Commercial scale process of galanthamine hydrobromide involving Luche reduction: Galanthamine process involving regioselective 1,2-reduction of α,β-unsaturated ketone

Article abstract of DOI:10.1021/op300337y

Effect of lanthanide chloride in the Luche regioselective 1,2-reduction of 1-bromo-11-formyl-nornarwedine (5) was studied. Thus, 1-bromo-11-formyl- nornarwedine (5) is reduced with sodium borohydride in the presence of lanthanide chloride to yield 1-bromo-11-formyl-galanthamine isomers (6), which is a key intermediate for the commercial production of highly pure galanthamine hydrobromide (1), a modern drug against Alzheimer's disease.

Full text of DOI:10.1021/op300337y

Article
pubs.acs.org/OPRD
Commercial Scale Process of Galanthamine Hydrobromide Involving
Luche Reduction: Galanthamine Process Involving Regioselective
1
,2-Reduction of α,β-Unsaturated Ketone
†
,‡
†
†
Ganala Naga Trinadhachari, Anand Gopalkrishna Kamat, Koilpillai Joseph Prabahar,
Vijay Kumar Handa, Kukunuri Naga Venkata Satya Srinu, Korupolu Raghu Babu,
and Paul Douglas Sanasi*
†
†
‡
,‡
†Chemical Research and Development, APL Research Center, Aurobindo Pharma Ltd., Survey No. 71 & 72, Indrakaran (V),
Sangareddy (M), Medak Dist-502329, Andhra Pradesh, India
‡
Department of Engineering Chemistry, A. U. College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh,
India
ABSTRACT: Effect of lanthanide chloride in the Luche regioselective 1,2-reduction of 1-bromo-11-formyl-nornarwedine (5)
was studied. Thus, 1-bromo-11-formyl-nornarwedine (5) is reduced with sodium borohydride in the presence of lanthanide
chloride to yield 1-bromo-11-formyl-galanthamine isomers (6), which is a key intermediate for the commercial production of
highly pure galanthamine hydrobromide (1), a modern drug against Alzheimer’s disease.
INTRODUCTION
■
Galanthamine (1) is a tertiary alkaloid which is chemically
known as [4aS,6R,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-
1
1-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol. The
chemical structure of galanthamine hydrobromide (1) is as
shown in Figure 1.
Figure 1. Structure of galanthamine hydrobromide.
The molecular structure of galanthamine has three chiral
centers, and hence, theoretically eight stereoisomers are
possible. However, due to steric constraints, it could exist
only in two racemic pairs (four stereoisomers), viz.,
Figure 2. Structures of galanthamine stereoisomers.
[
[
(4aS,6R,8aS)-isomer, (−)-galanthamine] (1a),
(4aR,6S,8aR)-isomer, (+)-galanthamine] (2), [(4aS,6S,8aS)-
Alzheimer’s disease with cerebrovascular disease, mild cognitive
impairment, schizophrenia, Parkinson’s disease, and other
diseases wherein cognition is impaired.
isomer, (−)-epigalanthamine] (3), and [(4aR,6R,8aR)-isomer,
(
and therapeutically active isomer is (−)-galanthamine (1a),
which has the configuration of (4aS,6R,8aS).
+)-epigalanthamine] (4) (Figure 2). The naturally occurring
(
−)-Galanthamine is usually isolated from plants belonging
to the Amaryllidaceae family, such as the daffodil (Narcissus
(
−)-Galanthamine is a competitive and reversible acetylcho-
linesterase inhibitor, which is approved for the treatment of
mild to moderate Alzheimer’s disease and is under develop-
ment for other indications such as vascular dementia,
Received: November 20, 2012
Published: January 17, 2013
©
2013 American Chemical Society
406
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pseudomarcissus), snowdrop (Galanthus nivalis), and snowflake
Scheme 1
(
Leucojum aestivum). These plants have (−)-galanthamine in
concentrations up to 0.3% with only small amounts of
companion alkaloids, so that the extraction method can be
used. This process of extraction is expensive and time-
1
consuming, hence not feasible for industrial scale operations.
