First way of enantioselective synthesis of moxifloxacin intermediate

Article abstract of DOI:10.1007/s11426-012-4803-7

A new method of enantioselective synthesis of (S,S)-2,8-diazobicyclo [4.3.0] nonane was found by using (R)-2-amino-2- phenyl-ethanol as chiral induction reagent. The entire synthetic process included 8 steps which were easy to operate with high yield. The purification method was only simple recrystallization or even used directly in the next step without further purification. The total yield was 29%.

Full text of DOI:10.1007/s11426-012-4803-7

SCIENCE CHINA
Chemistry
March 2013 Vol.56 No.3: 307–311
doi: 10.1007/s11426-012-4803-7
• ARTICLES •
· SPECIAL TOPIC · The Frontiers of Chemical Biology and Synthesis
First way of enantioselective synthesis of moxifloxacin intermediate
LI GuangXun1, 2, WU Lei1, FU QingQuan1, TANG Zhuo1* & ZHANG XiaoMei2*
1Natural Products Research Center, Chengdu Institution of Biology, Chinese Academy of Science, Chengdu 610041, China
2Key Laboratory for Asymmetric Synthesis and Chiraltechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China
Received October 14, 2012; accepted November 12, 2012; published online December 10, 2012
A new method of enantioselective synthesis of (S,S)-2,8-diazobicyclo [4.3.0] nonane was found by using (R)-2-amino-2-
phenyl-ethanol as chiral induction reagent. The entire synthetic process included 8 steps which were easy to operate with high
yield. The purification method was only simple recrystallization or even used directly in the next step without further purifica-
tion. The total yield was 29%.
enantioselective synthesis, moxifloxacin intermediate, (S, S)-2, 8-diazobicyclo [4.3.0] nonane
antibacterial effectiveness [1]. So far, many synthetic
1 Introduction
methods have been reported (Scheme 1). Most of these
synthetic routes start from the relatively cheap material
pyridine-2,3-dicarboxylic acid (1) which could be trans-
formed into the piperidine ring of the target molecule
through high pressure hydrogenation. The pyrrolidine ring
could be constructed through imide formation with benzyl
amine, reduction with LAH, and debenzylation with Pd/C
[2–6], or could be formed with 2, 3-bis(chloromethyl)pyridine
(4) and TsNH2 [4]. An alternative protocol using 2-allyli-
dene-1,1-dimethylhydrazine (8) and 1-benzyl-1H-pyrrole-
2,5-dione (7) as raw materials could construct 6-benzyl-
5H-pyrrolo[3,4-b]pyridine-5,7 (6H)-dione (10) in two steps
[710]. However, all those methods couldn’t avoid the res-
olution method which obtain the chiral product by using
different kinds of chiral sources, such as tartaric acid and
mandelic acid, (S)-α-phenylethylamine, or even enzymatic
resolution [11]. As we known, only up to 50% of a desired
enantiomer could be obtained through chiral resolution step,
which means relative low yield and great waste by using
those synthetic methods. Herein, we report the first enanti-
oselective way of synthesis (S,S)-2,8-diazobicyclo [4.3.0]
nonane (14) by using the cheap (R)-2-amino-2-phenylethal
as chiral source.
Moxifloxacin is a fourth-generation synthetic fluoroquino-
lone antibacterial agent developed by Bayer AG. It is mar-
keted worldwide (as the hydrochloride) under the brand
names Avelox, Avalox, and Avelon for oral treatment.
Since its appearance in the market in September 1999, its
sales increased rapidly year by year. In 2002, its sale was
$ 333 million, which ranked as the world’s top ten
best-selling antibiotic drugs of that year. In the same year, it
was listed in China and covered in the scope of the national
medical insurance in 2004. Meanwhile, its sale increased
dramatically and astonishingly. In 2007, the urban sample
hospital purchase amounted to 216 million RMB, with an
increase of 75.1% over the previous year. Due to the hot
market of moxiflxacin, it is becoming more and more im-
portant for developing new efficient synthetic method in
order to decrease the production cost.
(S,S)-2,8-diazobicyclo [4.3.0] nonane (14) is a crucial
intermediate of moxifloxacin, which was also used for con-
structing quinolone and naphtyridine derivatives having
*Corresponding authors (email: tangzhuo@cib.ac.cn; xmzhang@cioc.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

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Li GX, et al. Sci China Chem March (2013) Vol.56 No.3
Scheme 1 Synthetic routes in references.
