Alternative total synthesis of (-)-galanthamine hydrobromide

Article abstract of DOI:10.1080/00397910802029067

An alternative total synthesis of (-)-galanthamine (1) hydrobromide, employing ecofriendly amidation, oxidative coupling, and classical resolution strategies is accomplished. Copyright Taylor & Francis Group, LLC.

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Alternative Total Synthesis
of (-)-Galanthamine
Hydrobromide
Jambula Mukunda Reddy a , Kotagiri Vijay Kumar
a , Veeramalla Raju a , Bolguddu Vijay Bhaskar a ,
Vurumidi Himabindu b , Apurba Bhattacharya a ,
Venkatram Sundaram a , Rahul Banerjee c , Ghanta
Mahesh Reddy a & Rakeshwar Bandichhor a
a Integrated Product Development (IPD), Dr. Reddy's
Laboratories Ltd., Qutubullapur, India
b Institute of Science and Technology, Center
for Environmental Science, Jawaharlal Nehru
Technological (J. N. T.) University, Hyderabad, India
c Discovery Research, Dr. Reddy's Laboratories Ltd,
Hyderabad, India
Version of record first published: 18 Aug 2008
To cite this article: Jambula Mukunda Reddy, Kotagiri Vijay Kumar, Veeramalla Raju,
Bolguddu Vijay Bhaskar, Vurumidi Himabindu, Apurba Bhattacharya, Venkatram
Sundaram, Rahul Banerjee, Ghanta Mahesh Reddy & Rakeshwar Bandichhor
(2008): Alternative Total Synthesis of (-)-Galanthamine Hydrobromide, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:13, 2138-2149
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Synthetic Communications1, 38: 2138–2149, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802029067
Alternative Total Synthesis of (–)-Galanthamine
Hydrobromide
Jambula Mukunda Reddy,1 Kotagiri Vijay Kumar,1
Veeramalla Raju,1 Bolguddu Vijay Bhaskar,1 Vurumidi Himabindu,2
Apurba Bhattacharya,1 Venkatram Sundaram,1 Rahul Banerjee,3
Ghanta Mahesh Reddy,1 and Rakeshwar Bandichhor1
1Integrated Product Development (IPD), Dr. Reddy’s Laboratories Ltd.,
Qutubullapur, India
2Institute of Science and Technology, Center for Environmental Science,
Jawaharlal Nehru Technological (J. N. T.) University, Hyderabad, India
3Discovery Research, Dr. Reddy’s Laboratories Ltd., Hyderabad, India
Abstract: An alternative total synthesis of (ꢀ)-galanthamine (1) hydrobromide,
employing ecofriendly amidation, oxidative coupling, and classical resolution
strategies is accomplished.
Keywords: Amidation; Galanthamine; Oxidative coupling
INTRODUCTION
Galanthamine 1, active against the acetylcholinesterase enzyme that
increases postsynaptic membrane susceptibility to acetylcholine,[1] is an
alkaloid base extracted from the leaves of the plant Galanthus nivalis L.[2]
Hydrobromide salt of 1 is commercially available as a registered drug under
the trade name Nivalin and many others for the treatment of Alzheimer’s
disease.[2] In the search for more robust, ecofriendly, and cost-effective
synthetic routes, we are engaged in developing an alternate synthesis of 1.
Received October 12, 2007
Dr. Reddy’s IPDO Communication IPDO-IPM-00050.
Address correspondence to Rakeshwar Badichhor, Innovation Plaza, IPD,
R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42,45,46 & 54, Bachupally,
Qutubullapur, R. R. Dist-500073, India. E-mail: rakeshwarb@drreddys.com
2138

