chlorophthalazines are fairly inert to aqueous base due to
their limited solubility. Chlorophthalazine acid 32 carboxylate salt is water
soluble, which can explain its unusual hydrolytic lability.
Quenching of the reaction mixture with cyclopropylamine
followed by aqueous workup and chromatographic isolation
from a complex mixture afforded 31 in 25-40% yield, and then
J. Org. Chem. Vol. 74, No. 2, 2009 803

Achmatowicz et al.
SCHEME 17. Proposed Structure of Dimeric Side Products MS 621 and MS 639 (Route C)
SCHEME 18. Dimerization of 1,6-Dichlorophthalazine (35)
by filtration (42-71% yield). Unfortunately, the wet solids
isolated from the water-miscible solvents generally hydrolyzed
back to 24 to some extent upon drying at room temperature.
Alternatively, application of water-immiscible 1,2-dichloroet-
hane (DCE) as cosolvent provided 1,6-dichlorophthalazine (35)
in 85% yield after phase-cut and solvent evaporation, and we
found that a solution of 35 in DCE was relatively stable47 to
dilute aqueous HCl even at 70 °C. Thus, a workup that would
include extraction of the product into an organic solvent was
preferable for further development of this chlorodehydroxylation
reaction. Several potential solvents48 were considered on the
basis of their water immiscibility, boiling point, compatibility
with POCl3, product solubility, and ICH solvent limit. Eventu-
ally, the selection was narrowed down to toluene or chloroben-
zene, both of which facilitated complete conversion of the
reaction within 3-5 h at 90 °C. Formation of a viscous material
was observed in toluene, whereas the reaction mixture in
chlorobenzene remained a stirable suspension making it the
solvent of choice for further development. The reaction in
chlorobenzene (5.0 vol) proceeded to completion with as little
as 1.5 equiv of POCl3, but since the reaction rate was found to
be sensitive to particle size of 24,49 2.0 equiv of POCl3 was
used to ensure consistent conversion (e1.0% 24 by LC).
Controlled addition of 2.5 N NaOH aq (20 vol) was used to
quench excess POCl3 (e5 °C). Dilution of the mixture with
dichloromethane (10 vol.) during NaOH quench was found to
be important to keep 35 in the organic layer.50 Isolation of crude
35 (>96.6% by LC) was performed by either removal of the
organic solvent,51 or crystallization was induced Via addition
of heptane to the CH2Cl2/chlorobenzene solution (>99% by LC,
approximately 80% overall yield). Occasionally, solutions of
hydroxyl function of 34 into a suitable leaving group using
sulfonyl chlorides (TsCl, MsCl) was also unsuccessful.
While Route A was able to deliver material for initial
biological testing, it was insufficient for further scale-up. The
limited success with the first-generation approach helped us
recognize that the functionalization of advanced intermediate
28 would be impractical and led us to focus on earlier
functionalization of building block 24, leading to a revision of
the synthetic plan (Scheme 2).
Development of the Second-Generation Process Synthesis.
The original transformation of 6-bromophthalazin-1-ol (5) to
1-chloro-6-bromopththalazine (6) was performed in neat phos-
phorus oxychloride (>10 equiv) with diisopropylethylamine (1
equiv)45 at reflux. Removal of excess POCl3 followed by
aqueous workup and chromatography afforded 6 in a good yield
(Scheme 1). The above protocol was successfully applied to
1-chlorophthalazin-1-ol (24); however, the large excess of
reactive POCl3 as well as the need for a chromatographic
purification were identified as potential development areas. A
brief screen of reaction conditions demonstrated that the
transformation of 24 to 35 may be carried out at a reasonable
rate with only 2.0 equiv of POCl3 and in the absence of a tertiary
amine additive using any number of cosolvents (MeCN, DME,
DCE, 1,4-dioxane, 84-93% conversion after 2.5 h).46 After 3-5
h at 80 °C, the heterogeneous reaction mixtures were quenched
with ice-water, and in the case of water-miscible solvents
(MeCN, DME, and dioxane), the resulting solids were isolated
(47) At least for a brief period of time (e.g., 10 min).
(48) 1,2-Dichlorethane (DCE), toluene, chlorobenzene, anisole. (a) Reaction
temperature of approx. 80 °C was required for conversion. (b) anisole was found
to undergo significant demethylation under POCl3 reaction conditions. (c) good
solubility was required for a phase-split after an aqueous quench. (d) DCE was
eliminated due to a low ICH guideline limit (5 ppm).
(49) 24 is sparingly soluble in most organic solvents (<5 mg/mL).
(50) 35 is not sufficiently soluble in pure chlorobenzene at room temperature
(0.05 g/mL).
(45) Addition of a tertiary amine provides a source of “soluble chlorides”
increasing the overall reaction rate, see: (a) VanSickle, A. P.; Rapoport, H. J.
Org. Chem. 1990, 55, 895.
(46) No conversion observed in 2-methyltetrahydrofuran or chloroform.
