A practical synthesis of a PI3K inhibitor under noncryogenic conditions via functionalization of a lithium triarylmagnesiate intermediate

Article abstract of DOI:10.1021/op3002992

We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API.

Full text of DOI:10.1021/op3002992

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Full Paper
A Practical Synthesis of a PI3K Inhibitor
Qingping Tian, Zhigang Cheng, Herbert M Yajima, Scott J Savage, Keena L Green,
Theresa Humphries, Mark E Reynolds, Srinivasan Babu, Francis Gosselin, David Askin,
Isao Kurimoto, Norihiko Hirata, Mitsuhiro Iwasaki, Yasuharu Shimasaki, and Takashi Miki
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op3002992 • Publication Date (Web): 16 Dec 2012
Downloaded from http://pubs.acs.org on December 25, 2012
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Organic Process Research & Development
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A Practical Synthesis of a PI3K Inhibitor under Nonꢀ
cryogenic Conditions via Functionalization of a Lithium
Triarylmagnesiate Intermediate
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Qingping Tian*, Zhigang Cheng, Herbert M. Yajima, Scott J. Savage, Keena L. Green, Theresa
Humphries, Mark E. Reynolds, Srinivasan Babu, Francis Gosselin and David Askin
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Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080
Isao Kurimoto, Norihiko Hirata, Mitsuhiro Iwasaki, Yasuharu Shimasaki and Takashi Miki
Health & Crop Sciences Research Laboratory, Sumitomo Chemical Co., Ltd., 3 Utajima,
Nishiyodogawa-ku, Osaka 555-0021, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according
to the journal that you are submitting your paper to)
*Corresponding author: qtian@gene.com
ABSTRACT
We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a
convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation
and reductive amination followed by SuzukiꢀMiyaura crossꢀcoupling.
Metalation of the
thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation
under nonꢀcryogenic conditions to produce the corresponding aldehyde. We also investigated
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aminoalkylation via a benzotriazolylꢀpiperazine substrate as an alternative to the reductive amination
route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzukiꢀ
Miyaura crossꢀcoupling. Final deprotection and salt formation afforded the API.
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Introduction
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The phosphatidylinositol 3ꢀkinase (PI3K) pathway plays a central role in cell proliferation, survival,
migration and metabolism. The lipid kinases of the PI3K family are responsible for the phosphorylation
of the 3'ꢀhydroxyl group of phosphatidylinositols, leading to the activation of the serine / threonine
protein kinase Akt and further downstream oncogenes.1 The PI3K pathway is one of the most
frequently activated pathways in tumors, with mutations in one of its components detected in a notable
percentage of human cancers.2 Thus, the essential role of PI3K in human cancer has spurred the
development of PI3K inhibitors.3 GDC-0941 (Pictilisib) is a novel small molecule PI3K inhibitor
discovered at Genentech and is currently being evaluated as an anticancer agent (Figure 1).4 Substantial
amounts of GDC-0941 were required to support onꢀgoing development activities. Herein we wish to
report a robust and practical synthesis of GDC-0941 suitable for preparation of multiꢀkilogram
quantities of GDC-0941.
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Figure 1. Structure of PI3K Inhibitor GDC-0941
The synthesis is outlined retrosynthetically in Scheme 1. We envisioned that GDC-0941 could be
prepared from chloropyrimidine 1 and indazole boronate 2 through a SuzukiꢀMiyaura crossꢀcoupling.
Further disconnection of 1 would lead to piperazine 3 and thienopyrimidine 4.
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Organic Process Research & Development
Scheme 1. Retrosynthetic Analysis
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Results and Discussion
Synthesis of Thienopyrimidine 4. The medicinal chemistry synthesis of thienopyrimidine 4 relied on
condensation of commercially available methyl 3ꢀaminothiophene 2ꢀcarboxylate (5) with urea at 190 ºC
(Scheme 2, Route A).4 We sought milder conditions for the condensation reaction and replaced urea
with potassium cyanate in aqueous AcOH and the reaction proceeded smoothly at rt to afford 6 in 77%
yield (Scheme 2, Route B).5 Pyrimidinone 6 was then chlorinated with POCl3 to afford the
dichloropyrimidine 7. Subsequent siteꢀselective SNAr reaction6 with morpholine in MeOH proceeded
under mild conditions and gave thienopyrimidine 4 in 96% yield.
Scheme 2. Synthesis of the Thienopyrimidine Core 4
We envisioned that intermediate 1 could be assembled from compounds 3 and 4 via a sequence of
metalation, formylation and reductive amination. In an alternative approach, the synthesis of
intermediate 1 would be achieved by a direct aminoalkylation.7
Reductive Amination Approach. The metalation and formylation of thienopyrimidine 4 is illustrated
in Scheme 3. Thus, thienopyrimidine 4 was deprotonated with nꢀBuLi at –70 °C. Warming the reaction
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mixture to –50 °C achieved complete deprotonation as ascertained by H NMR spectroscopic analysis
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of aliquots quenched into D2O. Formylation was performed by addition of DMF at –70 °C, followed by
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quenching the reaction mixture into cold aqueous HCl to afford the desired aldehyde 8.
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Scheme 3. Organolithium Formylation
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Although metalation of the thiophene ring could be performed with nꢀBuLi under cryogenic
conditions, the instability of the resulting organolithium species precluded its use on large scale.8
Lithium trialkylmagnesiates, have been used successfully in halogenꢀmagnesium exchange,9 and for
deprotonation of a variety of heterocycles including furans and thiophenes.10
Lithium
triarylmagnesiates are generally more stable than the corresponding organolithium species, and
reactions can thus be performed under nonꢀcryogenic conditions. To our delight, we found that use of
nꢀBu2iꢀPrMgLi allowed for deprotonation and formylation under nonꢀcryogenic conditions (–10 °C) and
provided aldehyde 8 in 87% yield (Scheme 4). The resulting lithium triarylmagnesiate 9 and the
components of the reaction mixture (after addition of DMF) were stable at –5 °C for > 6 h.11 In an
optimized procedure, iꢀPrMgCl and nꢀBuLi were added sequentially to a solution of 4 in THF at –10 °C.
This operationally simple process proved easy to perform on 20 kg scale and obviated the need for a
separate vessel to prepare nꢀBu3MgLi as reported previously.10
Scheme 4. Improved Formylation Reaction
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Organic Process Research & Development
The reductive amination of aldehyde 8 with piperazine 312 was performed using trimethyl orthoformate
as the dehydrating agent (Scheme 5). We evaluated a variety of solvents (CH2Cl2, THF, toluene, EtOAc
and CH3CN) for the reaction and found that CH3CN was superior and afforded the desired product 8 in
85% isolated yield. It was critical to allow sufficient time for complete iminium ion formation (ca. 2 h
under the optimized conditions) before the addition of the reducing agent, NaBH(OAc)3. Otherwise,
the corresponding alcohol 10 was observed at a higher level (> 10A% by HPLC) when the reducing
agent was added after aging for < 2 h.
