Development of a pilot scale process for the anti-alzheimer drug (-)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion

Article abstract of DOI:10.1021/op990019q

(-)-Galanthamine has been synthesised using an efficient nine-step procedure, which in large scale affords 12.4 (6.7-19.1)% overall yield. The process improvements and optimization of each step are described. Notable steps include (i) an oxidative phenol coupling and (ii) crystallisation-induced chiral conversion of (±)-narwedine to (-)-narwedine. This is a practical and cost-effective synthesis of (-)-galanthamine which is amenable to pilot plant scale-up to afford sufficient material for use in clinical trials.

Full text of DOI:10.1021/op990019q

Organic Process Research & Development 1999, 3, 425−431
Development of a Pilot Scale Process for the Anti-Alzheimer Drug
(-)-Galanthamine Using Large-Scale Phenolic Oxidative Coupling and
Crystallisation-Induced Chiral Conversion
Bernhard Ku¨enburg,† Laszlo Czollner,†,§ Johannes Fro¨hlich,*,‡,| and Ulrich Jordis*,‡,
Sanochemia AG, Landeggerstrasse 7, A-2491 Neufeld, Austria, and Institute of Organic Chemistry,
Vienna UniVersity of Technology, Getreidemarkt 9, A-1060 Vienna, Austria
Abstract:
(-)-Galanthamine has been synthesised using an efficient nine-
step procedure, which in large scale affords 12.4 (6.7-19.1)%
overall yield. The process improvements and optimization of
each step are described. Notable steps include (i) an oxidative
phenol coupling and (ii) crystallisation-induced chiral conver-
sion of (()-narwedine to (-)-narwedine. This is a practical and
cost-effective synthesis of (-)-galanthamine which is amenable
to pilot plant scale-up to afford sufficient material for use in
Figure 1. Structure of (-)-galanthamine, 1; HBr-salt (10):
nivalin, reminyl.
clinical trials.
these procedures are workable on a laboratory scale, their
scale-up to multi-kilogram scale is operationally prohibitive.
We have recently communicated a more efficient route.12
We report herein refinements to our earlier process which
allows for large-scale synthesis of galanthamine (Scheme 1).
Introduction
Galanthamine, an Amaryllidaceae alkaloid, has been used
clinically for 30 years for treatment of myasthenia gravis1
and other neurological illnesses such as poliomyelitis,2 as
an anti-curare agent,3 and as a parasympathomimetic.4 More
importantly, it has been approved for the treatment of
Alzheimer’s disease in Austria and is in phase III clinical
trials both in the United Kingdom and the Unites States.5-6
Galanthamine is produced by isolation from botanical sources
(e.g, Galanthus niValis, G. narcissus, G. leucojum, or G.
crinium7-9); despite renewed efforts,9 these sources are not
suitable for generation of large enough quantities of galanth-
amine (Figure 1).
We had requirements for large quantities of galanthamine
for in vitro and in vivo efficacy studies and pharmacokinetic
studies. Galanthamine was first synthesised by Barton10 with
a pivotal synthetic step being an oxidative phenol cyclization
(0.5% yield). Other researchers were able to increase both
the yields and the scale of the Barton procedure. Other
syntheses of galanthamine have been reported.11-13 While
Results and Discussion
Step 1: 2-Bromo-4,5-dimethoxybenzaldehyde (1). Bro-
mination of 3,4-dimethoxybenzaldehyde in acetic acid has
been reported previously.14 By substituting methanol for
acetic acid, we obtained 1 in 90-92% yield. While it has
been reported that reaction of bromine with methanol may
be vigorously exothermic,15 on the scale indicated in our
experimental only a mildly exothermic reaction occurred
(temperature increase from room temperature to about 40
°C) when bromine was added with water-cooling. On a 50
g laboratory scale in experiments using the same concentra-
tions as the 4.0 kg experiment, designed to identify potential
hazards, bromine was added at once without cooling,
resulting in an exotherm, but the reaction temperature never
exceeded 45-50 °C. The product contained less than 1% of
the 3-bromo-4,5-dimethoxy-benzaldehyde as determined by
HPLC and NMR. This procedure has been scaled up to 100
kg quantities with similar yields of 90-92%. Ethanol was
less suitable because of decreased solubility and lower yields.
Step 2: 2-Bromo-5-hydroxy-4-methoxybenzaldehyde
(2) by Regioselective Demethylation of 1. Substituted
† Sanochemia AG.
‡ Vienna University of Technology.
§ E-mail: l.czollner@sanochemia.at.
| E-mail: jfroehli@pop.tuwien.ac.at.
E-mail: ulrich.jordis@tuwien.ac.at.
(1) Chistoni, G.; Guaraldi, G. P. RiV. Neuropsichiatr. Sci. Affini (Parma) 1960,
6, 53.
(2) Go¨ppel, W.; Betram, W. Psychiatr. Neurol. Med. Psychol. 1971, 23, 712.
(3) Mayrhofer, O. South. Med. J. 1966, 59, 1364.
(4) Baraka, A.; Sami Harik, M. D. JAMA, J. Am. Med. Assoc. 1977, 238, 2293.
(5) Mucke, H. A. M. Drugs Future 1997, 33, 259.
(6) Rainer, M. Drugs Today 1997, 33, 273.
(7) Mikhno, V. V. Farm. Zh. (KieV) 1966, 21, 28.
(8) Bastida, J.; Viladomat, F.; Llabres, J. M.; Quiroga, S.; Codina, C.; Rubiralta,
M. Planta Med. 1990, 56, 123.
(11) Anonymous, Synform 1983, 283.
