Evaluation of kilogram-scale Sonagashira, Suzuki, and Heck coupling routes to oncology candidate CP-724,714

Article abstract of DOI:10.1021/op050039u

The synthesis of the anti-cancer compound 2-methoxy-N-(3-{4-[3-methyl-4-(6- methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}-E-allyl)acetainide (CP-724,714) (1) on multikilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthesis was investigated to identify a safe, environmentally friendly, and robust process for the production of this drug candidate. A convergent and selective synthesis of the candidate was identified which utilizes a Heck coupling of a protected allylamine to install the critical olefin.

Full text of DOI:10.1021/op050039u

Organic Process Research & Development 2005, 9, 440−450
Evaluation of Kilogram-Scale Sonagashira, Suzuki, and Heck Coupling Routes
to Oncology Candidate CP-724,714
David H. Brown Ripin,* Dennis E. Bourassa, Thomas Brandt, Michael J. Castaldi, Heather N. Frost, Joel Hawkins,
Phillip J. Johnson, Stephen S. Massett, Karin Neumann, James Phillips, Jeffery W. Raggon, Peter R. Rose,
Jennifer L. Rutherford, Barbara Sitter, A. Morgan Stewart, III, Michael G. Vetelino, and Lulin Wei
Chemical Research and DeVelopment, Pfizer Global Research DiVision, Pfizer Inc., Eastern Point Road,
Groton, Connecticut 06340
Abstract:
mixture was treated with activated carbon (KBB Darco) in
hot ethyl acetate to lower the amount of residual palladium
in the product. The ethyl acetate was replaced by 1:1
The synthesis of the anti-cancer compound 2-methoxy-N-(3-
{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)phenylamino]quinazo-
4
lin-6-yl}-E-allyl)acetamide (CP-724,714) (1) on multikilogram
scale using several different synthetic routes is described.
Application of the Sonogashira, Suzuki, and Heck couplings to
this synthesis was investigated to identify a safe, environmentally
friendly, and robust process for the production of this drug
candidate. A convergent and selective synthesis of the candidate
was identified which utilizes a Heck coupling of a protected
allylamine to install the critical olefin.
dichloroethane/THF, and 1 equiv of aniline 4 was added
based on the amount of acetylene 9 calculated from a
quantitative HPLC potency assay. The product obtained after
heating was isolated as a crystalline solid from ethyl acetate.
Assay by inductively coupled plasma mass spectroscopy
(ICPMS) indicated less than 50 ppm of copper and palladium
in the material at this stage in the synthesis. The residual
metal levels continued to decline throughout the synthesis
and were well below 20 ppm in the active pharmaceutical
ingredient (API). Compound 10 was recovered in 73% yield
over the two steps (3.5 kg scale).
Reduction of acetylene 10 with Red-Al proved to be
technically challenging. The reaction is sensitive to reaction
time, temperature, and stoichiometry. Over-reduction of the
acetylene and incomplete reaction both proved to be issues,
and the resultant impurities (unreacted starting material and
alkane) were difficult to purge from the relatively insoluble
drug substance. The reaction was optimally run using 2.8
equiv of Red-Al at -5 to 0 °C. Fewer impurities were
generated when the acetylene was added to the Red-Al (vs
the reverse order). Compound 10 was not soluble in THF at
the reaction temperature and had to be transferred to the Red-
Al as a slurry. This transformation was accomplished on 1.75
kg scale and provided material containing 3% unreacted 10
and 3% overreduced alkane, comparable to our best lab-scale
results. Deprotection of the BOC group was effected in THF
with aqueous HCl, resulting in the precipitation of the bis-
hydrochloride as an easily handled solid in 83% yield for
the two steps. Amide formation using excess triethylamine
to free-base the HCl salt and methoxyacetyl chloride in place
of methoxyacetic acid/carbonyldiimidazole produced amide
CP-724,714 (1) is a selective ErbB2 angiogenesis inhibitor
currently being investigated for the treatment of breast,
ovarian, and other types of cancer. Due to the large and rapid
bulk requirements of the clinical program as well as some
additional external factors, four synthetic routes to this
candidate were run on multikilogram scale. This unusual
history allowed for a comparison of some of the more
common palladium coupling reactions and their application
on large scale. All routes investigated utilized a common
retrosynthetic disconnection across the aryl-olefin bond,
utilizing different palladium-catalyzed cross couplings for
assembly (Scheme 1).
Sonogashira Coupling Route. The original Discovery
synthesis of CP-724,714 employing a Sonogashira coupling
and Red-Al reduction to introduce the trans-olefin side chain
is depicted in Scheme 2.
This route, with some minor modifications, was used to
produce 1.3 kg of 1. Sonagashira coupling of 6-iodo-4-
1
2,3
chloroquinazoline (7) with BOC-protected propargylamine
8) proceeded smoothly at room temperature to produce
(
acetylene 9 on 5.7 kg scale. The reaction was exothermic,
and the rate of heat generation was controlled by lowering
the copper and palladium catalyst levels. The reaction
1. Two recrystallizations to lower the levels of the acetylene
and alkane impurities were required (ethyl acetate followed
by acetonitrile) and provided a disappointing 38% yield for
the amide formation and purifications. It is noteworthy that
the crystal form of 1 which precipitated from the ethyl acetate
recrystallization was less soluble than the original form and
could not be redissolved in a workable volume of ethyl
acetate (<30 L/kg). This necessitated the switch to aceto-
*
To whom correspondence should be addressed. E-mail: David.B.Ripin@
pfizer.com.
(
(
(
1) Prepared in 75% by published methods from iodoanthranillic acid (5): (a)
Edincott, M. M.; Alden, B. W.; Sherrell, M. L. J. Am. Chem. Soc. 1946,
6
8, 1303. (b) Hudson, A. T.; Vile, S.; Barraclough, P.; Franzmann, K. W.;
McKeown, S. C.; Page, M. J. World Patent WO9609294, 1996.
2) Prepared from propargylamine and BOC anhydride in methylene chloride
at 0 °C. The material is a low-melting solid (MP ) ∼25-30 °C) and was
handled as a melt. Spectral data was consistent with that reported in the
literature (ref 6).
(4) Prepared by S
2-chloro-5-nitrotoluene (2) (K
tion to the aniline (10% Pd/C, H
N
Ar reaction between 3-hydroxy-6-methylpyridine (3) and
CO , DMF, 110 °C) followed by hydrogena-
, methanol, water).
3) Cheng, S.; Tarby, C. M.; Comer, D. D.; Williams, J. P.; Caporale, L. H.;
Myers, P. L.; Boger, D. L. Bioorg. Med. Chem. 1996, 4, 727.
2
3
2
4
40
•
Vol. 9, No. 4, 2005 / Organic Process Research & Development
10.1021/op050039u CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/01/2005

Scheme 1. Retrosynthesis of CP-724,714
Scheme 2. Discovery synthesis of CP-724,714a
ties to purge and exacted a significant yield penalty during
the purification.
From a worker-safety perspective, we also learned some
important lessons. 6-Iodo-4-chloroquinazoline 7 tested posi-
5
tive for sensitization in the LLNA test and was also found
to be an eye irritant. CP-724,714 was also found to be
positive as a sensitizer in the LLNA test. These results
affected our strategy with regard to regulatory starting
material selection as well as what equipment is selected to
process material through the chemistry developed.
Additionally, the solubility of CP-724,714 was character-
ized. The drug has a low solubility in most organic solvents
such as ethyl acetate and acetonitrile but is soluble in THF,
ethyl acetate with 10% THF, wet ethyl acetate, and wet
2
-methyltetrahydrofuran (MTHF). While some purification
of the API could be achieved at the free-base stage (vide
infra), recrystallization of the dimesylate salt failed to afford
any enrichment of the desired product.
Shortly after the 1.3 kg batch was produced, the di-
mesylate salt was found to be unstable. The salt was
hygroscopic and delequesced under humid conditions (>75%
humidity). Under acidic conditions in protic media, solvolysis
of the quinazoline-aniline bond to yield hydroxyquinazoline
1
2 and aniline 4 proved quite facile (Figure 1). This
a
decomposition provided warning against handling API or
intermediates bearing the 4-aminoquinazoline functionality
in highly acidic media. A number of salts, polymorphs, and
crystal forms of the API were screened, and the sesqui-
succinate (1.5×) salt was selected to progress in the drug
trials after extensive stability and bioavailability testing.