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Scheme 5. Reductive Amination
O
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1) NaOAc, CH3CN
HC(OCH3)3, rt
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OHC
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85%
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Aminoalkylation Approach. The reductive amination reaction performed well; however, there were
concerns about the alcohol impurity 10 which was carried in the downstream chemistry resulting in
formation of additional impurities that were difficult to remove. We therefore explored an alternative
route involving aminoalkylation, as an effort to avoid the formation of the alcohol 10. We envisioned
that the aminoalkylation could be performed by direct addition of lithium triarylmagnesiate 9 to an
iminium equivalent of piperazine 3. As indicated in Scheme 6, the iminium salt 13 was generated from
the aminal 11 or aminol ether 12.13 The resulting iminium salt was then subjected to the lithium
triarylmagnesiate 9 to afford the desired product 1. However, a significant amount of the starting
material 4 was observed in the crude product possibly due to the impurities present in the iminium salt.14
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Scheme 6. Synthesis of Intermediate 1 via Iminium Salt
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The iminium salt was also generated in situ by treating the aminol ether 12 with a Lewis acid (Scheme
7), followed by addition of the lithium triarylmagnesiate 9. We identified ZnCl2 as the preferred Lewis
acid with the desired product being obtained in ~ 80% yield.
Scheme 7. Synthesis of 1 from Iminium Salt Generated in situ from Aminol Ether
To further improve the aminoalkylation process, our efforts were then focused on the benzotriazole
substrates that have been widely used in the aminoalkylation reactions.15 Treatment of 3 with
benzotriazole, paraformadehyde and MeOH in the presence of KHCO3 afforded benzotriazolylꢀ
piperazine 14 in 90% yield after isolation by simple filtration (Scheme 8). Unlike the aminol ether 12,
compound 14 is not hygroscopic and can be isolated as a benchꢀstable solid. Treatment of compound 14
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Organic Process Research & Development
with ZnCl2 followed by addition to a solution of lithium triarylmagnesiate 9 afforded the desired
product 1 in 93% yield (Scheme 8).
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Scheme 8. Aminoalkylation via Benzotriazolyl-Piperazine 14
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This route achieved a slightly higher yield than the reductive amination route and did not generate the
alcohol impurity 10. Although a large excess of ZnCl2 (4 equiv) was needed, this route offered a
complementary process to the reductive amination.
Synthesis of Indazole Boronate. Next, our attention was shifted to synthesis of indazole boronate 2
needed for the SuzukiꢀMiyaura crossꢀcoupling reaction. The synthesis of the boronate is illustrated in
Scheme 9. We selected the THP protecting group to improve the solubility of the SuzukiꢀMiyaura
crossꢀcoupling product and facilitate the removal of residual Pd and impurities. The synthesis began
with diazotization of 3ꢀchloroꢀ2ꢀmethylaniline (15) and subsequent cyclization under basic conditions,
producing 4ꢀchloroindazole (16) in quantitative yield. Installation of the THP group was then
performed with 3,4ꢀdihydroꢀ2Hꢀpyran (DHP) in the presence of pyridinium pꢀtoluenesulfonate (PPTS),
leading to a mixture of indazole isomers 17a and 17b which were treated with bis(pinacolato)diboron in
the presence of PdCl2(PPh3)2 and PCy3 to afford boronates 2a and 2b, respectively (Scheme 9, Method
A).16
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Scheme 9. Synthesis of the Boronates 2a and 2b
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We found that the THP group at the 2ꢀposition could easily be removed after the crossꢀcoupling
reaction, but it proved difficult to deprotect the THP group at the 1ꢀposition. In general, the acidꢀ
catalyzed THP protection of indazole at the 2ꢀposition is favored kinetically and the 1ꢀTHP regioisomer
is the thermodynamic product.16b As such, installation of the THP group at the 2ꢀposition was achieved
under mildly acidic conditions.16b We applied the similar conditions in our process, and obtained a
mixture of 2ꢀTHP and 1ꢀTHP products (Table 1, entry 1). We found that the siteꢀselectivity of the
protection was solventꢀdependent and could be improved to 94:6 17a/17b using toluene/heptane (3:4,
v/v) as solvent mixture (Table 1, entry 4). At higher temperature and with prolonged reaction time, the
siteꢀselectivity was eroded as the kinetically favored product 17a would slowly be converted to the
thermodynamically favored product 17b. Under the optimized conditions, the reaction was performed at
40 ºC for 5 h. Palladium catalyzed borylation gave the desired 2ꢀTHP boronate ester 2a in 41% yield
over two steps, and chromatographic purification was required for removal of the undesired 1ꢀTHP
regioisomer 2b and residual Pd.
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Table 1. Regioselectivity of THP Protection of Indazole 16 in Various Solvents
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entry
solvents
CH2Cl2
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10 : 90
45 : 55
94 : 6
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CH3CN
DMF
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Toluene/heptane (3:4, v/v)
We next investigated the Niꢀcatalyzed borylation of indazoles 17a and 17b (Scheme 9, Method B).17
We found that in reactions using 4 mol% of Ni(NO3)2•6H2O/PPh3 as catalyst, the product could be
isolated in 53% yield over two steps and 99A% HPLC by a simple crystallization. Furthermore,
residual Ni was readily removed from the process stream by simple aqueous washes. Although a
relatively higher loading of the Ni catalyst (4 mol%) was employed, the process was still costꢀeffective
due to the significantly lower cost of the Ni catalyst, Ni(NO3)2•6H2O, compared to the expensive Pd
catalyst.
As a further improvement relative to metalꢀcatalyzed borylation, we opted to replace the boronates
with the corresponding boronic acids 18a and 18b in the SuzukiꢀMiyaura crossꢀcoupling reaction.
Indazoles 21a / 21b were prepared from 3ꢀbromoꢀ2ꢀmethylaniline (19) in two steps employing the
sequence used in Scheme 9. Halogenꢀmetal exchange on indazoles 21a/21b and borylation with B(Oꢀiꢀ
Pr)3 gave the desired boronic acids in 60% yield (Scheme 10).18
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Scheme 10. Synthesis of Indazole Boronic Acid
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Suzuki-Miyaura Cross-coupling. With intermediate 1 and the boronic acid 18a in hand, we turned to
the SuzukiꢀMiyaura crossꢀcoupling reaction to provide the THP protected GDCꢀ0941 22. We explored
the use of both Pd and Ni catalysts for the reaction and identified PdCl2(PPh3)2 in aqueous Na2CO3/1,4ꢀ
dioxane and Ni(NO3)2•6H2O/PPh3 in K3PO4/CH3CN as the catalyst systems of choice (Scheme 11). In
the Niꢀcatalyzed reaction, we found that boronic acid 18a performed better than the corresponding
boronate esters 2a and 2b and boronic acid 18b.19 The removal of the residual Pd contaminate required
®
the use of the expensive scavengers (Florisil® and ThioꢀSilica ) and large volume of solvents. In
contrast, the residual Ni catalyst could be easily removed from the crude reaction mixture through an
aqueous ammonia wash and crystallization. This route afforded the THP protected GDCꢀ0941 22 in
79% yield as the final key bond forming step.
Scheme 11. Pd or Ni-catalyzed Suzuki-Miyaura Cross-coupling Reaction
O
Method A:
O
N
1. PdCl2(PPh3)2, Na2CO3
1,4-dioxane, 88 oC
2. Florisil/Thio-Silica
60%
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Method B:
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Ni(NO3)2 6H2O, PPh3
K3PO4, CH3CN, 60 oC
79%
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End-Game Chemistry. The bisꢀmethanesulfonate salt of GDC-0941 was identified as a suitable
crystal form for development. Deprotection of the THP group and salt formation was performed in one
operation by using methanesulfonic acid in aqueous MeOH (H2O/MeOH, 1:19 (v/v)) and the product
was isolated by simple filtration (Scheme 12). The crude product was then purified by recrystallization
from MeOH/H2O to afford GDC-0941 in 90% yield, HPLC: >99 A%, ICPMS analysis: <20 ppm Ni.
