A novel synthesis of (4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine:An intermediate of Moxifloxacin Hydrochloride

Article abstract of DOI:10.14233/ajchem.2013.15245

A novel synthesis of (4aS, 7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (1) is demonstrated alongwith recovery and reuse of chiral auxiliary naproxen. Further to this alternative stereoselective reduction procedures on 6-benzyl-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione 3 enabling the desired chirality in the nonane 1 is demonstrated.

Full text of DOI:10.14233/ajchem.2013.15245

Asian Journal of Chemistry; Vol. 25, No. 15 (2013), 8701-8707
http://dx.doi.org/10.14233/ajchem.2013.15245
A Novel Synthesis of (4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine:
An Intermediate of Moxifloxacin Hydrochloride
1,*
G. PRASHANTH REDDY1,2 and RAKESHWAR BANDICHHOR
1API R&D, Integrated Product Development, Innovation Plaza, Dr. Reddy's Laboratories Ltd, Bachupally, Qutubullapur, Hyderabad-500 072, India
2Center for Environment, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 072, India
*Corresponding author: Fax: +91 40 446285; Tel: +91 40 44346117; E-mail: rakeshwarb@drreddys.com
(Received: 31 January 2013;
Accepted: 26 August 2013)
AJC-14030
A novel synthesis of (4aS, 7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (1) is demonstrated alongwith recovery and reuse of chiral auxiliary
naproxen. Further to this alternative stereoselective reduction procedures on 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione 3
enabling the desired chirality in the nonane 1 is demonstrated.
Key Words: Nonane, Racemization, Naproxen, Naproxamide, L-Proline.
polarimeter and at 589 nm. The chiral HPLC was recorded
on Agilent Model 1260 by using Chiral AGP, 150 × 4.0 mm,
5 µ.
INTRODUCTION
(4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine 1, is an
important intermediate in the manufacture of moxifloxacin
and commonly known as “nonane”. For the past few decades,
enormous amount of research has been carried out and several
processes are reported1-8.
Literature1-8 illustrated that the majority of manufacturers
follow the resolution process (Scheme-I), which involves
coupling of 2,3-pyridine dicarboxylic acid 2 with benzylamine
to obtain 3 followed by pyridine ring reduction to afford
intermediate 4 which upon reduction of carbonyl groups
afforded N-benzyl nonane intermediate 5. There after inter-
mediate 5 was subjected to resolution with D-(-) tartaric acid
in ethanol followed by deprotection to afford nonane 1.
Herein, we report alternative stereoselective reduction
procedures on dione 3 as a source of chirality in the nonane 1.
6-Benzyltetrahydro-1H-pyrrolo[3,4-b]pyridine-
5,7(6H,7aH)-dione (4): 50 g, (0.21 mol, 1.0 eq) of 6-benzyl-
5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione 3 was added to 250
mL of toluene in hydrogen vessel, 29 g, (0.252, 1.2 eq) of
L-proline was added and continued the stirring for 10 min,
3.5 g, (7 %) of palladium charcoal on carbon was added.
Stirring was continued for 15-30 min and warmed to 70 ºC
with 7-8 kg/cm2 hydrogen pressure for 5-6 h and further
warmed the reaction mass to 80-85 ºC with 8 kg/cm2 hydrogen
pressure for 9-10 h, after completion of the reaction cooled to
room temperature and catalyst was separated and washed with
100 mL of toluene. The clear filtrate was concentrated under
reduced pressure at below 70 ºC to furnish 49.5 g, ( 0.20 mol,
97.05 %) of 6-benzyltetrahydro-1H-pyrrolo[3,4-b]pyridine-
5,7 (6H, 7aH)-dione 4 with 15 % ee. IR (KBr, νmax, cm-1):
3382.49 (NH), 3034.40 (aromatic CH), 2957.04 (aliphatic CH),
1718.93 (C=O); 1H NMR (400 MHz, DMSO-d6): δ
(ppm).7.25-7.34 (m, 5H), 4.56 (s, 2H), 4.00 (d,1H, J = 6.8
Hz), 2.99 (q, 1H, J = 6.4 Hz),2.57-2.70 (m, 2H), 1.77-1.84
(m, 1H), 1.63-1.69 (m, 1H), 1.42-1.48 (m, 1H), 1.30-1.36 (m,
1H); 13C NMR (400 MHz, DMSO-d6): δ (ppm) 178.20, 177.09,
136.25, 128.52, 127.39, 127.30, 72.16, 54.47, 41.73, 41.15,
40.12, 21.67; MS (ESI): m/z calculated for C14H16N2O2 (M + H):
244.2; found: (M + H+) 245.5.