A search for a new route to the drug substance was
undertaken with the goals of increased convergency, im-
proved selectivity of the olefin installation, a minimal level
of worker safety issues, high purity, minimized raw material
costs, and minimized environmental impact. Several alterna-
tives to the Sonagashira coupling route were considered
including aldol condensation of a 6-aldehydoquinazoline with
an amide enolate or a late-stage Pd-catalyzed coupling of
the 6-haloquinazoline 13 with an appropriately functionalized
allylamine such as 14 or 15 (Scheme 3). We chose to focus
on Pd-catalyzed reactions to install the olefin as the 6-
Process conditions and results: a) K
O, 62%, 2 steps; c) formamidine acetate, EtOH, reflux, 80%; d)
, DMF, DCE, 53%; e) Pd(PPh Cl ; CuI, i-Pr NH, THF, 65 °C, 18 h;
f) DCE/t-BuOH, 80 °C, 1 h, 73%, 2 steps; g) Red-Al; THF; 0 °C; 2 h; h) HCl,
MeOH, 83%, 2 steps; i) i) MeOCH CO H, CDI, CH Cl , 93%; ii) EtOAc; iii)
H, PrOH. 93%.
2 3 2
CO , DMF, 110 °C; b) 10% Pd/C, H ,
MeOH, H
COCl)
2
(
2
3
)
2
2
2
2
2
2
2
i
MeCN, 38%; j) MeSO
3
nitrile for the second purification. Finally, dimesylate salt
formation was accomplished in 2-propanol in 93% yield to
complete the preparation of 1.3 kg of the API salt.
From a bulk-preparation perspective the route was oper-
able; however, there was room for improvement. Enolization
of the R-methoxyacetamide under the Red-Al reduction
conditions necessitated the protection of the amine as its BOC
carbamate, followed by late-stage deprotection and amide
formation. In addition to the required protection and depro-
tection steps, the Red-Al reduction of 10 proved to be
difficult to execute on large scale, with over-reduction and
incomplete reaction evident under all conditions investigated
and the quench being highly time-sensitive. The over-reduced
alkane and the unreduced acetylene proved difficult impuri-
(5) The LLNA (local lymph node assay) is an indicator as to whether a
compound is a sensitizer.
Vol. 9, No. 4, 2005 / Organic Process Research & Development
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441

production of ethereal byproducts resulting from reaction of
solvent with 7. Using 2-propanol was the preferred process
on scale as any 6-iodo-4-hydroxyquinazoline present in the
starting material (7) was effectively purged, as compared to
a number of other solvents in which the reaction could be
run. In the course of running a bulk campaign, nine batches
were run using as much as 50 kg of 7 with yields ranging
from 91 to 97% and purity from 98.5 to 99%.
Acetylene 16 was prepared by reaction of propargylamine
with methoxyacetyl chloride. The product was isolated in
good purity as an oil after aqueous work-up, obviating the
need for any additional purification. Differential scanning
calorimetry data (DSC) on 16 indicated that distillation was
not a safe option for the purification of this material.10
The hydroboration/Suzuki coupling sequence was care-
fully studied. Hydroboration of acetylene 16 required 2 equiv
of disubstituted borane to proceed to completion:11 the first
to deprotonate the amide and the second to effect hydro-
boration. Isoamylborane, thexylborane, and 9-BBN all
worked nicely to hydroborate 16. Isoamylborane was ex-
cluded from consideration due to the low flash point of
Figure 1. Decomposition of CP-724,714 under acidic, protic
conditions.
Scheme 3. Potential routes involving palladium couplings
to provide CP-724,714 directly
2
-methyl-2-butene (-45 °C), which precluded its use in our
haloquinazolines proved more inexpensive and stable than
the aldehyde counterparts. Most attractive of the Pd-catalyzed
routes would be a Heck coupling,6,7 as it would require a
less expensive and less functionalized coupling partner. As
a fall-back position, Suzuki coupling8,9 of trans-vinylborane
pilot plant. 9-BBN was selected over thexylborane as it is
sold either as a stable solid or a prepared solution that can
be easily handled. In addition, there is significant literature
on the hydroboration of acetylenes using 9-BBN. Concern
about removing alkylborane by-products after the Suzuki
coupling did lead us to investigate hydroborations using
catecholborane or dialkoxyboranes such as pinacolborane;
these reactions did not proceed to any useful extent, even in
the presence of catalysts such as Wilkinson’s or boranes
such as 9-BBN or dicyclohexylborane.
The Suzuki coupling could be run using the hydroboration
reaction mixture directly. The conditions initially investigated
were Pd(OAc)
12
15 derived from hydroboration of the acetylene would
provide a rapid route to the candidate using the same starting
materials as the first synthesis.
Suzuki Coupling Route. Immediate bulk requirements
drove the decision to investigate the Suzuki coupling first,
as it was considered less likely to pose problems with regard
to olefin geometry and substitution pattern than would a Heck
coupling.
1
3
1
4
2 3 2 3 2
, Ph P, K CO , H O, THF, 3 equiv of 9-BBN:
equiv of acetylene: 1 equiv of of iodide. The reaction was
Functionalized iodoquinazoline 13 was prepared by
heating 6-iodo-4-chloroquinazoline (7) with aniline 4 in
3
heated for 18 h and cooled, the water layer was separated,
and the product was extracted into aqueous HCl and washed
with ethyl acetate. The water layer was then basified, and
the product was extracted into ethyl acetate and crystallized.
Following this sequence, a 19% yield (following purification)
for the hydroboration-Suzuki sequence was achieved on 30
kg scale. Significant optimization was required prior to
proceeding further with this synthesis.
2
-propanol (Scheme 4). Product 13 was isolated as the HCl
salt by directly filtering the reaction mixture. Water or
primary alcohol solvents in the reaction mixture led to the
(
6) Reviews: (a) Heck, R. F. In ComprehensiVe Organic Synthesis; Trost, B.
M., Ed.; Pergamon: New York, 1991; Vol. 4, Chapter 4.3. (b) Br a¨ se, S.;
deMeijere, A. In Metal-catalyzed Cross-coupling Reactions; Deiderich, F.,
Stang, P. J., Eds.; Wiley: New York, 1998; Chapter 3. (c) Cabri, W.;
Candiani, I. Acc. Chem. Res. 1995, 28, 2. (d) deMeijere, A.; Meyer, F. E.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2379.
7) Heck reactions of aryl chlorides: (a) For an overview: Riermeier, T. H.;
Zapf, A.; Beller, M. Top. Catal. 1997, 4, 301. (b) Littke, A. F.; Fu, G. C.
J. Org. Chem. 1999, 64, 10. (c) Reetz, M. T.; Lohmer, G.; Schwickardi, R.
Angew. Chem., Int. Ed. 1998, 37, 481. (d) Beller, M.; Zapf, A. Synlett 1998,
Improved conditions for the hydroboration of 16 were
developed using 2 equiv of 9-BBN and 1 equiv of acetylene
(
1
6; the subsequent Suzuki reaction proceeded with much
higher purity than the reaction described above. Switching
to Pd (dba) (5 mol %), the reaction time was reduced to
7
92. (e) Ben-David, Y.; Portnoy, M.; Gozin, M.; Milstein, D. Organo-
metallics 1992, 11, 1995. (f) Portnoy, M.; Ben-David, Y.; Milstein, D.
Organometallics 1993, 12, 4734. (g) Portnoy, M.; Ben-David, Y.; Rousso,
I.; Milstein, D. Organometallics 1994, 13, 3465. (h) Herrmann, W. A.;
Brossmer, C.; O¨ fele, K.; Reisinger, C.-P.; Priermeier, T.; Beller, M.; Fischer
H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1844. (i) Herrmann, W. A.;
Elison, M.; Fischer J.; K o¨ cher, C.; Artus, G. R. J. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2371. (j) Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.;
Riermeier, T. H.; O¨ fele, K.; Beller, M. Chem. Eur. J. 1997, 3, 1357.
8) (a) Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Deiderich, F.,
Stang, P. J., Eds.; Wiley: New York, 1998; Chapter 3. (b) Miyamura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
2
3
less than 6 h, and the phosphine ligand was not necessary,
obviating the need for its removal at the end of the reaction.