(–)-Galanthamine Hydrobromide
2139
Figure 1. (ꢀ)-Galanthamine and norwedine.
The nonscalable and uneconomical isolation process of 1 from its natu-
ral source ($50,000 per kilogram)[3] has prompted various research groups
to devise several syntheses, particularly involving biomimetic oxidative
phenol coupling[4] and palladium-catalyzed enantio-divergent synthesiss,[5]
to create the structural type unique to 1 and its derivative (Figure 1).
All hitherto known biomimetic syntheses[4] are poor yielding whereas
asymmetric syntheses[5] are not cost-effective nor high yielding and there-
fore cannot be implemented in the industries for commercial production.
Classical resolution, the trivial but most reliable technique, has been
employed as one of the key strategies on a pilot-scale production of 1.[4]
Another key reaction, in the precedented synthesis, was an oxidative
ring closure that afforded severe skin allergen intermediate narwedine 2
in the later course of the synthesis of 1.
RESULTS AND DISCUSSION
The retrosynthetic analysis of 1, as shown in Figure 2, starts with the
installation of the northern part (i.e., bisphenol derivative 5) and the
southern part (p-hydroxy ethyl-N-methyl-phenyl amine derivative 8).
These two units (northern and southern) were bridged through an
amide tether. An oxidative coupling strategy was employed to forge the
spirocylic center, followed by furan ring formation. Finally, reduction
cascades and dehalogenation afforded the desired product (ꢁ) 1. Classi-
cal resolution provided the enantiomerically pure (ꢀ)-galanthamine 1.
The synthesis of the northern part,[6] bromobenzoic acid derivative 5,
commences with the isovanilline 3.
Benzylation of 3 afforded corresponding product 4 in 98% yield and
excellent purity. Bromination of resultant and subsequent KMnO4-
mediated oxidation gave rise to the bromobenzoic acid derivative 5 in
good yield (Scheme 1).
The synthesis of the southern part,[7] p-benzyloxy ethyl-N-methyl-
phenyl amine derivative 8, begins with the p-hydroxybenzylmethyl
carboxylate. Benzylation of carboxylate 6 afforded corresponding

2140
J. M. Reddy et al.
Figure 2. Retrosynthetic analysis.
product 7 in 98% yield. Amidation of the resultant and subsequent
borohydride-mediated reduction furnished the p-benzyloxy ethyl-
N-methyl-phenyl amine derivative 8 as an advanced synthonin good yield
(78% for two steps) as depicted in Scheme 2.
Ecofriendly phenyl boronic acid–catalyzed amidation[7] reaction of
intermediates 5 and 8 was performed to obtain amide 9.
In this reaction, as shown in Scheme 3, the acid moiety of 5 gets acti-
vated with phenyl boronic acid, which in turn provides an electron-deficient
acid carbonyl center that reacts with amine 8 to afford amide 9 in 93% yield.
Hydrogenolysis on 9 to afford 10 and efficient intramolecular oxidat-
ive coupling, in the presence of an amide bond, occurred with the substrate
10, resulting in a tetracyclic framework 11 in 62% yield. Formation of
radicals in both northern and southern units, mechanistically as shown
Scheme 1. Synthesis of northern part 5.

(–)-Galanthamine Hydrobromide
2141
Scheme 2. Synthesis of southern part 8.
in Scheme 4, is mediated by redox potential of ferric ions.[8] These two
radicals intimately succeeded to create a bond and furnished spirocyclic
intermediate 12. The southern part serves as a source of Michael acceptor
that facilitates the caging to form the furan ring, whereas o-quinonoid
(northern part), as a donor, afforded the tetracyclic skeleton 11 at the
expense of salvaging its aromaticity as depicted in Scheme 5.
Noticeably, we observed the formation of only one set of stereoi-
somer 11. The stereochemical outcome, supported by PM3 calculations,
may be considered as such because of an amide bond strain that brought
˚
both the subunits in a close proximity (C5–C11 ¼ 5.218 A) followed by
aligning them in an endo fashion and facilitating the formation of the
spirocyclic center in 12. Thus, an amide tether in framework 10 proved
to be advantageous over the amine intermediate.[9] Oxidative coupling
involving amine 14 (similar motif; Fig. 3)[9] is not high yielding, pre-
sumably because of the sp3 hybridized carbon that kept both the units
˚
away (C5–C11 ¼ 5.768 A) from each other.
In the cyclic ether formation events, spontaneous Michael addition
in the intermediate 12 progressed well, affording precursor 11 with
the desired diastereoselectivity.
Scheme 3. Ecofriendly amidation: Synthesis of amide 5.