(4S)-1, 6-dioxo-4-phenyl-1,3,4,6,7,8-hexahydropyrido-[2, 1-c]
[1,4]oxazine-9-carboxylic acid methyl ester (16)
2 Experimental
2.1 Reagents and instruments
Acryloyl chloride (7.5 g, 65 mmol) was added dropwise to a
solution of compound 15 (16 g, 65 mmol) in 300 mL THF
at room temperature. The reaction finished after refluxed for
3 h. Then the mixture was cooled to room temperature,
poured into 150 mL of saturated aqueous sodium bicar-
bonate solution, and extracted with dichloromethane (3 ×
200 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo. The resulting oil was recrystal-
lization from ether-petroleum ether to give compound 16 as
All reactions that required anhydrous conditions were car-
ried by standard procedures under nitrogen atmosphere.
Commercially available reagents from Alfa Aesar and Al-
drich were used as received. The solvents were dried by
1
distillation over the appropriate drying reagents. H NMR
spectra were recorded on commercial instruments (600
MHz or 300 MHz). Chemical shifts were reported in ppm
from tetramethylsilane with the solvent resonance as the
internal standard (CDCl3,  = 7.26). Spectra were reported
as follows: chemical shift ( ppm), multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constants (Hz), integration and assignment. 13C NMR spec-
tra were collected on commercial instruments (151 MHz or
75 MHz) with complete proton decoupling. Chemical shifts
are reported in ppm from the tetramethylsilane with the
solvent resonance as internal standard (CDCl3,  = 77.0).
a white powder. Yield was 85%. Mp: 128 °C. []2D0 : +102
(c = 1.1, CHCl3) [13].
[4S-4,9,9]-1, 6-dioxo-4-phenyloctahydropyrido [2, 1-c]
[1, 4] oxazine-9-carboxylic acid methyl ester (17)
A solution of lactam 16 (15 g, 50 mmol) and 5% Pd/C (5 g)
in 150 mL of EtOH/EtOAc (10:1) was placed under hydro-
gen (1 atm) for 6 h. The catalyst was removed by filtration
on celite. After concentrated in vacuo, compound 17 was
isolated as a white solid (14.3 g, 95%). Mp: 108 °C. []2D0 :
+119 (c = 1.0, CHCl3) [14].
2.2 Synthesis
(R)-3-methoxycarbonylmethlene-5-phenyl-3,4,5,6-tetrahydro-
2H-1,4-oxazin-2-one (15)
(2R,3S)-methyl-2-(benzylcarbamoyl)-1-((R)-2-hydroxy-1-
phenylethyl)-6-oxopiperidine-3-carboxylate (18)
A solution of (R)-2-amino-2-phenyl-ethanol (13.7 g, 100
mmol) in 100 mL methanol was added dropwise to a solu-
tion of dimethyl acetylenedicarboxylate (14.2 g, 100 mmol)
in 150 mL of methanol with stirring for 1 h. After being
stirred for additional 3 h, the mixture was evaporated in
vacuo with temperature no more than 35 °C. Compound 15
was obtained as brown oil which after recrystallization from
ether-petroleum ether gave colorless needles. Yield was
To a solution of 17 (7.6 g, 25.2 mmol) in 100 mL toluene
was added benzyl amine (2.7 g, 25.2 mmol) and triethyla-
mine (7.65 g, 75.6 mmol) successively, the reaction was
stirred at 85 °C over 6 h until the full transformation of the
material. Then, the reaction was cooled to room temperature
and concentrated in vacuo. The residue was dissolved in
300 mL EtOAc and washed with water (100 × 3) and brine
(100 × 2). The combined organic layers were dried (Na2SO4)
85%. Mp: 67–69 °C. []20 : 258 (c = 0.6, CHCl3) [12].
D

Li G X, et al. Sci China Chem March (2013) Vol.56 No.3
309
and concentrated in vacuo to give brown crystalline solid.