(10) Decomposition with a release of >1000 J/g occurs ∼228 °C.
(11) If less than 2 equiv of hydroborating agent are employed in the acetylene
hydroboration, a number of impurities are formed in the Suzuki coupling
at higher levels (vide supra).
(12) Colberg, J. C.; Rane, A.; Vaquer, J.; Soderquist, J. A. J. Am. Chem. Soc.
1993, 115, 6065.
(13) Anon. Aldrichimica Acta 1989, 22, 80.
(14) (a) Evans, D. A.; Starr, J. T. Angew. Chem., Int. Ed. 2002, 41, 1787. b)
Arase, A.; Hoshi, M.; Mijin, A.; Nishi, K. Synth. Commun. 1995, 25, 1957.
(
(
9) Suzuki reactions of aryl chlorides: (a) Littke, A. F.; Fu, G. C. Angew. Chem.,
Int. Ed. 1998, 37, 3387. (b) Wolfe, J. P.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1999, 38, 2413. (c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem.
Soc. 2000, 122, 4020.
442
•
Vol. 9, No. 4, 2005 / Organic Process Research & Development

Scheme 4. Suzuki coupling route to CP-724,714a
a
3 2 3 2 3 2 3 4
Reagents and conditions: a) IPA, °C, 91-97%; b) MTHF, Et N; c) 9-BBN, THF, 30 °C; d) i) Pd (dba) , K CO , H O, THF; ii) H PO ; iii) NaOH, 55%.
The shorter reaction time also reduced the isolated amount
of primary amine resulting from amide hydrolysis. Due to
concern about the stability of 1 in strongly acidic water,
Scheme 5. First-generation Heck coupling route to
CP-724,714a
1
5
phosphoric acid was substituted for HCl to extract 1 into
water during the isolation. A greatly reduced rate of
decomposition was observed in this aqueous system as
compared to that in HCl. Methylene chloride was substituted
for ethyl acetate as the organic solvent during the extractions
to avoid acetamide formation from the primary amine
impurity (described above) during the work-up. As a result
of these changes, the isolated yield of desired product was
increased by almost 3-fold from 19% using the conditions
described above to ∼55% in lab-scale pilots using the
improved conditions.
a
2 3
Reagents and conditions: a) Pd (dba) , IPA, Et3N, 78 °C, 56% in situ yield.
analysis. The reaction profile was quite messy with a number
of impurities formed, one in greater than 30% yield. This
particular impurity has the equivalent mass to 1 and was
tentatively assigned as the 1,1-disubstituted olefin isomer.
Extensive optimization revealed that selectivity for 1 vs other
impurities, particularly the presumed 1,1,disubstituted olefin
isomer, jumped when the reaction was run using triethyl-
amine as solvent or cosolvent (e.g. with 2-propanol).
In practice, 9-BBN was used in solution in our pilot plant
in the course of a 10-kg bulk run.16 As the maximum
17
concentration of 9-BBN commercially available was 0.5M,
M borane-THF was procured to generate 9-BBN in situ
2
for a planned 50 kg campaign. After prolonged storage at
ambient temperature, and prior to any manipulation, one of
the cylinders of borane-THF spontaneously underwent a
BLEVE18 in a large explosion that injured a number of our
1
9
Pd
with Ph
0:1 2-propanol: triethylamine in the presence of 5 mol %
Pd (dba) for 2 h resulted in formation of 1 in >50% in situ
2
(dba)
3
without added phosphine was superior to Pd(OAc)
2
colleagues.
3
P or (o-tol) P in this reaction. Heating 13 and 14 in
3
The incident with 2 M borane-THF served to accelerate
efforts to replace the Suzuki coupling with a Heck coupling.
Provided the coupling could be run to give product in high
purity, the Heck coupling would have a number of advan-
tages over the Suzuki coupling including safety (handling
of borane/alkylborane reagents, acetylene thermal stability
issues), cost (no hydroborating agent required), ease of
execution, and environmental and purity issues (no need to
remove alkylborane side products).
First-Generation Heck Coupling Route. Initial attempts
at utilizing a Heck coupling to make API were encouraging.
The most aggressive strategy was investigated first, wherein
allylamine methoxyacetamide 1420 would be coupled with
quinazoline 13 to directly generate 1 (Scheme 5). Allylamide
1
2
3
yield and only 12% of the presumed 1,1-disubstituted olefin
impurity. Low yields of the desired product could be obtained
after crystallization from acetonitrile (<10%).
As 10 kg of material was required for clinical studies, a
campaign utilizing the Heck chemistry was run which
required bulk chromatography to purify the Heck coupling
reaction mixture (as the recovery from crystallization was
low). The allylamine methoxyacetamide was produced in
2
-methyltetrahydrofuran (MTHF) with allylamine, triethyl-
amine, and methoxyacetyl chloride at 25 °C. After acid and
base washes, the organic layer was dried via an azeotropic
distillation with MTHF until a water level of 0.5% was
achieved, followed by solvent removal to leave an oil suitably
pure for use in the Heck coupling.
Two batches were run through the Heck coupling using
the conditions described above on 15-kg scale, resulting in
identical in situ yields to those of the laboratory pilots. The
bulk reactions were filtered through Celite and concentrated
to the lowest stirrable volume, and the remaining solvent
was replaced via co-distillation with THF prior to concentrat-
1
4 (2 equiv) reacted with quinazoline 13 in the presence of
Pd(OAc) , Ph P, and NaOAc in DMF to provide the desired
product in ∼50% in situ yield as determined by HPLC
2
3
(
(
15) As precedented by the instability of the dimesylate salt.
16) Concern about the presence of residual borane in the solids, possibly
rendering them pyrrophoric, led to this decision.
17) Due to the solubility of 9-BBN.
(
(
(
(
18) Boiling Liquid Escaping Vapor Explosion.
19) Reisch, M. Chem. Eng. News 2002, 80, 7.
20) Sergeyev, S.; Hesse, M. Synth. Lett. 2002, 8, 1313.
Vol. 9, No. 4, 2005 / Organic Process Research & Development
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443

acetal, the product of which would require deprotection,
reductive amination, and amide formation to provide 1; (2)
coupling with acrylamide or acrylonitrile, the products of
which would require selective 1,2-reduction with a strong
reducing agent followed by amide formation to provide 1;
and (3) coupling with allylamine imides, the products of
which would require deprotection (followed by amide
formation in the case of 22) to provide 1.
Given the mild reaction sequence required to convert the
coupling products to the API, the allylamine imide couplings
were investigated first. The identity of the amine protecting
group influenced the regioselectivity in the Heck coupling.
Thus, selectivity of 85:15 was observed in the case of the
pthalimide protected allylamine (28), 90:10 in the case of
BOC-allyl methoxyacetamide (20), and 94:6 in the case of
bis-BOC allylimide (22). The postulate that the selectivity
is steric and not electronic in nature was bolstered in the
coupling reaction of 29, which is isosteric with 20 and also
gave a 90:10 ratio of products. On the basis of these results,
the Heck couplings with 20 and 22 were deemed preferable
to phthalimide 28. Both products were carried forward to 1,
and the bis-BOC allylimide coupling product distinguished
itself as a superior synthetic intermediate in a number of
ways (see Table 1). Advantages included easier preparation
of the starting material (22), higher olefin selectivity in the
Heck coupling, the opportunity to isolate primary amine 27
with purity upgrade, and the purification of 27 obviating the
need for recrystallizations of 1.
Following Heck coupling of 22 and 13, the reaction
mixture could be extracted with water to remove DMF, then
BOC deprotection could be effected in THF with concen-
trated aq. HCl to afford the HCl salt of primary amine 27 as
an off-white, crystalline solid. The overall yield for the Heck
coupling, deprotection, and salt formation was 90% on lab
scale, with the purity of the solids being >98% by HPLC
analysis. As the lab results were quite good, the synthesis
was optimized further prior to its implementation on large
scale.
Figure 2. Olefins screened in the Heck coupling with CP-
36,516.