Barton and Kirby first reported the reduction of
(
−)-narwedine (9) by lithium aluminum hydride to prepare
2
(
−)-galanthamine along with (−)-epigalanthamine. Szeczyk et
al. prepared (−)-galanthamine along with (+)-galanthamine,
i.e., (±)-galanthamine from 1-bromo-11-formyl-nornarwedine
(
5) and separated both (−)-galanthamine and (+)-galanth-
amine by resolving (±)-galanthamine with (1S)-(−)-camphanic
chloride followed by column chromatography and fractional
crystallization from methanol. Chaplin et al. prepared
3
(
−)-galanthamine by dynamic diastereomeric salt resolution
of (±)-narwedine (8) with di-p-toluoyl-D-tartaric acid salt of
(
−)-narwedine (9) and subsequently converting to (−)-gal-
4
anthamine by using L-selectride. Many other synthetic
approaches have been reported in the literature for the
5
−8
preparation of (−)-galanthamine.
We chose 1-bromo-11-formyl-nornarwedine (5) as a key
intermediate to develop commercial scale process for galanth-
amine hydrobromide as shown in the Scheme 1. Conversion of
1-bromo-11-formyl-nornarwedine (5) to galanthamine involves
1,2-reduction of cyclic enone group. In this present work, we
have studied the 1,2-reduction of cyclic enone of 1-bromo-11-
formyl-nornarwedine (5) to yield 1-bromo-11-formyl-galanth-
amine isomers (6) and further converting these 1-bromo-11-
formyl-galanthamine isomers (6) to (−)-galanthamine hydro-
bromide (1), as shown in Scheme 1.
RESULTS AND DISCUSSION
■
Synthesis of galanthamine involves a complex chemistry and
requires selective reagents to bring about the desired
transformations. The use of reagents quantity, catalyst, and
reaction conditions plays an important role to achieve desired
regioselective intermediates with lesser amount of impurities.
Reduction of keto group in 1-bromo-11-formyl-nornarwedine
(5) is bound to form secondary alcohol at C-6 along with the
reduction of double bond at C-7. This would result in the
production of galanthamine final product contaminated with C-
7
double bond reduced alcohol (1,4-reduction product) which
9
−11
is known as lycoramine (11)
as shown in Scheme 2.
In this scenario, it is required to find a synthetic strategy for
the regioselective reduction of keto group in 1-bromo-11-
formyl-nornarwedine (5), without disturbing the double bond
at C-7 to produce 1-bromo-11-formyl-galanthamine isomers
(
6) and subsequently conversion of 6 to highly pure
From these experiments, we concluded that sodium
borohydride predominantly favors 1,4-reduction yielding 1-
bromo-11-formyl-lycoramine (10) rather than the desired 1,2-
reduction products, 1-bromo-11-formyl-galanthamine isomers
(6). Therefore, to prevent the formation of this undesired
intermediate, we decided to adopt the conditions of the Luche
reduction in which regioselective reduction was carried out
using sodium borohydride in the presence of lanthanide halide
such as cerium(III) chloride heptahydrate. The lanthanide
chlorides are useful catalysts and are reported to result in
regioselective 1,2-reduction of α,β-unsaturated ketone. Initial
experiments were performed by using cerium(III) chloride
heptahydrate along with sodium borohydride, it was observed
that the formation of the undesired intermediate was drastically
galanthamine with the least formation of impurities.
The pharmacopoeial monograph of galanthamine hydro-
bromide prescribed the limit for lycoramine impurity to <0.35%
(in U.S. pharmacopoeia) and <0.4% (in European pharmaco-
poeia) in the active substance of the drug, galanthamine
12
hydrobromide (1). The reduction of the keto group of 1-
bromo-11-formyl-nornarwedine (5) was performed initially
with sodium borohydride and it was observed that the
undesired reduction of the C-7 double bond occurred
simultaneously with reduction of the keto group. The double
bond reduced alcohol was obtained around ∼75%, which is
identified as 1,4-addition product 1-bromo-11-formyl-lycor-
amine (10).
13
4
07
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Organic Process Research & Development
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Scheme 2
observed that, among the solvents tried, the mixture of
methylene chloride and methanol (1:1) is the best combination
to obtain the desired regioselective transformation of 5 and to
obtain highly pure 1-bromo-11-formyl-galanthamine isomers
(
6). When we have carried out the Luche reduction of 5 in
methylene chloride alone, it was observed that the reaction
failed to proceed and this indicates that methanol, a protic
solvent, is a requirement for Luche reduction. Other protic
solvents such as ethanol and isopropyl alcohol failed to give the
desired products, 1-bromo-11-formyl-galanthamine isomers
(
6). So, we presume that the reduction reaction failed to
proceed due to the poor solubility of 5 in the respective solvent
system. The results obtained by the use of different solvents
and combinations are summarized in Table 1.