The product was recrystallized from methanol to give col-
orless solid. Yield was 85%. 1H NMR (600 MHz, DMSO)  =
8.17 (s, 1H), 7.33 (dd, J =14.0, 6.5, 5H), 7.31–7.27 (m, 3H),
7.15–7.04 (m, 2H), 6.04 (dd, J = 11.7, 4.1, 1H), 4.51 (dd, J =
14.4, 6.0, 1H), 4.40 (dd, J = 14.4, 5.4, 1H), 4.26 (s, 1H),
4.03 (dd, J = 11.8, 4.1, 1H), 3.88 (t, J = 11.7, 1H), 3.41 (s,
1H), 3.20 (s, 4H), 2.75–2.57 (m, 1H), 2.47–2.29 (m, 1H),
2.04 (dd, J = 12.8, 7.0, 1H), 1.90 (dd, J = 14.4, 6.9, 1H). 13C
NMR (151 MHz, CDCl3) δ = 173.14, 171.95, 171.06,
137.90, 134.91, 128.91, 128.86, 128.76, 128.67, 127.98,
127.68, 61.60, 58.22, 58.16, 52.13, 44.17, 41.34, 29.46,
19.28. HRMS (ESI): calcd. for C23H27N2O5(M+H): 411.1914;
found: 411.1914.
was used directly without further purification. HRMS (ESI):
calcd. for C22H29N2O(M+H): 337.2274; found: 337.2276.
To the above brown oil in 20 mL methanol was added
Pd/C (10%, 500 mg) and the mixture was stirred under hy-
drogen atmosphere (90 °C/9 MPa) over 20 h. Then the
mixture was filtered through celite and concentrated in
vacuo to give brown residue. Then the residue was dis-
solved in 50 mL water and extracted the byproduct with
cyclohexane (50 × 2) which was washed again with water
(20 × 2). The aqueous solution was combined and the pH
was adjusted to 12 by adding sodium hydroxide. Then the
resulting solution was extracted with chloroform (100 × 2).
The combined organic layers were dried (Na2SO4) and con-
centrated in vacuo to give pale yellow oil. The yield of the
two combination steps was 60%. []2D0 : 2.46 (c = 1.0,
(R)-2-((4aR,7aS)-6-benzyl-2,5,7-trioxooctahydro-1H-pyrrolo
[3, 4-b]pyridin-1-yl)-2-phenylethyl acetate (20)
1
H2O). H NMR (600M, CDCl3)  = 1.40 (m, 1H), 1.51 (m,
1H), 1.62 (m, 2H), 2.21 (br, 2H), 2.49 (m, 1H), 2.57(td, 1H),
To a solution of 18 (2.05 g, 5 mmol) in 20 mL methanol
was added sodium hydroxide (300 mg, 7.5 mmol) dissolved
in 2 mL water, the resulting mixture was stirred at room
temperature over 5 h and then adjusted the solution pH to 2
with 3 mol L1 HCl at 0 °C. Then the solution was concen-
trated in vacuo below 40 °C and the resulting residue was
dissolved in 100 mL water and extracted with EtOAc (100 ×
2). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo to give a white foam product 19
which was used without further purification. HRMS (ESI):
calcd. for C22H25N2O5(M+H): 397.1758; found: 397.1767.
To the above dried product was added 30 mL acetic an-
hydride and excess lithium acetate, the mixture was stirred
at 100 °C over 12 h and then cooled to room temperature.
After filtration, the solution was evaporated in vacuo. After
usual workup, the product was purified by recrystallization
with methanol/ethyl ether. The combination of the two step
yield 80%. 1H NMR (300 MHz, CDCl3)  = 7.30 (m, 10H),
6.10 (t, J = 6.9, 1H), 4.90 (dd, J = 11.5, 6.8, 1H), 4.72–4.56
(m, 3H), 4.10 (d, J = 9.1, 1H), 2.83 (t, J = 8.6, 1H),
2.51–2.39 (m, 1H), 2.25 (d, J = 13.3, 1H), 2.00 (s, 3H), 1.78
(m, 2H)；13C NMR (151 MHz, CDCl3)  = 176.26, 174.78,
171.16, 170.86, 135.70, 135.23, 129.20, 128.92, 128.83,
128.70, 128.59, 128.35, 127.93, 127.85, 63.08, 54.29, 53.62,
42.88, 39.40, 30.62, 23.51, 20.88. HRMS (ESI): calcd. for
C24H24N2NaO5(M + Na): 443.1577; found: 443.1574.
