Synthesis Development of the Selective Estrogen Receptor Degrader (SERD) LSZ102 from a Suzuki Coupling to a C-H Activation Strategy

Article abstract of DOI:10.1021/acs.oprd.0c00076

The development of the synthetic process to the selective estrogen receptor degrader (SERD) drug candidate LSZ102 from the medicinal chemistry synthesis to the streamlined large-scale manufacturing route is described. The synthesis of LSZ102 could be sign

Full text of DOI:10.1021/acs.oprd.0c00076

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Full Paper
Synthesis Development of the Selective Estrogen Receptor Degrader
SERD) LSZ102 from a Suzuki coupling to a C-H activation strategy
(
Markus Baenziger, Marcel Baierl, Krishnaswamy Devanathan, Sumesh Eswaran, Peng Fu, Bjoern
Gschwend, Michael Haller, Gopu Kasinathan, Nikola Kovacic, Audrey Langlois, Yongfeng Li,
Friedrich Schuerch, Xiaodong Shen, Yinbo Wan, Regina Wickendick, Siwei Xie, and Kai Zhang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00076 • Publication Date (Web): 01 Jul 2020
Downloaded from pubs.acs.org on July 1, 2020
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Synthesis Development of the Selective Estrogen
Receptor Degrader (SERD) LSZ102 from a Suzuki
coupling to a C-H activation strategy
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#
*
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‡
‡
Markus Baenziger, Marcel Baierl, Krishnaswamy Devanathan, Sumesh Eswaran,
§
#
#
‡
#
Peng Fu, Bjoern Gschwend, Michael Haller, Gopu Kasinathan, Nikola Kovacic,
#
†
#
§
§
Audrey Langlois, Yongfeng Li, Friedrich Schuerch, Xiaodong Shen, Yinbo Wan,
#
†
†
Regina Wickendick, Siwei Xie, Kai Zhang,
#
Novartis Pharma AG, Chemical & Analytical Development, 4056 Basel, Switzerland
§
Suzhou Novartis Technical Development Co. Ltd., Chemical & Analytical Development,
8-1 Tonglian Road, Bixi Subdistrict, Changshu City, 215537 Jiangsu Province, China
1
†
Lianhe Chemical Technology Co. Ltd. 8 Yongjiao Road, Jiangkou Economic Zone,
Huangyan, Taizhou City, 318020 Zhejiang Province, China
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‡
Anthem Biosciences Private Ltd., 49 Canara Bank Road, Bommasandra, 560 099
Karnataka, India
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Table of contents graphic
Key step
Pd-cat. C-H activation
MeO2C
O
OH
HO
O
Br
F
F
F
COOH
SOCl2
OH
O
F
O
Br
Pd(OAc)2
PPh2Cy
NaO-t-Bu
THF
HO
S
Key step
Higa Cyclization
HO
S
F
F
ABSTRACT
The development of the synthetic process to the selective estrogen receptor degrader
SERD) drug candidate LSZ102 from the medicinal chemistry synthesis to the
(
streamlined large-scale manufacturing route is described. The synthesis of LSZ102 could
be significantly improved in regards of overall yield, removal of all chromatographic
purifications and reduction of number of steps by revisiting the original disconnection
strategy. Key features of the final process include construction of the benzothiophene
core via Higa cyclization, late-stage phenolation using a Pd-catalyzed hydroxylation of an
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aryl bromide and end-game assembly through a Pd-catalyzed C-H activation step. The
overall yield could be significantly improved and the costs reduced.
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KEYWORDS
Pd catalyzed reactions; Pd-catalyzed C-H activation; Higa cyclization; S Ar reaction; Pd
N
removal; LSZ102
INTRODUCTION
Despite recent advances in early detection and treatment, breast cancer remains
1
worldwide the leading type of cancer in women, accounting for 25% of all cases. Breast
cancer can be further classified in different sub-classes. Nearly 74% of breast cancers
belong to a sub-class that demonstrate high expression of estrogen receptor alpha (ERα),
a nuclear hormone receptor directly implicated in the progression of HR+ cancers
(
hormone receptor-positive).2 Cancer therapies with selective estrogen receptor
3
modulators (SERM), such as tamoxifen , and aromatase inhibitors (AIs), such as
4
letrozole , are often suffering from therapeutic resistance. On the other hand selective
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estrogen receptor degraders (SERDs) possess the ability to induce receptor degradation,
which may overcome mechanisms of resistance to AIs and SERMs. The only such
degrader currently approved for the treatment of ER positive breast cancer is the SERD
fulvestrant.5,6 Fulvestrant is a steroid-based drug, which exhibits poor oral bioavailability
and is therefore administered intramuscularly. The efforts of our research colleagues to
find a SERD with desired oral bioavailability finally culminated in the discovery of LSZ102
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(18) a clinical development candidate currently in Phase I/Ib trials for the treatment of
7
ERα positive breast cancer. LSZ102 is a selective estrogen receptor (ER) degrader
(SERD) with potential antineoplastic activity. Upon administration, LSZ102 binds to the
ER and induces the degradation of the receptor. This prevents ER activation and ER-
mediated signaling, and inhibits the growth and survival of ER-expressing cancer cells.8
Herein, we want to disclose our efforts toward the identification and the development of
an optimized route to the clinical candidate LSZ102 (18).