The nature of metallic ion was found to be an important
factor for the regioselective reduction of 1-bromo-11-formyl-
nornarwedine (5). Our aim was to study the effect of
lanthanide ions in the Luche reduction of 1-bromo-11-formyl-
nornarwedine (5). In addition, we proposed to study the
reduction of 1-bromo-11-formyl-nornarwedine (5) with
sodium borohydride in the presence of other metal ions such
1+
3+
2+
as Cu , Fe , and Zn . Replacement of the lanthanide with
1+
Cu ion favored 1,4- reduction rather than 1,2-reduction of 1-
bromo-11-formyl-nornarwedine (5). In the presence of other
ions such as Fe3+ and Zn , complete decomposition of the
reducing agent occurred very rapidly and the unreacted starting
material remained as the major component of the reaction
mixture. We have carried out the Luche reduction in the
presence of Lanthanide ions such as lanthanum, cerium,
neodymium, samarium, europium, terbium, and ytterbium.
The results obtained by use of different metal salts are
summarized in Table 2. Among the lanthanide chlorides tested,
cerium chloride is the most favored for economical reasons, as
cerium is one of the less expensive rare earth elements. For the
same reasons, we first optimized the quantity of CeCl ·7H O
reduced and the reaction yielded the desired intermediate 1-
bromo-11-formyl-galanthamine isomers (6).
Initially, we have studied the effect of solvent in this Luche
regioselective reduction of 1-bromo-11-formyl-nornarwedine
2+
(
5) by using different solvents such as methylene chloride,
methanol, ethanol, isopropyl alcohol, acetone, and mixtures
such as methanol and methylene chloride (1:1), methanol and
tetrahydrofuran (1:1), and methanol and water (1:1). It was
14−18
reported that protic solvents favored the Luche reduction.
However, solubility of 1-bromo-11-formyl-nornarwedine (5) in
methanol was found to be poor, so the Luche reaction in
methanol was slow and incomplete. Hence, we added
methylene chloride or THF as cosolvent to increase the
solubility of 1-bromo-11-formyl-nornarwedine (5). It has been
3
2
required for the Luche reduction of 1-bromo-11-formyl-
Table 1. Effect of Solvent on Reduction of 1-Bromo-11-Formyl-Nornarwedine (5)
a
b
Reaction conditions: 1.0 mol equiv of CeCl and 1.0 mol equiv of NaBH ; 1 h at 0−5 °C. Reaction conditions: 0.5 mol equiv of CeCl and 1.0 mol
3
4
3
c
d
equiv of NaBH ; 1 h at 0−5 °C. Chromatographic purity (by HPLC, by area normalization). HPLC sum of two rotamers area percentage.
4
4
08
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e
Table 2. Reduction of 1-Bromo-11-Formyl-Nornarwedine (5) in the Presence of Metallic Salts
a
b
c
d
0
.5 mol equiv of metallic salt. 1.0 mol equiv of metallic salt. Chromatographic purity (by HPLC, by area normalization). HPLC sum of two
e
rotamers area percentage. Reaction conditions: 0.10 M solution of enone (5) in a 1:1 mixture of methanol and methylene chloride; 1.0 mol equiv of
NaBH ; 30 min at 0−5 °C.
4
2
1
nornarwedine (5). It was found that 0.5 mol equiv of
CeCl ·7H O is sufficient to carry out the regioselective Luche
Vogel’s textbook and acetone was used as the reaction solvent
to obtain the desired purity of the product (±)-narwedine (8).
(
3
2
reduction of 1-bromo-11-formyl-nornarwedine (5) rather than
an equimolar quantity of CeCl ·7H O.
±)-Narwedine is further subjected to kinetic dynamic
3
2
resolution induced by (−)-narwedine seed in an aqueous
ethanolic solution containing triethylamine to obtain a single
isomer (−)-narwedine (9). This kinetic dynamic resolution was
reported to be carried out at 40−42 °C for 16 h to 7 days.