2.74 (d, 1H), 2.93 (m, 4H), 3.13 (t, 1H) [6].
3 Results and discussion
In planning the synthesis of 14, the key factor is how to
construct the two chiral centers. Interestingly, Claude
Agami had used (R)-2-amino-2-phenyl-ethanol as chiral
inductor to efficiently create two new stereogenic centers
similar to our target [13, 14]. Meanwhile, (R)-2-amino-2-
phenyl-ethanol was used as chiral induction reagent for
preparation of aspartic acid derivatives and alanine deriva-
tives by Kaoru Harada due to its cheap and easy to take off
properties [12]. As a result, we wish to construct the two chi-
ral centers by chiral induction with (R)-2-amino-2-phenyl-
ethanol. Based on their synthetic protocols, we put forward
our synthetic strategy (Scheme 2).
To begin our research, oxazinone 15 was prepared through
Michael addition/esterification tandem reaction described
by Kagan and Horeau, during their classical asymmetric
synthesis of aspartic acid [15]. We optimized their method by
strictly controlling the reaction condition. We found the dropping
rate should keep slowly or the reaction solution would become
very dark. What’s more, the concentration process should be done
in vacuo below 35 °C. After usual work up, the crude product was
used directly in the next step without further purifications. Then,
bicyclic product 16 was prepared by condensation of 15 with ac-
ryloyl chloride, following the Paulvannan and Stille proce-
dure [16]. In the purification process, we found that product 16
could be purified through recrystallization from ether-petroleum
ether without column chromatography. Then, bicyclic product 16
was hydrogenated in dry ethanol and intermediate 17 was received
as off white solid after usual workup without column chromatog-
raphy. As a result, we could get product 17 after three steps with
yield of 69% with simple purification workup. Deserve to be men-
tioned, the diastereomer formed by adding Na2CO3 as additive
during the hydrogenation process. So we could get the other dia-
stereomer with the same method.
(4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (14)
To a solution of 20 (2.1 g, 5 mmol) dissolved in 30 mL an-
hydrous THF was added 285 mg LAH slowly. The mixture
was stirred at 50 °C over 10 h. Then the mixture was cooled
to 0 °C and sodium sulfafe decahydrate was added slowly
with strong stirring until no bubbles. Then sodium hydrox-
ide (2 mol L1, 50 mL) was added into the above mixture
and the product was extracted with EtOAc (100 × 2). The
combined organic layers were dried (Na2SO4) and concen-
trated in vacuo to give intermediate 21 as brown oil which

310
Li GX, et al. Sci China Chem March (2013) Vol.56 No.3
Scheme 2 Synthetic way for construction of target molecule.
Then, we hoped to form imide by amino-ester exchange.
However, the reaction proceeded and only exchanged the
lactone. We tried several base such as LDA, LHMDS,
NaHMDS, KHMDS, and so on, nevertheless the yield was
low and little racemization product was found. So we sepa-
rate this transformation into two steps. Firstly, we hydro-
lyzed the methyl ester into acid with sodium hydroxide. The
hydrolysis condition should be done below 20 ℃ and the
equivalent load of sodium hydroxide should be strictly con-
trolled in case of racemization. In this way, the acid inter-
mediate was received quantitatively and was used in the
ring closing step without further purifications. Then we
closed the lactam ring with acetic anhydride. The lactam
was received by simple crystallization from ethyl ether and
methanol. As a result, the intermediate 20 was received af-
ter two simple steps with the yield of 70%.
Next, we reduced the three carbonyls with LHA in anhy-
drous THF under refluxing condition. Only 70% yield was
received. We tried other reduction method such as
NaBH4/TiCl4, NaBH4/BF3.Et2O, NaBH4/I2, however, LHA
was better than any of them. Finally, we chose LHA as re-
duction reagent. After usual workup, intermediate 21 was
received as brown oil which was used in the next step di-
rectly without further purification. In the final step, we used
high pressure hydrogenation condition to take off benzyl
group and benzyl alcohol simultaneously. After usual
workup, product 14 was received as palebrown oil. The
yield of the final two steps was 60%.
steps and total yield was up to 29%. All the raw materials
used were cheap and easy to buy, and what’s more, during
the entire process, all of the intermediate were easily puri-
fied by simple recrystallization or used in the next step di-
rectly without further purification. In all, this novel way is
expected to be an alternative for traditional method after
further scale-up experiment. Further experiment for opti-
mizing the entire process and scale-up are underway in our
group.
