A green bromination process for synthesis of a novel drug candidate

Article abstract of DOI:10.1016/j.tetlet.2014.08.094

A bromination process has been developed using a salt-based brominating reagent and a non-chlorinated solvent system. The process affords enhanced selectivity and enables product isolation by simple filtration of the reaction mixture, resulting in a substantially reduced waste stream.

Full text of DOI:10.1016/j.tetlet.2014.08.094

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Accepted Manuscript
A Green Bromination Process for Synthesis of a Novel Drug Candidate
Steven R. Mathieu, George A. Moniz
PII:
S0040-4039(14)01447-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.094
TETL 45061
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 August 2014
19 August 2014
22 August 2014
Please cite this article as: Mathieu, S.R., Moniz, G.A., A Green Bromination Process for Synthesis of a Novel Drug
Candidate, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.094
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
A Green Bromination Process for Synthesis
of a Novel Drug Candidate
Leave this area blank for abstract info.
Steven R. Mathieu and George A. Moniz*

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
1
Tetrahedron Letters
journal homepage: www.els evier.com
A Green Bromination Process for Synthesis of a Novel Drug Candidate
Steven R. Mathieu and George A. Moniz∗
aProcess Research, Pharmaceutical Science and Technology, Eisai, Inc., 4 Corporate Drive, Andover, MA 01810, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
A bromination process has been developed using a salt-based brominating reagent and a non-
chlorinated solvent system. The process affords enhanced selectivity and enables product isolation by
simple filtration of the reaction mixture, resulting in a substantially reduced waste stream.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Keyword_1
Keyword_2
Keyword_3
Keyword_4
Keyword_5
Introduction
Results and Discussion
E7016 (3) is an inhibitor of poly (ADP-ribose) polymerase
currently being investigated clinically as a potential anticancer
therapy. A key intermediate in the synthesis of E7016 is benzylic
bromide 2, which is prepared via bromination of methylxanthene
1. The original process for bromination of 1 employed N-
Bromosuccinimide in dichloromethane with benzoyl peroxide as
radical initiator. This process was employed on kilogram scale to
deliver an early batch of E7016. During the implementation of
this first-generation process, several problems were identified
that would require resolution to enable a robust process for future
synthesis of E7016.
The first-generation bromination process transferred to our
department had several challenges. First, the reaction generated
substantial quanitities (>15%) of dibromide 4 in addition to the
desired monobromide (2) requiring multiple reslurries to upgrade
the purity of 2. Second, the radical reaction was prone to
stalling, requiring repeated fresh charges of benzoyl peroxide and
N-bromosuccinimide to re-initiate the reaction. Finally, the
reaction used a halogenated solvent (dichloromethane) and
required multiple chases with ethanol to accomplish solvent
exchange resulting in a significant organic waste stream.
At the outset of our studies, we were attracted to a salt-based
bromination reagent reported by Adimurthy et al.1 This reagent
(5:1 NaBr/NaBrO3), the precursor of liquid bromine via cold
process manufacture, liberates bromine upon acidification. The
ratio of NaBr to NaBrO3 can also be adjusted using NaOCl via a
redox process according to:
5 NaBr + NaBrO3 + 3 NaOCl → 4 NaBr + 2 NaBrO3 + 3 NaCl
This allows one to achieve an optimal mixture for specific
bromination reactions.2 We recognized that this reagent would
afford superior
atom economy3 compared to N-
bromosuccinimide, which generates a substantial organic by-
product in succinimide. Further, since this reagent was salt-
based, it could be eliminated in the aqueous waste stream.
Our initial experiments (Table 1) focused on the optimization of
Scheme 1. Bromination en route to E7016
this reagent for the bromination of in the current
dichloromethane (10 mL/g) reaction solvent. After some
1
———
∗ Corresponding author. Tel.: +1-978-837-4734; fax: +1-978-837-4863; e-mail: george_moniz@eisai.com