We have optimized the process conditions and the resolution of
Based on the above experiments, we concluded the
optimized conditions of the Luche reduction of 1-bromo-11-
formyl-nornarwedine (5) to obtain maximum yield and highest
regioselectivity: the 1-bromo-11-formyl-nornarwedine (5) is
22−24
reduced with 1 mol equiv of NaBH in the presence of 0.5 mol
4
(
±)-narwedine was achieved effectively in aqueous ethanolic
solution of (±)-narwedine containing triethylamine at 70−73
C with (−)-narwedine seed and by gradual cooling over 3−4 h
period to achieve desired isomer (9) of >99.5% e.e. (by Chiral
HPLC) as well as >99.5% chromatographic purity (by HPLC).
In the final step of the synthesis, diastereoselective reduction
of (−)-narwedine (9) was achieved by treating it with L-
selectride in tetrahydrofuran at lower temperature conditions to
produce (−)-galanthamine. We have studied the behavior of
this reaction at different temperatures and the best result was
obtained when this reaction was carried out at −50 to −45 °C.
After aqueous workup of the reaction mixture, (−)-galanth-
amine base was obtained and it was further treated with
hydrobromic acid in aqueous ethanol to furnish the desired
final product, (−)-galanthamine hydrobromide (1) with the
chromatographic purity of >99.7% (by HPLC), chiral purity of
equiv of cerium(III) chloride heptahydrate in solvent mixture
of methylene chloride and methanol (1:1 ratio) at 0−5 °C.
Further, the desired allylic alcohols and 1-bromo-11-formyl-
galanthamine isomers (6) were obtained with high chromato-
graphic purity (>99% by HPLC).
°
The next task was converting of 1-bromo-11-formyl-galanth-
amine isomers (6) to the drug compound galanthamine
hydrobromide (1). Reduction of formyl group and debromi-
nation of the intermediates 1-bromo-11-formyl-galanthamine
isomers (6) may be achieved by treating with lithium
aluminium hydride (LAH). However, debromination of the
intermediates 1-bromo-11-formyl-galanthamine isomers (6)
was incomplete when they were treated either with excess
lithium aluminium hydride (LAH) at reflux temperature or by
continuation of the reaction for several hours. However,
debromination is successfully completed by purging of air into
22
5,19
the reaction mass as reported in the literature.
Thereafter,
>
99.9% (by HPLC), and the 1,4-reduction product, lycoramine,
is controlled to <0.3% (by HPLC).
The above optimized process was successfully scaled up to 60
kg input of 1-bromo-11-formyl-nornarwedine (5), and
(−)-galanthamine hydrobromide obtained from this process
meets all desired quality parameters.
galanthamine isomer (7) intermediates were isolated and
further oxidized with freshly prepared active manganese dioxide
to get (±)-narwedine intermediate (8). We have studied
different grades of manganese dioxide prepared by different
20
literature methods. The best results were obtained by using
active manganese dioxide prepared by the procedure given in
4
09
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CONCLUSION
4.44−4.61 (m, 2H), 4.90−4.95 (m, 1H), 5.73−5.76 (m, 1H),
■
6
.05−6.11 (m, 1H), 6.98−7.02 (d, 1H), 8.05 (d, 1H).
An efficient, scalable method for the preparation of galanth-
amine hydrobromide (1) involving Luche reduction was
elaborated. Luche reduction of 1-bromo-11-formyl-nornarwe-
dine (5) gives 1-bromo-11-formyl-galanthamine isomers (6),
and the process for conversion of 1-bromo-11-formyl-galanth-
amine isomers (6) is optimized to obtain highly pure
galanthamine hydrobromide (1) drug active substance.
Galanthamine hydrobromide is obtained with an overall yield
of 56% from 1-bromo-11-formyl-nornarwedine (5).