Because MeOH and methanesulfonic acid were used in the process, we had concerns about the
formation of methyl methanesulfonate, a known genotoxic impurity.20 Thus, water was employed as a
coꢀsolvent to suppress the formation of methyl methanesulfonate.21 The amount of methyl
methanesulfonate in the final product was determined to be <1 ppm by GC/MS analysis. In addition, no
methyl methanesulfonate was detected in the mother liquor. These analyses demonstrated that no
methyl methanesulfonate was produced in the process.22
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Scheme 12. Final Deprotection and API Salt Formation
Summary and Conclusion. We have developed a practical and convergent synthesis for GDC-0941
(Scheme 13). Nonꢀcryogenic conditions were employed in the formylation of 4 via a triarylmagnesiate
intermediate. The synthesis of the key intermediate 1 was achieved through an aminoalkylation reaction
with preformed benzotriazolylꢀpiperazine 14, a complementary process to the reductive amination. We
investigated both metalꢀcatalyzed borylation and halogenꢀmetal exchange/borylation for the synthesis of
the boronate and boronic acid. Both palladium and nickel catalysts were evaluated for the Suzukiꢀ
Miyaura crossꢀcoupling reaction. The endꢀgame featured THP deprotection and salt formation in one
operation to afford GDC-0941 in >99A% HPLC purity and 53% overall yield over four steps. This
preparation has been scaled up to a 55kg batch of API.
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Scheme 13. Multikilogram-scale Synthesis of GDC-0941
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Experimental Section
General. All reactions were performed under a nitrogen atmosphere. Melting points were measured by
differential scanning calorimetry (DSC). HPLC methods for purity and assay analysis are listed below.
HPLC method for compounds 1, 4, 5, 6, 7 and 8: column, ACE C18 (150 × 4.6 mm, 5 ꢁm); temperature, 30
oC; mobile phase A, 5% CH3CN in water; mobile phase B, CH3CN; gradient (25 min) 75:25 A/ B to 0:100 A/B
over 18 min, then hold at 0:100 A/B for 5 min, then change to 75:25 A/B in 0.1 min, 5 min equilibrium at 75:25
A/B; flow rate, 1.5 mL/min; detection, 210 nm; injection volume, 5 ꢁL; tR of 1 = 6.76 min, tR of 4 = 4.67 min, tR
of 5 = 3.65 min, tR of 6 = 7.54 min, tR of 7 = 6.83 min, tR of 8 = 6.53 min.
HPLC method for compound 16: column, Shiseido Capcell Pak MGꢀII (250 × 4.6 mm, 5 ꢁm); temperature, 40
oC; mobile phase A, 10 mM phosphate buffer and pH adjusted to 6.8 with KH2PO4; mobile phase B, CH3CN;
gradient (60 min) 75:25 A/B to 35/65 A/B over 13 min, hold for 8 min, then to 25:75 A/B over 2 min, hold for 27
min, then to 75:25 A/B over 0.01 min, 10 min equilibration at 75:25 A/B; flow rate, 1.0 mL/min; detection, 275
nm; injection volume, 1 ꢁL; tR of 16 = 13.4 min.
HPLC method for compounds 17a and 17b: column, Shiseido Capcell Pak MGꢀII (250 × 4.6 mm, 5 ꢁm);
temperature, 40 oC; mobile phase A, 10 mM phosphate buffer and pH adjusted to 6.8 with KH2PO4; mobile phase
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Organic Process Research & Development
B, CH3CN; gradient (50 min) 75:25 A/B to 35/65 A/B over 40 min, then to 75:25 A/B over 0.01 min, 10 min
equilibration at 75:25 A/B; flow rate, 1.0 mL/min; detection, 275 nm; injection volume, 1 ꢁL; tR of 16= 19.1 min,
tR of 17a = 34.2 min, tR of 17b = 38.4 min.
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HPLC method for compounds 2a and 2b: column, Shiseido Capcell Pak MGꢀII (250 × 4.6 mm, 5 ꢁm),
temperature, 40 oC; mobile phase A, 10 mM phosphate buffer and pH adjusted to 6.8 with KH2PO4; mobile phase
B, CH3CN; gradient (60 min) 75:25 A/B to 35:65 A/B over 13 min, hold for 8 min, then to 25:75 A/B over 2 min,
hold for 27 min, then to 75:25 A/B over 0.01 min, 10 min equilibration at 75:25 A/B; flow rate, 1.0 mL/min;
detection, 220 nm; injection volume, 1 ꢁL; tR of 17a = 19.6 min, tR of 17b = 21.7 min, tR of 2a = 24.0 min, tR
of 2b = 28.1 min.
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HPLC method for compound 18a, 20, 21a and 21b: column, Phenomenex Luna C8 (250 × 4.6 mm, 5 ꢁm);
temperature, 45 oC; mobile phase A, 0.02 M KH2PO4 and pH adjusted to 6.0 with KOH; mobile phase B, CH3CN;
gradient (30 min) 80:20 A/ B to 30:70 A/B over 20 min, then to 80:20 A/B over 5 min, then 5 min equilibration at
80:20 A/B; flow rate, 1.2 mL/min; detection, 210 nm; injection volume,10 ꢁL; tR of 18a = 6.15 min, tR of 20 =
8.23 min, tR of 21a = 12.3 min, tR of 21b = 13.1 min.
o
HPLC method for compound 22, Shiseido Capcell Pak C18 MGII (250 × 3.0 mm, 5 ꢁm); temperature, 40 C;
mobile phase A, water; mobile phase B, CH3CN; gradient (40 min) 60:40 A/ B to 10:90 A/B over 20 min, then to
60:40 A/B over 10 min, then 10 min equilibration at 60:40 A/B; flow rate, 0.4 mL/min; detection, 210 nm;
injection volume, 3 ꢁL; tR of 1 = 12.0 min, tR of 22 = 20.1 min.
o
HPLC method for GDC-0941: column, Zorbax Eclispe XDBꢀC18 (150 × 3.0 mm, 3.5 ꢁm); temperature, 35 C;
mobile phase A, 0.10% TFA in water; mobile phase B, 0.05% TFA in CH3CN; gradient (50 min) 95:5 A/ B for 2
min, then to 30:70 A/B over 33 min, hold for 10 min, then to 95:5 A/B over 0.1 min, 5 min equilibrium at 95:5
A/B; flow rate, 0.8 mL/min; detection, 230 nm; injection volume, 5 ꢁL; tR of 22 = 16.3 min, tR of GDC-0941 =
12.5 min.
23, 24
Thieno[3,2-d]pyrimidine-2,4-dione (6).4,
To a stirred mixture of methyl 3ꢀaminoꢀ
thiophenecarboxylate (5) (125 kg, 795 mol) and acetic acid (1018 L) was added a solution of potassium
cyanate (155 kg, 1911 mol) in water (313 L) in two portions in 2 h. After aging at rt for 2 h, more water
o
(812 L) was added. The reaction mixture was cooled to 10 C and stirred for 2 h. The resulting slurry
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was filtered and the filter cake was washed with water (344 L). The wet cake was then charged in two
portions in 1 h into a reactor containing a solution of NaOH (109 kg) in water (1875 L). The slurry was
stirred at rt for 12 h, the mixture was then cooled to 10 ºC and 35% aqueous HCl solution (~ 238 kg)
was added in one portion to adjust pH to 5−6. The resulting slurry was filtered and rinsed with water
(390 L), and the cake was dried under vacuum at 50 ºC for 24 h to afford 6 as an offꢀwhite solid (102.5
kg, 77% yield): mp 102.9 ºC; 1H NMR (300 MHz, DMSO−d6) δ 11.58 (s, 1H), 11.24 (s, 1H), 8.06 (d, J
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= 5.2 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H); C NMR (75 MHz, DMSO−d6) δ 159.0, 151.5, 146.4, 135.9,
117.2, 111.2; HRMS (ESI) calcd for C6H3N2O2S [MꢀH] 166.9921, found: 166.9922.