EXPERIMENTAL
General: Solvents and reagents were used for all the
reactions as received. The1H and 13C NMR spectra were recorded
in CDCl3/DMSO-d6 on Varian Gemini 400 MHz or 500 MHz
FT NMR spectrometer; the chemical shifts were reported in δ
ppm relative to tetramethylsilane TMS (0 ppm). The FT-IR
spectra were recorded in the solid state KBr/neat dispersion
using Shimadzu IR Prestige-21 spectrophotometer. The mass
spectra were recorded on SSMS PESCIEX,API-3000 machine
in electron spray mode. The melting points were determined
by using Polmon (Model No.: MP96) melting point apparatus.
The specific optical rotation was recorded on Jasco P-2000
2,3-Bis(chloromethyl)pyridine (7): 25 g, (0.142 mol,
1 eq) of pyridine-2,3-diyldimethanol hydrochloride was
dissolved in 51.3 g, (0.431 mol, 2.4 eq) of thionyl chloride

8702 Reddy et al.
Asian J. Chem.
O
O
H
H
H
COOH
a
b
c
N
N
N
90%
N
COOH
70%
N
N
H
N
H
H
O
O
5
4
2
3
d
35%
H
H
d
N
NH
90%
N
H
N
H
H
H
6
1
a) Ac2O, toluene, benzylamine, water; b) H2, Ru-C; b) LiAlH4, THF, 0 - 5°C, 10h; c) DMF, IPA, ethanol, D-(-)-tartaric
acid; d) Pd/C, methanol.
Scheme-I: Precedented approach for 11,2
with stirring at 0-10 ºC and temperature increased to 15-20 ºC
for 1 h, 60 mL of MTBE was added and continued stirring for
30-60 min. Reaction mass was cooled to 0-5 ºC for 1 h, filtered
the precipitated material and washed with 20 mL of MTBE to
furnish 27 g of dichloro compound in the form of hydrochloride
salt as a white solid. This material was added to 150 mL of
DCM with stirring, 100 mL of water also added and pH of the
reaction mass was adjusted to 7.5-8.0 with 5 % sodium carbonate
solution. Organic layer was separated and extracted aqueous
layer with 50 mL of DCM. Combined extracts were concen-
trated under reduced pressure at below 40 ºC to furnish 20 g,
(0.113 mol, 88 %) of 3-bis(chloromethyl)pyridine 7 as a light
brown coloured oil. IR (KBr, νmax, cm-1): 3033.52 (aromatic
continued stirring for 30-60 min stirring. Filtered the material
and washed with 100 mL of water. Wet material dried at 60 ºC
to furnish 95 g (0.414 mol, 95.4 %) of 2-(6-methoxynaphthalen-
2-yl)propanamide 8 as a off-white powder. IR (KBr, νmax, cm-1):
3350.04 (NH), 3195.34 (aromatic CH), 2983.51 (aliphatic CH),
1606.38 (aromatic C=C); 1H NMR (400 MHz, DMSO-d6): δ
(ppm).7.70-7.78 (m, 3H), 7.43 (q, 1H, J = 2 Hz), 7.40 (s, 1H),
7.26 (s, 1H), 7.12 (d, 1H), J = 2.4 Hz), 6.83 (s, 1H), 3.85 (s,
1H), 3.70 (q, 1H, J = 6.8 Hz), 1.37 (d, 3H, J = 6.8 Hz); 13C
NMR (400 MHz, DMSO-d6): δ (ppm) 176.47, 157.42, 137.76,
133.58, 129.27, 128.79, 127.12, 126.86, 125.75, 119.03,
106.12, 55.59, 45.21, 18.67; MS (ESI): m/z calculated for
C14H15NO2 (M + H): 229.27; found: (M + H+) 230.4.
1
CH), 2928.21 (aliphatic CH), 1612.04 (aromatic C=C); H
NMR (400 MHz, DMSO-d6): δ (ppm).8.68 (q, 1H, J = 2Hz),
8.23 (q, 1H, 1.6Hz), 7.68 (q,1H, J = 5.2 Hz), 5.05 (s, 2H),
5.01 (s, 2H); 13C NMR (400 MHz, CDMSO-d6): δ (ppm)
153.12, 147.63, 140.97, 133.25, 125.08, 42.69, 41.54; MS
(ESI): m/z calculated for C7H7Cl2N (M + H): 175.0; found:
(M + H+) 176.0.