(12) Czollner, L.; Frantsits, W.; Ku¨enburg, B.; Hedenig, U.; Fro¨hlich, J.; Jordis,
U. Tetrahedron Lett. 1998, 39, 2087.
(13) a) Chaplin, D. A.; Fraser, N.; Tiffin, P. D. Tetrahedron Lett. 1997, 38, 7931.
The same process was presented in more detail: (b) McCague, R. Complete
Industrial Total Synthesis of the Alkaloid (-)-Galanthamine; presented at
Chiral USA ‘98, May 18-19, San Francisco, 1998.
(14) Pschorr, R. Ann. Chem. 1912, 391, 23.
(15) Hazards in the Chemical Laboratory 3rd ed.; Bretherick, L., Ed.; Royal
Society of Chemistry:London, 1981; p 99.
(9) Hille, Th.; Hoffmann, H. R.; Kreh, M.; Matusch, R. DE 19,509,663 Lts,
Lohmann Therapie-Systeme; Chem. Abstr. 125, 230784
(10) Barton, D. H. R.; Kirby, G. W. J. Chem. Soc. 1962, 806.
10.1021/op990019q CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry
Published on Web 11/04/1999
Vol. 3, No. 6, 1999 / Organic Process Research & Development
•
425

Scheme 1
dimethoxybenzaldehydes can be demethylated regioselec-
tively.16-17 Other methods for the preparation of 2, such as
the bromination of isovanilline with bromine18-20 or thionyl
bromide21 provided poor regioselectively and/or mediocre
yields. Selective 5-O-demethylation of 1 was achieved with
concentrated sulfuric acid at 90 °C. Optimal conversion and
yield is obtained after 6 h with a 5:1 sulfuric acid/substrate
ratio.
Increased reaction times afforded increased side products
(2-bromo-4,5-dihydroxybenzaldehyde and tar). The quality
of sulfuric acid used is important for ease of work-up.
Technical grade sulfuric acid gives a dark coloured product
that is difficult to filter. While high quality sulfuric acid still
afforded a dark colored product, it was easier to filter.
Crystallisation of the crude product required adding water
to an acetone solution of the crude product (and not vice
versa), and cooling to 0-5 °C in order to obtain nicely
filterable crystals. On a 100 kg scale, yields ranged from 65
to 72%.
Step 3: Reductive Amination. The condensation of 2
with tyramine was performed in ethanol instead of a mixture
of toluene and n-butanol (as reported previously). The crude
2-bromo-5-hydroxy-4-methoxybenzylidene-2-(4-hydroxy-
phenyl)ethylamine 3 is subsequently reduced to intermediate
4 using sodium borohydride in 90-95% yield. This step has
been performed on 100 kg scale uneventfully.
Step 4: Formylation. Intermediate 4 is formylated with
a mixture of ethyl formate and formic acid in dioxane. On
smaller scales we found it advantageous to catalyse the
reaction using 4-(dimethylamino)pyridine, but on larger scale
this is not necessary. For process safety considerations,
substitution of dioxane with ethylene glycol monomethyl
ether had no detrimental effects on the productivity of the
reaction. Product 5 is isolated by crystallisation, with yields
of 80-91% on 100 kg of starting material.
Step 5: Oxidative Phenol Coupling. This step (conver-
sion of 5 to 6) was optimised for 12-kg production scale by
multifactorial analysis of reaction parameters. We studied
reaction temperature, concentration, and mode-of-addition
of reagents, cosolvent effects (toluene, chloroform, methylene
chloride, ethyl acetate, xylene, or anisole), phase-transfer
(16) Brossi, A.; Gurien, H.; Rachlin, A.; Teitel, S. J. Org. Chem. 1967, 32, 1269.
(17) Bulavka, B. H.; Tolkatschew, O. H.; Tschawlinskij, A. H. Khim. Farm. Zh.
1990, 24, 59.
(18) Henry, H.; Sharp, T. M. J. Chem. Soc. 1930, 2279
(19) Pauli, H. Chem. Ber. 1915, 48, 2010.
(20) Raiford, L.; Ravely, M. J. Chem. Soc. 1940, 204.
(21) Bulavka, V.; Tolkatschew, O. H.; Tschawlinskij, A. H. Khim. Farm. Zh.
1991, 25, 46.
426
•
Vol. 3, No. 6, 1999 / Organic Process Research & Development

Table 1. Influence of varying amounts of K3Fe(CN)6 and
K2CO3
Table 2. Influence of reaction temperature and of reaction
time
10%
active
temp
stirring
isolated
content by chemical
amount K3Fe(CN)6 K2CO3 physical content by yield
entry (°C) time (min) yield (%) HPLC (%) yield (%)
entry 5 (g)
(g)
soln (L) yield (%) HPLC (%) (%)
9
10
11
12
60
80
45
20
15.