2142
J. M. Reddy et al.
Scheme 4. Debenzylation and oxidative phenolic intramolecular cyclization.
PM3 calculation revealed that 12 (phenolic form) had a shorter dis-
˚
tance between the phenolic oxygen and Cb1 (2.510 A) than that between
˚
the oxygen and Cb2 (3.864 A) (Fig. 3c). Cb1 and Cb2 are the equivalent
Michael acceptor positions in the same plane that allows the formation
of only one set of enantiomers (RR andSS). The resulting stereoselecti-
vity can be presumed as a result of furan ring formation in the b plane.
A wide range of reagents for substrate-controlled stereoselective
reduction of a,b-unsaturated ketone was intensively investigated. Among
reagents screened, L-selectride was found to be a reagent of choice. The
L-selectride-mediated reaction of a,b-unsaturated ketone 11 (Table 1)
proceeded smoothly, affording alcohol 13 in excellent yield (80%) and
diastereoselectivity (de; 99.6%) (entry 9).
Vitride-mediated debromination and amide reduction[10] of 11 both
happened simultaneously in one pot to afford a diastereomeric mixture
Scheme 5. Plausible oxidative coupling mechanism.

(–)-Galanthamine Hydrobromide
2143
˚
Figure 3. (a) Distance between C5-C11 ¼ 5.218 A in amide 10; (b) Distance
˚
between C5-C11 ¼ 5.768 A in amine 14; (c) Phenolic O-Cb1 & Cb2 bond lengths
in intermediate 12.
of 1 in good yield (75%). Classical resolution of the diastereomeric
mixture of 1 employing (þ)-DPTTA monohydrate[11] furnished the ena-
tiomerically pure product (ꢀ)-1 with scalable yield (70% based on avail-
able enantiomer in the racemate) and chiral purity (99.91%).
A conventional method for the HBr salt formation using aq. HBr
afforded (ꢀ)-galanthamine hydrobromide [(ꢀ) 1 HBr] in 85% yield as
shown in Scheme 6.
EXPERIMENTAL
Unless otherwise stated, all nonaqueous reactions and distillations were
carried out under an atmosphere of dry nitrogen in dried glassware.
Commercially available starting materials and reagents were purchased
from Suven Pharmaceuticals, Hyderabad, India, and were used as
received. When necessary, solvents and reagents were dried prior to
use. Laboratory reagents (LR)-grade toluene, tetrahydrofuran, diethyl
ether, methanol, ethanol, and dichloromethane were used as received
from the supplier.

2144
J. M. Reddy et al.
Table 1. Stereoselective reduction to 13
Time
(h)
Temp.
(ꢂC)
Yield
(%)
No.
Reagents (eq.)
Solvents
AcOH
AcOH
AcOH
dr (a:b)
1
2
3
HCO2H (3.0)
NaBH4(2.5)
NaBH4 (3.0)=
I2 (cat.)
12
3
2.5
100
50:50
65:35
65:35
60
65
60
80
80
4
5
6
7
8
NaBH4 (3.0)
Vitride (5.0)
DIBALH (3.5)
BH3.DMS (4.5)
Camphenyl
Sec. BuOH
Toluene
1,4-Dioxane
Toluene
Toluene
2.5
8
6
9
10
80
25:75
55:45
30:70
30:70
70:30
70
55
60
65
40
110
110
70
80
borane (3.0)
L-selectride (2.5) THF
9
3
ꢀ10 to ꢀ0 0.2:99.8
80
Analytical thin-layer chromatography (TLC) was performed on EM
reagents 0.25-mm silica-gel aluminium support plates bought from
Merck. Visualization was accomplished by irradiation under a 254-nm
UV lamp.
1H NMR spectra were recorded on a Varian 400 MHz instrument
13C NMR spectra were recorded on a Varian 200-MHz spectrometer.
Chemical shifts are reported in parts per million (ppm) from tetramethyl-
silane (0 ppm) or with the solvent resonance as the internal standard
(CDCl3 7.26 ppm, DMSO-d6 2.49 ppm, acetone-d6 2.04 ppm, benzene-d6
Scheme 6. End-game strategy to (ꢀ) 1 HBR.

