G Model
CCLET 3280 1–3
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3
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and the volatiles were removed under reduced pressure to give 4 as
a colorless oil.
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3: Mp: 82–83 C. 1H NMR (300 MHz, DMSO-d6):
d 7.74 (d, 1H,
J = 2.0 Hz), 7.69 (d, 1H, J = 8.9 Hz), 7.61 (dd,1H, J = 8.9, 2.0 Hz), 7.48 (s,
1H), 7.30–7.33 (m, 2H), 7.26–7.20 (m, 3H), 4.08 (s, 3H), 4.02 (s, 2H).
4: 1H NMR (300 MHz, CDCl3):
d 8.57 (d, 1H, J = 8.4 Hz), 7.98 (d,
1H, J = 8.4 Hz), 7.87 (d, 2H, J = 7.3 Hz), 7.65–7.40 (m, 3H), 3.24 (t,
2H, J = 7.3 Hz), 2.81 (t, 2H, J = 7.3 Hz), 2.29 (s, 6H).
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3. Results and discussion
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Bedaquiline and its other three stereoisomers were prepared
using the patent route as shown in Scheme 1. A mixture of 5
containing four isomers was obtained in four steps. Further chiral
separation was performed by spontaneous crystallization to give
diastereoisomer A and diastereoisomer B. The desired (1R, 2S)
enantiomer (i.e. Bedaquiline) was isolated using (R)-(-)-BNP ACID
as a resolving agent from the diastereoisomer mixture A.
Scheme 2. Proposed mechanism for the base-catalyzed cleavage of 7.
atoms was cleaved to form the corresponding ketone 4 and benzyl 132
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When inactive stereoisomes 7 was treated with sodium
carbanion. Subsequently, carbanion will be protonated to give the 133
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hydroxide in THF at room temperatures, the C–C bond between
the two benzylic carbon atoms was cleaved, resulting in the
formation of 3 and the corresponding ketone 4. This finding implies
that the recovery of inactive stereoisomes can be achieved using a
simple method. This reaction appeared to be a retro-aldol reaction,
likely driven by a combination of the highly strained steric
environment in the crowded carbinol 7, the acidity of 3, and the
special proximity of the dimethyl amino group to the hydroxyl
group in 7. So we speculated that the progress of the decomposi-
tion reaction may depend on the solvent and the base employed.
Three factors, namely solvent, base, and temperature were selected
to evaluate the decomposition step and the results are summarized
in Table 1.
After an initial screening of diffident conditions, we found that
the base and solvent are both crucial for this decomposition
reaction. Relative mild bases such as NaOH, KOH, LiOH could lead
to the cleavage of 7 in THF in comparably high yields (Table 1,
entries 1–3). However, weaker bases, such as K2CO3 and Na2CO3
(Table 1, entries 4 and 5), stronger bases, such as NaH and NaNH2
(Table 1, entries 7 and 8), as well as amine bases (Table 1, entries 9
and 10), were all completely ineffective when other conditions
were the same as those shown in entry 2. In contrast, the strong
base LDA at low temperature was found to be less effective with a
large amount of byproducts produced and only a low yield of
desired products was achieved (Table 1, entry 11). Notably, using
catalytic amount of t-BuOK was proved to be more active than
other bases, furnishing products in 83% yield (Table 1, entry 6).
Replacing THF with other solvents such as ethyl acetate, acetone,
acetonitrile in the presence of NaOH, can also result in satisfactory
yields (>80%) (Table 1, entries 17, 19 and 20). However, reactions
in dichloromethane, carbon tetrachloride, dioxane, toluene and
diethyl ether were not initiated completely (Table 1, entries 15, 16,
18, 22 and 23) and shows a much slower rate in acetone
(containing 10% H2O) compared to anhydrous acetone (Table 1,
entry 21). As shown in entry 12–14, weaker bases K2CO3 and
Na2CO3 could not lead to the decomposition of substrate in THF,
but this could be achieved in DMF. However, the reaction mixture
was quite complicated. These results revealed that DMF could
accelerate the reaction but produced more by-products. Similar
results were also founded in DMSO (Table 1, entry 24). When
considering the applicability in the scale-up and costs, catalytic
amount of t-BuOK may be the best choice.
other products 3.
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4. Conclusion
In summary, we have developed a simple, inexpensive, efficient 136
method to recycle the inactive stereoisomers of Bedaquiline. The 137
process described here can be utilized for the large scale 138
preparation of Bedaquiline at low production costs. To date, the 139
carbon–carbon bond cleavage of Bedaquiline and its stereoisomers 140
catalyzed by bases has never been reported. Notably, unlike the 141
retro-aldol reaction, the carbon–carbon bond cleavage between 142
two benzylic carbons has only been sporadically studied [8]. After 143
exhaustive evaluation of different reaction parameters, we have 144
discovered the most proper bases for promoting the decomposi- 145
tion of Bedaquiline and its stereoisomers. Our study will provide 146
new insights for further industrial preparation of drugs that have 147
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similar structures.
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Acknowledgment
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This research was financially supported by the National Science Q2150
and Technology Major Project of China (No. 521042).
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Appendix A. Supplementary data
152
Supplementary data associated with this article can be found, in 153
154
References
155
[1] E. Cox, K. Laessig, FDA approval of bedaquiline-the benefit-risk balance for drug- 156
resistant tuberculosis, N. Engl. J. Med. 371 (2014) 689–691.
[2] R.V. Patel, S.D. Riyaz, S.W. Park, Bedaquiline: a new hope to treat multi-drug 158
resistant tuberculosis, Curr. Top Med. Chem. 14 (2014) 1866–1874.
[3] C.U. Ko¨ser, B. Javid, K. Liddell, et al., Drug-resistance mechanisms and tuberculosis 160
drugs, Lancet 385 (2015) 305–307.
[4] (a) G. Jerome EmileGeorges, V. Gestel, J.F. Elisabetha, etal., Quinoline derivatives and 162
their use as mycobacterial inhibitors, PCT Int. Appl. (2004), WO2004011436A1;
157
159
161
163
(b) P. Frank Ralf, H. Stefan, B. Thomas, Process for preparing (aS, bR)-6-bromo-a-[2- 164
(dimethylamino)ethyl]-2-methoxy-a-1-naphthaleny-b-phenyl-3-quiolineethanol,
PCT Int. Appl. (2006), WO2006125769.
165
166
[5] N. Lounis, J. Guillemont, N. Veziris, et al., R207910 (TMC207): a new antibiotic for 167
´
the treatment of tuberculosis, Med. Mal. Infect. 40 (2010) 383–390.
[6] Y. Saga, R. Motoki, S. Makino, et al., Catalytic asymmetric synthesis of R207910, J. 169
Am. Chem. Soc. 132 (2010) 7905–7907.
[7] S. Chandrasekhar, G.S. Kiran Babu, D.K. Mohapatra, Practical syntheses of (2S)- 171
R207910 and (2R)-R207910, Eur. J. Org. Chem. 11 (2011) 2057–2061.
168
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A tentative mechanism for the carbon–carbon bond cleavage is
proposed in Scheme 2. Firstly, bases may remove the proton of
hydroxyl and then the C–C bond between two benzylic carbon
[8] P.J. Hamrick Jr., C.R. Hauser, The reversible addition of sodiodiphenylmethide to 173
benzophenone in liquid ammonia, base-catalyzed cleavage of 1,1,2,2-tetrapheny- 174
lethanol, J. Am. Chem. Soc. 81 (1959) 3144–3147.
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Please cite this article in press as: D.-L. Kong, et al., A highly efficient way to recycle inactive stereoisomers of Bedaquiline into two