5
30
60
49.5
48.2
48.7
47.9
83.6
84.4
85.6
85.2
41.1
40.7
41.7
40.8
1
2
3
4
5
6
7
8
50
100
200
200
100
100
100
200
208
416
832
832
300
416
500
600
1
2
4
2a
2
2
2
2a
52.6
49.5
43.4
30.7
42.8
49.5
51.3
30.7
84.6
83.6
87.8
75
84.5
83.6
82.5
75
44.5
41.1
38.1
23.0
36.2
41.1
42.3
23.0
Table 3. Reproducibility of the cyclization reaction
isolated yield
(%)
content by HPLC
(%)
chemical yield
(%)
entry
a Heterogeneous reaction due to incomplete solubility of K3Fe(CN)6
13
13
15
16
47.1
48.2
49.1
49.2
85.3
85.2
85.9
83.6
40.2
41.1
42.2
41.1
catalysts, various bases (potassium carbonate, sodium hy-
drogen carbonate, lithium carbonate, sodium hydroxide), and
various oxidizing agents (nickel peroxide, Fremy’s salt,
manganese dioxide, iron chloride, lead acetate). Our results
continue to support the reaction mechanism summarised by
Barton.22 Further, the mode of agitation of the reaction
mixture had profound effect on product yield, irrespective
of reaction scale. On the scale indicated in the experimental,
the best results were obtained using a vertical stream agitator
(IKA, driven by a 10 kW electric motor). Using conventional
impeller agitators and buffles resulted in a decrease of the
yield of 10-15%. The highest yields (50-54%) were
obtained on a 20-g scale with higher dilution factor.
Operationally, it was more economical to use reaction
conditions with higher concentrations and compromise on
product yields. As described in the experimental, yields of
40-42% have been consistently obtained on scales up to
12 kg.
Multifactorial Analysis of Parameters for the Oxida-
tive Ring Closure Reaction. After numerous experimental
permutations, we focused on optimising reaction conditions
that employed toluene, water, K2CO3, and K3Fe(CN)6. These
studies are described below.
Varying the Amount of K3Fe(CN)6 and K2CO3. These
reactions were conducted using 13.5 L of toluene at 60° with
a reaction time of 15 min. Results are summarised in Table
1.
Thus, lower concentrations resulted in higher yields, with
the concentration of the aqueous phase limited by the
solubility of K3Fe(CN)6. Further, at higher reaction concen-
trations, the filtration time of the reaction by-products
increased significantly. In more dilute reaction conditions,
filtration was accomplished in 10-15 min; in contrast, at
higher concentrations, filtration and washing times ranged
3-12 h.
Once an optimal reagent and substrate combination was
established, we then studied the effect of variations on
reaction times and reaction temperatures on process through-
put. These runs were done using 100 g of 5, 416 g of
K3Fe(CN)6, 2 L of K2CO3 solution, and 13.5 L of toluene.
The results are summarised in Table 2. Additional experi-
mentson a gram scale at 0 °C resulted in reaction times of
4-6 h for completion and yields around 40%.
While the mode of the addition of 5 (in one or in several
portions, powdered, lumpy, or as a slurry) did not influence
the yields, the more critical aspect was to add 5 to a
vigorously agitated two-phase reaction mixture of the other
reactants.
Reproducibility. In four identical campaigns (100 g of
5, 13.5 L of toluene, 416 g of K3Fe(CN)6 and 2 L of 10%
potassium carbonate solution at 60° and 15 min reaction
time) similar yields and product purity was obtained (Table
3).
Step 6: Ketal Formation. In earlier studies it was found
that lithium aluminum hydride reduction of the ethylene ketal
of 6 was problematic: poor reproducibility and inferior
purity. In contrast, reduction of the 1,2-propylene glycol ketal
of 6 occurred cleanly. Further, ketal 7 can be purified by
crystallisation. While 7 is obtained as a mixture of diastereo-
isomers, it is not relevant strategically since the protecting
group is removed during the work-up in step 7. The ketal is
formed with p-toluenesulfonic acid catalysis and azeotropic
removal of the water using toluene as solvent. The 1,2-
propylene glycol ketal 7 is obtained, after extractive work-
up, as a solid that can be used in the subsequent reduction
without further purification. Yields range from 75 to 85%
on batch runs up to 10 kg.
Step 7: Reduction of 7 Using Lithium Aluminum
Hydride and Air: (()-Narwedine (8). CAUTION: Nar-
wedine and narwedine salts are classified as moderate to
severe sensitising agents and, after prolonged exposure, cause
severe allergic skin reactions. For this reason, personnel
handling narwedine are equipped with full protective cloth-
ing, including protective helmet with controlled air stream,
to avoid any contact with this substance.
Initially we had carried out lithium aluminum hydride
reductions on reaction scales up to 10-20 g. However, on a
100-g scale, product formation was negligible; neither
prolonging reaction times nor adding excess LiAlH4 were
effective in producing satisfactory reactivity. It was discov-
ered that aeration of the solution resulted in complete
(22) Barton, D. H. R. Some Recollections of Gap Jumping; Seeman, J. I., Series
Ed.; Profiles, Pathways, and Dreams; American Chemical Society: Wash-
ington, DC,1991; pp 61-68 and references therein.
Vol. 3, No. 6, 1999 / Organic Process Research & Development
•
427

Table 4. Reproducibility of the crystallisation-induced chiral
transformation
Summary
An efficient nine-step process for the synthesis of ga-
lanthamine hydrobromide (nivalin, remenyl) is reported. The
process successfully generates multikilogram quantities of
the bulk drug that is used in phase II and III clinical studies.
physical yield
(g)
content by HPLC
(%)
active yield
(%)
entry
17
18
19
78.5
78.3
77.0
95.3
96.0
95.8
70.0
70.3
73.0
Experimental Section
1
General Procedures. H and 13C NMR spectra were
recorded using a Bruker AC 200 spectrometer (TMS as
internal standard, CDCl3 or DMSO-d6 as solvent, δ values
in ppm). Melting points were determined with a Kofler
melting point apparatus; results are uncorrected. Optical
rotation was recorded at 20 °C at 589, 578, 546, 436, and
365 nm and is reported for 589 nm. Elemental analyses were
performed by the Microanalytical Laboratory, Institute of
Physical Chemistry, University of Vienna (Mag. J. Theiner).