8
ing to an oil and chromatographic purification. An estimated
6% in situ yield was achieved. The material was purified
5
by chromatography on silica gel using an ethyl acetate/
acetone solvent system to purify the product. Following an
acetone crystallization, the sesquisuccinate complex was
produced in an acetone/water solvent system. The complex
formation proved difficult, and the desired complex only
crystallized after three attempts. To achieve a solution that
could be filtered through a 1 µm filter prior to crystalliza-
tion,21 the solution of CP-724,714 and succinic acid had to
be made up more dilute than optimal for crystallization.
Following the filtration, the solution was reduced in volume,
and a specific final volume and solvent ratio had to be
achieved for sesquisuccinate complex to crystallize in
preference to the free base (which is also quite insoluble
under the crystallization conditions). Separate dissolution
followed by filtration of the two components needed for the
complex formation was considered as an alternative to the
filtration of the mixture, but the two as a mixture proved to
be more soluble than the two individually.
Second-Generation Heck Coupling Route. Other olefins
which would be expected to couple more cleanly in the Heck
reaction were investigated. The low selectivity in the Heck
reaction with allylamine methoxyacetamide was not particu-
larly surprising given the literature precedents.22 We thus
turned to an evaluation of several other allylamines (Figure
Olefin Preparation. The synthesis of the starting bis-
2).
24
BOC allylamine is straightforward; di-tert-butyliminodi-
BOC-protected allylamine 2123 reacted with similar
carboxylate can be treated with KOH to precipitate the
selectivity to 14 in the Heck coupling. Acrylamide (24) and
acrylonitrile (23) both coupled cleanly and quickly to provide
single products. Acrolein acetals 25 and 26 provided
potentially useful results. The bisacetoxy acetal of acrolein
25
potassium salt out of ethanol followed by addition of
26
allylbromide in DMF to afford the desired product. After
aqueous work-up, the product can be precipitated from a
small volume of cold hexanes as a low-melting solid. This
sequence was modified to a one-pot biphasic reaction using
aqueous KOH, di-tert-butyliminodicarboxylate, MTHF, and
25 coupled to provide two products cleanly: one was the
coupled acetal and the other was the coupled aldehyde
resulting from acetal deprotection. Finally, bis-BOC allyl-
imide 22 and BOC-allyl methoxyacetamide 20 both coupled
cleanly with quinazoline 13 to provide product in >90% in
situ yield.
With a number of efficient Heck couplings identified, the
products were prioritized for follow up. Three classes of
couplings were identified: (1) coupling with an acrolein
2
7
allylbromide. The reaction is greatly accelerated by the
addition of small amounts of phase-transfer catalyst such as
tetrabutylammonium bromide (TBABr, 1.5%) and proceeds
to completion in less than 2 h when run at 45 °C. Carrying
the reaction mixture into the Heck coupling after solvent
(
(
23) Kawamoto, A. M.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2001, 16, 1916.
24) Connell, R. D.; Rein, T.; Akermark, B.; Helquist, P. J. Org. Chem. 1988,
53, 3845.
(
(
4
21) All materials going into the final drug substance crystallization are filtered
in solution or neat through a 1 µm filter prior to crystallization per an internal
operating procedure.
(25) Allan, R. D.; Johnston, G. A. R.; Kazlauskas, R.; Tran, H. W. J. Chem.
Soc., Perkin Trans. 1 1983, 2983.
(26) Johnson, T. R.; Silverman, R. B. Bioorg. Med. Chem. 1999, 7, 1625-1636.
(27) Ripin, D. H. B.; Vetelino, M. Synlett 2003, 2353.
22) Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001, 66,
5
44.
44
•
Vol. 9, No. 4, 2005 / Organic Process Research & Development

Table 1. Selectivity of a variety of allylimides in the Heck coupling with quinazoline 13
Scheme 6. Second-generation Heck coupling route to CP-724,714a
a
Reagents and conditions: a) IPA, °C, 91-97%; b) MTHF, H
COCl, 80%.
2 4 2 3 3
O, NaOH, Bu NCl; c) Pd (dba) , Et N, IPA; d) concentrated HCl, 79-84%, two steps; e) MTHF,
H
2
O, NaOH, MeOCH
2
28
exchange is preferred to isolating solids on scale; the crude
material which contains 1.5% of a mixture of TBABr and
TBAOH actually reacts more rapidly in the Heck coupling
than isolated solids which lack the salts.29
during the subsequent deprotection reaction to the primary
amine. Triethylamine proved to be the optimal base for the
reaction and while the reaction would proceed with 3 equiv
3
of Et N, the rate was significantly increased if 5 equiv or
Heck Coupling/Deprotection. The Heck coupling be-
tween 22 and 13 was extensively optimized prior to its
execution on scale. The catalyst was switched to Pd (dba)
2 3
without added ligand. DMF could be replaced by a number
of alcohols including 2-propanol, ethanol, n-butanol, sec-
butanol, and n-propanol, as well as acetonitrile and methyl
ethyl ketone. Residual MTHF from the previous step (10-
more were used. Decreasing the amount of bisBOC allyl-
imide (22) to 1.1 from 2 equiv did not significantly decrease
the rate of reaction. The Pd loading could be lowered from
an initial 5 mol % to less than 1 mol % with a 9 h reaction
time. At the end of the reaction, activated carbon (Darco
KBB) was added, and the precipitated catalyst was filtered
over Celite. The filtrate was diluted with 2-propanol (7 L/kg
of 13), and the BOC groups were removed with aqueous
30
20%) was found to retard the rate of reaction, but did not
otherwise adversely affect the reaction profile. The alcohols
were selected for further study, as residual acetonitrile or
ketone solvent from the Heck could result in side reactions
(
30) A majority of the optimization for the Heck reaction described in this section
was conducted on an Anachem SK233 Workstation (www.reactarray.com).
In this workstation, up to 10 reactions can be run at once with individual
stirring and temperature control. Samples are taken via the liquid handler
from the reactions at defined intervals and are quenched and diluted. Online
HPLC analyses are then conducted to monitor quantities of starting materials,
products, and byproducts. For another study using the Anachem SK233
Workstation, see: Armitage, M. A.; Smith, G. E.; Veal, K. T. Org. Process
Res. DeV. 1999, 3, 189.
(28) The solids melt into a solid wax if they are not entirely dried of residual
solvent at a low temperature.
(
29) This rate acceleration was also observed on the salt-free isolated solids when
TBABr was added. The TBABr is likely accelerating the Heck reaction via
the Jeffery affect. Jeffery, T. Tetrahedron 1996, 52, 10113.
Vol. 9, No. 4, 2005 / Organic Process Research & Development
•
445

HCl (10 equiv). 2-Propanol proved to be superior to THF
for the deprotection in three regards: a solvent exchange
was unnecessary, tars are not deposited on the reactor, and
the deprotection is significantly slower. The slower reaction
was advantageous as it maximized the efficiency of the
isobutylene scrubber (MsOH/toluene). The acidic conditions
in protic solvent, which had previously been demonstrated
to decompose 1, appeared to have the same deleterious effect
on any product that did not immediately precipitate. The
isolated solids contained 450-550 ppm residual palladium
after this procedure. The solids generally had a potency of
the 450-550 ppm level to an acceptable level of 5-10 ppm
in the isolated product.
A few new impurities were generated in the amidation
step resulting from MOMCl present in the methoxyacetyl
3
1
chloride. To avoid formation of these impurities and
circumvent any residual MOMCl testing which might be
required, the acylimidazole of methoxyacetic acid or the
anhydride could be utilized to form the desired amide.
Salt Formation. A modified procedure was used to form
the salt in the final campaign. Formation of the proper form
is sensitive to total reaction volume, water level, and
temperature. The salt formation in previous campaigns had
presented difficulty when the large volume of water/acetone
required for the spec-free filtrations was reduced to the
volume needed for the proper form to precipitate. Achieving
the tight range for water content and total volume was
difficult in those attempts. This problem was circumvented
by dissolving the free-base and acid in a lower than required
volume of acetone, with enough water for the final crystal-
lization conditions. The drug substance and acid dissolved
at a relatively low temperature (∼35 °C) in this solvent
system containing a higher water/acetone ratio than required
for the crystallization. Acetone could then be added to the
solution following filtration to achieve the desired volume
and water/acetone ratio for crystallization. This procedure
allowed more precise makeup of the crystallization solution,
thus leading to good reproducibility on scale. Additionally,
as large particles were desired for formulation (100-200 µm
needles instead of 10-15 µm needles), an Ostwald ripening32
procedure was applied to grow the crystal size. After five
heating/cooling cycles, the desired particle size was achieved
in good uniformity and yield. The larger particles greatly
reduced the volume of the isolated solids as well as
eliminating problems with fine particles breaking through
during filtration.