2,4-Dichlorothieno[3,2-d]pyrimidine (7).4, 23, 24 Phosphorus oxychloride (510 kg, 3326 mol) was
slowly added to a cold solution of thieno[3,2ꢀd]pyrimidineꢀ2,4ꢀdione (6) (102 kg, 606 mol) and N,Nꢀ
dimethylaniline (50.7 kg, 418 mol) in CH3CN (604 L) in 2 h at ≤ 20 ºC. The mixture was then heated
to 80−85 ºC and was aged for 24 h. The reaction mixture was cooled to 40 ºC and then was quenched
into a reactor containing water (1425 L) in 2 h. The resulting slurry was filtered and the cake was rinsed
with water (100 L). The cake was dried under vacuum at 40 ºC for 24 h to afford 7 as an offꢀwhite solid
(111 kg, 89% yield): mp 137.7 ºC, lit. 138.8−139.3 oC;23 1H NMR (300 MHz, DMSO−d6) δ 8.71 (d, J =
13
5.4 Hz, 1H), 7.74 (d, J = 5.4 Hz, 1H); C NMR (75 MHz, DMSO−d6) δ 163.5, 154.71, 154.69, 142.3,
129.2, 124.0; HRMS (APCI) calcd for C6HCl2N2S [MꢀH] 202.9243, found: 202.9245.
4-(2-Chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (4).4, 24 Morpholine (117 kg, 1343 mol) was
added to a solution of 2,4ꢀdichloroꢀthieno[3,2ꢀd]pyrimidine (7) (111 kg, 541 mol) in methanol (1110 L).
o
The reaction mixture was cooled to 0 5 C and filtered. The cake was then triturated in water (450 L)
at rt for 2 h and the resulting slurry was filtered, and the cake was rinsed with water (60 L) and dried
under vacuum at 45 ºC for 24 h to give an offꢀwhite solid 4 (133 kg, 96% yield): mp 197.5 ºC; 1H NMR
(300 MHz, DMSO d6) δ 8.32 (d, J = 5.4 Hz, 1H), 7.42 (d, J = 5.4 Hz, 1H), 3.93ꢀ3.89 (m, 4H), 3.79ꢀ
3.74 (m, 4H); 13C NMR (75 MHz, DMSOꢀd6) δ 162.7, 158.2, 155.9, 135.4, 123.7, 112.5, 65.7, 45.9;
HRMS (ESI) calcd for C10H11ClN3OS [M+H] 256.0306, found: 256.0305.
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Organic Process Research & Development
24
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde
(8).4,
A
mixture
of
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2ꢀchlorothieno[3,2ꢀd]ꢀpyrimidinꢀ4ꢀylꢀ)morpholine (4) (19.8 kg, 77.4 mol) and THF (197 L) was cooled
to below ꢀ10 ºC, and a 20% solution of iꢀPrMgCl in THF (20.1 kg, 39.1 mol) was added in 1.5 h,
followed by addition of a 15% solution of nꢀBuLi in hexanes (32.6 kg, 76.3 mol) in 1.5 h at ≤ ꢀ10 ºC.
The mixture was stirred at –10 ºC for 1 h and anhydrous DMF (8.8 kg, 120 mol) was then slowly added
while maintaining the internal temperature between ꢀ15 ºC and ꢀ5 ºC. The reaction mixture was stirred
for 4 h and then was transferred to a cold mixture of AcOH (58.7 kg), 35% aqueous HCl (21.3 kg) and
water (159 kg) in 1.5 h. After aging for 1 h, the slurry was heated to 55 ºC in 4 h and stirred for 3 h.
The mixture was then cooled to 20ꢀ30 ºC in 1 h and then was aged for 1 h. The product was isolated by
filtration and the filter cake was washed with water (4 × 25 kg), dried under vacuum at 50 ºC to afford a
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brownꢀyellow solid 8 (19.2 kg, 87% yield): mp 239.4 ºC; H NMR (300 MHz, DMSOꢀd6) δ 10.21 (s,
1H), 8.29 (s, 1H), 4.01ꢀ3.87 (m, 4H), 3.83ꢀ3.67 (m, 4H); 13C NMR (75 MHz, DMSOꢀd6) δ 186.5, 161.3,
158.6, 156.6, 147.0, 132.8, 116.3, 65.7, 46.1; HRMS (ESI) calcd for C11H11ClN3O2S [M+H] 284.0255,
found: 284.0260.
2-Chloro-6-(4-methylsulphonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
(1) (Scheme 5, Reductive Amination).4, 24 To a suspension of 2ꢀchloroꢀ4ꢀmorpholinꢀ4ꢀylꢀthieno[3,2ꢀ
d]pyrimidineꢀ6ꢀcarbaldehyde (8) (36.2 kg, 128 mol), 1ꢀ(methylsulfonyl)piperazine hydrochloride (3)
(37.2 kg, 185 mol) and NaOAc (15.2 kg, 185 mol) in CH3CN (540 L) was added trimethyl orthoformate
o
(136.3 kg, 1284 mol) and the mixture was heated to 45 C in 40 min. After aging for 2 h and 40 min,
sodium triacetoxyborohydride (43.9 kg, 207 mol) was added in 10 portions in 4 h and the reaction
mixture was stirred for 3 h. The reaction was then quenched with water (363 L) and the mixture was
heated to 70 ºC in 1 h and 25 min and stirred for 3 h. The mixture was cooled to 20−30 ºC in 4 h and 50
min and stirred for 1 h. The resulting slurry was filtered and rinsed successively with a mixture of
CH3CN (67 L) and water (45 L), water (3 × 72 L) and CH3CN (36 L), and the cake was dried under
vacuum at 50 ºC for 10 h to give 1 as an offꢀwhite solid (49.0 kg, 95.9wt%, 85% yield): mp 238.6 ºC;
1H NMR (300 MHz, CDCl3) δ 7.19 (s, 1H), 4.05−3.94 (m, 4H), 3.89−3.76 (m, 6H), 3.36−3.19 (m, 4H),
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2.81 (s, 3H), 2.73−2.57 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 163.2, 158.3, 156.9, 150.5, 122.8, 112.8,
66.7, 57.1, 52.4, 46.3, 45.7, 34.6; HRMS (ESI) calcd for C16H23ClN5O3S2 [M+H] 432.0925, found:
432.0916.
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1-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-1H-benzotriazole (14). 1ꢀ(Methylsulfonyl)piperazine
hydrochloride (3) (200 g, 1.00 mol), methanol (4.5 L) and water (0.5 L) were charged into a 12ꢀL
reactor, followed by the addition of KHCO3 (120 g, 1.20 mol) and benzotriazole (119 g, 1.00 mol).