H2N
O
OMe
(S)-2-(6-Methoxynaphthalen-2-yl)propanamide (8)
(S)-2-(6-methoxynaphthalen-2-yl)-1-(5H-pyrrolo[3,4-
b]pyridin-6(7H)-yl)propan-1-one (9): A mixture of 6,7-
dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride 12 (20 g,
0.12 mol) and dichloromethane was stirred for 10-15 min. To
this mixture diisopropylethylamine (82.42 g, 0.63 mol, 5.25
eq), was added slowly through addition dropper at 10-20 ºC,
followed by (S)-2-(6-methoxynaphthalen-2-yl)propanoyl
chloride (40 g, 0.16 mol, 1.34 eq), in dichloromethane (500
mL) was added at below 25 ºC and maintained for 2 h at 25-
35 ºC. After completion of the reaction water (400 mL) was
added and stirred for 15 min. Organic layer was separated and
extracted aq. layer with dichloromethane (2 × 200 mL), com-
bined organic layer was washed with 10 % sodium carbonate
solution. Final organic layer was dried with sodium sulphate
and solvent was evaporated under reduced pressure at below
40 ºC to afford 22 g, (0.094 mol, 74 %) of (S)-2-(6-methoxy-
naphthalen-2-yl)-1-(5H-pyrrolo[3,4-b]pyridin-6(7H)-
yl)propan-1-one 9 as a light brown coloured liquid. IR (KBr,
Cl
Cl
N
2,3-Bis(chloromethyl)pyridine (7)
(S)-2-(6-Methoxynaphthalen-2-yl)propanamide (8):
100 g, (0.43 mol, 1.0 eq) of (S)-naproxen 13 was dissolved in
500 mL of DCM and 1 mL of DMF with stirring and cooled
to 0-5 ºC. 103.47 g, (0.86 mol, 2.0 eq) of thionyl chloride was
added through addition dropper at 0-5 ºC, reaction mass was
heated to reflux for 6-8 h, after completion of the reaction,
concentrated under reduced pressure at below 50 ºC and diluted
with 500 mL of dichloromethane. Anhydrous ammonia was
continuously added up to pH of the reaction mass was 10 and
stirring was continued for 1 h. Filtered precipitated material
and washed with 200 mL of dichloromethane, this wet material
was added to 200 mL of 2 % sodium carbonate solution and

Vol. 25, No. 15 (2013)
A Novel Synthesis of (4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine 8703
1
νmax, cm-1): 3035.30 (aromatic CH), 2965.07 (aliphatic CH),
1606.37 (C=C), 1163.61 (C-O); 1H NMR (400 MHz, DMSO-
d6): δ (ppm).8.39-8.43 (m, 1H), 7.68 – 7.81 (m, 4H), 7.46 (d,
1H, J = 4 Hz), 7.23-7.27 (m, 2H), 7.13 (dd, 1H, J = 2.8 Hz,
J = 2.8 Hz), 5.10 (t, 1H, J = 16.8 Hz), 4.41-4.77 (m, 3H),
4.15-4.20 (m, 1H), 3.84 (s, 3H), 1.42 (d, 3H, J = 7.2 Hz); 13C
NMR (400 MHz, DMSO-d6): δ (ppm) 172.12, 157.17, 152.72,
148.86, 136.40, 133.17, 131.39, 130.30, 129.09, 128.47,
127.18, 126.35, 125.70, 122.48, 118.68, 105.69, 55.12, 52.21,
50.31, 42.68, 20.07; HRMS (ES) calcd. (%) for C21H21N2O2
(MH+) 333.1603 and found 333.1587; SOR: [α]D25 = 67.5º
(c = 0.04 % in ethanol).
(aromatic C=C); H NMR (400 MHz, DMSO-d6): δ (ppm).
10.07 (s, 1H), 8.52(d, 1H, J = 4.4 Hz), 7.85 (d, 1H, J = 7.2
Hz), 7.38 (q, 1H, J = 4.8 Hz), 4.65 (s, 2H), 4.54 (s, 2H); 13C
NMR (400 MHz, CDCl3): δ (ppm) 191.92, 160.18, 138.19,
134.15, 132.27, 131.03, 127.86, 127.67, 123.54, 119.87,
106.04, 55.39; MS (ESI): m/z calcd. (%) for C7H8N2 (M + H):
120.15; found: (M + H+) 121.1.