85-90%; the remainder of the material was water and some
HCl in excess of the 2 equiv tied up as the salt.
As the reaction times and workups for the alkylation, Heck
coupling, and deprotection were similar, it was possible to
run all three steps in our pilot plant sequentially in one week.
Three batches of the alkylation reaction starting with 50 kg
of di-tert-butyliminodicarboxylate were each carried through
the Heck coupling and deprotection to produce 27 as the
bis-HCl salt (87.7-91.6 kg, potency 87%) in 79-84% yield
(corrected for potency) over the three steps. This sequence
will lend itself to semi-batch production on a commercial
scale.
Further improvement was made to this reaction after its
execution in the pilot plant. The reaction time could be
decreased to 3 h with 2.5 equiv of triethylamine if the higher-
boiling n-propanol (97 °C) or sec-butanol (98 °C) were used
as solvent; by using sec-butanol the deprotection can also
be telescoped without solvent replacement as in IPA. The
reaction is unaffected by up to 40% water; higher levels result
in partial loss of the BOC groups during the Heck coupling
and a decrease in reaction rate as solubility becomes an issue.
2 3
Several types of Pd/C can be used in place of Pd (dba) with
a Pd loading as low as 0.25%. As the reaction can tolerate
water, the less hazardous 50% wet catalysts can be used.
Even when utilizing the Pd/C catalysts, the residual palladium
levels in the isolated product were just as high as the results
Conclusion
In comparing the various Pd coupling reactions run, a
number of points can be made. Although the Sonogashira
coupling was the most facile palladium coupling investigated,
the thermal hazards associated with handling acetylenes in
conjunction with the need to reduce the acetylene to the
trans-olefin stood as significant flaws with this approach.
The Suzuki coupling route suffered from the same flaws:
acetylene intermediates and acetylene reduction were re-
quired for this route to be implemented. The olefin geometry
was established in high selectivity prior to the coupling
reaction. The production of alkylborane byproducts requiring
purging (possibly after an oxidative treatment) was a further
detriment to this approach. The first-generation Heck chem-
istry did not suffer from any of these liabilities; however,
the poor olefin selectivity in the coupling reaction and
difficulty in purification of the product were significant
obstacles. In addition, the Suzuki and first-generation Heck
2 3
with Pd (dba) when run in 2-propanol, but signifi-
cantly lower when the sequence was run in sec-butanol (10
ppm).
Amide Formation. The amide formation was run under
Schotten-Baumann conditions with slow addition of the
methoxyacetyl chloride to control the heat generated in the
reaction. MTHF was used to replace methylene chloride as
the reaction solvent. As wet MTHF was also demonstrated
to be a very good solvent for the crystallization of 1 with
impurity purge, the organic layer could be separated, distilled
to a low volume (6 L/kg of 1), adjusted to a water level of
∼
1% v/v by addition of water (measured by KF titration),
and the product was precipitated in >99.5% purity with no
single impurity greater than 0.3%. The product was filtered
in a stirred filter-drier with a containment system to minimize
worker exposure to the sensitizing API. Prior to concentration
and crystallization, the organic layer of the reaction mixture
was treated with 50% w/w activated carbon (Darco KBB)
at 65 °C for 18 h to lower the level of residual palladium in
the product. The prolonged hot treatment with a high loading
of carbon was necessary to lower the palladium levels from
(
31) MOMCl is the product of methoxyacetyl chloride decomposition. Stadl-
wieser, J. Synthesis 1985, 5, 490. In addition to the hazards associated with
MOMCl present in the reagent, one drum of methoxyacetyl chloride actually
swelled on storage, presumably due to CO buildup during decomposition.
(32) Ostwald, W. Lehrbuch Algemeinen Chem. 1896, 2, 444.
446
•
Vol. 9, No. 4, 2005 / Organic Process Research & Development

Table 2. Comparison of some key metrics between the four syntheses executed on large scale
Sonogashira Suzuki
1st Heck
bis-BOC Heck
overall yield
reducing agent required
safety
11%
Red-Al
acetylene reqd.
reducing agent
1023 L/kg
900 L/kg
92 L/kg
17%
12%
none
∼57%
9-BBN (from borane)
acetylene reqd.
reducing agent
1105 L/kg
801 L/kg
46 L/kg
none
no significant hazard
no significant hazard
total waste/kg
7730 L/kg
7716 L/kg
0 L/kg
132 L/kg
111 L/kg
0 L/kg
organic waste/kg
chlorinated waste/kg
metal waste produced
Pd, Cu 236 g/kg,
Pd 31 g/kg,
1 equiv B
Pd 155 g/kg
Pd 26 g/kg
1
equiv Al
approaches required that any purification had to be done on
the API itself, which had been shown to be a sensitizer.
Although less attractive on paper due to the requirement for
protecting groups and additional chemistry after coupling,
the second-generation route proved to meet all of our process
requirements for safety, selectivity, yield, purity, and envi-
ronmental impact. A summary of these advantages is
depicted in Table 2.
As a result of process changes and improvements, 100
kg of CP-724,714 was produced in our pilot facility with
high throughput. The final process proceeded in 57% overall
yield with a waste production of 132 L/kg of CP-724,714
produced (as compared to ∼1100 L/kg for the Sonogashira
and Suzuki routes). The process identified has a high margin
of safety in its execution from a thermal as well as worker-
exposure perspective. Additionally, the amounts of key raw
materials required to produce 1 kg of CP-724,714 was
reduced by 71%. In general, the utilization of a Heck
coupling in place of a Sonogashira or Suzuki coupling for
the installation of a trans-disubstituted olefin results in a safer
process that produces significantly less metal waste if it can
be applied.
confirm reaction completion. The aqueous layer was re-
moved, 3 kg of activated carbon (Darco KBB) was added,
and the pot was heated to 72 °C for 18 h. The slurry was
cooled to 40 °C, filtered over Celite, and the cake was
washed with 20 L of MTHF. The reaction was concentrated
atmospherically to 10-15 L final volume, cooled to 10 °C
over 4 h, granulated for 8 h, and then filtered on a stirred
filter/drier. The cake was washed with 13 L of MTHF and
then dried at 45 °C with a nitrogen sweep under vacuum.
The product was isolated in 80% (5.24 kg, 11.1 mol). R )
f
1
0
.16 (silica gel, EtOAc/MeOH ) 9/1). H NMR (CDCl
3
,
2
50 MHz) δ ) 8.71 (s, 1H), 8.25 (d, J ) 1.7 Hz, 1H), 7.90
(
s, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.66 (d, J ) 2.5 Hz, 1H),
.54 (dd, J ) 8.7, 2.6 Hz, 1H), 7.15-7.07 (m, 2H), 6.91 (d,
J ) 8.7 Hz, 1H), 6.83 (bt, 1H), 6.65 (d, J ) 15.9 Hz, 1H),
.34 (dt, J ) 15.9 Hz, J ) 6.1 Hz, 1H), 6.29 (dt, J ) 15.9
Hz, J ) 6.1 Hz, 1H), 4.14 (dt, J ) 6.1 Hz, 2H), 3.97 (s,
H), 3.45 (s, 3H), 2.53 (s, 3H), 2.29 (s, 3H). C NMR
CDCl , 75 MHz) δ ) 169.76, 157.90, 154.93, 152.367,
52.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16,
7
6
d
t
d
t
13
2
(
3
1
1
1
1
30.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65,
21.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57,
6.41. IR (powder) 3350, 3138 (br), 2997, 2926, 2824, 1640,
Experimental Section
1574, 1531, 1476, 1423, 1386, 1270, 1209, 1196, 1122, 1070,
-1
961, 938, 883, 826, 802 cm . Anal. calcd (found): C, 69.07
General. Reaction completion and product purity were
evaluated by HPLC using the following RP-HPLC condi-
tions: Symmetry Shield RP18, 75 mm × 4.6 mm; flow 1.0
mL/min; 205/210/220/245 nm; temp 25 °C; injection vol-
(
68.96); H, 5.80 (5.76); N, 14.92 (14.89). HPLC t (min)
R
6
.02; mp 75-95 °C.