The resulting mixture was stirred at rt for 30 min and 37% aqueous formaldehyde solution (162 g, 2.00
mol) was added. After aging at rt for 15 h, the reaction mixture was filtered and the filter cake was
washed with water (4 L). The wet cake was reꢀslurried in water (4 L) for 3 h, filtered, washed with
water (500 mL), and dried under vacuum at 50 ºC for 16 h to afford 14 as a white solid (265 g, 90%
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yield): mp 210.7 ºC; H NMR (300 MHz, DMSO−d6) δ 8.07 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz,
1H), 7.59 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 5.64 (s, 2H), 3.19−3.00 (m, 4H), 2.85 (s, 3H),
2.74−2.53 (m, 4H); 13C NMR (75 MHz, DMSO−d6) δ 144.9, 133.8, 127.5, 124.0, 119.0, 111.1, 67.8,
49.0, 45.1, 34.0.
2-Chloro-6-(4-methylsulphonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
(1) (Scheme 8, Aminoalkylation via Benzotriazolyl-piperazine 14).4, 24 A mixture of 4ꢀ(2ꢀ
chlorothieno[3,2ꢀd]pyrimidinꢀ4ꢀylꢀmorpholine (4) (10.0 g, 39.1 mmol) and THF (anhydrous, 100 mL)
was cooled to −5 ºC and iꢀPrMgCl (9.8 mL, 19.6 mmol, 2 M in THF) was added at ≤ 0 ºC. The
resulting slurry was stirred for 30 min and was then cooled to −20 ºC. A solution of nꢀBuLi (15.6 mL,
39.0 mmol, 2.5 M in hexanes) was added at ≤ −10 ºC.
At the same time, 1ꢀ((4ꢀ
(methylsulfonyl)piperazinꢀ1ꢀyl)methyl)ꢀ1Hꢀbenzotriazole (14) (13.9 g, 46.9 mmol) and THF (60 mL)
were charged into a 1ꢀL flask. The solution was cooled to 10 ºC and a solution of ZnCl2 (313 mL, 156
mmol, 0.5 M in THF) was added. The mixture was stirred for 30 min and cooled to −20 ºC. The
resulting slurry was slowly added to the lithium triarylmagnesiate mixture formed in the 2ꢀL flask via
cannula while maintaining the temperature below −10 ºC. Additional amounts of 14 (7.50 g, 25.4
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Organic Process Research & Development
mmol) were added to the reaction mixture in two portions with a 2 h interval, and the reaction was then
stirred below −10 ºC for 12 h. Water was then added to the reaction mixture and the resulting slurry
was aged for 1 h and filtered. The filtrate was concentrated to remove THF and the resulting slurry was
filtered. The filter cakes from both filtrations were combined, stirred in CH2Cl2 (500 mL) at 30 ºC for
30 min, filtered and rinsed with CH2Cl2 (350 mL). The filtrate was concentrated to afford an offꢀwhite
solid (19.4 g) that was then triturated in MeOH (100 mL) at rt for 1 h. The product was collected by
filtration, rinsed with MeOH (10 mL), and dried under vacuum at 50 ºC for 12 h to afford an offꢀwhite
solid 1 (16.6 g, 93% yield).
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4-Chloro-1H-indazole (16).25, 26 To a mixture of 2ꢀmethylꢀ3ꢀchloroaniline (15) (53.1 kg, 375 mol) and
KOAc (44.2 kg, 450 mol) in 1,2ꢀdimethoxyethane (458 L) was slowly added acetic anhydride (115 kg,
1126 mol) in 3 h. The mixture was stirred at rt for 3 h and isoamyl nitrite (87.2 kg, 744 mol) was added.
The reaction mixture was heated to 60 ºC and stirred for 15 h. The mixture was cooled to 0 ºC, water
(159 L) was added, followed by addition of a 28% NaOH aqueous solution (286 kg, 2000 mol). The
phases were separated and the aqueous phase was extracted with 1,2ꢀdimethoxyethane (122 L). The
organic phases were combined, washed with brine (130 L) and concentrated to a volume of 280 L.
Water (398 L) was added and the mixture was concentrated to remove 1,2ꢀdimethoxyethane, followed
by addition of water (319 L). The resulting slurry was filtered and the filter cake was rinsed with a
o
mixture of water (53 L) and methanol (17 L), dried under vacuum at 50 C to yield an orange solid 16
1
(53.6 kg, 92wt%, 86% yield): mp 153.8 ºC; H NMR (300 MHz, DMSO−d6) δ 13.46 (s, 1H), 8.15 (s,
13
1H), 7.56 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H); C NMR (75 MHz,
DMSO−d6) δ 140.9, 131.6, 126.9, 124.6, 121.8, 119.8, 109.3; HRMS (ESI) calcd for C7H4ClN2 [MꢀH]
151.0068, found 151.0070.
4-Chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (17a) and 1-THP isomer 17b.26, 27 4ꢀChloroꢀ
1Hꢀindazole (16) (53.6 kg, 92wt%, 323 mol), pyridinium pꢀtoluenesulfonate (1.60 kg, 6.37 mol), 3,4ꢀ
dihydroꢀ2Hꢀpyran (59.5 kg, 707 mol), toluene (248 L) and heptane (318 L) were added to a reactor. The
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mixture was heated to 40 ºC and stirred for 11 h and then cooled to 25 ºC, followed by addition of 5%
aqueous NaHCO3 solution (164 kg). The phases were separated and the organic phase was washed with
5% aqueous NaHCO3 solution (2 × 164 kg). To the organic phase was added toluene (23 L) and
NaHCO3 (0.50 kg). The mixture was concentrated, flushed with MeOH (186 L), and concentrated to a
volume of ~ 100 L. The product was filtered and the filter cake was rinsed with MeOH (19 L) to afford
a filtrate as a 15:1 mixture of isomers 17a and 17b (121.2 kg, 63wt%, 100% yield). The filtrate was
used in the next step without further purification. Pure samples of 17a and 17b were isolated by
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chromatography (silica, 5ꢀ10% EtOAc in hexanes) for the characterization. Major isomer 17a (oil): H
NMR (300 MHz, CDCl3) δ 8.25 (d, J = 1.0 Hz, 1H), 7.62 (dd, J = 8.4, 1.0 Hz, 1H), 7.20 (dd, J = 8.4, 7.5
Hz, 1H), 7.06 (dd, J = 7.5, 1.0 Hz, 1H), 5.69 (dd, J = 8.4, 3.8 Hz, 1H), 4.21−4.07 (m, 1H) 3.85−3.70 (m,
13
1H), 2.31−2.12 (m, 2H), 2.12−1.95 (m, 1H), 1.88−1.56 (m, 3H); C NMR (75 MHz, CDCl3) δ 149.0,
126.6, 125.6, 121.8, 121.0, 120.8, 116.6, 89.1, 68.0, 31.4, 24.9, 22.0; HRMS (ESI) calcd for
C12H14ClN2O [M+H] 237.0789, found: 237.0786. Minor isomer 17b (solid): mp 65.2 ºC, 1H NMR (300
MHz, CDCl3) δ 8.10 (s, J = 1.0 Hz,1H), 7.49 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.4, 7.5 Hz, 1H), 7.13 (d,
J = 7.5 Hz, 1H), 5.70 (dd, J = 9.2, 2.9 Hz, 1H), 4.07−3.94 (m, 1H), 3.80−3.66 (m, 1H), 2.66−2.45 (m,
13
1H), 2.25−2.00 (m, 2H), 1.86−1.51 (m, 3H); C NMR (75 MHz, CDCl3) δ 140.5, 132.4, 127.1, 126.5,
124.0, 120.8, 108.9, 85.7, 67.4, 29.4, 25.1, 22.4; HRMS (ESI) calcd for C12H14ClN2O [M+H] 237.0789,
found: 237.0784.