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RESULTS AND DISCUSSION
Medicinal Chemistry Route
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The medicinal chemistry route to LSZ102 is outlined in Scheme 1. The synthetic strategy
featured a Suzuki cross-coupling as end game between two key building blocks: bromo-
benzothiophenol derivative 14 and fluorinated arylboronic ester 17. Bromo-
benzothiophenol derivative 14 was assembled in an 11-step linear sequence, starting
from 3-methoxybenzenethiol (1), which upon alkylation with 2-bromo-1,1-diethoxyethane
.
9
and cyclization in the presence of BF OEt gave 6-methoxybenzothiophene (3) in 20%
3
2
yield after purification by distillation. Functionalization of the benzothiophene core was
subsequently accomplished through a series of oxidation-reduction steps. Thus, sulfone
4, readily prepared by oxidation with meta-chloroperbenzoic acid (m-CPBA), was treated
with bromine to yield dibromide intermediate 5.10 Oxidation at sulfur enabled the
subsequent facile aromatic nucleophilic substitution reaction with 4-bromophenol (6) in
the presence of cesium carbonate. The bromo-substituent at the C2-position and the
sulfone functionality were then removed, respectively via reduction with sodium
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borohydride (NaBH ) and DIBAL, to afford benzothiophene 9. A Heck reaction with
4
excess methyl acrylate (10) as the alkene partner and Pd(PPh ) Cl as catalyst provided
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cinnamic ester derivative 11. Intermediate 11 was brominated with N-bromosuccinimide
(NBS), thereby re-introducing a Br-substituent at the C2 position to set the stage for the
ultimate Suzuki cross-coupling. Finally, two-step deprotection of intermediate 12 was
accomplished by hydrolysis of the cinnamic ester functionality using lithium hydroxide
followed by BBr -mediated cleavage of the methyl ether group. The overall yield of this
3
11-step linear sequence to the intermediate 14 was 2%. The side chain synthesis of the
fluorinated arylboronic ester 17 was a 2-step process from 2-bromo-5-fluoro
acetophenone (15). Fluorination of 15 to the corresponding gem-difluoro compound 16
could be accomplished using SF / HF chemistry. Subsequent Miyaura borylation using
4
bis(pinacolato)diboron under standard reaction conditions [Pd(PPh ) Cl , KOAc] gave
3
2
2
boronic ester 17 in 55% isolated yield after chromatographic purification. Both coupling
partners were eventually assembled in a Suzuki cross-coupling using standard reaction
conditions [Pd(PPh ) , K CO ]. Isolation of amorphous API LSZ012 (18) was achieved
3
4
2
3
through extensive processing (e.g. extraction followed by crystallization as tert-butyl
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amine salt, acid liberation, purification by reversed-phase chromatography, second
crystallization as tert-butyl amine salt and final acid liberation). The overall yield of
LSZ102 from 3-methoxybenzenethiol (1) was 1%.
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While this first-generation route enabled the preparation of initial batches of LSZ2012
(18), it suffered from significant limitations, which needed to be adressed for further scale-
up. First, the construction of the densely functionalized benzothiophene scaffold was
inefficient and made use of undesirable reagents and solvents (critical points of the
medicinal chemistry synthesis are highlighted in bold in scheme 1). Second, several
column chromatographic purifications, especially of the last-stage intermediates, had to
be performed. Finally, it was desirable to identify a crystalline form of LSZ102 to ease its
isolation.