MeCN ) acetonitrile, DME ) 1,2-dimethoxyethane, DCE ) 1,2-dichloro-
ethane.
(51) Remaining chlorobenzene (approximately 10 wt %) was readily tolerated
in the subsequent step.
804 J. Org. Chem. Vol. 74, No. 2, 2009

Practical Synthesis of a p38 MAP Kinase Inhibitor
SCHEME 19. Second-Generation Process Synthesis of Drug Candidate 1
crude 35 in CH2Cl2/chlorobenzene developed a highly colored
(orange-red) insoluble precipitate which consisted of a complex
mixture of oligo- and polymeric products, the dimer 36 with
MS 343 was identified as a major component of the complex
mixture (Scheme 18).52
rophthalazine (35) was treated with morpholine (4 equiv) at 80
°C to produce 37, which was isolated in 79-81% overall yield
(100% by LC) by filtration56 (Scheme 19).
The Suzuki reaction of 37 and 27 using conditions similar to
the ones developed earlier (0.50 mol % of Pd2(dba)3, 2.0 mol
% of MePhos, 2 equiv of K2CO3, 1-butanol, water, 100 °C)
provided a clean coupling reaction to afford 33. Compared to
the previous substrate combination, far less protodeboronation
of boronic acid 27 was observed, even in the presence of an
inorganic base, and complete conversion of 37 could be obtained
with only 1.1 equiv of boronic acid.57 Although 33 could be
cleanly produced in 1-butanol/water mixture, product isolation
from this solvent system was problematic. Addition of acid to
the postreaction mixture led to extensive foaming due to CO2
evolution from the carbonate base and did not lead to precipita-
tion of the product. Extractive workups of the acidified mixtures
afforded crude 33 with poor recovery and purity. 1-Butanol was
identified as a major factor complicating product isolation,
causing biphasic mixtures with water in which the zwitterion
33 would partition in a pH-dependent manner. In order to solve
these isolation issues, a screen for alternative Suzuki conditions
was initiated. Water-miscible alcoholic solvents (ethanol, 1-pro-
panol) with a number of bases (Na2CO3, K2CO3, NaOH,
dicyclohexylamine) were compared. Clean conversion58 was
observed in most cases at 80 °C, however, the EtOH/NaOH
combination was particularly attractive, as the reaction mixture
could be concentrated by vacuum distillation and then pH
The stability of 35 was therefore investigated under a broad
range of conditions. Addition of an aqueous acid or an aqueous
base to a solution of 35 in CH2Cl2/PhCl had no effect.53
Similarly, presence of air or visible light would not trigger the
decomposition. Aliquots of a solution of 35 could be aged under
most any given conditions (acid, base, light, air, etc.) for multiple
days without any apparent change, however, the product would
typically rapidly decompose soon after the first sampling.54
Eventually, this key observation led to a hypothesis of a Lewis
acid55 triggered decomposition. Indeed, rapid decomposition of
35 with concomitant formation of an orange-red precipitate was
observed in the presence of Lewis acids such SbCl5 (solution
in CH2Cl2) or MgCl2 (solid).
These stability issues encountered with compound 35 led us
to develop the chlorodehydroxylation and SNAr amination step
into a through-process. Thus, 1,6-dichlorophthalazine (35)
solution in CH2Cl2/PhCl was prepared and partially concentrated
to remove volatile CH2Cl2. After dilution of the resulting
chlorobenzene solution with 2-methyl-THF, the 1,6-dichlo-
(52) Similar dimerization of 1-chlorophthalazine in the presence of Brønsted
acid has been described: Badger, G. M.; McCarthy, I. J.; Rodda, H. J. Chem.
Ind. 1954, 964.
(53) This was presumably due to immiscibility and the resulting poor phase
transfer.
(54) Samples were pulled using Hamilton microsyringes equipped with a
steel needle.
(56) Water was added to solubilize the morpholine hydrochloride byproduct.
(57) The potency of the boronic acid was determined by quantitative 1H NMR
using maleic acid as internal standard.
(55) A steel needle used during sampling was a source of Lewis acid.
(58) Crude LC purity: 84-89% 33 (NaOH), 93% 33 (Na2CO3 or K2CO3).
J. Org. Chem. Vol. 74, No. 2, 2009 805

Achmatowicz et al.
FIGURE 2. Acylimidazolide, Benzylamide, and Anhydride.
adjusted using aq HCl to give crystalline 33. Additional
advantages of using NaOH were shorter reaction time and no
foaming during acidification. Eventually, the Pd/L ratio was
increased to 1.00:1.2559 to improve catalyst reactivity, which
allowed lowering of the palladium loading to 0.50 mol %. The
EtOH to caustic ratio was conserved at 4:1 (v/v) as reducing
the amount of caustic gave sluggish reactions, while more dilute
base led to increase in the relative rate of protodeboronation.