Preparation of 4a,5,9,10,11,12-hexahydro-3-methoxy-11-
methyl-6H-benzofuro[3a,3,2-ef ][2]benzazepin-6-ol isomers
(±)-Epigalanthamine (7a) and (±)-Galanthamine (7b)
[
mixture](7). A solution of 1-Bromo-4a,5,9,10-tetrahydro-3-
methoxy-6-hydroxy-6H-benzofuro[3a,3,2-ef ][2]benzazepin-11-
(12H)carboxaldehyde isomers [(±)-1-bromo-11-formyl-epiga-
lanthamine and (±)-1-bromo-11-formyl-galanthamine mixture]
2
5
(
6, 210 g, 0.553 mol) in tetrahydrofuran (2000 mL) was added
to a suspension of lithium aluminium hydride (80.40 g, 1.84
mols) in tetrahydrofuran (2000 mL) at 25−50 °C. The reaction
mixture was stirred at reflux (55−60 °C) for about 1 h and
EXPERIMENTAL SECTION
■
General. 1-Bromo-11-formyl-nornarwedine (5) was pre-
pared from readily available Isovanilline and Tyramine
according to the literature procedure. Lanthanide salts of
laboratory grades were used which were procured from Central
Drug House (P) Ltd., New Delhi, India. Other reagents and
solvents were obtained from commercial suppliers and used
without further purification. Narwedine and narwedine salts are
classified as moderate to severe sensitizing agents and, after
reaction mixture was cooled to 25−30 °C. Air (∼80% N ,
2
∼20% O ) was purged into the reaction mass with a flow rate of
2
3
600 mL/min while stirring at 25−30 °C for 2 h, and
completion of the reaction was monitored by qualitative
HPLC analysis . The reaction mass was quenched by sequential
addition of DM water (80 mL), 15% (w/v) sodium hydroxide
solution (80 mL), and DM water (250 mL). The reaction mass
was stirred at 50−55 °C for 1 h and the inorganic residue was
removed by filtration. The filtrate was concentrated under
reduced pressure and the product was extracted with
chloroform (2000 mL). The chloroform extract was washed
with water (400 mL) and concentrated under reduced pressure
to obtain (±)-epigalanthamine and (±)-galanthamine mixture
(7) as a pale yellow semisolid mass (165 g).
5
prolonged exposure, cause severe allergic skin reactions. For
this reason, suitable personal protective equipment should be
used while handling. Melting points were determined on a
Polmon MP96 capillary melting point apparatus and are
1
13
uncorrected. H and C NMR spectra were recorded on a
Bruker 300 MHz spectrometer in DMSO-d ; chemical shift
6
data are reported in ppm from the internal standard TMS. The
reaction monitoring and chromatographic purity (area
percentage) were analyzed qualitatively by HPLC on Waters
Chromatographic purity: 95.33% (by HPLC, sum of two
−1
peaks corresponds to 7a and 7b). IR (KBr) (cm ): 3388,
+
1
1623, 1508, 1444. HRMS: m/z = 288.1609 [M + H] . H
2
695 with 2996 PDA detector using Phenomenex Gemini C18
NMR (DMSO-d ): δ 1.35−2.03 (m, 2H), 2.07−2.18 and 2.43
6
column (250 mm × 4.6 mm, 5 μ). HRMS were taken on Xevo
G2 Q TOF HRMS instrument with electrospray ionization
(m, 2H), 2.21 (bs, 3H) 2.88 and 3.14 (dd, 2H), 3.52 and 4.04
(dd, 2H), 3.70 (d, 3H), 4.21 (d, 1H), 4.46 (brt, 1H), 4.93 (d,
(
positive) mode in units of mass (m/z). The IR spectra were
1H, exchangeable with D O), 5.67 (m, 1H), 5.99 (m, 1H),
2
recorded on KBr pellets on Perkin-Elmer FTIR (spectrum one)
spectrophotometer.
6.51and 6.65 (2m, 1H each).
Preparation of (±)-4a,5,9,10,11.12-Hexahydro-3-me-
thoxy-11-methyl-6H-benzofuro[3a,3,2-ef ][2]benzazepin-6-
one [(±)-Narwedine] (8). To a mixture of 4a,5,9,10,11.12-
hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef ][2]-
benzazepin-6-ol isomers [(±)-Epigalanthamine and (±)-Gal-
anthamine mixture] (7, 165 g, 0.575 mols) in acetone (6000
mL), active manganese dioxide (600 g, 6.9 mol) was added and
stirred for 20 h at 25−30 °C. The completion of the reaction
was monitored by qualitative HPLC analysis. After the
completion of the reaction, the inorganic residue was removed
by filtration, and the filtrate was concentrated under reduced
pressure at 40−50 °C. The concentrated mass was triturated
with ethyl acetate (200 mL) for 1 h at 25−30 °C and the
product was filtered, washed with ethyl acetate (100 mL), and
dried at 50−55 °C under reduced pressure to yield
(±)-Narwedine (8) as a pale yellow powder (110 g, 72.94%
yield from 5).