This work was supported by Chinese Academy of Science (Hundreds of
Talents Program), the National Natural Sciences Foundation of China
(225013) and Opening Foundation of Zhejiang Provincial Top Key Disci-
pline.
1
2
Hoogkamp-Korstanje JAA, Roelofs-Willemse J. Comparative in vitro
activity of moxifloxacin against Gram-positive clinical isolates. J An-
timicrob Chemother, 2000, 45: 31–39
Petersen U, Krebs A, Schenke T, Schriewer M, Grohe K, Krebs A,
Haller I, Metzger KG, Bremm KD, Endermann R, Zeiler HJ. Quino-
lone and naphthyridone carboxylic acid derivative. Japan Patent,
200304889, 2003-02-21
3
4
Takemura M, Kimura Y, Matlsuhashi N. Bicyclic amine derivatives.
European Patent, 603887, 1994-06-29
Wang ZQ, Feng SS, Cheng YZ. A novel and economical process for
preparing(S, S)-2, 8-diazabicyclo [4, 3, 0] nonane and its enantiomer.
PCT patent, 2008085480, 2007-07-17
5
6
Klemm L, Johnson W, White D. Thieno (3, 4-b) pyridine and thieno
(3, 4-c) pyridine. American patent, 3709894, 1973-01-09
Riccardo M, Giancarlo A, Elisabetta B, Andrea C, Stefano F, Marco
G. Synthesis of (4aS, 7aS)-octahydro-1H-pyrolo [3, 4, b] pyridine.
PCT patent, 100215, 2010-10-09
7
8
Uwe P, Andreas K, Thomas S. Eantiomerenreine chinolincarbonsǎ
ure derivate. Germany patent, 4208792, 1993-09-23
Uwe P，Andreas K，Thomas S．Chinolon-und naph-thridon-carbons
4 Conclusion
ǎur derivatcals antibakterieUes mittel. European patent, 550903,
l992-12-28
Wuppertal FP. Method for producing (S, S)-benzyl-2, 8-diazabicyclo
[4, 3, 0] nonane. American patent, 6235908, 2001-03-22
In summary, we found a simple and economic way of syn-
thesizing (S, S)-2, 8-diazobicyclo [4.3.0] nonane which is a
valuable intermediate used for constructing quinolone and
naphtyridine derivatives having antibacterial effectiveness
such as moxifloxacin. The synthetic process included 8
9
10 Uwe P, Andreas K, Thomas S. Eantiomerenreine chinolincarbonsǎ
ure derivate. Germany patent, 4208789, 1993-09-23

Li G X, et al. Sci China Chem March (2013) Vol.56 No.3
311
11 Dreisbach C. Method for racemic biochemical resolution of cis-and
trans-pyrrolopiperidine. PCT patent, 9909200, 1999-02-25
12 Minoru T, Kaoru H. Asymmetric synthesis of aspartic acid by hy-
drogenation of optically active 1, 4-oxazine derivative. Bull Chem
Soc Jpn, 1980, 53: 561–562
13 Agami C, Kadouri-Puchot C, Le Guen V, Vaissermann J. Neurome-
diator analogs: Synthesis of cis (2R, 3S) and trans (2S, 3S)-2,
3-piperidine dicarboxylic acids from (2S)-2-phenylglycinol. Tetrahe-
dron Lett, 1995, 36: 1657–1660
14 Claude A, Louis H, Catherine KP, Valérie Le G. Enantioselective
synthesis ofconformationally restricted analogs of NMDA: Cis- and
trans-piperidine-2, 3-dicarboxylic acids and methylated derivatives. J
Org Chem, 1996, 61: 5736–5742
15 Vigneron JP, Kagan H, Horeau A. Synthese asymetrique de l’acide
aspartique optiquement pur. Tetrahedron Lett, 1968, 9: 5681–5683
16 Paulvannan K, Stille JR. Formation of 1, 2, 3, 4-tetrahydro-2-
pyridones by aza-annulation of imines with acrylate derivatives. J
Org Chem, 1992, 57: 5319–5328