At least 3 equiv of NaOH was required for a smooth reaction
(with 2.0 equiv, reaction stalled at 80% conversion). The
reaction proceeded at temperatures as low as 65 °C, but at the
expense of reaction rate. Prolonged heating of the reaction
mixture led primarily to an increased hydrolytic cleavage of
the morpholine moiety from both 33 and 37, which contributed
to an increased level of 28. Most of this side product was cleared
to the mother liquors during isolation, along with other process
impurities such as 29 and des-chloro-37. During early develop-
ment of this reaction it was noted that addition of THF before
final pH adjustment had a beneficial effect on the crystallinity
of 33. Moreover, a large fraction of the residual palladium and
other colored impurities were cleared by this cosolvent. After
optimization, isolation of the product was performed by adjust-
ing the crude aqueous THF solution to pH 3.4, at which point
33 was determined to be the least soluble.
In summary, the optimized Suzuki coupling protocol devel-
oped thus far was as follows, aryl chloride 37 was reacted with
boronic acid 27 (1.15 equiv) in the presence of Pd2(dba)3 (0.25
mol %) and MePhos (0.63 mol %) in a mixture of 10 N NaOH
aq (2 vol) and EtOH (8 vol) at reflux (78-80 °C, 2.5 h).
Extraction of the crude product into the aqueous layer was
followed by dilution with THF, pH adjustment using aq HCl
(pH 3.4) and filtration to afford advanced intermediate 33 in
70-81% yield (97.7-98.9% by LC). This proved to be a
scaleable process that could be carried out efficiently on >2 kg
scale (Scheme 19).
The introduction of the cyclopropylamide moiety was the last
remaining challenge for the completion of the synthesis of 1.
Initial attempts at activation of 33 as the acid chloride using
oxalyl chloride or thionyl chloride in a variety of solvents (THF,
toluene, dichloromethane), followed by reaction with cyclopro-
pylamine were unsuccessful. The acidic reaction conditions led
to the formation of insoluble salts and complete conversion to
1 could not be achieved. In contrast, activation of 33 using 1,1-
carbonyldiimidazole was successful. The neutral reaction condi-
tions led to the clean formation of acylimidazolide 38, which
was hydrolytically unstable under the HPLC conditions (0.1%
TFA in MeCN/water) and could not be monitored directly. The
activation reaction could, however, be monitored by quenching
an aliquot of the reaction mixture with an excess of benzylamine
to the give benzylamide 39, which was readily monitored by
HPLC. Reaction of the activated intermediate 38 with cyclo-
propylamine was facile, and complete conversion was usually
observed within 2 h at rt. The CDI-coupling reaction could be
successfully carried out in a variety of solvents including THF,
dichloromethane, DMF, ethyl acetate, isopropyl acetate, MTBE,
or toluene. All investigated reaction conditions led to 2-4% of
starting material 33 remaining (as judged by HPLC), and the
addition of excess CDI or heating of the reaction mixture to
elevated temperatures (50 °C) did not increase the conversion.
A subtle effect of imidazole as an additive was noted in the
reaction, as the presence of imidazole (1 equiv) led to slightly
less formation of the acid (2-3 vs ∼4%). Investigation of the
CDI reaction by 1H and 13C NMR (THF-d8 as solvent) showed
the presence of two distinct sets of signals. The major one could
clearly be attributed to acylimidazolide 38, and the minor set
of signals was assigned as the anhydride 40.60 The formation
of the anhydride is consistent with the HPLC data. Quench of
the reaction mixture with an amine leads to formation of 1 equiv
each of 33, and the starting acid molecule per anhydride. The
observation that imidazole as an additive reduces anhydride
formation is consistent with the mechanism of the CDI
activation, in which the initially formed acyl 1H-imidazole-1-
carboxylate is either attacked by imidazole to form 38, or by a
second equivalent of acid to form anhydride 40. Since 33 has
low solubility in the reaction solvent, making the reaction
dissolution controlled, the imidazole has the additional beneficial
effect increasing the solubility of 33 and hence the rate as well.61
In an optimized procedure, the reaction was carried out in
ethyl acetate using 1.5 equiv of CDI and 1 equiv of imidazole.
Activation proceeded smoothly at rt, followed by a short heating
to 50 °C to achieve maximum conversion. Cyclopropylamine
was added at room temperature to give the amide 1, which could
be isolated in high yield (85%). Since the isolated material
contained high levels of ethyl acetate (2-3%) that could not
be removed by drying of the material, a reslurry of the crude
product in a mixture of isopropanol and water was implemented
to reduce the solvent levels to <5000 ppm (82% recovery). The
CDI-coupling procedure efficiently reduces residual palladium
in the final product from 100-150 ppm Pd to <10 ppm.
Presumably imidazole acts as a good ligand for palladium
thereby keeping the metal residues in solution during the
crystallization of 1.
Summary
A concise synthesis of p38 MAP kinase inhibitor 1 was
developed. ortho-Metalation of a simple raw material was
(60) The chemical shifts of the second set are distinct both from 33 and the
imidazolium salt of 33. Integration compared to 38 and comparison of this data
point with the amount of starting material by HPLC suggest a dimeric structure.