General Procedure for the Preparation of 1-Bromo-
a,5,9,10-tetrahydro-3-methoxy-6-hydroxy-6H-benzofuro-
3a,3,2-ef ][2]benzazepin-11(12H)carboxaldehyde Isomers
(±)-1-Bromo-11-Formyl-Epigalanthamine (6a) and (±)-1-
Bromo-11-Formyl-Galanthamine (6b) mixture](6). A mixture
of 1-Bromo-4a,5,9,10-tetrahydro-3-methoxy-6-oxo-6H-
benzofuro[3a,3,2-ef ]-[2]benzazepin-11(12H)carboxaldehyde
4
[
[
(
1-bromo-11-formyl nornarwedine) (5, 200 g, 0.529 mol),
lanthanide chloride (LnCl ·nH O, 0.5 mol equiv) was taken in
3
2
methylene chloride/methanol mixture (1:1 v/v, 6000 mL). The
mixture was stirred at 25−30 °C for 30 min and cooled to 0−5
C. Sodium borohydride (20g, 0.529 mol) was added in
portions at 0−5 °C for 30 min and the completion of the
reaction was monitored by qualitative HPLC analysis. Water
°
(
1200 mL) was added to the reaction mixture and then
concentrated under reduced pressure to a volume of ∼2500
mL. The concentrated mass was extracted with methylene
chloride (3000 mL) and washed with water (400 mL). The
methylene chloride extract was concentrated under reduced
pressure to obtain mixtures of (±)-1-bromo-11-formyl-
epigalanthamine and (±)-1-bromo-11-formyl-galanthamine
mixture (6) as a viscous oily mass (210 g).
Chromatographic purity: 99.29% (by HPLC). (−)-Narwe-
dine content: 49.43% (by chiral HPLC) and (+)-Narwedine
content: 50.57% (by chiral HPLC). Mp: 186−189 °C. IR
−1
(KBr) (cm ): 1682, 1620, 1507, 1439. HRMS: m/z =
+
1
286.1454 [M + H] . H NMR (DMSO-d ): δ 1.81 and 2.16
6
(dd, 2H), 2.28 (s, 3H), 2.76 and 3.01 (dd, 2H), 3.07 and 3.18
(dd, 2H), 3.33 and 4.13 (dd, 2H), 3.65 (s, 3H), 4.71 (d, 1H),
5.90 (d, 1H), 6.63 and 6.76 (2d, 1H each), 7.14 (d, 1H).
Preparation of [4aS,8aS]-4a,5,9,10,11,12-hexahydro-3-
methoxy-11-methyl-6H-benzofuro[3a,3,2-ef ][2]benzazepin-
6-one [(−)-Narwedine](9). (±)-4a,5,9,10,11.12-Hexahydro-3-
Chromatographic purity: 99.13% (by HPLC, sum of four
−1
peaks corresponding to 6a and 6b). IR (KBr) (cm ): 3431,
654, 1617−1491. HRMS: m/z = 380.0493/382.0475 [M + H]
1
+
1
.
H NMR (DMSO-d , mixture of two rotamers): δ 1.23−2.45
6
(
m, 4H), 3.60 (m, 1H), 3.75 (s, 3H), 4.15−4.23 (m, 2H),
4
10
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methoxy-11-methyl-6H-benzofuro-[3a,3,2-ef ][2]benzazepin-6-
one [(±)-Narwedine] (8, 95 g, 0.333 mol) was dissolved in a
mixture of DM water (72.2 mL), ethanol (1381 mL), and
triethylamine (161.5 mL) at 75−80 °C. Thereafter, the reaction
mixture was cooled to 70−73 °C and (−)-Narwedine (1.9 g)
was added as seed to the solution. The resulting mixture was
gradually cooled to 40−42 °C and stirred at the same
temperature for 3 h for complete kinetic dynamic resolution
of (−)-Narwedine. The completion of the reaction was
monitored by qualitative chiral HPLC analysis. After
completion of the reaction, the slurry mass was cooled to
AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: pauldouglas12@gmail.com. Tel: +91-9347098430.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors thank the management of Aurobindo Pharma Ltd.,
Hyderabad, for permission to publish this work. Authors are
grateful to the entire Analytical Research Department for their
valuable analytical support to this work.
2
5−30 °C, and the product filtered and dried at 55−65 °C
under reduced pressure to get (−)-Narwedine (9) as cream-
colored crystalline powder (85.5 g, 90% yield).