HPLC analyses were performed using a Waters 600 pump
and 486 detector at 285 nm. The column, Phenomenex C18
ODS3 (5 µm) 250 × 4.6 mm, was eluted with mixtures of
0.0015 M 3-cyclohexylamino-propane sulfonic acid (d
CAPS) pH 2.0, MeOH, and THF.
substrate reduction.23 Details of this reaction are reported
elsewhere.24 The reduction of 7 is monitored by TLC. Careful
quenching of the reaction with water and extractive work-
up gives the crystalline product 8. The batch size of 14.4 kg
was the largest performed so far by us with yields of 78-
92%. On larger scale campaigns, 8 was not dried but used
as a wet cake to avoid dust.
Step 8: (-)-Narwedine. A consistently reproducible
procedure has been developed for the crystallisation-induced
chiral transformation of 8 to 9 without the use of a chiral
auxiliary other than seed crystals of 9. Barton10 first reported
that 8 can be converted to 9, with further refinements by
Shieh and Carlson.25 The success of the crystallisation-
induced chiral transformation is based on two phenomena
- (i) narwedine crystallises as a conglomerate and (ii) (-)-
narwedine equilibrates with (+)-narwedine via a retro-
Michael intermediate. Chaplin26 recently reported the dy-
namic diastereomeric resolution of salts of narwedine with
di-p-toluoyl-D-tartaric acid followed by L-Selectride reduc-
tion to 10. Using the conditions detailed in our experimental,
on scales up to 7 kg, reproducible yields of 70-80% of 9
with a specific rotation of -400 to -410° (c ) 1 in CHCl3)
are obtained. Our results are in contrast to the report of
McCague13b who reported difficulties in performing this
method.
Step 1: 2-Bromo-4,5-dimethoxybenzaldehyde (1). A
30-L (nominal capacity: 30 L, total capacity: 45 L,
manufactured by Schott) glass reactor is charged with 25 L
of methanol, and mill-powdered 3,4-dimethoxybenzaldehyde
(4.0 kg, 24.07 mol) is added with stirring, resulting in a 5-8
°C temperature drop. The filling tube is rinsed with 2 L of
methanol and closed. The mixture is heated to 30 °C, if
necessary, to achieve a homogeneous solution. Bromine (4.4
kg, 27.53 mol) is added, with cooling (T < 40 °C), followed
by stirring at this temperature for 1 h. The reaction mixture
is then heated under reflux to remove 9.5 L of methanol by
distillation. At this point, the product may start to precipitate
from solution. After cooling to 20 °C, 15 L water is added
with stirring. The resultant slurry is filtered using a 60-L
pressure filter and washed with cold methanol (3 × 5 L).
The colourless to slightly yellowish product is dried in vacuo
at 50 °C and 40 mbar for 18-24 h. Product yield is 5.4 kg
(91.4%), mp 143-146 °C (lit.14 149-150 °C). TLC: Rf )
0.55 (hexane/ethyl acetate, 6:4).
Reproducibility. In three identical campaigns [8 (106.8
g dry weight), 1170 mL of ethanol 96% and 113 mL of
triethylamine and seeding with 1.07 g of 9] similar yields
and product purity were obtained (Table 4).
Step 9: L-Selectride Reduction of (-)-Narwedine (9)
to (-)-Galanthamine‚HBr (10). We examined various
reducing reagents for their ability to stereoselectively reduce
narwedine (details will be reported elsewhere). L-Selectride
was optimally suited, as galanthamine hydrobromide (nivalin)
is isolated in nearly quantitative yield which can be used
for the pharmaceutical bulk material. Since solutions of 9 in
tetrahydrofuran undergo racemisation, it is important that
solid 9 be added to solutions of L-Selectride at temperatures
below -15 °C to minimise formation of epi-galanthamine.
We have consistently obtained yields of 97-99% with
reaction batches as large as 4.2 kg.
1H NMR (CDCl3) δ 3.9 (s, 3H), 3.98 (s, 3H), 7.05 (s,
1H), 7.40 (s, 1H), 10.20 (s, 1H). 13C NMR (CDCl3) δ 190.3,
154.2, 148.6, 126.2, 120.1, 115.2, 110.1, 56.3, 55.9
Step 2: 2-Bromo-5-hydroxy-4-methoxybenzaldehyde
(2). A 100-L glass vessel is charged with 95% sulphuric acid
(80 L, 1.42 kmol), under argon, is heated with stirring at 90
°C. Stirring is stopped, and 2-bromo-4,5-dimethoxybenz-
aldehyde (1) (16.0 kg, 65.3 mol) is added within 10 min,
and the reaction is allowed to proceed at 90 °C for 6 h. This
mixture is then added quickly, using a glass transfer tube,
to a 500-L reactor charged with 300 L of water, and 60 kg
of ice to precipitate the product. The resultant temperature
rise (to 60 °C) is further reduced by cooling with water, until
a temperature of 20 °C is reached. The mixture is filtered
using a 60-L pressure filter, and the crude product is washed
with water (4 × 15 L) to pH 5-7. The product is distributed
between four trays and dried in a vacuum desiccator
overnight at 60 °C and 40-50 mbar. A 100-L glass vessel
is charged with acetone (80 L) and the dried, dark brown,
(23) Czollner, L.; Fro¨hlich, J.; Jordis, U.; and Ku¨enburg, B. PCT Int. Appl. WO
9,852,885; Chem. Abstr. 1998, 789106
(24) Czollner, L.; Ku¨enburg, B.; Frantsits, W.; Bobrovsky, R.; Jordis, U.;
Fro¨hlich, J. LiAlH4 and oxygen: a new efficient method for the smooth
reduction of (hetero)aryl halides. Tetrahedron Lett., submitted for publica-
tion.