(61) Solubility of 33 at rt with and without imidazole as determined by HPLC:
0.9 vs 0.2 mg/mL in ethyl acetate; 3.5 vs 2.3 mg/mL in THF.
(59) Initially, 1.00:2.00 Pd/L was used.
806 J. Org. Chem. Vol. 74, No. 2, 2009

Practical Synthesis of a p38 MAP Kinase Inhibitor
[C12H15ClNO2]+ 240.07858, found 240.07800; IR 3227, 2968, 1665,
1614, 1458, 1419, 1389, 1368, 1360, 1302, 1259, 1210, 1199, 1151,
1120, 1073, 1048, 1021, 935, 911, 886, 863, 845, 811, 772, 685
cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 7.60-7.53 (m, 3 H), 6.43
(d, J ) 10.0 Hz, 1 H), 6.02 (d, J ) 10.0 Hz, 1 H), 1.52 (s, 9 H)
ppm; 13C NMR (DMSO-d6, 101 MHz) δ 165.8, 146.8, 136.4, 131.3,
129.3, 123.7, 123.3, 80.9, 53.9, 28.0 ppm. Anal. Calcd for
C12H14ClNO2: C, 60.13; H, 5.89; N, 5.84. Found: C, 59.65; H, 6.13;
N, 5.87.
leveraged for the efficient construction of the phthalazine core
24, and the boronic acid building block 27 could be accessed
by direct iodine-magnesium exchange of a substituted benzoic
acid 8. Judicial choice of the order of bond disconnections
facilitated assembly of the two key fragments to the final
molecule. Detailed optimization of the final four reaction steps
(chlorodehydroxylation, SNAr with morpholine, Suzuki coupling,
and final amide coupling) provided an efficient, scaleable, and
inexpensive synthesis of key target 1 in good overall yield (31%
in six steps from 4-chlorobenzoyl chloride).
6-Chlorophthalazin-1-ol (24). A 30 L jacketed reactor equipped
with mechanical stirrer, reflux condenser, nitrogen blanket, dropping
funnel, and temperature probe was made inert with nitrogen and
charged with 2-tert-butyl-5-chloro-3-hydroxyisoindolin-1-one (16)
(2.06 kg, 8.59 mol) and glacial acetic acid (6.4 L). The resulting
thick slurry was heated to 90 °C with agitation. At approximately
80 °C, a homogeneous solution was obtained. Hydrazine hydrate
(54 wt%) (0.53 kg, 9.0 mol) was added dropwise (exotherm)
keeping the internal temperature between 90 and 93 °C over
approximately 3 h. The resulting suspension was continued to stir
at 90 °C as the conversion of starting material was monitored by
LC (<1% within 1.5 h). Deionized water (12.8 L) preheated to 80
°C was transferred into 30 L jacketed reactor maintaining the
reaction mixture at 80-90 °C followed by ramping down to 20 °C
over approximately 4 h time. At this point, the resulting uniform
suspension was transferred onto a filter. The filter cake was rinsed
with deionized water (2-3.0 L). The wet cake was air-dried
overnight to afford crude product as a large yellow crystals
(1.67-1.92 kg, 108-124% theory). Two batches of crude 6-chlo-
rophthalazin-1-ol (3.59 kg) from two identical runs were combined
in a 30 L reactor and slurried in dichloromethane (18.0 L) at 20 °C
for 1 h with efficient agitation. Product was collected by filtration,
rinsed with dichloromethane (4.0 L), and oven-dried at 50 °C to
constant weight to afford 6-chlorophthalazin-1-ol (24) as pale yellow
crystals (2.76 kg, >99% LC purity, 89.0% yield): mp 271-273
°C (lit.62 mp 272.2-273.5 °C); HRMS (m/z) [M + H+] calcd for
[C8H6ClN2O]+ 181.01632, found 181.01591; IR 3160, 3063, 3043,
2913, 1649, 1610, 1595, 1556, 1489, 1411, 1362, 1329, 1248, 1217,
Experimental Section
N-tert-Butyl-4-chlorobenzamide (12c). A 1 L jacketed reactor
equipped with mechanical stirrer, reflux condenser, nitrogen blanket,
dropping funnel, and temperature probe was charged with 4-chlo-
robenzoyl chloride (95%, 110 g, 0.60 mol) and dichloromethane
(0.44 L). The resulting solution was cooled to 0 °C under nitrogen
with stirring. tert-Butylamine (142 mL, 1.32 mol) was slowly added
from a dropping funnel at e10 °C, followed by dichloromethane
(10 mL) rinse. The reactor contents were warmed to 23 °C over
approximately 30 min. NaOH aq (5 N) was slowly added from a
dropping funnel at e25 °C. The reaction mixture was stirred until
all the solids dissolved. The layers were separated, and the upper
aqueous layer was discarded. The lower organic layer was
concentrated by vacuum distillation (300-400 Torr, 33 °C) until
approximately 0.35 L of the distillate was collected. Heptane (0.20
L) was charged, and the distillation was continued until ap-
proximately 0.12 L of the additional distillate was collected. The
precipitated product was collected by filtration, rinsed with heptane
(0.20 L), and oven-dried at 40 °C to afford N-tert-butyl-4-
chlorobenzamide (12c) as colorless needles (129 g, 99.3% LC
purity, 96.6% yield): mp 136-137 °C; HRMS (m/z) [M + H+]
calcd for [C11H15ClNO]+ 212.08367, found 212.08363; IR 3357,
2981, 2963, 2929, 1635, 1592, 1569, 1538, 1485, 1452, 1399, 1386,
1362, 1313, 1277, 1220, 1137, 1113, 1092, 1012, 873, 846, 758,
1
1161, 1084, 1064, 920, 898, 872, 845, 780, 675 cm-1; H NMR
1
722 cm-1; H NMR (DMSO-d6, 400 MHz) δ 7.85 (bs, 1 H), 7.83
(DMSO-d6, 400 MHz) δ 12.79 (bs, 1 H), 8.34 (s, 1 H), 8.22 (d, J
(d, J ) 8.5 Hz, 2 H), 7.49 (d, J ) 8.5 Hz, 2 H), 1.38 (s, 9 H) ppm;
13C NMR (DMSO-d6, 101 MHz) δ 165.1, 135.4, 134.4, 129.2,
127.9, 50.8, 28.5 ppm. Anal. Calcd for C11H14ClNO: C, 62.41; H,
6.67; N, 6.62. Found: C, 62.53; H, 6.88; N, 6.64.