Scheme 1: Medicinal Chemistry Synthesis of LSZ102
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Br
Br
a
b
c
d
O
O
O
O
O
O
9
0%
O
20%
S
88%
S
82%
S
SH
O
O
O
O
S
1
2
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4
5
O
Br
Br
O
Br
e
f
g
h
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0
O
O
9
0%
80%
75%
O
78%
O
O
O
O
Br
S
S
S
O
O
O
O
O
S
7
8
9
11
O
O
O
O
HO
HO
i
j
k
O
HO
8
8%
86%
50%
O
O
O
O
O
HO
Br
Br
Br
S
S
S
n
12
13
14
O
F
5
0%
F
B
HO
F
F
S
F
l
m
F
8
7%
55%
F
F
18 = LSZ102
O
O
Br
O
Br
F
F
15
16
17
Reagents and conditions: (a) 2-bromo-1,1-diethoxyethane; K CO ; acetone; 40 – 45 °C;
2
3
.
(
b) BF OEt ; CH Cl ; 25 – 30 °C; high vacuum distillation; (c) m-CPBA; CH Cl ; 0 – 30
3
2
2
2
2
2
°
C; (d) Br ; NEt ; CH Cl ; 0 – 5° C; (e) 4-bromophenol (6); Cs CO ; THF; 40 – 45 °C; (f)
2
3
2
2
2
3
NaBH ; DMSO; MeOH; 25 – 30 °C; (g) DIBAL; toluene; THF; 25 – 30 °C; (h) methyl
4
acrylate (10); NEt ; Pd(PPh ) Cl ; DMF; 95 – 100 °C; (i) NBS; THF; 25 – 30 °C; (j) LiOH;
3
3 2
2
THF; H O; 40 – 45 °C; (k) BBr ; heptane; CH Cl ; -70 °C – 0 °C; RP-chromatography; (l)
2
3
2
2
SF ; HF; (m) B (Pin) ; Pd(PPh ) Cl ; KOAc; 1,4-dioxane; 100 °C; chromatography; (n)
4
2
2
3 2
2
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Pd(PPh ) ; K CO ; 1,2-dimethoxyethane; H O; 77 – 83 °C; t-butylamine; RP-
3 4
2
3
2
chromatography.
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Process Development for the synthesis of coupling partners 14 and 17
Higa-cyclization to construct the benzothiophene core. Central to our development work
was to get a more efficient assembly of the densely functionalized benzothiophene
scaffold, while avoiding usage of dichloromethane and m-CPBA. As a potential shortcut
to the sequence, the Higa cyclization of 4-methoxycinnamic acid (19)11 caught our
attention. We hence set out to and investigated the alternative route to intermediate 8 as
shown in Scheme 2, which would be significantly simpler than the original synthesis.
Scheme 2: Alternative route to intermediate 8 and second-generation synthesis of
intermediate 14
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Br
Cl
O
e
O
O
14
S
63%
S
(scheme 1)
O
O
O
O
2
3
8
d
98%
0
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Cl
Cl
CO2H
a
b
c
Cl
O
O
O
O
O
O
S
47%
(2 steps)
S
92%
S
Cl
O
O
O
19
20
21
22
f
69%
Cl
O
g
O
O
S
S
86%
O
O
28
29
h
O
O
O
HO
O
O
j
i
14
(
scheme 1)
73%
3 steps)
O
O
O
(
O
O
O
Br
Br
S
S
S
1
3
12
11
Reagents and conditions: (a) SOCl pyridine, chlorobenzene; 60 – 125 °C; (b) MeOH, 50
2;
.
–
60 °C; (c) NMP; NaOH, 85 – 138 °C; (d) H O ; Na WO 2H O; EtOH; 65 °C; (e) 4-
2
2
2
4
2
bromophenol; K CO ; DMF; 70 °C; (f) H O ; TFA; CH Cl ; 20 °C; (g) methyl-4-
2
3
2
2
2
2
hydroxycinnamate; K CO ; DMF; 95 °C, (h) TMSCl; PPh ; THF; 70 °C; (i) NBS; 2-Me-
2
3
3
THF; 10 – 25 °C; (j) NaOH; MeOH; H O; 20 – 30 °C.
2
The key Higa cyclization step was the reaction of 4-methoxycinnamic acid (19) with SOCl2
to the non-isolated acid chloride 20, which was directly converted to the methyl ester 21
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in 47% yield. The carboxy methyl ester was initially hydrolyzed in DMSO / NaOH and then
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thermally decarboxylated at 130 – 138 °C for 20 h to give the benzothiophene derivative
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8
9
0
22 in 75% yield. Due to known process safety issues of DMSO under basic conditions at
elevated temperature, we soon changed the solvent mixture to NMP / NaOH.13 With
additional optimizations, the yield of this decarboxylation step could be increased to 92%.
.