(25) Shieh, W.; Carlson, J. A. J. Org. Chem. 1994, 59, 5463.
(26) Chaplin, D. A.; Johnson, N. B.; Paul, J. M.; Potter, G. A. Tetrahedron Lett.
1998, 39, 6777.
428
•
Vol. 3, No. 6, 1999 / Organic Process Research & Development

crude material is added. Initial stirring at 20 °C results in a
dark brown solution. Undissolved product is solubilised by
heating to 30 °C. Activated carbon (1.2 kg) is added, and
the mixture is stirred for 30 min at 20 °C. Then diatomaceous
earth (1.2 kg) is added, and stirring is continued for 15 min.
The suspension is filtered using a 60-L filter press, and the
filtrate is pumped into a 500-L reactor. Water (120 L) is
added, with stirring, followed by the addition of ice (40 kg).
The precipitated product is filtered using a 60-L filter press
and washed with ice-cold acetone/water (3 × 15 L, 1:1 v/v).
The solid is distributed between four trays and dried in the
vacuum desiccator overnight at 60 °C and 40-50 mbar to
yield 13.34 kg (88.5%) of 2 as gray powder, mp 104-106
°C (lit.18 105-108 °C).
5 is 4.88 kg (80%), mp 164-165 °C [lit.27 148-149 °C]. Rf
) 0.25 (EtOAc/hexane, 8:2).
IR (KBr) 3381, 2976, 2802, 1626, 1503, 1440, 1388,
1
1345, 1268, 1207, 1159, 1016, 825, 792 cm-1; H NMR
(mixture of two rotamers, CDCl3) δ 2.60 (m, 2H), 3.25 (m,
2H), 3.80 (s, 3H), 4.35 (br d, 2H), 6.65-7.00 (m, 6H); 7.80
(br s, 1H, exchangeable with D2O), 8.20 (s, 1H, exchangeable
with D2O), 9.00 (s, 1H, CHO); 13C NMR (mixture of two
rotamers, CDCl3) δ 163.0 and 162.8 (d), 155.7 and 155.8
(s), 148.2 and 147.9 (s), 146.4 and 146.3 (s), 129.7 and 129.4
(d), 128.7 and 128.4 (s), 127.7 and 127.4 (s), 116.9 and 116.3
(d), 116.1 and 115.8 (d), 115.8-115.1 (3*d), 111.2 and 110.8
(s), 55.9 and 55.5 (q), 50.0 and 47.9 (t), 43.8 and 43.2 (t),
33.5 and 31.9 (t).
1H NMR (CDCl3) δ 3.95 (s, 3 H), 5.80 (s, 1 H), 7.05 (s,
1 H), 7.48 (s, 1 H), 10.15 (s, 1H); 13C NMR (DMSO-d6) δ
189.9, 152.9, 145.8, 125.8, 117.1, 114.9, 114.1, 55.6.
Step 3: (2-Bromo-5-hydroxy-4-methoxybenzylidene)-
2-(4-hydroxoxyphenyl)ethylamine (3) and (2-Bromo-5-
hydroxy-4-methoxybenzyl)-2-(4-hydroxoxyphenyl)eth-
ylamine (4). A double-walled 30-L (nominal capacity: 30
L, total capacity: 45 L, Schott) glass reactor is charged with
ethanol (30 L), and intermediate 2 (3500 g, 15.15 mol) is
added with stirring. Following the addition of tyrosine (2.05
kg, 15.0 mol), the mixture is heated at reflux for 4 h. Ethanol
(15 L) is removed by distillation, and the resulting suspension
of intermediate 3 is cooled to 5 °C. A solution of sodium
borohydride (465 g, 11.6 mol) in water (750 mL), stabilized
by addition of 30% sodium hydroxide (1.5 mL), is added
slowly, at such a rate so as to minimize foaming and to
maintain the temperature <30 °C. The mixture is stirred for
1 h at room temperature and then added, with stirring, to
water (80 L) in an open 120-L polypropylene container. The
suspension is left to settle overnight, filtered using a 60-L
filter press, and washed with water (3 × 10 L). After drying
at 70 °C at 40 mbar, 5.02 kg (94.2%) of product 4 is
recovered, mp 122-125 °C. TLC: Rf ) 0.25 (EtOAc:
methanol 9:1).
Step 5: 4r,5,9,10,11,12-Hexahydro-1-bromo-3-meth-
oxy-11-formyl-6H-benzofuro[3a,3,2-ef][2] benzazepine-6-
one (6). An 800-L steel reactor is charged with toluene (600
L) and water (120 L). Potassium hexacyanoferrate (III) (48
kg, 66.8 mol) and potassium carbonate (2 kg) are added.
The reactor is heated to 50 °C with steam. Intermediate 5
(12 kg, 31.5 mol) is added at once, and the biphasic mixture
is stirred for 1 h at 50-60 °C. Diatomaceous earth (30 kg)
is added, and the pulpy mixture is filtered under pressure in
12 portions. The partly polymeric, insoluble filtered solids
are removed following the filtration of each portion and
placed in the filter press. The filtrate is transferred to the
phase separator vessel. The lower, aqueous phase is removed
to the cyanide waste tank. The toluene phase is washed with
water (2 × 40 L) and pumped into the 500-L reactor. Toluene
(2 × 30 L) is used to rinse the 800-L reactor. The washings
are added to the filter press to resuspend the solids, and then
it is filtered into the phase separator. The toluene phase is
added to the 500-L reactor, and the combined toluene extracts
are reduced by distillation at normal pressure to 50 L. The
hot solution is added rapidly (within 5 min), with stirring,
to petroleum ether (60 L, Bp. 80-110 °C). The crystalline
product, obtained after cooling to 10-20 °C, is pressure-
filtered, washed with petroleum ether (2 × 5 L, bp 80-110
°C), and dried at 80 °C and 40 mbar to yield 4.75 kg (40%)
of the product 6, mp 200-205 °C (lit.27 181-183 °C).