) 8.5 Hz, 1 H), 8.08 (s, 1 H), 7.88 (d, J ) 8.5 Hz, 1 H) ppm; 13
C
NMR (DMSO-d6, 101 MHz) δ 159.0, 138.3, 137.2, 131.9, 131.3,
127.9, 126.2, 126.1 ppm. Anal. Calcd for C8H5ClN2O: C, 53.21;
H, 2.79; N, 15.51. Found: C, 53.08; H, 2,92; N, 15.62.
2-tert-Butyl-5-chloro-3-hydroxyisoindolin-1-one (16). A 50 L
jacketed reactor equipped with mechanical stirrer, reflux condenser,
nitrogen blanket, dropping funnel, and temperature probe was
inerted with nitrogen and charged with N-tert-butyl-4-chloroben-
zamide (12c) (2.33 kg, 11.0 mol) and anhydrous THF (18.6 L).
The resulting solution was cooled to e-20 °C under nitrogen.
Methyllithium solution in diethoxymethane (8.40 wt %, 5.90 kg,
22.5 mol) was slowly added at e-17 °C (methane off-gas,
exotherm) resulting in a gradual color change from light orange to
deep red. The resulting solution was allowed to warm and held at
-10 °C with efficient agitation for at least 3 h during which a deep
red solution gradually turned into a thick pinkish suspension. The
reaction mixture was cooled back to e-20 °C, and DMF (1.7 L,
22 mol) was added slowly at e-15 °C and then allowed to react
as it warmed to -10 °C. Saturated aq NH4Cl (8.0 L) was slowly
added at e-5 °C (ammonia off-gas, exotherm) with efficient
agitation. The internal temperature was then adjusted to 20 °C
over approximately 30 min. After settling, the phases were
separated, and the lower aqueous layer was discarded. The organic
layer was evaporated to dryness yielding crude product as a yellow
paste. The pasty solid was slurried in toluene (10 L) and stirred at
100 °C for 1 h followed by cooling to 20 °C over approximately
5 h. The product was isolated by filtration, the wet cake was rinsed
with toluene (2 - 1 L), and dried in a vacuum oven at 50 °C to
constant weight to afford 2-tert-butyl-5-chloro-3-hydroxyisoindolin-
1-one (16) as an off-white powder (2.15 kg, 98.5% LC purity,
85.4% yield): mp 185-186 °C; HRMS (m/z) [M + H+] calcd for
3-Borono-4-methylbenzoic Acid (27) (Organomagnesium
Process). A 0.5 L jacketed reactor equipped with mechanical stirrer,
reflux condenser, nitrogen blanket, and temperature probe was
charged with 3-iodo-4-methylbenzoic acid (8) (30.0 g, 114 mmol)
and anhydrous THF (150 mL). The batch temperature was adjusted
to <-50 °C, and isopropylmagnesium chloride solution (1.93 M
in THF, 125 mL, 240 mmol) was added at a controlled rate keeping
the batch temperature between -60 and -50 °C. The mixture was
aged at -50 °C for 1 h, at which point HPLC analysis (aliquot
quenched into THF/water) showed <2% starting material remaining.