NH
N
.HCl
6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine (12)
(S)-1-[(4aS,7aS)-Hexahydro-1H-pyrrolo[3,4-b]pyridin-
6(2H)-yl]-2-(6-methoxynaphthalen-2-yl)propan-1-one (10):
10 g, (0.03 mol, 1.0 eq) of (S)-2-(6-methoxynaphthalen-2-
yl)-1-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propan-1-one 9 was
added to 100 mL of toluene, 3 g, of 5 % palladium carbon was
added in hydrogen pressure vessel. Reaction mass was warmed
to 80 ºC under 8 kg/cm2 hydrogen pressure for 20-24 h, after
completion of the reaction was cooled to room temperature,
catalyst was separated by filtration on hyflow and washed with
100 mL of methanol. The combined filtrates were concen-
trated under reduced pressure to obtain crude in the form of
residue. This residue was dissolved in IPA and dry HCl gas
was passed up to reaction mass pH attained to below 2 and
continued stirring for additional 5 h. Precipitated material was
filtered and washed with 5 mL of chilled IPA. This wet material
was extracted into DCM by adjusting the pH to 10 with 5 %
Na2CO3 solution. Volatiles were removed under reduced
pressure at below 45 ºC under reduced pressure to afford 4.5 g,
(0.013 mol, 45 %) of (S)-1-((4aS,7aS)-hexahydro-1H-
pyrrolo[3,4-b]pyridin-6(2H)-yl)-2-(6-methoxynaphthalen-2-
yl)propan-1-one 10 as a light yellow coloured liquid. IR (KBr,
νmax, cm-1): 3127.82 (aromatic CH), 2933.73 (aliphatic CH),
1635.64 (C=O), 1504.48 (aromatic C=C), 1172.72 (C-O); 1H
NMR (400 MHz, DMSO-d6): δ (ppm).7.77 (d, 2H, J = 8.5
Hz), 7.70 (s, 1H), 7.42 (t, 1H, J = 7 Hz), 7.27 (s, 1H), 7.14
(dd, 1H, J = 2.5 Hz, 2 Hz), 3.89-4.00 (m, 1H0, 3.86 (s, 3H),
3.60-3.66 (m, 1H), 3.03-3.45 (m, 7H), 2.32-2.44 9m, 1H), 1.96-
2.06 (m, 1H), 1.50-1.55 (m, 2H), 1.35 (d, 3H, J = 6.5 Hz); 13C
NMR (400 MHz, DMSO-d6 ): δ (ppm) 191.92, 160.18, 138.19,
134.15, 132.27, 131.03, 127.86, 127.67, 123.54, 119.87,
106.04, 55.39; HRMS (ES) calcd. (%) for C21H27N2O2 (MH+)
339.2073 and found 339.2056; SOR: [α]D25 = 122.8º (c =
0.01% in ethanol).
(4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine (1):
5 g (0.014 mol, 1eq) of (S)-1-((4aS,7aS)-hexahydro-1H-
pyrrolo[3,4-b]pyridin-6(2H)-yl)-2-(6-methoxy naphthalen-2-
yl)propan-1-one 10 was added into round bottom flask. To
this 30 mL of 20 % aq. methanol and 8.2 g, (0.14 mol, 10 eq)
of KOH was added with stirring at room temperature. Warmed
the reaction mass to reflux for 72 h, after completion of the
reaction, methanol was evaporated under reduced pressure at
below 60 ºC. 25 mL of water was added, extracted aqueous
layer with 3 × 25 mL of CHCl3; combined organic layer was
dried over Na2SO4, clear filtrate was concentrated under
reduced pressure at below 50 ºC to furnish 1.8 g, (0.014 mol,
96 %) of (4aS, 7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine 1
as a light brown coloured liquid.
Aqueous layer was taken and adjusted the pH to 2 with
aqueous HCl and extracted into toluene; isolated racemic
naproxen 14 from toluene at 0-5 ºC after charcoal treatment
as half white coloured powder (3.23 g, 95 % yield with 97 %
purity).