The thiophene was oxidized with H O and catalytic Na WO 2 H O (2.7 mol%) to the
2
2
2
4
2
corresponding sulfone 23 in 98% yield. 14 The known intermediate 8 of the original
synthesis was then generated by reaction of 23 with 4-bromophenol under basic
conditions in 63% isolated yield. This S Ar reaction to form 8 using K CO as the base
N
2
3
required elevated temperature (65 – 75 °C) and is, to our knowledge, not described in the
literature for similar 3-chlorobenzothiophene derivative. Only the reaction of the
analogous 2,3-dibromobenzothiophene with 4-bromophenol at room temperature in the
7,10
presence of Cs CO has been described.
By implementing this alternative approach,
2
3
the overall yield to the intermediate 8 could be increased from 9.4% to 22% and the
number of isolated intermediates could be reduced from 6 to 4.
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6
While performing the subsequent transformations to LSZ102 (not shown in Scheme 2;
refer to Scheme 1), a new impurity, 7-chloro derivative 24, was observed on intermediate
0
1
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4
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7
8
9
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8
9
0
14 in about 0.5%. This impurity was identified as a carry-over originating ultimately from
compound 25 generated during the Higa cyclization . Analysis of the intermediates 8 and
13 with optimized HPLC methods unveiled the presence of related impurities 26 and 27
respectively in the corresponding intermediates (Figure 1). Intermediate 8 contained
about 5.2% (LC/MS) of the impurity 26, whereas a purity of 99.5% was determined with
the old method. A depletion factor of about 10 in the reaction sequence from intermediate
8
to 14 of this chloro-impurity was unfortunately not sufficient to reduce the level of this
new impurity below 0.2% in the API 18. As consequence, intermediate 14 had to be
recrystallized twice (instead of once in the original synthesis) in order to fulfill the purity
requirements for the API 18.
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O
O
HO
HO
Br
Cl
O
O
O
O
O
O
HO
O
S
S
Br
S
Cl
Cl
Br
O
O
O
S
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
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3
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3
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3
4
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4
4
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4
4
5
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5
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0
1
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3
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9
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8
9
0
1
2
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5
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8
9
0
1
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cl
Cl
24
25
26
27
Figure 1: Chloro-impurities on various stages of the Higa-cyclization route
Although the alternative sequence to intermediate 8 (Scheme 2, upper part) provided a
significant overall yield improvement, some challenges remained to be addressed. First,
the reduction of the sulfone moiety in intermediate 8 required the use of DIBAL (see
Scheme 1), which we wanted to replace for large-scale production. To this end, we sought
options to oxidize 3-chloro-6-methoxybenzothiophene (22) only to the corresponding
sulfoxide 28.15 The latter could then directly react in a S Ar reaction with methyl-4-
N
hydroxycinnamate to the intermediate 29, thereby eliminating the Heck reaction. The
reduction of the sulfoxide back to the benzothiophene 11 could then be performed under
milder conditions, being compatible with an ester functionality. The replacement of 4-
bromophenol by methyl 4-hydroxycinnamate would also address another issue.
Commercial 4-bromophenol contains traces of 2,4-dibromophenol and 2,4,6-
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tribromophenol. Ortho halophenols are known to form halogenated dioxins under certain
reaction conditions. These bromodioxins (see supplementary info for structures) would
have to be controlled at ppb level, as they exhibit high toxicity even at low concentration.16
Our toxicologists advised a control at levels of 0.2 ppb for the sum of tetrabromodioxins,
0
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2
ppb for the sum of tribromodioxins and 650 ppb of the sum of dibromodioxins. Although
we could show that neither 4-bromophenol itself nor intermediate 13 contained critical
levels of bromodioxins, the determination required a specialized laboratory and
sophisticated technology to quantify bromodioxins at such low levels. As this would have
to be shown for all future batches, we sought to avoid the bormodioxine saftey risk by
design, (Scheme 2; lower part).
Oxidation of the thiophene 22 with 1 equiv H O in dichloromethane and 3.3 equiv TFA
2
2
gave after isolation from TBME rather clean (98.5%) sulfoxide 28 in 69% yield. The
conversion of intermediate 28 (added in three portions every 3 h) with 1.05 equiv methyl-
4
-hydroxycinnamate in the presence of 3 equiv K CO at 93 °C – 98 °C gave product 29
2
3
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in 86% yield after partial DMF distillation and H O addition, followed by filtration and
2
reslurry in EtOAc. The reduction of the sulfoxide 29 to the known intermediate 11 was
1
1
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9
0
14
17
achieved with PPh / TMSCl. Reduction of the sulfoxide using TMSCl / NaI was shortly
3
investigated, however due to potential iodine formation not further developed. In contrast
to the initial synthesis, intermediates 11 and 12 were not isolated and compound 13 was
obtained after ester hydrolysis and recrystallization from THF / n-heptane in > 98% purity
in an overall yield of 73% over these three telescoped steps. The corresponding 7-chloro
impurities (Figure 1), which were shown to be problematic in the first Higa-cyclization
scale-up synthesis, were monitored on all isolated intermediates and could be controlled
to levels < 0.1% on intermediate 13. It was found that the chloro-impurity 25 must not be
present in more than 2% in 21, in order to meet the specifications of < 0.1% of the carry-
over side product 27 at intermediate 13-stage. This target could be achieved by reducing
the excess of SOCl in the first step from 3.1 equiv to 3.0 equiv.