(–)-Galanthamine Hydrobromide
2145
7.15 ppm). Data are reported as follows: chemical shift, multiplicity
(s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, app qui ¼ apparent
quintet, br ¼ broad, m ¼ multiplet), coupling constants, and number of
protons. IR spectra were taken on a Perkin-Elmer equipment. Mass spectra
were obtained on a low-resonance Q-trap machine in electron spray mode.
Melting points were obtained on a Polmon apparatus and are uncorrected.
2-Bromo-4-methoxy-5-(4-methoxy-benzyloxy)-benzoic Acid 5
To a stirred solution of benzylated isovanilline 4 (100 g, 0.31 mol) in
methanol (1.0 L), bromine (190 g, 1.18 mol) was added over a period of
30–45 min at 25–35ꢂC. After stirring at 25–35ꢂC for 1 h, water (3.0 L)
was added and cooled to 5–10ꢂC; the reaction mixture was further stirred
for 1 h. The precipitated material was separated by filtration, and the wet
solid was taken in water (600 mL), stirred for 30 min, filtered, and washed
with water (400 mL) and toluene (100 mL). Ethyl acetate was added to
the wet solid, heated to reflux, stirred for 30 min, and cooled to 10–
15ꢂC with continuous stirring for an additional 30 min. The precipitate
was filtered, washed with toluene (50 mL), and dried at 40 to 45ꢂC for
5 h to obtain 106 g of the corresponding bromo intermediate in 80%
yield. This intermediate (100 g 0.31 mol) was dissolved in acetone
(2.0 L) and heated to reflux. A mixture of water (1.5 L) and KMnO4
(100 g, 0.63 mol) was added at refluxing temperature and stirred for
60–90 min at 50–55ꢂC. The solvent was removed by distillation below
60ꢂC. The undesired by-product MnO2 was removed by filtration on a
Celite1 bed and washed with 10% KOH solution (100 mL). The pH of
the filtrate was adjusted to 2–2.5 using 1 N aq. HCl at 0–5ꢂC, and the con-
tents were stirred for about 30–45 min. The separated solid was isolated
by filtration and dried at 65–70ꢂC to afford 5 (73.4 g) in 70% yield as a
1
white solid. H NMR (DMSO, 400 MHz): d 3.87 (s, 3H), 5.12 (s, 2H),
7.25–7.40 (m, 7H), 13.1 (s, 1H).
p-Benzyloxy-N-methyl Phenethyl-amine 8
To a solution of p-benzyloxy phenyl methyl acetate 7 (144 g, 0.576 mol),
17% aqueous methyl amine (636 mL, 3.46 mol) was added and stirred for
3 h at 25–35ꢂC. The precipitated solid was filtered, and the wet cake was
taken into ethyl acetate (576 mL) and refluxed for 30 min. The resultant
solution cooled to 25–35ꢂC to obtain a precipitate that was isolated by
filtration to obtain p-benzyloxy phenyl acetic acid- N-methyl amide
(107.5 g) in 75% yield. The resultant p-benzyloxy phenyl acetic acid N-
methyl amide (50.0 g, 0.196 mol) was dissolved in 1,4 dioxane (500 mL)