(4aS,7aS)-Octahydro-1H-pyrrolo[3, 4-b]pyridine (1):
Purity by HPLC:96.7 %;chiral purity by HPLC:98.93 %;1H
NMR (400 MHz, DMSO-d6): δ (ppm). 2.95-2.98 (m, 1H),
2.63-2.82 (m, 4H), 2.54 (dd,1H, J = 1.6 Hz, J = 1.2 Hz ), 2.39-
2.45 (m, 1H), 2.16-2.45 (br, s, 2H), 1.81-1.89 (m, 1H), 1.59-
1.66 (m, 2H), 1.35-1.46 (m, 1H), 1.24-1.31(m, 1H); 13C NMR
(400 MHz, DMSO-d6): δ (ppm) 57.43, 53.37, 47.78, 44.49,
37.85, 23.51, 21.90; MS (ESI): m/z calcd. (%) for C7H14N2
(M + H): 126.20; found (%): (M + H+) 126.7; SOR: [α]D25 =
-3.769º (c = 2 % in ethanol).
Racemic naproxen (14): m.p. 155-158 ºC; 1H NMR (400
MHz, DMSO-d6) δ 7.66-7.68 (d, 3H, J = 8.8Hz), 7.39 (dd,
1H, J = 1.5Hz, J = 8.3Hz), 7.08-7.13 (m, 2H), 3.8 (s, 3H),
3.82-3.86 ( m, 1H), 1.56 (d, 3H, J = 6.8); 13C NMR (400 MHz,
CDCl3): δ 180.91, 157.65, 134.83, 133.77, 129.27, 128.84,
127.20, 126.16, 126.11, 119.01, 105.52, 55.27, 45.21, 18.10;
MS: calcd. (%) for C14H14O3 230 (M+), found 23 (MH+); IR
(KBr, νmax, cm-1): 3201.02 (OH), 1728 (C=O), 3002.9 (aromatic
CH), 855.66 (C=C), 1264.69 (CO); SOR: [α]D25 = 0.02º (c =
1 % in chloroform).
6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine (12): 17 g,
(0.062 mol, 1.0 eq) of 6-(2,4-dimethoxybenzyl)-6,7-dihydro-
5H-pyrrolo [3,4-b] pyridine was added to 15 mL of
trifluoroacetic acid and 5 mL of triethyl silane with stirring at
room temperature. This mixture was heated to 60-65 ºC for
4 h, after completion of the reaction, 50 mL of ethyl acetate
was added with stirring and cooled to room temperature, 50 mL
of 5 % HCl in ethyl acetate was added slowly drop by drop at
room temperature in 30-45 min and stirring was continued till
material precipitation, filtered the precipitated material and
washed with 25 mL of ethyl acetate to furnish 11 g, (0.056
mol, 90 %) of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydro-
chloride 12 as a brown solid. IR (KBr, νmax, cm-1): 3431.58
(NH), 3031.97 (aromatic CH), 2971.44 (aliphatic CH), 1622.84
RESULTS AND DISCUSSION
In our endeavor, we attempted to improve the enantio-
selectivity during the reduction of 6-benzyl-5H-pyrrolo[3,4-
b]pyridine-5,7(6H)-dione (3) involving the reduction of pyridine
ring using L-proline as a chelating agent and 5 % palladium

8704 Reddy et al.
Asian J. Chem.
TABLE-1
REDUCTION OF COMPOUND 3 IN PRESENCE OF L-PROLINE
*Chiral HPLC (%)
Entry
Solvent
Reducing agent
L-Proline qty (eq)
Yield (%)
Desired
50.5
50.2
57.4
53.6
54.1
53.5
51.5
57.5
Undesired
49.4
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Methanol
AcOH
Pd/C
Pd/C
0.00
0.10
1.2
1.2
1.2
1.2
00
94
96
96
96
90
92
90
91
49.8
Pd/C
42.6
Pd/C
46.4
Pd/C
45.9
Ethanol
Toluene
Toluene
Pd/C
46.5
Pd-Cu/C
Pd-Cu/C
48.5
1.2
42.5
*Intermediate 4 was further converted to 1 and analyzed for chiral HPLC.
on carbon as reducing agent. The required amide 3 for employed
in the reduction was synthesized using known procedure3.
Present studies involve varying the mole ratio of L-proline by
using Pd/C and Pd-Cu/C as a reducing agents were conducted
and the results are summarized in Table-1. When the reaction
was performed with the catalytic quantity of L-proline there
was no enhancement in the ee and it was similar to racemic
mixture (entry 2 in Table-1). Increasing the quantity of addi-
tive (L-proline) to stoichiometric amount brought about a
marginal increase in ee in favour of the desired isomer (entry
3 in Table-1).
benzamide and being chiral it might help in getting selectivity
during the reduction.