2-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole
(2a)
(Scheme 9, Ni catalyst).24, 26 To a reactor was added bis(pinacolato)diboron (100 kg, 394 mol),
methanol (271 L), triethylamine (79.7 kg, 788 mol), and the product of the previous step, a 15:1 mixture
of 17a / 17b (113.8 kg, 63wt%, 303 mol). The mixture was cooled to 0 ºC, followed by addition of
Ni(NO3)2•6H2O (3.50 kg, 12.0 mol) and PPh3 (6.40 kg, 24.4 mol). The resulting slurry was warmed to
25 ºC and was aged for 3.5 h. tertꢀButyl methyl ether (1064 L), water (72 L) and 5% aqueous HCl
solution (307 L) were added to adjust the pH to 7.5. The aqueous phase was separated and then
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Organic Process Research & Development
extracted with tertꢀbutyl methyl ether (871 L), and the combined organic phases were concentrated
under reduced pressure, flushed with toluene (331 L) and concentrated under reduced pressure. The
residue was dissolved in toluene (248 L) and the solution was washed with an aqueous MeOH solution
(MeOH/H2O, 1:3 v/v, 3 × 283 L). To the resulting organic phase was added activated carbon (3.6 kg)
and the slurry was aged for 1 h, and then filtered over a pad of Celite®. The filtrate was concentrated
under reduced pressure and toluene (2 L) and heptane (163 L) were added. The mixture was heated to
45 ºC and seeded with 2a (140 g). The mixture was cooled to 0 ºC, filtered and rinsed successively with
a cold mixture of heptane (29 L) and toluene (10 L), and heptane (57 L). The cake was dried under
reduced pressure to afford an offꢀwhite solid 2a (56.7 kg, 93wt%, 53% yield): 1H NMR (300 MHz,
CDCl3) δ 8.47 (d, J = 0.8 Hz, 1H), 7.84 (dt, J = 8.8, 0.9 Hz, 1H), 7.63 (dd, J = 6.5, 0.8 Hz, 1H), 7.30
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(dd, J = 8.8, 6.6 Hz, 1H), 5.69 (dd, J = 9.5, 2.9 Hz, 1H), 4.22−4.06 (m, 1H), 3.85−3.68 (m, 1H),
2.42−2.13 (m, 2H), 2.12−1.94 (m, 1H), 1.92−1.59 (m, 3H), 1.42−1.29 (s, 12H); 13C NMR (75 MHz,
CDCl3) δ 147.9, 131.0, 125.8, 124.7, 123.4, 121.2, 89.1, 83.7, 68.1, 31.3, 24.99, 24.96, 22.4; HRMS
+
(ESI) m/z calcd for C18H26BN2O3 (M+H)+ 329.2031, found 329.2035.
4-Bromo-1H-indazole (20).4 To a mixture of 3ꢀbromoꢀ2ꢀmethylaniline (19) (14.0 kg, 75.2 mol) and
KOAc (8.90 kg, 90.7 mol) in chloroform (168 L) was slowly added acetic anhydride (9.20 kg, 90.1
mol). The reaction mixture was heated to 60 ºC and was stirred for 1 h; HPLC analysis confirmed
complete consumption of 19. Isoamyl nitrite (44.5 kg, 377 mol) was added and the reaction mixture
was stirred at 60 ºC for 22 h. Chloroform was removed under reduced pressure, water (70 L), THF (140
L) and LiOH•H2O (12.6 kg, 300 mol) were added, and the reaction mixture was stirred at ambient
temperature for 1 h. THF was then removed under reduced pressure, water (20 L) was added, and the
aqueous layer was extracted with EtOAc (3 × 84.0 L). The organic phases were combined, washed
sequentially with water (70 L) and brine (70 L). The organic phase was dried over anhydrous Na2SO4
(5.25 kg), filtered and concentrated under reduced pressure. To the residue was added water (70 L) and
hexanes (28 L), and the slurry was stirred at ambient temperature for 1 h, filtered and rinsed with
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hexanes (8.3 L). The cake was dried under reduced pressure to yield 20 (12.0 kg, 81% yield): mp 163.7
ºC; 1H NMR (300 MHz, DMSOꢀd6) δ 13.47 (br s, 1H), 8.06 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.35 (d, J
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= 7.4 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H); C NMR (75 MHz DMSO−d6) δ 140.5, 133.0, 127.3, 123.6,
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+
123.0, 113.0, 109.8. HRMS (APCI) m/z calcd for C7H6BrN2 (M+H)+ 196.9709, found 196.9707.
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4-Bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (21a) and 1-THP isomer 21b.27, 28 A mixture of
4ꢀbromoꢀ1Hꢀindazole (20) (11.2 kg, 56.8 mol), pyridinium pꢀtoluenesulfonate (285 g, 1.13 mol), 3,4ꢀ
dihydroꢀ2Hꢀpyran (15.3 kg, 182 mol) in toluene (45.9 L) and heptane (45.9 L) was heated to 40 ºC and
stirred for 9 h. The reaction mixture was cooled to 25 ºC and toluene (56 L) was added. The solution
was sequentially washed with 5% of aqueous NaHCO3 solution (3 × 56 L) and water (56 L). The
organic phase was dried over anhydrous MgSO4 (5.6 kg), filtered and concentrated to yield a brown
solid as a 92:8 mixture of 21a and 21b (15.2 kg, 95% yield). The product was used in the next step
without further purification. Pure samples of 21a and 21b were isolated by chromatography (silica, 5ꢀ
1
10% EtOAc in hexanes) for the characterization. 21a: mp 52.6 ºC; H NMR (300 MHz, CDCl3) δ 8.19
(s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 7.1 Hz, 1H), 7.13 (dd, J = 8.6, 7.2 Hz, 1H), 5.66 (dd, J =
8.4, 3.8 Hz, 1H), 4.18−4.08 (m, 1H), 3.83−3.71 (m, 1H), 2.30−2.10 (m, 2H), 2.10−1.93 (m, 1H),
1.85−1.56 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 148.4, 127.0, 124.4, 123.6, 122.2, 117.1, 113.4, 89.1,
68.0, 31.4, 24.9, 22.0; HRMS (APCI) m/z calcd for C12H14BrN2O+ (M+H)+ 281.0284, found 281.0280.
21b: mp 73.9 ºC; 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 7.4
Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 5.71 (dd, J = 9.1, 2.8 Hz, 1H), 4.08−3.91 (m, 1H), 3.81−3.65 (m, 1H),
2.64−2.42 (m, 1H), 2.24−2.00 (m, 2H), 1.90−1.57 (m, 3H); 13C NMR (300 MHz, CDCl3) δ 140.1,
133.9, 127.4, 125.8, 124.1, 114.6, 109.4, 85.7, 67.4, 29.4, 25.1, 22.4; HRMS (APCI) m/z calcd for
C12H14BrN2O+ (M+H)+ 281.0284, found 281.0285.
2-(Tetrahydro-2H-pyran-2-yl)-2H-indazol-4-ylboronic acid (18a).