TLC: Rf ) 0.45 and 0.55 (2 spots corresponding to 2
rotamers) (CHCl3/MeOH, 95:5).
IR (KBr) 3370-3200 (br), 1554, 1511, 1448, 1409, 1246,
1
1166, 1023, 825, 800, 656 cm-1; H NMR (CDCl3) δ 2.45
(s, 1H), 2.50-2.65 (m, 4H), 3.50 (s, 2H), 3.70 (s, 3H), 6.60-
6.95 (m, 6H); 13C NMR (CDCl3 + DMSO-d6 ) 1:1) δ 155.5,
147.3, 146.0, 130.5, 129.7, 129.2, 116.9, 115.6, 115.0, 111.0,
55.8, 51.8, 50.2, 34.5;
IR (KBr) 3440 (br), 1655, 1590, 1491, 1449, 1280, 1212,
1
1190, 1058, 1030, 455 cm-1; H NMR (mixture of two
rotamers, CDCl3 + DMSO-d6 ) 1:1) δ 8.18 (s+s, 1 H),
6.95 (s, 1 H), 6.80 (dd, 1 H, J ) 12.8 Hz, J ) 6.4 Hz), 6.10
(d, 1 H, J ) 12.8 Hz), 5.70 and 5.15 (d+d, 1 H, J ) 16.0
Hz), 4.70 (bs, 1 H), 4.50 (d, 0.5 H, J ) 15.0 Hz), 4.40 and
4.05 (d+d, 1 H, J ) 16.0 Hz), 4.05-3.90 (m, 0.5 H), 3.85
(s+s, 3 H), 3.80-3.60 (m, 0.5 H), 3.40-3.20 (m, 0.5 H),
3.15 (d, 1 H, J ) 18.0 Hz), 2.85-2.65 (m, 1 H), 2.30-1.90
(m, 2 H); 13C NMR (mixture of two rotamers, CDCl3+DMSO-
d6) δ 193.3 (d), 162.0 and 161.6 (s), 146.8 and 146.6 (s),
144.2 and 143.9 (s), 143.0 and 142.6 (d), 130.48 and 134.43
(s), 127.2 and 127.1 (d), 126.9 and 126.8 (s), 116.0 (d), 113.2
(d), 112.0 (s), 87.3 and 87.2 (d), 55.9 (q), 51.1 and 45.7 (t),
Step 4: N-(4-Hydroxyphenethyl)-N-(2-bromo-5-hy-
droxy-4-methoxybenzyl)formamide (5). A double-walled
30-L (nominal capacity: 30 L, total capacity: 45 L, Schott)
glass reactor is charged with dioxane (28 L), and intermediate
4 (5.00 kg, 14.2 mol) is added with stirring. Ethyl formate
(1900 mL, 23.6 mol), dimethylformamide (900 mL), and
formic acid (150 mL) are added, and the mixture is refluxed
for 10 h, followed by removal of volatiles using a 10-L rotary
evaporator. Methanol (20 L) is added to the residue; the
mixture is transferred to an 80-L polypropylene container
and water and ice (60 L) are added with stirring. The
suspension is stirred for 1 h, filtered using a 60-L filter press,
washed with water (3 × 5 L) and dried in a vacuum
desiccator at 60 °C and 40 mbar overnight. Yield of product
(27) Szewczyk, J.; Lewin, A. H.; Caroll, F. I. J. Heterocycl. Chem. 1988, 25,
1809.
Vol. 3, No. 6, 1999 / Organic Process Research & Development
•
429

40.2 and 34.3 (t), 37.6 and 34.2 (t). Calcd. for C17H16BrNO3
(378.23) C, 53.99; H, 4.26; N, 3.70. Found: C, 53.70; H,
4.47; N, 3.41.
course of 1 h. Again, this addition produces an exothermic
reaction and results in the evolution of hydrogen. During
this decomposition a gel is formed intermittently, which is
difficult to stir. Continued addition of water returns the
mixture to a stirrable suspension. At this stage, 15% sodium
hydroxide (2.5 L) is added rapidly and stirred for 15 min
followed by the addition of diatomaceous earth (2.5 kg) as
a filter aid. The solution is stirred for 30 min at reflux and
filtered while hot, using a process filter, into a 100-L glass
cylinder. The precipitate is extracted with warm solvent
(toluene/THF, 1:1 v/v, 3 × 20 L) and the combined filtrates
are evaporated with a 50-L rotary evaporator. The crude
narwedine propylene ketal is deprotected by adding 4 N
hydrochloric acid (25 L) with stirring (rotary evaporator) for
20 min at 60 °C. The pH of the solution is adjusted to <1
by addition of 4 N hydrochloric acid. The solution is
transferred to the 100-L glass reactor, cooled to 40 °C by
the addition of ice (5 kg), and extracted with ethyl acetate
(2 × 15 L). The acidic, aqueous phase is concentrated by
vacuum distillation (40 °C, 20-30 mbar) to a volume of 15
L. The residue after evaporation is collected and then added
slowly with stirring to a polypropylene container charged
with 25% ammonium hydroxide (20 L). Ice (10 kg) is added,
the suspension of crystalline material is stirred for 30 min,
pressure filtered, and washed with water (3 × 5 L). The wet
cake is dried at 70 °C and 40 mbar to give the product 8
(7.53 kg, 80%) as white to pale yellow powder, mp 191-
193 °C (lit.10 186-190 °C). TLC: Rf ) 0.45 (CHCl3/MeOH,
95:5).