Suzuki Coupling Method. To a dry and oxygen-free
reaction vessel was added 6-iodo-quinazolin-4-yl)-[3-methyl-
-(6-methylpyridin-3-yloxy)phenyl]amine hydrochloride (13)
10.3 g, 20.4 mmol) in tetrahydrofuran (40 mL). In another
ume: 10 µL of a ca. 0.5% solution in ACN/H
eluent: B ) ACN, C ) 0.01 mmol NH OAc in H O, pH )
.0; and gradient: 0 min: B ) 30%, C ) 70%; and 20 min:
B ) 85%, C ) 15%. Melting points were measured in open
2
O 9/1;
4
(
4
2
6
reaction vessel N-propargyl-2-methoxyacetamide (16) (5.0
g, 39.3 mmol) was added to a 1.0 M solution of 9-BBN (86.5
mL, 86.5 mmol) and warmed to 30 °C for 2 h. A solution
of potassium carbonate (28.4 g, 205.6 mmol) in water (40
mL) was prepared. The solution of potassium carbonate was
added to the 9-BBN/N-propargyl-2-methoxyacetamide solu-
tion. The potassium carbonate/N-propargyl-2-methoxyacet-
amide solution was added to the THF/6-iodo-quinazolin-4-
yl)-[3-methyl-4-(6-methylpyridin-3-yloxy)phenyl]amine hy-
1
13
capillary tubes and are uncorrected. H NMR and C NMR
spectra were measured in CDCl unless otherwise indicated.
IR spectra were recorded as thin films on NaCl plates unless
otherwise indicated.
3
6
-(N-Methoxyacetyl-3-amino-propen-1-yl)-4-[3-methyl-
-(6-methylpyridine-3-yloxy)phenylamino]quinazoline (1).
Amidation method: To [6-(3-Aminopropenyl)quinazolin-
-yl]-[3-methyl-4-(6-methylpyridin-3-yloxy)phenyl]amine
4
4
dihydrochloride (27) (6.55 kg, 13.9 mol) was charged 105
L of 2-methyltetrahydrofuran (MTHF), 52 L of water, and
NaOH (16.8 kg), and the contents were agitated for 1 h. To
the reaction was added methoxyacetyl chloride (2.27 kg, 20.9
mol) while keeping the temperature below 25 °C. The
reaction was stirred for 1 h and then assayed by HPLC to
2 3
drochloride (13) slurry. A solution of Pd (dba) (1.8 g, 1.96
mmol) in THF (40 mL) was added to the reaction. The
contents were heated to 50-55 °C. The reaction was
complete in 5-6 h by HPLC.
The bottom aqueous layer was removed, and the organic
layer was washed with a pH 2-4 acidic aqueous solution.
Vol. 9, No. 4, 2005 / Organic Process Research & Development
•
447

1
The organic layer was washed with 50 mL of CH
the organic layer was removed. The aqueous layer was
2
Cl
2
, and
3-(2-Methyl-4-aminophenoxy)-6-methylpyridine (4): H
NMR (CD OD, 400 MHz) δ )7.96 (d, J ) 2.5 Hz, 1H),
3
basified to pH 10-12 with sodium hydroxide, and the water
layer was extracted two times with 100 mL of CH Cl and
2 2
concentrated to an oil (8.55 g, 85% potency, 55% yield based
on potency).
7.17 (d, J ) 8.3 Hz, 1H), 7.11 (dd, J ) 8.3, 2.9 Hz, 1H),
6.72 (d, J ) 8.3 Hz, 1H), 6.66 (d, 1H, J ) 2.9 Hz), 6.58
(dd, J ) 8.3, 2.5 Hz, 1H), 4.90 (s, 2H), 2.44 (s, 3H), 2.04
1
3
(s, 3H). C NMR (CD OD, 100 MHz) δ ) 154.16, 150.84,
3
Heck Coupling Method. To a 200-L reaction vessel was
charged (6-iodo-quinazolin-4-yl)-[3-methyl-4-(6-methyl-
pyridin-3-yloxy)phenyl]amine hydrochloride (13) (15.0 kg,
145.32, 144.84, 137.02, 130.80, 124.19, 124.00, 121.50,
117.98, 114.11, 22.03, 15.48. IR (powder) 3422 (br), 3328
(br), 3199 (br), 1640, 1610, 1571, 1500, 1480, 1386, 1254,
1235, 1217, 1201, 1160, 1130, 1024, 863, 820, 802, 721
3
2.0 mol), N-allyl-2-methoxyacetamide (14) (4.94 kg, 38.2
mol), sodium acetate (7.88 kg, 96.1 mol), Pd (dba) (1.17
kg, 1.28 mol), triethylamine (54.0 kg, 528 mol), and 2-B
-
1
2
3
cm . Anal. calcd (found) C, 72.87 (72.79); H, 6.59 (6.42);
N, 13.07 (12.98); mp 95-97 °C.
3
3
ethanol (90 L). The mixture was heated to 70 °C, held for
h, cooled to 40 °C, and filtered through Celite. Two batches
(
3-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)phenyl-
6
amino]quinazolin-6-yl}prop-2-ynyl)carbamic Acid tert-
Butyl Ester (10). To a clean and dry nitrogen-purged 300-
gal glass-lined reactor was charged 5.7 kg (20 mol) of
were combined, and the liquors were concentrated and
chromatographed on silica gel using an ethyl acetate/acetone
solvent system. Following chromatography, the product-rich
fractions were concentrated, and the desired product was
crystallized from acetone. The final product was isolated in
4
-chloro-6-iodoquinazoline (7), 247 g (0.35 mol) of trans-
bis-triphenylpalladium chloride, and 67 g (0.35 mol) of CuI.
To this was charged 25 gal of THF and a slurry of
N-propargyl-2-methoxyacetamide (16) in 12 L of THF (5.0
kg, 32 mol). To the slurry was charged 3.3 L (2.4 kg, 23
mol) of diisopropylamine chased with 2 gal of THF. The
reaction mixture was stirred at 22-23 °C for 3 h. The
reaction was sampled for HPLC and then filtered via an 18-
in. diameter sparkler filter precoated with Celite to a clean
and dry nitrogen-purged 100-gal reactor. The filter and lines
were rinsed with 10 gal of THF and then concentrated
atmospherically to 15 gal. To the crude oil was charged 30
gal of toluene and 6.0 kg of Darco KBB. The slurry was
heated to 85 °C and held for 1 h. The batch was cooled to
3
6% yield (10.4 kg, 23.3 mol).
-(N-Methoxyacetyl-3-aminopropen-1-yl)-4-[3-methyl-
-(6-methylpyridine-3-yloxy)phenylamino]quinazoline
6
4
Sesquisuccinate (1‚1.5 Succinate). 6-(N-Methoxyacetyl-3-
aminopropen-1-yl)-4-[3-methyl-4-(6-methyl-pyridine-3-
yloxy)phenylamino]quinazoline sesquisuccinate (1) (24.0 kg,
51.1 mol) and succinic acid (18.1 kg, 153 mol) were
dissolved in 8.9 gal of water and 82 gal of acetone at 45 °C.
The solution was filtered through a 1 µm filter, and an
additional 13 gal of acetone was added. With slow stirring,
the solution was cooled to 43 °C and 240 g (1 wt %) of
6-(N-methoxyacetyl-3-aminopropen-1-yl)-4-[3-methyl-4-(6-
6
0 °C and then filtered via an 18 in. diameter sparkler
methylpyridine-3-yloxy)phenylamino]quinazoline sesqui-
succinate (1‚1.5 succinate) was added. The slurry was held
at 43 °C for 2 h and then cooled to 20 °C over 1 h. The
slurry was reheated to 38 °C over 1 h, held for 1 h, and then
cooled to 20 °C over 1 h and held for 45 min. This heating/
cooling cycle was repeated twice more, and then the pot was
heated to 38 °C and cooled to 33 °C over 3 h, 29 °C over 2
h, 24 °C over 1 h, and to 0 °C over 4 h. The slurry was
stirred for 3 h, filtered on a filter dryer, and rinsed with 13
gal of acetone. After drying for 18 h at 45 °C, 28.2 kg of
precoated with 60 °C toluene and Celite. The filtrate was
concentrated to 5 gal and held for the next step. Some product
was caught in the carbon cake so the Darco cake was
reslurried in hot ethyl acetate and refiltered. The product-
rich ethyl acetate solution was combined with the toluene
solution and carried on to the next step.