A mixture of 4ꢀbromoꢀ2ꢀ
(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)ꢀ2Hꢀindazole (21a) (5.25 kg, a 92:8 mixture of 21a:21b, 18.7 mol) and
triisopropylborate (14.1 kg, 75.0 mol) in THF (105 L) was cooled to −70 °C and 2.5 M solution of nꢀ
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BuLi in THF (22.4 L, 56.0 mol) was slowly added at ≤ −60 °C. The reaction mixture was stirred at −60
oC to −50 °C for 1 h and cooled to −70 °C, and triisopropylborate (7.1 kg, 37.8 mol) and 2.5 M solution
of nꢀBuLi in THF (15 L, 37.5 mol) were slowly added sequentially at ≤ −60 °C. The reaction mixture
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was stirred at −50 °C for 1 h and was slowly quenched with water (53.0 L) at ≤ −50 °C. The mixture
was allowed to slowly warm to ambient temperature; water (53.0 L) was added and the mixture was
aged for 4 h. After being concentrated under reduced pressure to remove THF, the residue was
extracted with tertꢀbutyl methyl ether (1 × 53.0 L), and the organic phase was backꢀextracted with 0.50
M aqueous NaOH solution (53.0 L). The aqueous phases were combined and ammonium acetate (5.7
kg, 73.9 mol) was added, and the mixture was stirred for 30 min. After the mixture was cooled to 0−10
°C, 10% sodium dihydrogen phosphate buffer solution (1155 L) was added to adjust the pH to 5.8. The
slurry was stirred for 4 h, cooled to 0−10 °C, filtered and rinsed with cold water (5.3 L). The cake was
dried under reduced pressure at 45 °C to afford light brown solid 18a (2.92 kg, 60% yield): mp 121.2
ºC; 1H NMR (300 MHz, DMSO−d6) δ 8.52 (s, 1H), 8.17 (s, 2H), 7.67 (d, J = 8.4 Hz, 1H), δ 7.57 (d, J =
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6.6 Hz, 1H), 7.25 (dd, J = 8.4, 6.6 Hz, 1H), 5.76 (dd, J = 9.3, 2.7 Hz, 1H), 4.06−3.94 (m, 1H), 3.81−3.66
(m, 1H), 2.27−1.45 (m, 6H); 13C NMR (75 MHz, DMSOꢀd6) δ 147.1, 129.1, 125.3, 124.4, 124.0, 119.5,
87.9, 67.0, 30.7, 24.6, 21.7; HRMS calcd for C12H16BN2O3 [M+H] 247.1248, found 247.1246.
4-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-
yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (22) (Scheme 11, Pd catalyst). To a solution of 2ꢀchloroꢀ
6ꢀ(4ꢀmethylsulphonylꢀpiperazinꢀ1ꢀyl methyl)ꢀ4ꢀmorpholinꢀ4ꢀylꢀthieno[3,2ꢀd]pyrimidine (1) (96.5 g, 223
mmol) in 1,4ꢀdioxane (1.75 L) was added water (772 mL), sodium carbonate (47.4 g, 447 mmol) and 2ꢀ
(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)ꢀ2Hꢀindazolꢀ4ꢀylboronic acid (18a) (68.6 g, 279 mmol). The mixture was
degassed for 30 min with subsurface nitrogen sparge. Bis(triphenylphosphine)palladium (II) chloride
(6.28 g, 9.94 mmol) was added and the resulting slurry was degassed for 30 min with subsurface
nitrogen sparge. The mixture was heated to 88 oC and stirred for 16 h. The reaction mixture was cooled
to 50 ºC, concentrated under reduced pressure to one half of the original volume, cooled to 15 ºC and
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CH3CN (900 mL) was added. After aging for 2 h, the resulting slurry was cooled to −5 ºC, filtered and
rinsed sequentially with CH3CN (40 mL), water (90 mL), and CH3CN (40 mL). The cake was dissolved
in CH2Cl2 (1.93 L) and Florisil® (60−100 mesh, 193 g) was then added. After aging at ambient
temperature for 5 h, ThioꢀSilica® (68.0 g) was added and the slurry was aged for at least 10 h, then was
filtered and rinsed successively with CH2Cl2 (2 L), and a mixture of CH2Cl2 and EtOAc (4 L, 1:1 (v/v)).
The filtrate and the rinses were combined and concentrated to give an offꢀwhite solid 22 (80.0 g, 60%
yield): mp 190.9 ºC; 1H NMR (300 MHz, DMSO−d6) δ 9.17 (s, 1H), 8.26 (d, J = 6.9 Hz, 1H), 7.78 (d, J
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= 8.4 Hz, 1H), 7.54 (s, 1H), 7.41 (t, J = 7.7 Hz, 1H), 5.55 (d, J = 8.6 Hz, 1H), 4.14−3.62 (m, 12H),
3.23−3.01 (m, 4H), 2.90 (s, 3H), 2.72−2.55 (m, 4H), 2.34−1.88 (m, 3H,), 1.88−1.43 (m, 3H); 13C NMR
(75 MHz, DMSO−d6) δ 162.1, 159.2, 157.4, 149.9, 148.4, 131.2, 125.7, 124.5, 123.6, 122.6, 120.0,
119.1, 112.3, 88.0, 67.0, 66.0, 56.1, 51.8, 46.0, 45.3, 33.8, 30.5, 24.6, 21.7; HRMS (ESI) m/z calcd for
C28H36N7O4S2 [M+H] 598.2265, found 598.2264.
4-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-
yl)thieno[3,2-d]pyrimidin-4-yl)morpholine (22) (Scheme 11, Ni catalyst). To a mixture of 2ꢀchloroꢀ
6ꢀ(4ꢀmethylsulphonylꢀpiperazinꢀ1ꢀylmethyl)ꢀ4ꢀmorpholinꢀ4ꢀylꢀthieno[3,2ꢀd]pyrimidine (1) (47.6 kg,
110 mol) in acetonitrile (477 L) was added water (0.6 kg), potassium phosphate (70.1 kg, 330 mol) and
2ꢀ(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)ꢀ2Hꢀindazolꢀ4ꢀylboronic acid (18a) (40.7 kg, 165 mol). The mixture was
degassed for 30 min with subsurface nitrogen sparge. Nickel(II) nitrate hexahydrate (9.05 g, 31.1
mmol) and triphenylphosphine (16.4 g, 62.5 mmol) were added, and the resulting slurry was degassed
for 60 min with subsurface nitrogen sparge. The mixture was heated to 60 oC in 1.5 h and stirred for 25
h. A mixture of water (390 L) and 28% aqueous ammonium hydroxide solution (85 kg) was slowly
added in 2 h and the slurry was aged for 2 h. The resulting solution was cooled to 10−20 ºC in 4 h and
the phases were separated. To the organic phase was added CH3CN (190 L), and the mixture was
heated to 40−50 ºC in 1.5 h and then aged for 1 h. The mixture was cooled to 20−30 ºC in 4 h and aged
for 1 h. The slurry was filtered and rinsed successively with CH3CN (237 L), water (238 L), and
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Organic Process Research & Development
acetonitrile (237 L). The cake was dried under vacuum at 50 ºC for 16 h to afford an offꢀwhite solid 22
(54.4 kg, 95.9wt% by HPLC, 79% yield).
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4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-
yl)morpholine (GDC-0941). A mixture of 4ꢀ(2ꢀ(1ꢀ(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)ꢀ2Hꢀindazolꢀ4ꢀyl)ꢀ6ꢀ((4ꢀ
(methylsulfonyl)piperazinꢀ1ꢀyl)methyl)thieno[3,2ꢀd]pyrimidinꢀ4ꢀyl)morpholine (22) (53.7 kg, 95.9wt%,
86.2 mol) in MeOH (1920 L) and water (101 L) was cooled to 5 oC. Methanesulfonic acid (41.1 kg, 428
mol) was slowly added in 2 h (a mild exotherm was observed) and the resulting slurry was heated to 65
ºC in 5 h. After aging for 4 h, the reaction mixture was cooled to 0−5 ºC in 6.5 h and stirred for 4 h.