Step 6: 4r,5,9,10,11,12-Hexahydro-1-bromo-3-meth-
oxy-11-formyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-
(1,2-propanediol) Ketal (7). A 100-L glass reactor is
charged with toluene (70 L), intermediate 6 (10.0 kg, 26.4
mol), p-toluene-sulfonic acid (150 g) and 1,2-propanediol
(10 L, 133 mol) (Solution A). A separate 15-L addition vessel
is charged with a solution of p-toluenesulfonic acid (350 g)
in 1,2-propanediol (5 L, 66 mol) (Solution B). After Solution
A was heated for 1 h, 250 mL aliquots of Solution B is added
to the refluxing mixture at 15 min intervals for total of 5 h.
The mixture is refluxed, with stirring, for 6 h to remove
water. The reaction mixture is cooled to 20 °C. The lower
phase is transferred to a 40-L polypropylene container and
extracted with toluene (4 × 10 L). The combined toluene
phases are concentrated in the 100-L glass reactor to a
volume of 70 L. This solution then is cooled to 20 °C and
washed successively with 10% acetic acid (20 L), saturated
sodium hydrogen carbonate solution (2 × 20 L) and finally
with water (2 × 20 L). The toluene phase is evaporated to
dryness using a 50-L rotary evaporator to yield the product
7 (9.22 kg, 80%) as a dry foam. The foam was crystallised
using ligroin (25 L, bp 80-110 °C) to give the product as
pale yellow crystals mp 170-171 °C. TLC: 2 interconvert-
ible spots at Rf ) 0.70 and 0.75 (CHCl3/MeOH, 95:5).
1H NMR (mixture of diastereoisomers and rotamers,
CDCl3) δ 8.12 (s+s, 1 H), 6.88 (s, 1 H), 5.96-6.17 (m, 1
H), 5.60-5.85 (m, 1.5 H), 5.10 (d, 0.5 H, J ) 18.5 Hz),
4.53 (bs, 1 H), 3.90-4.40 (m, 5 H), 3.82 (s, 3H), 3.10-
3.75 (m, 3 H), 2.56-2.80 (m, 1 H), 1.80-2.40 (m, 3 H),
1.30 (d+d, 3H); 13C NMR (mixture of diastereoisomers and
rotamers, CDCl3) δ 162.5, 161.7, 147.2, 144.9, 144.6, 132.2,
129.0, 128.5, 128.6, 127.8, 127.7, 127.6, 115.7, 115.5, 127.1,
126.8, 126.5, 113.2, 111.7, 102.4, 102.2, 87.3, 87.1, 73.4,
72.5, 71.7, 71.4, 71.2, 70.6, 70.3, 55.9, 51.5, 46.2, 48.4, 40.8,
39.3, 36.1, 35.9, 34.6, 33.7, 33.4, 33.1, 18.7, 17.6, 17.5.
Step 7: (()-Narwedine (8). CAUTION: Narwedine and
narwedine salts are classified as moderate to severe sensi-
tising agents and, after prolonged exposure, cause severe
allergic skin reactions. For this reason, all personnel handling
narwedine are equipped with full protective clothing, includ-
ing protective helmet with controlled air stream, to avoid
any contact with this substance.
IR (KBr) 3014, 2919, 2844, 1681, 1618, 1587, 1540,
1505, 1440, 1285, 1265, 1212, 1167, 1146, 1133, 1102, 1050,
1
1029, 1000 cm-1; H NMR (CDCl3) δ 6.93 (d, 1 H, J )
12.8 Hz), 6.64 (AB, 2 H, J ) 8.5 Hz), 6.00 (d, 1 H, J )
12.8 Hz), 4.68 (m, 1 H), 4.06 (d, 1 H, J ) 16.0 Hz), 3.80 (s,
3 H), 3.70 (d, 1 H, J ) 16.0 Hz), 3.02-3.28 (m, 3 H), 2.71
(dd, 1 H, J ) 19.2 Hz, J ) 3.2 Hz), 2.41 (s, 3 H), 2.15-
2.30 (m, 1 H), 1.75-1.90 (m, 1 H); 13C NMR (CDCl3) δ
194.4, 147.0, 144.4, 144.0, 130.6, 129.4, 127.1, 122.0, 111.9,
88.0, 60.7, 56.0, 54.1, 49.0, 42.5, 37.3, 33.3.