REFERENCES
■
Chromatographic purity: 99.90% (by HPLC). (+)-Narwe-
(
1) (a) Sagdullaev, Sh. Sh. Chem. Nat. Compd. 2005, 41 (2), 239.
(b) Halpin, C. M.; Railly, C.; Walsh, J. J. J. Chem. Educ. 2010, 87 (11),
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2) Barton, D. H. R.; Kirby, G. W. J. Chem. Soc. 1962, 806.
(3) (a) Szewczyk, J.; Lewin, A. H.; Carroll, F. I. J. Heterocycl. Chem.
dine content: 0.20% (by chiral HPLC). Mp 190−192 °C. [α]
D
2
5
−1
(
c = 1, in CHCl ): −411.1°. IR (KBr) (cm ): 1682, 1620,
3
1
(
+
1
1
507, 1439. HRMS: m/z = 286.1453 [M + H] . H NMR
(
DMSO-d ): δ 1.81 and 2.12 (dd, 2H), 2.28 (s, 3H), 2.76 and
6
2
3
1
.96 (dd, 2H) 3.01 and 3.18 (dd, 2H), 3.60 and 4.13 (dd, 2H),
.71 (s, 3H), 4.71(brs, 1H), 5.90 (d, 1H), 6.63 and 6.76 (2d,
H each), 7.14 (d, 1H).
1988, 25, 1809. (b) Szewczyk, J.; Wilson, J. W.; Lewin, A. H.; Carroll,
F. I. J. Heterocycl. Chem. 1995, 32, 195.
(
4) Chaplin, D. A.; Johnson, N. B.; Paul, J. M.; Potter., G. A.
Tetrahedron Lett. 1998, 39 (37), 6777.
5) Kuenburg, B.; Czollner, L.; Frohlich, J.; Jordis, U. Org. Process Res.
Dev. 1999, 3, 425.
6) Poschalko, A.; Welzig, S.; Treu, M.; Nerdinger, S.; Mereiter, K.;
Preparation of [4aS,6R,8aS]-4a,5,9,10,11,12-hexahydro-3-
(
methoxy-11-methyl-6H-benzofuro[3a,3,2-ef ][2]-
benzazepine-6-ol [(−)-Galanthamine hydrobromide] (1).
Lithium tri-sec-butyl borohydride [L-selectride] (1 molar
solution in THF, 433 mL) was added dropwise to a suspension
of [4aS,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-
(
Jordis, U. Tetrahedron. 2002, 58, 1513.
(7) Kodama, S.; Hamashima, Y.; Nishide, K.; Node, M. Angew. Chem.,
Int. Ed. 2004, 43, 2659.
(
8) Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127
42), 14785.
9) Lee, T. B. K.; Goehring, K. E.; Ma, Z. J. Org. Chem. 1998, 63,
535.
6
H-benzofuro[3a,3,2-ef ][2]benzazepin-6-one [(−)-Narwedine]
(
(9, 65 g, 0.228 mol) in THF (1300 mL) at −50 to −45 °C for 1
(
h and the reaction mixture stirred at −50 to −45 °C for 3 h.
The completion of the reaction was monitored by qualitative
HPLC analysis. The reaction mixture was quenched by adding
aqueous hydrogen peroxide (40% w/w, 110.5 g, 1.3 mol), and
the excess peroxide was destroyed by stirring the reaction
mixture with aqueous sodium sulfite solution. The reaction
mixture was concentrated under reduced pressure and the
product was extracted with toluene (1625 mL). The organic
extract was concentrated under reduced pressure at 50−55 °C
to obtain galanthamine base as an oily mass, and galanthamine
base was dissolved in a mixture of ethanol (260 mL) and DM
water (65 mL). Aqueous hydrobromic acid (48% w/w, 40.42 g,
4
(10) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262.
(11) Guillou, C.; Beunard, J.; Gras, E.; Thal, C. Angew. Chem., Int. Ed.
2
(
001, 40 (24), 4745.
12) (a) US Pharmacopoeia US 36, 3705. (b) European
Pharmacopoeia 7.0, 2083.
13) (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226. (b) Gemal, A.
(
L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454. (c) Shich, W. C.;
Carlson, J. A. (Ciba Geigy Corporation, Ardsley, N.Y.) Method of
manufacture of (-)-Galanthamine in high yield and purity substantially
free of epigalanthamine. U. S. Patent 5,428,159, June 27, 1995; Chem.