2
As for the demethylation of 13, the best conditions found at the onset of our development
work (see Scheme 1) were adding a 1 M solution of BBr in n-heptane to a solution of 13
3
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in dichloromethane at – 75 °C to – 70 °C. After aqueous work up crude 14 was isolated
in about 75 - 87% yield. Other reagents for the methoxy ether cleavage were investigated
0
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9
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18
19
(
e.g. pyridine hydrochloride ; sodium thioethylate or HBr), however only BBr in n-
3
heptane gave satisfying results. Under the optimized conditions, crude 14 always
contained about 1% desbromo side product 30, 0.6% of the dibromo side product 31 and
around 0.5% of the dimer 32 (Figure 2). 32 could be hydrolyzed with NaOH (aq) and
limited to < 0.2% as part of the normal production process.
O
O
Br
O
HO
HO
S
OH
O
O
O
O
OH
HO
HO
Br
Br
S
S
S
O
O
Br
30
31
32
Figure 2: Side products in the demethylation step with BBr3
Crude 14 was then recrystallized from 2-methyltetrahydrofuran / n-heptane reaching a
purity of > 98% with side product 30 in the range of 0.3 - 0.7% and 31 in the range of 0.2
–
0.4%. The overall yield of the demethylation reaction, including recrystallization could
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be optimized to around 83%. Following this process, the chromatographic purification of
intermediate 14 could be successfully eliminated.
1
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1
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2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
The overall yield to the key intermediate 14 starting from 4-methoxycinnamic acid (19)
was 15.5% on scale for the second-generation synthesis, compared to < 2% overall yield
achieved in the medicinal chemistry synthesis as described in Scheme 1. In addition, the
number of isolated intermediates could be reduced from 10 to 5.
Development towards an alternative to the use of BBr . The protection of the phenol group
3
as methyl ether proved useful for the synthesis of the early steps but had a clear drawback
when coming to the deprotection. Although significant improvements in regards to yield
(
80% on plant scale) and purity (> 98.5%) were achieved during development, BBr3
remains a problematic reagent. It cannot be shipped easily across the world, requires
special precautions and handling, and should therefore be substituted for large-scale
production process. Furthermore, the reaction conditions for this demethylation required
low temperature equipment (< -70 °C). While all alternative reagents tested proved
inferior to BBr , the use of distinct phenol protecting groups was considered. Among the
3
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options explored, we identified the possibility to mask the phenolic hydroxy group as a
bromide, which means starting the synthesis from 4-bromocinnamic acid (33), which is
also available in bulk. More precisely, the strategy consisted in a late-stage conversion of
the aromatic bromide to the corresponding phenol by a Pd-catalyzed reaction. This led to
the third-generation synthesis of key intermediate 14, as depicted in scheme 3.
0
1
2
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6
7
8
9
0
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9
0
1
2
3
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6
7
8
9
0
Scheme 3: Third-generation synthesis of intermediate 14
OMe
O
Cl
O
Cl
Cl
COOH
a; b
c
d
e
CO2Me
Br
55%
S
89%
S
78%
Br
S
O
81%
Br
S
O
Br
Br
33
34
35
36
37
OMe
OH
OH
OH
O
O
O
O
f
g
h
i
8
6%
85%
87%
O
S
O
O
O
(
2 steps)
Br
Br
Br
S
HO
S
HO
S
38
39
30
14
Reagents and conditions: (a) SOCl pyridine, chlorobenzene; 60 – 125 °C; (b) MeOH, 60
2,
–
70 °C; (c) NBP; NaOH, 85 – 140 °C; (d); H O ; TFA; CH Cl ; 20 °C; (e) methyl (E)-4-
2
2
2
2
hydroxycinnamate; K CO ; acetonitrile; 80 – 85 °C; (f) TMSCl; PPh ; THF; 70 °C; (g) KOH;
2
3
3
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MeOH; H O; 20 – 30 °C; (h) THF; KOH (aq); NBu Br; allyl palladium chloride dimer; t-Bu-
2
4
X-Phos; 60 °C (i) NBS; acetonitrile; 2-Me-THF; 30 – 35 °C.