2146
J. M. Reddy et al.
and stirred for 15–20 min, and sodium borohydride (18.6 g, 0.48 mol) was
added at 15–20ꢂC. After stirring for 5 min, a solution of acetic acid
(41.2 g, 0.68 mol) in 1,4-dioxane (250 mL) was added slowly at 15–20ꢂC.
The reaction mass was heated to 60–70ꢂC and stirred for 3 h. The solvents
were distilled off under reduced pressure. Water (500 mL) was added to
the residue and stirred for about 45 min. A white solid appeared and
was isolated by filtration, washed with water (100 mL), and dried at
60ꢂC for 3 h to obtain 8 (37.8 g) in 80% yield. 1H NMR (CDCl3,
400 MHz): d 2.65 (s, 3H), 3.19 (m, 4H), 5.02 (s, 2H), 6.86 (d, 2H,
J ¼ 8.0 Hz), 7.09 (d, 2H, J ¼ 8.0 Hz), 7.29 (m, 5H), 9.62 (s, 1H).
5-Benzyloxy-N-[2-(4-benzyloxy-phenyl)-ethyl]-2-bromo-4-methoxy-
N-methyl-benzamide 9[1]
Phynylboronic acid (1.8 g, 0.148 mmol) was added to a solution of
5-benzyloxy-2-bromo-4-methoxy-benzoic acid (50 g, 1.48 mmol) in
o-xylene (850 mL). The reaction mixture was heated to 120ꢂC. To this
mixture, [2-(4-benzyloxy-phenyl)-ethyl] methylamine (44.69 g, 1.48 mmol)
was added in one portion. The reaction mixture was heated at reflux for
30 h, and water was collected in the Dean–Stark trap. The solvent was
completely distilled and cooled to 25ꢂC, and methanol (50 mL) was
charged. The reaction mixture was heated to reflux and maintained for
15 min to get a clear solution. At reflux, 5% alkaline methanol
(150 mL) was added and maintained for 45 min before cooling to 0–5ꢂC
for 4 h. Then the precipitate was filtered and washed with 2 ꢃ 50-mL
portions of methanol and dried in vacuum at 60ꢂC for 6 h to afford 9
1
(71.4 g) in 86% yield. H NMR (400 MHz, DMSO-d6): d 2.61 (t, 2H,
J ¼ 4.0 Hz), 3.10 (t, 2H, J ¼ 4.0 Hz), 3.30 (s, 3H), 3.81 (s, 3H), 4.98 (d,
2H, J ¼ 12.0 Hz), 5.02 (s, 2H), 6.90 (s, 1H), 6.98 (d, 1H, J ¼ 8.0 Hz),
7.18–7.48 (m, 14H).
Debenzylated Amide 10[1]
To asolution of 9 (162 g, 0.289 mol) in MIBK (91.6 L), 36.5% aqueous
hydrochloric acid (2.1 L) was added and heated to 70ꢂC. After 2 h of
stirring, the reaction content was cooled to 30ꢂC and water (810 mL)
was added. pH was adjusted to 3 using caustic lye at 20–45ꢂC. After stir-
ring at 45ꢂC for 30 min, the aqueous layer was separated and extracted
with MIBK (812 mL). Solvents were distilled off, and the residue was dis-
solved in 500 mL of dichloromethane and cooled to 0–5ꢂC. After 90 min,
the precipitated solid was filtered and washed with dichloromethane
(160 mL). Solid material was dried at 75ꢂC under reduced pressure for
5 h to obtain 10 (86 g) in 78% yield.1H NMR (400MHz, DMSO-d6) d