Step 8: (-)Narwedine (9). A 100-L glass reactor is
charged with ethanol/triethylamine (9:1 v/v, 75 L), and
racemic narwedine (8, 7.0 kg, 24.5 mol) is added. The
mixture is heated to reflux, and ethanol/triethylamine (9:1
v/v, 10 L) is added to give a homogeneous solution. The
solution is cooled to 65-68 °C, seeded with 9 (70 g, [R]20
D
A 100-L glass reactor is dried under argon and charged
with anhydrous THF (30 L). Intermediate 7 (14.4 kg, 33 mol)
is added and the addition funnel rinsed with THF (2 L). A
10% solution of LiAlH4 in THF (22 L, 57.9 mol) is added
slowly with stirring to the suspension. The addition vessel
again is rinsed with THF (2 × 2 L). Initially, the reaction is
exothermic with hydrogen evolution. Synthetic air (80%
nitrogen, 20% oxygen) is bubbled into the solution at a rate
of 20-25 L/min, with stirring at 60-65 °C without external
heating. The reaction is monitored by TLC and is allowed
to continue until the starting material has been consumed
completely (approximately 3 h). Toluene (20 L) is added,
followed by dropwise addition of water (2.5 L) over the
) -400°, c ) 1.5 in CHCl3; lit.25 [R]25D ) -415°, c ) 1 in
CHCl3), cooled to 40 °C within 1 h, and stirred for 3 h. The
suspension is concentrated at 40 °C and 20-40 mbar to a
volume of 25-30 L and transferred to a 40-L polypropylene
container. The reactor is rinsed with ethanol (1 L); the
washing is added to the polypropylene container. The
suspension is cooled to 5-10 °C with stirring, pressure
filtered, and washed with cold ethanol (4 L, 0-5 °C). After
drying at 60 °C and 40 mbar, 5.6 kg (80%) of 9 ([R]D )
-400°, c ) 1.5% in CHCl3) is recovered.
IR (KBr) 3014, 2919, 2844, 1681, 1618, 1587, 1540,
1505, 1440, 1285, 1265, 1212, 1167, 1146, 1133, 1102, 1050,
1
1029, 1000 cm-1; H NMR (CDCl3) δ 6.93 (d, 1 H, J )
430
•
Vol. 3, No. 6, 1999 / Organic Process Research & Development

12.8 Hz), 6.64 (AB, 2 H, J ) 8.5 Hz), 6.00 (d, 1 H, J )
12.8 Hz), 4.68 (m, 1 H), 4.06 (d, 1 H, J ) 16.0 Hz), 3.80 (s,
3 H), 3.70 (d, 1 H, J ) 16.0 Hz), 3.02-3.28 (m, 3 H), 2.71
(dd, 1 H, J ) 19.2 Hz, J ) 3.2 Hz), 2.41 (s, 3 H), 2.15-
2.30 (m, 1 H), 1.75-1.90 (m, 1 H); 13C NMR (CDCl3) δ
194.4, 147.0, 144.4, 144.0, 130.6, 129.4, 127.1, 122.0, 111.9,
88.0, 60.7, 56.0, 54.1, 49.0, 42.5, 37.3, 33.3.
temperature below 20 °C, 48% hydrobromic acid (3.5 L, 20.8
mol) is added with stirring over the course of 30 min. Seed
crystals of 10 (10 g) are added, and the pH is adjusted to
<1 using 48% hydrobromic acid. The suspension is stirred
at 0-5 °C for 1 h, pressure filtered, washed with ethanol (3
× 4 L), and dried at 60 °C at 40 mbar) to give 10 (5366 g,
99%) as colourless crystals, mp 264-267 °C (lit.28 246-
247 °C). [R]D ) -92° (c ) 1,5%, H2O) [lit.28 -93° (c )
1,5%, H2O)].
1H NMR (DMSO-d6) δ 10.50 (bs, 1 H), 6.85 (AB, 2 H,
J ) 9.6 Hz), 6.15 (d, 1 H, J ) 7.9 Hz), 5.95 (dd, 1 H, J )
7.9 Hz, J ) 3.2 Hz), 4.85 (d, 1 H, J ) 16.0 Hz), 4.60 (s, 1
H), 4.47 (bs, 1 H), 4.35 (d, 1 H, J ) 16.0 Hz), 4.10 (bs, 1
H), 3.70-3.90 (s+m, 4 H), 3.50 (d, 1 H, J ) 12.8 Hz), 2.85
(bs, 3 H), 2.40-2.00 (m, 3 H), 1.90 (d, 1 H, J ) 16.0 Hz);
13C NMR (DMSO-d6) (clearly distinguishable signals; b )
very broad and small signals) δ 146.3, 144.8, 132.8, 129.8,
125.4, 122.9, 121.2 (b), 111.9, 86.3, 59.4, 57.5 (b), 55.6,
53.7 (b), 46.4, 30.9.
Step 9: (-)-Galanthamine Hydrobromide (10). A
double-walled 30-L (nominal capacity: 30 L, total capac-
ity: 45 L, Schott) glass reactor, under argon, is charged with
1 M L-Selectride in THF (18.0 L, 18 mol). Anhydrous THF
(4 L) is added, and the mixture is cooled, with stirring, to
-20 °C. While the reactor temperature is maintained below
-15 °C, solid (-)-narwedine 9 (4200 g, 14.72 mol) is added
portionwise over the course of 2 h. The solid-addition funnel
is rinsed with anhydrous THF (1 L), and the reaction mixture
stirred at -15 °C for 30 min. The mixture then is heated to
20 °C over the course of 1 h to give an amber-coloured
solution. Ethanol (1.5 L) is added dropwise, resulting in a
temperature rise to 30 °C, and the mixture stirred for an
additional 30 min. The reaction mixture is transferred to a
60-L pressure filter, and the reactor is rinsed with THF (1
L). The filtrate is returned to the glass reactor and the filter
is rinsed with THF (2 × 2 L). The solution is diluted with
ethanol (5 L) and cooled to 0 °C. While maintaining the
Received for review March 18, 1999.
OP990019Q
(28) Carroll, P.; Furst, G. T.; Han, S. Y.; Joullie´, M. Bull. Soc. Chim. Fr. 1990,
127, 769.
Vol. 3, No. 6, 1999 / Organic Process Research & Development
•
431