1
1
1
1
1
1
1
1
1
1
2
2
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2
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2
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9
0
Similarly as in the second-generation synthesis, 4-bromocinnamic acid (33) was
subjected to the conditions of the Higa cyclization with SOCl (3.2 equiv) in the presence
2
of pyridine. Product 34 was isolated in 55% yield. As a side product of the first step, the
corresponding 6-chloro analogue 40 (Figure 3) was formed in about 0.4% in the isolated
product 34. The level of side product 40 could be controlled by the prolonged addition of
the second portion of SOCl (2 equiv) over 8 h. This impurity was converted and carried
2
over in all the following steps without depletion and intermediate 39 contained 0.35% of
the corresponding 6-chloro side product 41. The ester decarboxylation of intermediate 34
was performed under similar conditions as for the methoxy series, except that N-
butylpyrrolidone (NBP) was employed, as a solvent13 Product 35 was isolated in 89%
yield. For the polar aprotic solvents NMP, DMF and DMAC, REACH restrictions might be
introduced by ECHA (European Chemicals Agency) due to their reproductive toxicity, for
NBP not yet. The oxidation was performed with 1.1 equiv H O in a trifluoroacetic acid /
2
2
dichloromethane mixture, to obtain the sulfoxide 36 in 78% yield and a purity of almost
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5%. The major side product in the isolated product 36 was the hydroxy sulfone 42,
originating from over-oxidation. With a well-controlled reaction temperature (20 – 30 °C),
side product 42 could be limited to around 6% in the reaction mixture, with additional
depletion to < 5% in the isolated product 36. As this side product contains a hydroxy group
in C3 position instead of a chloride, it cannot participate in the subsequent nucleophilic
aromatic substitution with methyl-4-hydroxycinnamate and remains unchanged. Side
product 42 was successfully removed during the crystallization steps of the downstream
process steps to intermediate 39.
0
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1
2
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4
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8
9
0
OH
O
OH
Cl
O
CO2Me
S
Br
S
S
O
Cl
Cl
O
40
41
42
Figure 3: Key side products in the third generation synthesis of intermediate 14
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Intermediate 36 was then reacted with methyl 4-hydroxycinnamate in the presence of 2
equiv K CO in acetonitrile to the biaryl ether 37. No S Ar reaction onto the C6 position
2
3
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
4
4
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4
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5
5
5
5
5
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0
1
2
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9
0
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0
1
2
3
4
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9
0
of either intermediate 36 or the corresponding 6-chloro analogue of 36 was observed. In
the lab the reaction usually took about 24 h to reach levels of <2% remaining 36. On plant
scale, the reaction time had to be increased to 48 h! This behavior was assigned to large
lumps in the starting material 36. The increased reaction time with larger agglomerates
could also be verified in lab experiments. Fortunately, the longer reaction time at 80 °C
had no negative effect on the quality of the isolated product 37, which could be isolated
in 81% isolated yield from 36 with a purity of 96%. The next two steps from 37 to 39 were
telescoped. The reduction of the sulfoxide was performed in THF, using 1.05 equiv PPh3
and 2.0 equiv TMSCl at 60 – 65 °C for 5h to reach >98% conversion. Then 5 equiv
aqueous KOH were added to hydrolyze the methyl ester in the non-isolated intermediate
38. After complete ester hydrolysis, the THF was distilled off, the aqueous product phase
acidified with conc. HCl, the crude product (purity 87%; Ph PO: 8.4%) was isolated after
3
centrifugation and reslurried in methanol (4.5 fold to starting 37) at 60 – 65 °C. After
cooling and filtration, the purity could be increased to > 98% with Ph PO at a level of
3
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about 0.2%. This crude wet product was finally recrystallized from THF / n-heptane to
obtain the purified product 39 in an overall yield of 86% and a purity of 99.4%, starting
from 37. The major impurity in the isolated product 39, was the already mentioned chloro
impurity 41 in around 0.35%.