(–)-Galanthamine Hydrobromide
2147
2.72 and 2.98 (2 ꢃ s, 3H), 2.69–2.71 (m, 2H), 3.23 and 3.60 (2ꢃ m, 2H),
3.84 (s, 3H), 6.50–6.84 (m, 4H), 7.01–7.07 (m, 2H), 9.09 (s, 1H), 9.22
and 9.70 (2 ꢃ s, 1H).
Tetracyclic System 11
To a refluxed solution of potassium ferricyanide (327.6 g, 0.996 mol) in
chloroform (18 L), 5% NaHCO3 (3.3 L) solution was added followed
by 10 (90 g, 0.237 mol) for a period of 45 min in two portions under
continuous stirring. After refluxing for 1 h, the reaction mixture was
cooled to 50ꢂC, filtered through a Celite1 bed, washed with chloro-
form (2.7 L), and separated into organi layers. The organic layer was
washed with water (2.7 L). Solvents were removed, n-heptane (2.0 L)
was added, and the reaction content was cooled, stirred for 30 min,
and filtered to afford the desired compound 11 (55.5 g) in 62% yield.
1H NMR (400 MHz, DMSO-d6): d 2.08–2.16 (m, 1H), 2.40 (ddd, 1H,
J ¼ 14.5, 2.4, 2.4 Hz), 2.84 (dd, 1H, J ¼ 17.5, 3.9 Hz), 3.18–3.21 (m,
4H), 3.40 (ddd, 1H, J ¼ 14.8, 2.4, 3.7 Hz ), 3.65–3.79 (m, 1H), 3.90
(s, 3H), 5.01 (s, 1H), 5.95 (d, 1H, J ¼ 10.1 Hz), 6.22 (dd, 1H,
J ¼ 10.1, 2.3 Hz), 7.29 (s, 1H); 13C NMR (200 MHz, CDCL3)
d192.9, 164.7, 146.7, 146.2, 145.7, 129.4, 125.9, 122.9, 118.7, 114.1,
89.3, 56.4, 48.7, 48.6, 36.7, 36.6, 34.1; IR (neat) 3374, 2853,
1698 cmꢀ1; MS (CI) calcd. for C17H16BrNO4 (Mþ); 378.22 found
(MHþ) 379.00, 381.00.
Alcohol 13[1]
To a solution of 11 (20 g, 0.053 mol) in THF (1.0 L), a 1.0 M solution
of L-selectride (134 mL, 0.134 mol) in THF was slowly added over 2 h
at ꢀ10 to 0ꢂC. After stirring for 2 h, the reaction mixture was
quenched with water (40 mL) and hydrogen peroxide solution (35 mL
of hydrogen peroxide in 110 mL of water) at ꢀ 10 to 0ꢂC. Sodium
hydroxide solution (10%, 8.0 g in 88 mL of water) was added below
35ꢂC and stirred for about 60 min at 35ꢂC, then extracted with dichlor-
omethane (110 mL). Solvents were removed, and the isolated solid was
washed with sodium hydroxide solution (4 g in 50 mL of water) fol-
lowed by water (100 mL). The solid material was under vacuum at
ꢂ
1
75 C for 4 h to obtain 13 (16.0 g) in 80% yield. H NMR (400 MHz,
DMSO): d 1.82 (d, 1H, J ¼ 8.0 Hz), 2.00–2.03 (m, 3H), 3.20–3.30
(m, 1H), 3.40–3.50 (m, 1H), 3.70 (s, 3H), 3.82 (s, 3H), 4.07–4.09 (m,
1H), 4.79–4.81 (m, 1H), 5.32 (d, 1H, J ¼ 8.0 Hz), 5.79 (dd, 1H,
J ¼ 4.0, 8.0 Hz), 7.19 (s, 1H); 13C NMR (200 MHz, CDCL3) d 164.9,
146.0, 144.7, 131.9, 130.7, 126.3, 123.2, 117.8, 113.6, 89.8, 60.8, 56.2,

2148
J. M. Reddy et al.
48.7, 48.2, 38.1, 33.9, 29.7; MS (CI) calcd. for C17H18BrNO4 (Mþ )
380.23; found 381.00, 383.00.
Galanthamine 1 HBr
To a refluxing solution of 70% vitride (152 g, 0.526 mol) in toluene
(1.2 L), a solution of compound 13 (40 g, 0.105 mol) in toluene (2.4 L)
was added in about 3 h. After stirring for an additional 1 h, the reaction
mixture was cooled to 0–10ꢂC, and 5% sodium potassium tartarate sol-
ution (121 g in 700 mL of water) was added in 20 min. The precipitate
was filtered through the Celite1 bed and washed with toluene
(200 mL). The organic layer was washed with saturated sodium chloride
solution (120 mL). Solvents were distilled off completely under the
reduced pressure at less then 60ꢂC, and the resultant crude material
(25 g, 0.087 mol, 83.3%) was dissolved in 100 mL of methanol. (þ)-Di-
p-tolyl tartaric acid (37.6 g, 0.093 mol), was added, and the resultant
mixture was stirred for about 24 h at 35ꢂC. The precipitated solid was
filtered and washed with methanol (25 mL). The residue was taken into
methanol (100 mL) and stirred for 10 min, and 47% aq HBr (12.5 mL)
in methanol (25 mL) was added over a period of 45 min at 25–30ꢂC.
The contents were stirred for about 1 h at less then 25–30ꢂC. Further,
the temperature was reduced to 0–5ꢂC and stirred for about 60 min.
The desired product was isolated by filtration and washed with 25 mL
of methanol. The solid product was dried at 65ꢂC under reduced pressure
for 6 h to afford bromide salt of galanthamine 1 (10 g) in 80% yield.
Spectral data matched perfectly with the standard sample.
In conclusion, we have succeeded in developing a novel synthetic
route that has been implemented at our facility.
ACKNOWLEDGMENTS
We thank the analytical division, Intellectual Property Management
(IPM), and Dr. Reddy’s Laboratories (DRL) for spectroscopic data,
literature, and financial support, respectively.
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