The mixture was warmed to -40 °C, and then triisopropyl borate
(40 mL, 171 mmol) was added between -40 and -30 °C. The
reaction mixture was warmed to -10 °C and aged for 3 h, at which
point HPLC analysis (aliquot quenched into THF/water) showed
<15% p-toluic acid. Water (150 mL) was added while keeping
the batch temperature <20 °C, followed by adjustment to pH 1-2
by addition of hydrochloric acid and stirring for 12 h. The layers
were separated, and the bottom aqueous layer was extracted with
THF (60 mL). The combined organic layers were washed with half-
saturated brine (60 mL), and the solvent was partially removed by
vacuum distillation keeping the batch temperature <45 °C. The
final volume was adjusted to ∼150 mL. Heptane (450 mL) was
slowly charged to the stirred THF solution, and the resulting
suspension was aged for >60 min with stirring before the product
(62) Vaughan, W. R.; Baird, S. L., Jr. J. Am. Chem. Soc. 1946, 68, 1314.
J. Org. Chem. Vol. 74, No. 2, 2009 807

Achmatowicz et al.
was collected by vacuum filtration. The wetcake was rinsed with
heptane/THF (3/1 v/v, 120 mL) and dried on the filter under a
stream of nitrogen for >60 min affording the crude product. The
crude product was charged into a clean reactor. THF (120 mL)
was added, and the resulting mixture was subjected to a polishing
filtration (Teflon, 0.45 µm) and transferred into a second clean
reactor. The first reactor was rinsed with THF (15 mL), and the
rinse was transferred through the filter into the second reactor.
Heptane (450 mL) was slowly charged to the stirred THF solution.
The resulting suspension was aged for >60 min with stirring before
the product was collected by vacuum filtration (Teflon 0.45
µm). The wet cake was rinsed with heptane/THF (3/1 v/v, 60 mL)
and dried on the filter under a stream of nitrogen for >60 min
affording 3-borono-4-methylbenzoic acid (27) (12.9 g, 86 wt %,
99.95% LC purity, 54% corrected yield): mp 157-167 °C; HRMS
(m/z) [M - H+] calcd for [C8H8O4B]- 179.05211, found 179.05191;
IR 3280, 2833, 2558, 1683, 1605, 1571, 1493, 1408, 1347, 1304,
1266, 1205, 1176, 1135, 1095, 1030, 936, 921, 852, 819, 769, 760,
730, 699, 656 cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 8.24 (br s,
2H), 8.00 (d, J ) 1.9 Hz, 1 H), 7.78 (dd, J ) 8.0 Hz, J ) 1.9 Hz,
1H), 7.23 (d, J ) 8.0 Hz, 1H), 2.42 (s, 3H) ppm; 13C NMR (DMSO-
d6, 101 MHz) δ 168.3, 147.4, 136.7, 134.7, 130.3, 130.0, 127.3,
22.7 ppm.
6-Chloro-1-morpholinophthalazine (37). A 1 L jacketed reactor
equipped with mechanical stirrer, reflux condenser, nitrogen blanket,
and temperature probe was charged with 6-chlorophthalazin-1-ol
(24) (22.3 g, 123 mmol), chlorobenzene (112 mL), and phosphoryl
chloride (23.0 mL, 247 mmol). The resulting suspension was heated
to 90 °C63 with efficient agitation. After approximately 2 h at 90
°C, the reaction mixture was checked periodically for conversion
(stirred aliquots were diluted with aq phosphate pH 7 buffer/
acetonitrile mixtures and analyzed by HPLC). Complete conversion
(e1% 6-chlorophthalazin-1-ol) was typically obtained within 6 h.
At this point, the resulting thick slurry was cooled to room
temperature. Dichloromethane (223 mL) was added, and the
suspension was cooled to e-10 °C. Aqueous sodium hydroxide
(2.5 N, 445 mL, 1.11 mol) was added dropwise with efficient
agitation maintaining internal temperature at approximately -4 °C
(e0 °C) (approximately 2.5 mL/min using a peristaltic pump over
3 h time). The reaction mixture was then allowed to warm to room
temperature with stirring. After settling, the lower organic layer
was retained. The upper aqueous layer (pH 10) was extracted with
dichloromethane (112 mL). The combined organic layers contained
approximately 21.3 g of 1,6-dichlorophthalazine (35) (87% assay
yield) by HPLC. The crude 1,6-dichlorophthalazine solution (ca.
0.25 M, 433 mL) was transferred into a clean and dry 1 L jacketed
reactor fitted with distillation head. Dichloromethane was removed
by vacuum distillation (130-290 Torr/45 °C jacket, batch e39 °C).