To a nitrogen-purged and clean 100-L glass-lined reactor
was charged the product-rich ethyl acetate and toluene
solution from the previous step. The solution was concen-
trated via full vacuum and concentrated to 4-10 L of oil.
To the reaction mixture was charged 41 L of tert-butyl
alcohol and 41 L of dichloroethane. To this solution was
charged 2.1 kg (9.8 mol) of 3-(2-methyl-4-aminophenoxy)-
1
product (43.4 mol) was isolated in 85% yield. H NMR
(
8
7
CD
3
OD, 400 MHz) δ ) 8.39 (s, 1H), 8.13 (s, 1H), 8.07-
.08 (m, 1H), 8.16 (s, 1H), 7.77 (dd, J ) 1.6, 8.7 Hz, 1H),
.53-7.60 (m, 3H), 7.18-7.22 (m, 2H), 6.87 (d, J ) 8.3
) 16.0 Hz,
) 5.6 Hz, 1H), 5.24 (br, s, 4H), 4.04 (d, J ) 5.0 Hz, 2H),
6
-methylpyridine (4), and the solution was stirred at 26 °C
Hz, 1H), 6.57 (d, J ) 15.8 Hz, 1H), 6.40 (dt, J
J
3
d
for 1.5 h. The reaction was judged incomplete (all the 3-(2-
methyl-4-aminophenoxy)-6-methylpyridine (4) was con-
sumed) by HPLC so another 100 g (0.47 mol) of 3-(2-
methyl-4-aminophenoxy)-6-methylpyridine (4) was added to
the reaction. The reaction mixture was stirred another 1.5 h.
The reaction mixture was then concentrated to 8 L under
vacuum. The crude product was diluted with 50 L of ethyl
acetate, heated to reflux for 1 h, and then allowed to stir at
0 °C overnight. The product was isolated (3.56 kg, 14.6 mol,
t
1
3
.95 (s, 2H), 2.55 (s, 6H), 2.45 (s, 3H), 2.17 (s, 3H).
-DMSO, 100 MHz) δ ) 174.43, 169.72, 158.23,
54.77, 152.74, 152.39, 150.28, 149.44, 138.99, 136.10,
35.36, 131.48, 129.87, 129.75, 129.30, 128.38, 126.06,
25.07, 124.45, 122.32, 120.69, 119.98, 115.82, 72.24, 59.29,
0.72, 29.46, 23.56, 16.60. IR (powder) 3294, 2927, 2465
C
NMR (d
6
1
1
1
4
(
1
br) 1931 (br), 1698, 1637, 1572, 1532, 1491, 1423, 1385,
358, 1262, 1217, 1171, 1119, 957, 836, 826, 802, 670 cm .
-1
73%) via filtration and washed with 4 L of EtOAc. Palladium
Anal. calcd (found): C, 61.29 (61.28); H, 5.61 (5.43); N,
0.83 (10.77). HPLC t (min) 6.02; mp 143 °C.
and copper levels were both under 50 ppm as measured by
1
R
1
ICPMS analysis. H NMR (d
6
-DMSO, 400 MHz) δ ) 9.87
(33) Toluene denatured ethanol.
(s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 8.16 (s, 1H), 7.80-7.77
448
•
Vol. 9, No. 4, 2005 / Organic Process Research & Development

(
m, 2H), 7.73-7.68 (m, 2H), 7.45 (br t, J ) 5.8 Hz, 1H),
content was <0.5% (KF). The material was carried into the
next step in solution. R ) 0.36 (silica gel, heptane/EtOAc
, 300 MHz) δ ) 6.72 (br, s, 1H),
4.09 (dd, J ) 5.5, 2.6 Hz, 2H), 3.92 (s, 2H), 3.43 (s, 3H),
7
5
1
1
1
1
.24-7.17 (m, 2H), 6.94 (d, J ) 8.7 Hz, 1H), 4.05 (d, J )
f
13
1
.8 Hz, 2H), 2.42 (s, 3H), 2.19 (s, 3H). C NMR (d
6
-DMSO,
) 7/3). H NMR (CDCl
3
00 MHz) δ ) 157.78, 156.02, 155.86, 152.73, 152.48,
50.34, 149.89, 139.18, 136.05, 135.84, 129.68, 128.89,
26.97, 125.94, 125.03, 124.45, 122.19, 120.64, 119.98,
15.75, 89.49, 81.70, 79.01, 30.82, 28.85, 23.77, 16.72. IR
1
3
2.24 (t, J ) 2.6 Hz, 1H). C NMR (CDCl
3
, 75 MHz) δ )
169.14, 79.11, 71.63, 71.41, 59.04, 28.26. IR (neat) 3286
-
1
(br), 2936, 2829, 1665, 1526, 1199, 1115 cm .
(
1
6
powder) 3308, 3194, 3006, 1677, 1574, 1530, 1501, 1480,
Allylmethoxyacetylcarbamic Acid tert-Butyl Ester (20).
N-Allyl-2-methoxyacetamide (14) (6.95 g, 54 mmol) was
420, 1361, 1284, 1251, 1223, 1195, 1167, 1115, 832, 786,
-
1
61 cm ; mp 141 °C dec.
6-Iodo-quinazolin-4-yl)-[3-methyl-4-(6-methylpyridin-
-yloxy)phenyl]amine Hydrochloride (13). In a 300-gal
dissolved in a solution of dry CH
methylamine)pyridine (54 mmol, 6.6 g) and Et
mmol) were added to the solution. The solution was cooled
to 0 °C, and BOC O (108 mmol, 23.6 g) was added dropwise.
2
Cl
2
(100 mL). 4-(Di-
(
3
N (5.5 g, 54
3
reactor, 4-chloro-6-iodoquinazoline (7) (49.9 kg, 172 mol),
2
3
-(2-methyl-4-aminophenoxy)-6-methylpyridine (4) (36.8 kg,
The solution was allowed to warm to room temperature and
was stirred overnight. The reaction mixture was diluted with
i
172 mol), and PrOH (200 gal) were heated to reflux for 2
h and then cooled to 25 °C over a period of 6 h. The slurry
was filtered, and the cake was washed with 25 gal of PrOH.
After drying at 55 C for 24 h, 83.1 kg of desired material
100 mL of H
2
O and extracted with CH
2
Cl
2
(3 × 50 mL).
i
The combined organic solvents were removed in vacuo to
give an oil. This material was then chromatographed on silica
gel, eluting with 10-20% EtOAc/hexane to give 6.6 g of
(
9
9
164 mol, 95.8%). R
/1). H NMR (CDCl
f
) 0.45 (silica gel, EtOAc/MeOH )
, 300 MHz) δ ) 11.40 (br, s, 1H),
.29 (m, 1H), 8.91 (s, 1H), 8.36-8.32 (m, 2H), 7.74-7.73
1
1
3
(54%) of title compound as a colorless oil. H NMR (300
MHz, CDCl
3
) δ ) 5.60-5.65 (m, 1H), 4.96-5.02 (m, 2H),
(
7
m, 2H), 7.62 (dd, J
.06 (d, J ) 8.7 Hz, 1H), 2.54 (s, 3H), 2.26 (s, 3H).
1
) 8.7, 2.6 Hz, 1H) 7.49-7.46 (m, 2H),
4.38 (s, 2H), 4.15 (d, J ) 4.5 Hz, 2H), 3.30 (s, 3H), 1.37 (s,
9H). C NMR (CDCl , 100 MHz) δ ) 172.74, 152.78,
3
1
3
13
C
NMR (CDCl
3
+ d
6
-DMSO, 75 MHz) δ ) 159.51, 153.63,
133.07, 117.08, 83.66, 74.35, 59.30, 46.26, 28.06. IR (neat)
1
1
1
1
1
7
53.17, 152.82, 152.70, 145.26, 141.37, 138.01, 134.75,
34.65, 131.05, 129.10, 128.74, 126.77, 124.86, 124.43,
20.41, 116.98, 94.89, 23.54, 17.67. RP-HPLC t (min)
R
2980, 1728, 1720, 1368, 1338, 1222, 1199, 1144, 1100, 991,
938, 852, 779 cm . Anal. calcd (found): C, 57.62 (57.36);
H, 8.35 (8.45); N, 6.11 (6.03).