0
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0
For the key transformation of the 6-bromo compound 39 to the hydroxy analogue 30, a
catalyst screening was performed. It was found that 0.3 mol% of palladium allyl chloride
dimer as Pd source and 1 mol% t-BuXPhos provided the best catalytic system, as
20
21
described by Buchwald. Cu-catalyzed conversion was also shortly investigated; but
the Pd-catalyzed reaction demonstrated superior performance. The reaction was run in a
THF / water system in the presence of 7.5 mol% NBu Br. KOH was essential as base;
4
the reaction did not perform well with NaOH. Aqueous KOH (50%) had to be added in two
portions – the second portion added after about 3 h reaction time. When the entire amount
of KOH was added from the beginning, the catalyst system did not work well and
incomplete turnover was observed. After about 12 h total reaction time at 65 °C starting
39 was < 0.2% The chloro- side product 41 was also converted to the desired product
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0; however HPLC investigations showed that the conversion of 41 to the desired product
0 only takes place after all of the bromo starting material 39 has been consumed. Usually
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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5
5
5
5
5
5
5
6
0
1
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5
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9
0
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0
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0
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2
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7
8
9
0
1
2
3
4
5
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8
9
0
the chloro impurity 41 could be consumed to < 0.1% at the end of the reaction. After
aqueous work up, treatment with an aqueous N,N-diethyl dithiocarbamate solution,
followed by filtration over a charcoal filter (both to remove Pd), the product 30 was isolated
in around 85% yield after crystallization from 2-methyl THF / n-heptane. The purity of the
isolated product 30 was always > 98% with a residual Pd content ranging from 15 – 40
ppm. The synthesis of intermediate 30 was executed several times on more than 100 kg
scale. Intermediate 30 could be brominated with NBS in 2-methyltetrahydrofuran /
acetonitrile mixture in 87% yield and > 99.0% purity to the key intermediate 14 (scheme
3). This step was also demonstrated on kg scale.
Side chain intermediate 17. Whereas 2-bromo-5-fluoro acetophenone (15) was
purchased as starting material in the early supply route, we ultimately had to develop a
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
synthesis and chose the route outlined in Scheme 4, starting from 2-bromo-5-fluoro
benzoic acid (43).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
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9
0
1
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3
4
5
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7
8
9
0
Scheme 4: Synthesis of side chain intermediate 17
F
F
F
F
F
F
a
b
O
O
O
O
c
e
d
OH
Cl
O
9
1%
(3 steps)
87%
75%
F
F
B
F
O
O
Br
O
Br
O
Br
Br
O
Br
F
43
44
45
15
16
17
Reagents and conditions: (a) SOCl toluene; DMF; 70 – 75 °C; (b) diethyl malonate;
2,
MgCl ; NEt ; 25 – 30 °C; (c) H SO ; HOAc; H O, 90 – 100 °C; (d); SF ; HF; CH Cl ; 75 -
2
3
2
4
2
4
2
2
8
0 °C; (e) KOAc; B (Pin) ; Pd(PPh ) Cl , dioxane; 100 °C.
2
2
3 2
2
In the first step the carboxylic acid was converted to the acid chloride 44, followed by
MgCl mediated Knoevenagel reaction with diethyl malonate to the non-isolated
2
intermediate 45.22 Under acidic conditions, a sequential ester hydrolysis and
decarboxylation of intermediate 45 gave the desired product 15,23 which was isolated
after distillation in an overall yield of 91%. Fluorination of ketone 15 was achieved with
SF / HF in dichloromethane under pressure at 75°C – 80 ° C in a Hastelloy C276 reactor
4
to give product 16 after distillation in 87% yield and > 99.8% purity (GC area%).
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The synthesis of the arylboronic ester 17 was also improved. Potassium acetate was kept
as base in anhydrous 1,4-dioxane. However, as potassium acetate is very hygroscopic,
we had to perform an azeotropic distillation from the KOAc slurry in 1,4-dioxane to remove
traces of water, which would disturb the outcome of the following Miyaura coupling. The
coupling reaction took 22 h at 100 °C to reach complete conversion. The salts were
filtered off, followed by a solvent switch from 1,4-dioxane to n-heptane. The n-heptane
solution of the product 17 was filtered over silica gel to remove polar impurities and
product 17 was then crystallized from n-heptane at – 50 °C. As the solubility of 17 in n-
heptane is considerable, the product filter had to be cooled to about -20 °C during filtration
and washing. As an additional challenge, the melting point of 17 is only about 33 °C. This
step was performed on 40-kg scale with isolated yields in the range of 60 – 75%. With
these process improvements, the column purification on step 17 could be reduced to a
silica gel plug filtration that only required a simple filter nutch.