To the resulting thick orange slurry was added 2-methyltetrahy-
drofuran (89 mL) followed by morpholine (43 mL, 0.49 mol). The
resulting fluid suspension was heated to 80 °C with stirring to afford
briefly a dark solution at approximately 40 °C, and then heavy
crystalline material started to appear. After 15 h at 80-85 °C,
complete conversion of 1,6-dichlorophthalazine (36) was determined
by HPLC. The resulting suspension was cooled to 20 °C over 40
min. Deionized water (156 mL) was added, and the resulting
triphasic mixture was cooled and aged at 4 °C until a constant
product concentration in mother liquors was obtained. The light
orange suspension was passed through a filter. The filter cake was
rinsed sequentially with deionized water (45 mL) and 2-methyltet-
rahydrofuran (2 - 22 mL). The wet cake was air-dried and then
vacuum-dried at 60 °C to afford 6-chloro-1-morpholinophthalazine
(37) as a dense crystalline material (24.6 g, >99.5% LC purity,
80.0% yield): mp 166-168 °C; HRMS (m/z) [M + H+] calcd for
[C12H13ClN3O]+ 250.07417, found 250.07351; IR 3076, 2968, 2894,
2863, 2846, 1608, 1578, 1537, 1480, 1462, 1449, 1410, 1394, 1355,
1302, 1267, 1258, 1219, 1167, 1151, 1130, 1110, 1073, 1033, 1002,
1
974, 942, 923, 871, 851, 834, 784, 722, 675, 655 cm-1; H NMR
(DMSO-d6, 400 MHz) δ 9.29 (s, 1 H), 8.24 (d, J ) 2.0 Hz, 1 H),
8.14 (d, J ) 8.5 Hz, 1 H), 7.94 (dd, J ) 2.0 Hz, 8.5 Hz, 1 H),
3.91-3.84 (m, 4 H), 3.44-3.38 (m, 4 H) ppm; 13C NMR (DMSO-
d6, 101 MHz) δ 158.9, 147.0, 136.3, 132.4, 129.2, 126.7, 126.0,
118.8, 66.0, 51.3 ppm. Anal. Calcd for C12H12ClN3O: C, 57.72; H,
4.84; N, 16.83. Found: C, 57.67; H, 4.89; N, 16.83.
4-Methyl-3-(1-morpholinophthalazin-6-yl)benzoic Acid (33).
A 250 mL three-necked round-bottom flask equipped with me-
chanical stirrer, nitrogen blanket, reflux condenser, and temperature
probe was charged with 6-chloro-1-morpholinophthalazine (37)
(10.0 g, 40.0 mmol), 3-borono-4-methylbenzoic acid (27) (84.4 wt
%, 9.22 g, 43.4 mmol), Pd2(dba)3 (91.7 mg, 100 µmol), and 2′-
methyl(dicyclohexylphosphino)biphenyl (91.2 mg, 250 µmol), and
made inert with nitrogen. Ethanol (64 mL) was added, and the
mixture was stirred until a uniform suspension was obtained.
Aqueous sodium hydroxide (10 N, 16.0 mL, 0.16 mol) was added
in one portion (adiabatic temperature change from 20 to 32 °C).
The resulting biphasic mixture was heated and held at reflux with
stirring (78-80 °C). Conversion of 6-chloro-1-morpholinophthala-
zine in the upper organic layer was monitored by LC (<0.5% within
2.5 h).64 After complete conversion was determined, the reaction
mixture was allowed to cool. Activated carbon (Darco KB-B, -100
mesh, 2.0 g) was added at e30 °C, followed by deionized water
(40 mL). The resulting mixture was stirred overnight at 20 °C. The
contents of the flask were passed through a pad of Celite. The filter-
medium was rinsed sequentially with water (40 mL) and ethanol
(2 × 20 mL). Combined filtrates were concentrated by distillation
(155 mL of distillate was collected). The remaining cloudy orange
solution (65 mL) was diluted with deionized water (35 mL) and
extracted with isopropyl acetate (2 × 50 mL). The crude aqueous
solution of the sodium salt of the product was transferred into a
clean 250 mL three-necked round-bottom flask (equipped with a
mechanical stirrer, pH probe, and dropping funnel) and diluted with
tetrahydrofuran (50 mL). The solution was adjusted to pH 3.4 using
conc. HCl aq. The resulting fine suspension was aged at 20 °C and
filtered through a fine fritted funnel. The filter cake was rinsed
sequentially with deionized water (15 mL) and tetrahydrofuran (2
× 15 mL). The wet cake was air-dried and vacuum-dried at 55 °C
to a constant weight to afford 4-methyl-3-(1-morpholinophthalazin-
6-yl)benzoic acid (33) as a light tan crystalline solid (10.8 g, 77.0%
yield): mp 190-192 °C; HRMS (m/z) [M + H+] calcd for
[C20H20N3O3]+ 350.14992, found 350.14897; IR 3421, 2994, 2887,
2886, 2399, 1704, 1621, 1568, 1555, 1485, 1426, 1398, 1363, 1301,
1271, 1262, 1229, 1129, 1110, 1070, 1032, 1019, 949, 933, 919,
1
864, 839, 792, 767, 716, 700, 681, 658 cm-1; H NMR (DMSO-
d6, 400 MHz) δ 13.03 (bs, 1 H), 9.38 (s, 1 H), 8.20 (d, J ) 8.5 Hz,
1 H), 8.15 (bs, 1 H), 7.99 (dd, J ) 2 Hz, 8.5 Hz, 1 H), 7.94 (dd,
J ) 2 Hz, 8.0 Hz, 1 H), 7.89 (s, 1 H), 7.52 (d, J ) 8.0 Hz, 1 H),
3.95-3.86 (m, 4 H), 3.51-3.43 (m, 4 H), 2.35 (s, 3 H) ppm; 13C
NMR (DMSO-d6, 101 MHz) δ 166.9, 159.0, 148.0, 143.7, 140.4,
139.8, 133.0, 131.0, 130.4, 128.9, 128.8, 128.2, 126.8, 124.0, 119.2,
66.1, 51.2, 20.2 ppm. Anal. Calcd for C20H19N3O3: C, 68.75; H,
5.48; N, 12.03. Found: C, 66.56; H, 5.48; N, 11.43.