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
2
Tetrahedron
experimentation, it was found that the 5:1 mixture of
the reaction mixture, reducing the formation of dibromide 4 and
providing a simple isolation procedure for 2 that would mitigate
additional solvent use for extraction and solvent exchange.
Additionally, α,α,α-trifluorotoluene has received attention as a
green solvent alternative to halogenated hydrocarbons such as
dichloromethane.6
NaBr/NaBrO3 derived from the bromine cold manufacturing
process was useful directly in this process (entries 2-8), using
NaOCl and HCl as co-reactants as described by Adimurthy et al.2
Importantly, the reaction was confirmed to be photoinitiated by
two experiments conducted in the dark to prevent photoinitiation
(entries 6 & 7).
Adapting the process to a production
Adapting the optimal reaction conditions in dichloromethane to
this new solvent revealed that, at reasonable volumes of α,α,α-
trifluorotoluene with water as co-solvent, reactivity could be
maintained while simultaneously controlling levels of dibromide
4. Furthermore, the desired monobrominated product 2 could be
isolated directly by filtration of the reaction mixture, thus
eliminating the need for additional solvent for extractions and
chases.
environment with closed reactors and thus limited ambient light
would require chemical initiation. Since it was desirable to
conduct the reaction at near-ambient temperatures, we introduced
the initiator V-70 to good effect (entry 8).4
Table 1. – Evaluation of NaBr/NaBrO3 Brominating Reagent as
Substitute for N-Bromosuccinimide in Dichloromethane
Product Distribution
at End of Reaction
(%)
Equiv
NaBr/NaBr
O3 (ratio)
Equiv
NaOCl
Equiv
HCl
T
(ºC)
Entry
Other
1
2
4
Table 3. – Optimization of NaBr/NaBrO3 Reaction Conditions in
α,α,α-Trifluorotoluene (TFT) and Water Solvent Systema
1.1 equiv
NaBr/NaBrO3
(2:1)
2.0 equiv.
NaBr/NaBrO3
(5:1)
1
2
0
1.1
2.2
22
22
-
-
16
64
12
Product
1.0
1
74
5
Distribution at
End of Reaction
(%)
Equiv
NaBr/NaBrO3
(ratio)
Volumes
TFT
(mL/g)
Volumes
Water
(mL/g)
Equiv
NaOCl
Equiv
HCl
T
1.8 eq.
Entry
(ºC)
3
4
5
NaBr/NaBrO3
(5:1),
1.8 eq.
NaBr/NaBrO3
1.8 eq.
0.9
0.9
0.9
2.0
1.1
1.1
22
22
0
-
-
-
5
6
5
84
82
87
11
12
8
1
2
6
4
2
4
12
6
1.8 eq.
NaBr/NaBrO3
(5:1)
1
2
3
1.0
1.0
1.0
1.1
1.1
1.1
22
22
22
10
5
4
4b
8
83
88
88
NaBr/NaBrO3
(5:1)
1.8 eq.
1.8 eq.
NaBr/NaBrO3
(5:1)
1.8 eq.
NaBr/NaBrO3
(5:1)
6
7
NaBr/NaBrO3
(5:1)
1.8 eq.
NaBr/NaBrO3
(5:1)
0.9
0.9
1.1
1.1
22
40
In the dark
In the dark
100
100
0
0
0
0
5.5
8
aAll reactions employed 0.1 equiv of V-70 initiator.
bReaction mixture was viscous and difficult to stir using only 4 volumes of water.
In the dark
+ V-70
initiator
1.8 eq.
NaBr/NaBrO3
(5:1)
8
0.9
1.1
22
10
80
10
Scheme 2 and Table 4 show the results of a kilo-scale
demonstration of this new bromination process. The
(0.1equiv)
monobrominated product 2 was isolated directly from the
reaction mixture with 93% HPLC purity, which is suitable for
use directly in the downstream process as subsequent steps
effectively control levels of residual 1 and 4. A simple
recrystallization procedure provides higher purity material if
desired.7
While these new reaction conditions afforded reliable
bromination without need of N-bromosuccinimide, the problems
of significant dibromination, chlorinated solvent use, and an
organic solvent-intensive workup remained. We theorized that
one cause of dibromination might be the solubility of the initial
monobromide product 2 in the reaction solvent. Exposure of 2 to
additional brominating agent within the reaction matrix would
presumably give rise to 4. With this in mind, we assessed the
solubilities of the starting material 1 and monobromide 2 in
several solvents in an effort to identify a solvent(s) that might
solubilize 2 to a lesser extent than 1 and potentially have less
environmental impact than dichloromethane.
1) 5:1 NaBr/NaBrO3 (1.9 equiv)
NaOCl (0.95 equiv), HCl (1.2 equiv)
V-70 (0.04 equiv)
TFT (5.5 V), Water (8 V)
22 oC, 18h
MeO
O
MeO
O
O
O
CH3
Br
2) Filter & Wash with Water (2V)
(89% yield)
O
O
Table 2 shows absolute and relative solubility data for 1 and 2 in
three solvents that also afforded reasonable extent of reaction for
the bromination. The cost of each solvent from a commmon
chemical supplier are also listed.5
1
2
Optional Recrystallization :
Toluene/IPA 2:1 (6V), 80 - 22 oC
(75% overall yield recrystallized)
Table 2. – Solubility Data for 1 and 2 in Several Organic
Solvents Compatible with NaBr/NaBrO3 Bromination Reaction
Scheme 2. Final Bromination Process
Table 4. Results of Kilo-scale Demonstration of New
Bromination Process
Solubility Data
Compound
DCM
($45/L)
Chlorobenzene
($80/L)
α,α,α-
Trifluorotoluene
($51/L)
Product Distribution at
End of Reaction (%)
Overall
Yield Post-
Recrystalli
zation
Intial Isolated
Purity
(HPLC Area%)
Recrystallized
Purity
(HPLC Area%)
Isolated
Yield
Starting
Material
(1)
Starting Material 1
Monobromide 2
125 mg/mL
104 mg/mL
1.20 : 1
83 mg/mL
47 mg/mL
1.76 : 1
19 mg/mL
5 mg/mL
3.8 : 1
2
4
93%
Residual 1: 5%
Residual 4: 2%
98%
Residual 1: 1.5%
Residual 4: 0.2%
Relative Solubility ½
6
84
10
89%
75% Yield
As can be seen from Table 2, α,α,α-trifluorotoluene (TFT, a.k.a.
trifluoromethylbenzene) afforded preferential solubility for
starting material 1 over the desired monobrominated product 2,
while reducing overall solubility. It was hoped that reaction
conditions could be found where 2 might crystallize directly from
A comparison of waste generated by the original and new
bromination procedures is presented in Table 5. The new