1
1
1
1
1
1
1
1
1
1
2
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2
2
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2
2
2
2
2
3
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3
3
3
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3
3
4
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4
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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7
8
9
0
1
2
3
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5
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9
0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
One major concern of this Miyaura coupling process was thermal safety. Compound 17
exhibits a very strong thermal exothermic decomposition energy of -883 kJ /kg above 200
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°
C. The decomposition started relatively close to the process temperature and in the
presence of unidentified catalytic impurities, the onset of the decomposition was even
shifted to lower temperature and showed signs of autocatalytic behavior. Therefore, it
was required to measure a DSC of the product solution prior to solvent exchange from
0
1
2
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9
0
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0
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9
0
1
,4-dioxane to n-heptane for each production batch to confirm the thermal behavior. As
an additional safety measure, the distillation vessel had to be connected with a
pressurized tank of cold n-heptane for dilution of the reaction mixture in case of an
unexpected internal temperature increase during the solvent swap.
Process Development of the key assembly step
Suzuki cross-coupling optimization. Besides the process development work associated
with the key Suzuki cross coupling step, our major focus was to revisit and streamline the
purification and isolation strategy.
Scheme 5: Suzuki cross-coupling and downstream purification strategies
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d
RP-chromatography
6
2%
O
H
O
H
O
HO
N
HO
N
HO
O
HO
F
B
a
b
c
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
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4
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5
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5
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5
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5
5
6
0
1
2
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5
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8
9
0
1
2
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8
9
0
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9
0
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9
0
1
2
3
4
5
6
7
8
9
0
+
O
F
O
F
O
F
F
F
82%
85%
79%
O
O
O
HO
HO
HO
S
S
S
HO
F
F
F
Br
S
F
F
F
14
17
crude 46
pure 46
LSZ102 = 18
Reagents and conditions: (a) Pd(PPh ) ; K CO ; 1,4-dioxane; 73 °C; dicyclohexylamine
3
4
2
3
(
b) MeOH, H O; 60 – 65 °C; (c) NaOH; n-heptane; HCl; 5 – 25 °C; (d); NaOH; TBME; RP-
2
chromatography; aq. HCl.
For the Suzuki cross-coupling, an extensive catalyst and reaction condition screening
was performed, but no catalyst system proved superior to the initially used tetrakis
7
triphenylphosphine palladium. The main side product of the Suzuki cross-coupling was
not surprisingly the debrominated compound 30. We were able to minimize its formation
by decreasing the reaction temperature to 70-75 °C, using 1,4-dioxane/water instead
DME/water as solvent and by slowly dosing a solution of 14 into the reaction mixture
containing the boronate 17 (1.7 equiv) and Pd(PPh ) (7 mol%). When conversion
3
4
reached >98%, a charcoal treatment followed to achieve some palladium removal and
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ease the further work-up. By solubilizing the reaction product in basic aqueous media, we
were able to remove many apolar, non-acidic impurities, such as triphenyphosphine,
triphenylphosphinoxide and residual boronate ester 17 by simple extractions with toluene.
To address the residual palladium levels, the product had be dissolved in 2-
methyltetrahydrofuran by acidification with conc. HCl to allow cysteine extractions and
treatment with Quadrasil MP (supplied by Johnson Matthey) as a Pd scavenger. Product
isolation was achieved by salt formation with dicyclohexylamine to give crude46 (scheme
5). The use of 0.85 equiv of dicyclohexylamine (with regard to starting material 14)
resulted in the highest yield and quality of the isolated product crude46. Using this process
crude46 was manufactured multiple times on 40 kg scale with 82% yield and 95% purity.
The most prominent side products present in the isolated product crude46 were the
desbrominated side product 30 with around 4% and the impurity 47 (bearing a vinyl
function from a HF elimination process) (figure 4) in around 0.3% - 0.5%.
0
1
2
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9
0
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9
0
1
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The process was running stable in several campaigns and we were very surprised when
a batch of the starting material 14 suddenly did not dissolve anymore in 1,4-dioxane at
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ambient temperature in the plant. We were able to continue the batch by heating the
suspension to 40 - 50 °C to form the required solution. This behavior was never observed
in the lab before, but upon seeding a corresponding solution of 14 in 1,4-dioxane with the
solid obtained from the plant, the crystallization could be reproduced. We speculated that
the changes in the isolation procedure of 14, coming from the second generation
synthesis depicted in scheme 2, resulted in a different impurity pattern which caused the
product to crystallize from 1,4-dioxane in a more stable (and less soluble) form. For the
following batches, we simply increased the amount of 1,4-dioxane to dissolve the starting
material 14 in the Suzuki reaction.
1
1
1
1
1
1
1
1
1
1
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2
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0
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9
0
1
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9
0
1
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9
0
1
2
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9
0
1
2
3
4
5
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8
9
0
O
HO
O
HO
O
O
HO
F
F
F
S
HO
S
OH
F
F
F
O
O
HO
O
HO
S
F
S
OH
F
O
30
47
48
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