N-Cyclopropyl-4-methyl-3-(1-morpholin-4-yl-phthalazin-6-yl)-
benzamide (1). A three-necked flask equipped with mechanical
stirrer, nitrogen blanket, reflux condenser, and temperature probe
was charged with 4-methyl-3-(1-morpholinophthalazin-6-yl)benzoic
acid (33) (47.0 g, 135 mmol), imidazole (9.16 g, 135 mmol), and
ethyl acetate (235 mL). Stirring was established, and 1,1-carbon-
yldiimidazole (32.7 g, 202 mmol) was added in one portion. The
reaction mixture was stirred for 1 h at 20 °C and then heated for
2 h at 50 °C. Quenching an aliquot of the reaction mixture into
neat benzylamine followed by HPLC analysis indicated high
conversion (>97%) to the acylimidazolide 38. The reaction mixture
(63) Internal temperature should not exceed approximately 95 °C as it leads
to formation of sticky and highly colored byproducts that can compromise the
batch.
(64) Prolonged heating adversely affects the impurity profile.
808 J. Org. Chem. Vol. 74, No. 2, 2009

Practical Synthesis of a p38 MAP Kinase Inhibitor
was cooled to rt and filtered through a medium glass frit into a
clean three-necked flask to remove trace inorganic impurities.
Cyclopropylamine (37.3 mL, 538 mmol) was added over 10 min,
keeping internal temperature at <30 °C. The product started
crystallizing out within 30 min. After the mixture was stirred for
16 h at rt, the solids were collected by vacuum filtration, rinsed
with ethyl acetate (25.0 mL), and dried on the filter under a stream
of nitrogen to afford crude 1 (42.6 g). A three-necked flask equipped
with mechanical stirrer, nitrogen blanket, reflux condenser, and
temperature probe was charged with 2-propanol (308 mL), water
(103 mL), and the crude product 1 (41.2 g). Stirring was initiated,
and the mixture was heated to 70-75 °C for 4 h. The suspension
was cooled to rt and aged at rt for 1.5 h. The solids were collected
by vacuum filtration, rinsed with a mixture of 2-propanol/water
(1/1 v/v, 50 mL), and dried in the vacuum oven at 60 °C for 15 h
to afford N-cyclopropyl-4-methyl-3-(1-morpholin-4-yl-phthalazin-
6-yl)benzamide (1) as a colorless solid (35.5 g, 70%): mp 235-237
°C; HRMS (m/z) [M + H+] calcd for [C23H25N4O2]+ 389.1972,
found 389.1972; IR 3238, 1650, 1537, 1455, 1392, 1364, 1307,
(s, 3H), 0.90-0.83 (m, 2H), 0.67-0.62 (m, 2H) ppm; 13C NMR
(CDCl3, 101 MHz) δ 168.2, 159.7, 148.1, 144.7, 140.1, 138.9,
132.9, 132.5, 130.9, 128.6, 128.5, 126.7, 126.6, 124.0, 120.2, 66.9,
51.6, 23.2, 20.4, 6.7 ppm.
Acknowledgment. We thank Dr. A. S. Tasker, Dr. D. Zhang,
and the discovery team4 for valuable discussions; C. Bolcato,
Dr. E. Chen, Dr. T. Correll, Dr. L. Hong, Dr. M. Ma, R. Munger,
Dr. H. Tan, and M. Wacker for analytical support; Dr. K. McRae
and B. Riahi for the initial deliveries of the target compound;
and J. Clare, A. Maheshwari, J. Manley, S. Riznikove, G. Sukay,
J. Tomaskevitch, and J. Tvetan for support and valuable input
during scale up. Dr. R. Milburn and Dr. K. Hansen are gratefully
acknowledged for proofreading.
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra for compounds 1, 12c, 16, 17a, 17b, 23a,
24, 27, 28, 33, 34, 35, (1H NMR), 37 and 39. Experimental
procedures and characterization data for 17a,b, 23a,b, 26-28,
34, and 39. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
1263, 1113, 1025, 941, 923, 865, 840, 818, 720 cm-1; H NMR
(CDCl3, 400 MHz) δ 9.13 (s, 1 H), 8.07 (d, J ) 8.3 Hz, 1 H),
7.80-7.72 (m, 4H), 7.38 (d, J ) 8.3 Hz, 1 H), 6.65 (br s, 1H),
4.02-3.97 (m, 4H), 3.59-3.53 (m, 4H), 2.98-2.88 (m, 1H), 2.31
JO802186M
J. Org. Chem. Vol. 74, No. 2, 2009 809