Substantial improvement was observed in reaction time
and yield. Unprecedented reaction conditions employed for
condensation involved reaction temperature of 80-90 ºC using
5 mol equivalents of sodium hydride in 10 volume toluene.
The results are summarized in Table-2.
TABLE-2
OPTIMIZATION OF NaH QUANTITY
Entry
Base
NaH
NaH
NaH
Solvent Base Qty (Eq)
Temp. (ºC)
80-90
9 (%)
60
1
2
3
Toluene
Toluene
Toluene
3
4
5
In the next step, various solvents were screened to find
out the impact on selectivity. It can be observed that there was
no big impact on enantioselectivity with various solvents
screened except toluene as shown in Table-1 (entry 3).
80-90
75
80-90
90
*Confirmed by TLC.
Thereafter (S)-2-(6-methoxynaphthalen-2-yl)-1-(5H-
pyrrolo [3,4-b]pyridin-6(7H)-yl)propan-1-one 9 was subjected
to hydrogenation with 5 % palladium catalyst followed by
deprotection with HBr in acetic acid to afford the target nonane
1 (Scheme-III). The resulted nonane was analyzed for chiral
purity and it was found to be a racemic. However, the reaction
time was reduced along with the improvement in the yield.
In order to understand whether the zero enantioselectivity
was due to non-selective hydrogenation or early on racemization
of chiral centre present in naproxen amide 8 under basic condi-
tions or not, we performed control experiment by employing
similar reaction condition i.e., NaH/toluene. Chiral HPLC
analysis of the product showed the complete racemization
(Scheme-IV). Results are summarized in Table-3.
O
O
H
a
N
N
96%
N
H
N
H
O
O
3
4
a) Pd/C, L-proline, toluene, 80°C, 24h.
Scheme-II: Reduction of 3
While the possible hydrogen bonding effect of L-proline
was demonstrated to achieve the selectivity up to 15 % ee
further study focused on the reducing agent. Copper-palla-
dium couple on carbon catalyst was used as a reducing agent.
However selectivity could not be improved (Table-1; entry 7).
It was observed that there was no remarkable effect of
solvent and additive L-proline on the selective hydrogenation
of the pyridine ring. In continuation with the studies, we shifted
our focus to find an alternative route that could furnish the
enantiomerically pure nonane.
TABLE-3
CHIRAL HPLC RESULTS OF 8
(S)-2-(6-Methoxynaphthalen-2-
yl)propanamide (8)
S-Isomer R-Isomer
(%)
Entry
(%)
1
2
Initial
98
2
After 0.5 h maintenance at 80-90 ºC
55
45
Since the reaction conditions employed for di-alkylation
was leading to racemization of the (S)-2-(6-methoxynaphthalen-
2-yl)propanamide 8, we adopted another approach featuring
the preparation of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine 12
following the known procedure10. Alkylation of the 6,7-dihydro-
5H-pyrrolo[3,4-b]pyridine 12 with (S)-naproxen 13 was carried
out in presence of phenyl boronic acid as catalyst in o-xylene
at 145 ºC. The intermediate obtained after 2-(6-methoxy-
naphthalen-2-yl)-1-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propan-
At first bis(chloromethyl)pyridine 7 was synthesized
following the known procedure9. Our attempts to cyclize the
chloro intermediate 7 by using benzamide was not successful.
In addition to this, various other bases screened to couple the
benzamide and chloro intermediate and attempts were unsuc-
cessful.
In order to increase the reactivity of amide component,
(S)-2-(6-methoxynaphthalen-2-yl)propanamide 8 was selected
for condensation assuming that it is more reactive than the

Vol. 25, No. 15 (2013)
Cl
A Novel Synthesis of (4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine 8705
O
O
a
b
N
OMe
N
OMe
Cl
N
70%
N
95%
N
H
7
9
10a
85%
c
H
H
NH
N
H
1
a) (S)-Naproxamide (8), toluene, NaH, 80 - 90°C, 5h, AcOH, EA, H2O, n-heptane; b) 5% Pd/C, toluene,80°C, 8 kg/cm2,24h;
c) 48% HBr, propionic acid,phenol, reflux, 6 - 7h, MTBE, EA, NaOH, H2O, NaCl, CHCl3.