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The slurry was filtered and rinsed sequentially with cold MeOH (154 L, 0−5 ºC), a mixture of EtOAc
(259 L) and tertꢀbutyl methyl ether (513 L), and tertꢀbutyl methyl ether (51 L). The filter cake was
dried under vacuum for 12 h and was then charged into a hot mixture of methanol (112 L) and water (67
o
L) at 55 C. After aging for 1 h, the resulting solution was filtered through a 0.5 ꢂm inꢀline filter and
o
rinsed with a hot mixture of water (6 L) and MeOH (23 L) at 55 C. To the hot filtrate was slowly
added MeOH (233 L) in 1 h and 10 min, followed by addition of crystal seeds of GDC-0941 (50 g).
More MeOH (693 L) was slowly added in 6 h and methanesulfonic acid (15.3 kg, 159 mol) was then
o
added in 35 min. After aging for 3 h, the mixture was cooled to 5 C in 7 h and stirred for 3 h and 40
min. The slurry was filtered and rinsed sequentially with cold MeOH (168 L, 0−5 ºC), a mixture of
EtOAc (282 L) and with tertꢀbutyl methyl ether (559 L), and tertꢀbutyl methyl ether (56 L). The filter
cake was dried under vacuum at 55 ºC for 12 h to afford GDC-0941 bisꢀmethanesulfonate as an offꢀ
white solid (54.9 kg, 99.4wt%, 90%yield): mp 288.6 ºC; 1H NMR (300 MHz, D2O) δ 8.18 (s, 1H), 7.58
(d, J = 7.1 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 4.74 (s, 2H),
3.95−3.85 (m, 4H), 3.85−3.75 (m, 4H), 3.62−3.50 (m, 4H), 3.49−3.36 (m, 4H), 3.01 (s, 3H), 2.71 (s,
6H); 13C NMR (125 MHz, D2O) δ 155.7, 154.6, 148.9, 140.1, 140.0, 133.3, 126.3, 123.8, 123.7, 122.4,
119.0, 114.9, 113.6, 65.5, 53.0, 51.3, 46.6, 42.8, 38.5, 35.5; HRMS (ESI) calcd for C23H28N7O3S2
[M+H] 514.1690, found 514.1684.
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Supporting Information. Copies of 1H and 13C spectra for all the compounds listed in the experimental
section. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. Jane Li, Dr. Jackson Pellett, Mr. Hong Lin and Ms. Stefanie Gee for
analytical support, Dr. Alan Deese for help with NMR analysis, and Dr. Christine Gu for HRMS
analysis. We also thank Professor Scott E. Denmark (University of Illinois at UrbanaꢀChampaign) for
his valuable suggestions during the preparation of this manuscript.
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References
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550−562.
(2) Luo, J.; Manning, B. D.; Cantley L. C. Cancer Cell, 2003, 4, 257−262.
(3) (a) Ihle, N. T.; Powis, G. Mol. Cancer Ther. 2009, 8, 1−9. (b) Maira, S. M.; Stauffer, F.; Brueggen,
J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chene, P.; De Pover, A.; Schoemaker, K.; Fabbro,
D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; GarciaꢀEcheverria, C. Mol. Cancer
Ther. 2008, 7, 1851−1863. (c) Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Nature Rev. Drug
Discovery 2009, 8, 627−644.
(4) Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. J.; Box, G.; Chuckowree, I. S.;
Clarke, P. A.; Depledge, P.; Eccles, S. A.; Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kugendradas, A.;
Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.; Patel, S.; PerglꢀWilson, G. H.; Raynaud, F. I.; Robson,
A.; Saghir, N.; Salphati, L.; Sohal, S.; Ultsch, M. H.; Valenti, M.; Wallweber, H. J.; Wan, N. C.;
Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. J. Med. Chem. 2008,
51, 5522−5532.
(5) Bandurco, V. T.; Schwender, C. F.; Bell, S. C.; Combs, D. W.; Kanojia, R. M.; Levine, S. D.;
Mulvey, D. M.; Appollina, M. A.; Reed, M. S.; Malloy, E. A.; Falotico, R.; Moore, J. B. Tobia, A. J. J.
Med. Chem. 1987, 30, 1421−1426.
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(6) (a) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036−1045; (b) Large, J. M.; Clarke, M.;
Williamson, D. M.; McDonald, E.; Collins, I. Synlett, 2006, 861−864.
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9
(7) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044−1070; (b) Millot,
N.; Piazza, C.; Avolio, S.; Knochel, P. Synthesis 2000, 941−948.
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o
(8) The stability of the organolithium species was investigated at different temperatures (−35 C, −50
oC, −60 C and −70 C) by taking samples over 24 h, quenching with methanol/water, and HPLC
o
o
o
analysis. The experimental data revealed that the organolithium species decomposed even at −70 C
with assay yield eroding from 98% to 92% over 7 h. The decomposition was worse at higher
o
o
temperatures and with extended aging. At our operating temperatures (−50 C and −60 C), only 90%
of compound 4 was recovered at 6 h. This instability led to irreproducible reactions with yields ranging
from 67% to 91% on large scale (> 4 kg).
(9) (a) Gallou, F.; Haenggi, R.; Hirt, H.; Marterer, W.; Schaefer, F.; SeegerꢀWeibel, M. Tetrahedron
Lett. 2008, 49, 5024−5027; (b) Mase, T.; Houpis, I.; Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.;
Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.;
Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.;
Reider, P. J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775−6786. (c) Dolman, S. J.; Gosselin, F.;
O'Shea, P. D.; Davies, I. W. Tetrahedron 2006, 62, 5092−5098.
(10) (a) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Bischoff, L.; Trécourt, F.; Quéguiner, G.;
Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R. J. Org. Chem. 2005, 70, 5190−5196. (b) Mongin, F.;
Bucher, A.; Baureau, J.P.; Bayh, O.; Awad, H.; Trécourt, F. Tetrahedron Lett. 2005, 46, 7989−7992. (c)
Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Trécourt, F.; Quéguiner, G.; Marsais, F.; Blanco, F.;
Abarca, B.; Ballesteros, R. Tetrahedron 2005, 61, 4779−4784.
(11) The stability of the lithium triarylmagnesiate was investigated in the same way as described for the
organolithium species in footnote 8. Compound 4 was recovered in 97% after the lithium
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triarylmagnesiate solution was aged at −5 C for 6 h. The reaction mixture after addition of DMF was
also stable as no change on the HPLC purity and the assay yield of the aldehyde product 8 was observed
after the reaction mixture was aged at −5 oC for 20 h.
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(12) Sulfonylation of NꢀBocꢀpiperazine with methanesulfonyl chloride and deprotection with HCl in
EtOH gave piperazine•HCl 3 in 85% yield.
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(13) (a) Heaney, H.; Papageorgiou, G.; Wilkins, R. Tetrahedron, 1997, 53, 2941−2958. (b) Bryson, T.
A.; Bonitz, G. H.; Reichel, C. J.; Dardis, R. E. J. Org. Chem. 1980, 45, 524−525.
1
(14) The assay purity of the isolated iminium iodide salt was only 90% based on quantitative H NMR
analysis. One of the major impurities in the iminium salt was tentatively assigned as the residual 3
1
based on the H NMR data. In addition, other iminium salts (chloride, trifluoromethanesulfonate and
trifluoroacetate) were also investigated, but the iodide salt performed best in the reaction.
(15) (a) Katritzky, A. R.; Manju, K.; Singh, S. K.; Meher, N. K. Tetrahedron 2005, 61, 2555−2581. (b)
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