-
1
2.13. IR (powder) 3098 (br), 1570, 1529, 1476, 1416, 1387,
376, 1354, 1262, 1226, 1211, 1196, 1134, 1115, 1016, 824,
N,N-Bis(tert-butoxycarbonyl)allylamine (22). To a 200-
gal reactor were charged di-tert-butyliminodicarboxylate
(50.0 kg, 230 mol), allyl bromide (33.4 kg, 276 mol),
terabutylammonium bromide (1.11 kg, 3.45 mol), NaOH
(50% w/w, 24.3 gal, 1150 mol), water (66 gal), and MTHF
(66 gal), and the mixture was heated to 42 °C for 2 h with
rapid agitation. The aqueous layer was removed, and the
material was concentrated atmospherically to a volume of
50 gal. The solution was filterd through a 1 µm filter, and
-
1
92, 721, 667 cm . Anal. calcd (found): C, 53.86 (53.87);
H, 3.66 (3.47); N, 11.96 (11.77); I, 27.10 (27.27); mp 220-
253 °C dec.
N-Allyl-2-methoxyacetamide (14). To a solution of
allylamine (2.50 kg, 43.8 mol) and triethylamine (4.92 kg,
8.2 mol) in MTHF (32 L) was added methoxyacethyl
4
chloride (5.23 kg, 48.2 kg) at -10 to 25 °C. The reaction
was stirred for 4 h, washed with 1 N HCl (6.00 kg) followed
by 1 N NaOH (7.55 kg), and MTHF was distilled atmo-
spherically until the water content was <0.5% (KF). The
i
24 gal of PrOH was added. The solution was concentrated
to a final volume of ∼20 gal, and an additional 53 gal of
i
PrOH was added. This solution was used as is in the next
1
material was carried into the next step in solution. H NMR
step of the process. The yield was 95-98%. Spectral data
was comparable to that reported in the literature.
(
300 MHz, CDCl
.2 Hz, J
3
) δ ) 6.60 (br, s, 1H), 5.84 (ddt, 1H, J
) 10.4, 17.6 Hz), 5.20 (dq, J ) 16.8 Hz, J
.6 Hz, 1H), 5.14 (dq, J ) 10.4 Hz, J
.91 (m, 1H), 3.91 (s, 3H), 3.42 (s, 3H). 13C NMR (CDCl
00 MHz) δ ) 169.46, 134.14, 116.35, 72.03, 59.26, 41.17.
t
)
5
1
3
1
d
d
q
)
[6-(3-Aminopropenyl)quinazolin-4-yl]-[3-methyl-4-(6-
methylpyridin-3-yloxy)phenyl]amine Dihydrochloride (27).
To a 300-gal reactor was charged (6-iodo-quinazolin-4-yl]-
[3-methyl-4-(6-methylpyridin-3-yloxy)phenyl]amine hydro-
chloride (13) (101.0 kg, 200.0 mol), N,N-Bis(tert-butoxy-
carbonyl)allylamine (22) (solution as prepared above, ∼220
d
q
) 1.6 Hz, 1H), 3.94-
3
,
IR (neat) 3307 (br), 3080, 2987, 2916, 2826, 1660, 1524,
-
1
1451, 1428, 1278, 1198, 1112, 989, 922 cm . Anal. calcd
(found): C, 55.80 (55.50); H, 8.58 (8.87); N, 10.84 (10.85).
2 3
mol), Pd (dba) (1.83 kg, 2.00 mol), triethylamine (102.0
i
N-Propargyl-2-methoxyacetamide (16). To a 250-mL
kg, 1000 mol), and PrOH (160 gal), and the headspace was
well purged with nitrogen. The reaction was heated to 78
°C for 18 h. The mixture was cooled, activated carbon (Darco
KBB, 15.0 kg) was charged, and the mixture has heated to
50 °C for 3 h. The mixture was filtered through Celite and
reactor was added 2-methyl-THF (90 mL), propargylamine
1.6 g, 27.9 mmol), and triethylamine (3.10 g, 30.7 mol).
(
The reaction vessel was cooled to -15 to -5 °C, and a
solution of methoxyacetyl chloride (3.33 g, 30.7 mol) in
MTHF (10 mL) was added via an addition funnel slowly
while keeping the temperature in the reaction below -5 °C.
The reaction was heated to 20-25 °C, stirred for 4 h, washed
with 1 N HCl (10 mL) followed by 1 N NaOH (10 mL),
and MTHF was distilled atmospherically until the water
i
diluted with 135 gal of PrOH. Concentrated HCl (54.3 gal,
2500 mol) was added and the reaction was heated to 40 °C
for 14 h. The off-gasses were swept with nitrogen through
a toluene/methanesulfonic acid scrubber. The reaction was
cooled to 20 °C and filtered, and the cake was washed with
Vol. 9, No. 4, 2005 / Organic Process Research & Development
•
449

i
2
7 gal of PrOH. After drying at 40 °C for ∼60 h, the product
Karen M. Alsante, George L. Reid, Lisa M. Newell, Stephen
M. Richoll, Thomas R. Sharp, and Silke Wunderwald for
analytical support; Paul Ahlijanian, Kevin W. Hettenbach,
Eric Dias, David R. Bill, and Neil Weston for safety and
engineering assistance; and Ben Hritzko, Glenn Wilcox,
Ronald C. Bates, Jr., and Randy J. Smith for bulk chroma-
tography support. We also thank Jeff Adler, Paul Allard,
Joseph Bellavance, Thomas Brooks, Todd Carden, Wayne
Crandall, Douglas Davis, Johnathan Dykema, Ronald Foular,
David Karlson, Thomas Limani, Larry Lumbert, Brian
Morgan, Richard Patterson, Alden Peckham, Steven Stott,
Ralph Scheck, III, Scott Schelkly, Walden Smolen, Elizabeth
Storms, Thomas Behan, Robert Buckingham, William P.
Buzon, William T. Gregory, Jeffery P. Haase, David J. Hall,
Chawn K. Johnson, Daniel J. Kramer, Gregorio C. Magee,
and Dennis B. Mooney for their execution of the large-scale
procedures.
was isolated (91.6 kg, 194 mol, 97% yield uncorrected for
potency). H NMR (300 MHz, D
d, J ) 1.8 Hz, 1H), 8.22 (d, J ) 2.4 Hz, 1H), 8.12 (dd, J
9 Hz, 1.5 Hz, 1H), 7.99 (dd, J ) 9 Hz, 2.7 Hz, 1H), 7.69-
.74 (m, 2H), 7.48 (d, J ) 2.7 Hz, 1H), 7.38 (dd, J ) 8.7
Hz, 2.4 Hz, 1H), 7.16(d, J ) 8.7 Hz, 1H), 6.9 (d, J ) 16.2
Hz, 1H), 6.5 (dt, J ) 16.2 Hz, 6.6 Hz, 1H), 2.61 (s, 3H),
.14 (s, 3H). IR (powder) 3438 (br), 2800 (br), 2623, 1616,
569, 1553, 1527, 1493, 1436, 1377, 1354, 1313, 1267, 1245,
1
2
O) δ ) 8.53 (s, 1H), 8.35
(
)
7
2
1
1
-
1
193, 1114, 976, 869, 840, 806, 782, 694, 653 cm .
Acknowledgment
We thank Stephane Caron, Robert Dugger, John Ragan,
and Stephen Ley for helpful discussions. We thank Daniel
Richter, Carl Thompson, John C. Kath, Joel Morris, and
Samit K. Bhattacharya who developed the discovery syn-
thesis of the candidate. Jane Li, Andrew W. Trask, Jason
Leonard, Stephan R. Anderson are thanked for their work
on final form issues. We thank Anne Obuchowski, Ivelisse
Colon-Rivera, Ricardo E. Borjas, Linda L. Lohr, Narasimhan
Kasthurikrishnan, Andrew J. Jensen, Dinos Santafianos,
Received for review March 9, 2005.
OP050039U
450
•
Vol. 9, No. 4, 2005 / Organic Process Research & Development