Abstr. 123:112051.
(
(
14) Adams, C. Synth. Commun. 1984, 14 (14), 1349.
15) Marchand, A. P.; LaRoe, W. D.; Sharma, G. V. M; Suri, S. C.;
0.24 mols) was added to the galanthamine base solution and
Reddy, D. S. J. Org. Chem. 1986, No. 51, 1622.
16) Tanaka, A.; Yamamoto, H.; Oritani, T. Tetrahedron Asymm.
995, 6 (6), 1273.
stirred at 15−20 °C for 2 h to obtain galanthamine
hydrobromide. The product was filtered and dried under
vacuum at 50−55 °C to obtain (−)-galanthamine hydro-
bromide (1) as a white crystalline powder (71.5 g, 85.4% yield).
Chromatographic purity: 99.79% (by HPLC). Lycoramine
content: 0.12% (by HPLC). (+)-Galanthamine content: Not
(
1
(17) Burnell, D. J.; Liu, C. Tetrahedron Lett. 1997, 38 (38), 6573.
(18) Mullina, R. J.; Gregg, J. J.; Hamilton, G. A. Name Reactions for
Functional Group Transformations, Li, J. J., Corey, E. J., Eds.; Wiley:
New York, 2007; p 112.
(19) Czollner, L.; Frohlich, J.; Jordis, U.; Kuenburg, B. (Sanochemia
Ltd., 136 St. Christopher Street, Valetta, Malta) Reduction of aromatic
halogenides; WO 98/52885; Nov. 26, 1998; Chem. Abstr. 130:40075.
25
detected (by chiral HPLC). Mp 253 °C (dec.). [α]
(c = 0.1,
in Water): −97.5°. IR (KBr) (cm ): 3561, 3043, 3022, 2946,
922, 2619, 2482, 1625, 1512, 1465, 1439, 1282, 1068. HRMS:
D
−1
2
(20) Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis;
+
1
m/z = 288.1604 [M + H] . H NMR (DMSO-d ): δ 1.91 and
John Wiley & Sons, 1995; Vol. 5, p 3229.
(21) Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Addison
Wesley Longman Limited, 1989; p 445.
6
2
4
1
.04 (2m, 4H), 2.97 (m, 3H), 3.45 (m, 1H), 3.76 (brs, 4H),
.10 (s, 1H), 4.34 and 4.48 (m, 2H), 4.60 (s, 1H), 4.80 (dd,
H), 5.87 (dd, 1H), 6.13 (dd, 1H), 6.79 and 6.85 (2d, 1H
(
(
22) Shieh, W. C.; Carlson, J. A. J. Org. Chem. 1994, 59 (18), 5463.
23) Czollner, L.; Frohlich, J.; Jordis, U.; Kuenburg, B. (Sanochemia
1
3
each), 9.84 and 10.59 (2brs, 1H). C NMR (DMSO-d ): δ
6
Pharmazeutica, Aktiengesellschaft, Boltzmanngasse, Austria) Process
for the preparation of derivatives of 4a,5,9,10,11,12-hexahydro-6h-
benzofuro-[3a,3,2-ef][2]benzazepine. U. S. Patent 6,043,359, Mar. 28,
2000; Chem. Abstr.: 132:237232.
31.8 (2 × CH ), 35.6 (CH ), 47.3, 55.4 (CH ), 56.5 (OCH ),
2 3 2 3
59.7 (CH ), 60.4 (CH), 87.3 (CH), 112.8 (CH), 121.5, 123.7
2
(
CH), 126.2 (CH), 130.7 (CH), 133.8, 145.8, 147.3.
4
11
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Organic Process Research & Development
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24) Krikorian, D. A.; Parushev, S. P.; Mechkarova, P. D.; Petrova, V.;
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(
25) Prabahar, K. J.; Trinadhachari, G. N.; Naveen, K. P.; Lakshmi, U.
V.; Ramesh, D.; Sivakumaran, M. (Aurobindo Pharma Ltd.,
Hyderabad, India) Process for the preparation of Galanthamine
hydrobromide. European Patent EP 2 009 015 B1, Jan. 11, 2012;
Chem. Abstr. 150:77837.
4
12
dx.doi.org/10.1021/op300337y | Org. Process Res. Dev. 2013, 17, 406−412