Scheme-III: Novel approach for 1
TABLE-4
CHIRAL HPLC RESULTS OF 13
NH2
NH2
a
S-Isomer R-Isomer
O
O
Entry
(S)-Naproxen (13)
MeO
(%)
99.8
51.5
(%)
0.2
MeO
1
2
Initial
8
11
After 10 h, maintenance at 145 ºC
48.5
a) NaH, toluene, 85 - 90°C, 30 minutes.
Scheme-IV: Racemization of 8
Hence, we concluded that the racemization of the coupling
agent was not only due to presence of strong base, but also due
to the reaction temperature in the presence of acidic catalyst.
Keeping in view of the extreme reaction conditions leading
to racemization of the coupling agent, the coupling agent was
primarily activated by making its acid chloride and then
coupled with the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine 12
using DIPEA as a HCl scavenger at 0-5 ºC. The coupled inter-
mediate 9 was further reduced with 5 % palladium on carbon
to get the reduced intermediate 10 followed by de-coupling
with HBr to afford the target intermediate nonane 1. The
obtained nonane was analyzed for chiral purity and the enantio-
selectivity was found to be much improved (20 % ee) but still
it is extremely poor proposition from synthesis standpoint
(Scheme-VII).
1-one 9 was subjected to reduction of pyridine ring using 5 %
palladium on carbon catalyst in toluene to afford the 1-(hexahydro-
1H-pyrrolo [3, 4-b] pyridin-6(2H)-yl)-2-(6-methoxynaphthalen-
2-yl) propan-1-one 10, which was subjected to de-coupling to
yield the target intermediate nonane 1 (Scheme-V).
To our surprise, we once again encountered with racemi-
zation. The reason for ending up with racemic compound was
found to be due to racemization of the (S)-naproxen 13 during
the coupling with 6,7-dihydro-5H-pyrrolo[3,4-b] pyridine 12.
This was confirmed by chiral HPLC analysis of (S)-naproxen
13 before and after reflux in o-xylene in presence of phenyl
boronic acid as a catalyst and in absence of intermediate 12,
respectively. Chiral HPLC results are summarized in Table-4
(Scheme-VI).
N
H
OMe
b
N
a
N
NH
70%
O
N
H H
O
N
MeO
12
10a
9
c
85%
H
H
NH
N
H
1
a) (S)-Naproxene (13), o-xylene, phenylboronic acid, Na2CO3, H2O, reflux, 24h; b) 5% Pd/C, toluene, 80°C, 8 kg/cm2,24h; c)
HBr in AcOH, phenol, propionic acid, reflux, 6 - 7h, NaCl, NaOH, CHCl3.
Scheme-V: Modified novel approach for 1

8706 Reddy et al.
Asian J. Chem.
TABLE-5
SCREENING OF BASES
OH
OH
a
Entry
Base
Temp. (ºC)
% of 1
% of 32
96
O
O
MeO
MeO
1
2
3
4
5
KOH
KtOBU
LiOH
80
80
80
80
80
92
90
97
13
14
Reaction incomplete
Reaction incomplete
Reaction incomplete
a) o-xylene, phenyl boronic acid, ref lux, 10h.
NaOMe
NaOC2H5
Scheme-VI: Racemization of 13
*Reactions carried out in aq. methanol.
Having gained intellectual control over reaction sequence,
we decided to develop a simple method for purification and
hydrolysis of 10 to obtain the nonane 1 and naproxen 13. At
first the required isomer was isolated by making the HCl salt
in IPA thereafter various bases were screened to hydrolyze
10. Among all the bases KOH and KtOBU were afforded the
best results (Table-5, entry-1 and 2).
workup was purified through column chromatography to
afford the coupled intermediate 9. The pyridine ring of the
intermediate 9 was reduced using palladium on carbon as
catalyst in toluene solvent. The catalyst was filtered off and
the target diastereomeric intermediate was obtained as a crude.
Diasteriomers were separated by making the hydrochloride
salt in isopropyl alcohol. After separation, intermediate 10
converted to nonane by hydrolyzing with KOH in aqueous
methanol to afford nonane 1 and racemic naproxen 14 with
an excellent yield (95 and 90 %) was recovered (Scheme-
VIII).
Based on the results and observations from the experiments
conducted to attain enantioselectivity of nonane, the following
process was finalized. The cyclic amine intermediate10 12 was
coupled with the acid chloride of (S)-naproxen 13 in presence
of DIPEA at 0-5 ºC. The crude material obtained after
N
H
OMe
a
N
b
NH
N
74%
95%
O
N
NH
O
MeO
H
12
10a
9
c
85%
H
H
NH
NH
1
20% ee
a) (S)-Naproxenacidchloride, toluene, DIEPA, Na2CO3, H2O, 0 - 5°C, 2h; b) 5% Pd/C, toluene, 80°C, 8 kg/cm2, 24h; c) HBr
in AcOH, phenol, propionic acid, reflux, 6 - 7h, NaCl, NaOH, CHCl3.
Scheme-VII: Modified novel approach for 1
H
O
O
b
a
N
OMe
N
OMe
NH
N
H
N
95%
74%
N
H
10a
12
9
c
40%
H
H
H
H
O
95%
N
OMe
NH
d
N
H
N
H
.HCl
10
1
98% ee
a) (S)-Naproxenacidchloride, DIEPA, MDC, Na2CO3, H2O, 0 -5°C, 1h; b) 5% Pd/C, toluene, 80°C, 8 kg/cm2, 24h; c) IPA,
dry HCl; d) KOH, Aq.methanol, reflux, 72h, NaCl, CHCl3, Aq.HCl, toluene.
Scheme-VIII: Optimized Final novel scheme for 1

Vol. 25, No. 15 (2013)
A Novel Synthesis of (4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine 8707
2. U. Petersen, A. Krebs, T. Schenke, T. Philipps, K. Grohe, K.D. Bremm,
R. Endermann, K.G. Metzger and I. Haller, EP0, 550, 903 (1992).
Conclusion
An efficient process for pyridine ring reduction with 15-
20 % ee has been developed by using L-proline or naproxene
as a chiral auxiliary. Enantiomerically enriched novel process
has been developed for (4aS,7aS)-octahydro-1H-pyrrolo[3,4-
b]pyridine by investigating three different approaches. We
demonstrated coupling between 2,3-bis(chloromethyl)pyridine
7 and (S)-2-(6-methoxynaphthalen-2-yl)propanamide 8 for the
first time in presence of sodium hydride in toluene with 70 %
of yield and recovery process for racemic naproxen 14 by
hydrolyzing of 10 with KOH in aq. methanol was also estab-
lished.
3. A. Ramakrishnan and S.B. Narayan, V. WO 125,425 (2009).
4. J.W. Kim, H.T. Park, H.M. Kim, J.B. Kim and D.N. Pearson, US Patent
5,770,597 (1998).
5. (a) W. Zheqing, F. Shushan and C. Yongzhi, WO085480 (2008); (b) Z.
Wang, S. Feng and Y. Cheng, US Patent 0,221,329 (2008).
6. W. Tianjun, Faming Zhuanli Shenqing, 7 (2010).
7. O. Masatoshi and N. Akira, WO 122,774 (2010).
8. (a) F. Peter, WO58, 532, 1999; (b) D. Claus, Ger.Offen. WO 09, 200,
1999; (c) F. Peter, US Patent 6, 235, 908 (2001); (d) D. Herbert, K.
Andreas, L. Walter, P. Hanns-Ingolf, S. Dietrich, G. Rolf and R. Tobias,
US Patent 0,044,205 (2004); (e) L. Mingliang, W.Yonggang, S. Lanying
and G. Huiyuan, Zhongguo Yiyao Gongye Zazhi, 35, 129 (2004); (f) P.
Xianhua, T. He, O. Wenhua, R. Libo and Y. Wenqiu, Faming Zhuanli
Shenqing, 13 (2009); (g) M. Riccardo, A. Glancarlo, B. Elisabetta, C.
Andrea, F. Stefano and G. Marco, WO100,215 (2010).
ACKNOWLEDGEMENTS
9. J.S. Grimm, C.A. Maryanoff, M. Patel, D.C. Palmer, K.L. Sorgi, S.
Stefanick, R.R.H. Webster and X. Zhang, Org. Process Res. Dev., 6,
938 (2002).
The authors thank the Management of R&D-CTO and
IPDO, Dr. Reddy's Laboratories Ltd., for supporting this work.
Cooperation from the colleagues fromAnalytical Development
is highly appreciated.
10. M.S. Sakya, D.V.M. Berg, K. Pouwer, M.J. Humphrey, J.C. Helal and
J.C. O’Donnel, Tetrahedron Lett., 51, 5859 (2010).
REFERENCES
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K. Metzger, R. Endermann and H. Zeiler, EP 0,350,733 (1990).