Practical chemical and enzymatic technologies for (S)-1,4-benzodioxan-2-carboxypiperizine intermediate in the synthesis of (S)-doxazosin mesylate

Article abstract of DOI:10.1016/S0957-4166(01)00368-8

(S)-1,4-Benzodioxan-2-carboxypiperazine (S)-2, the key chiral intermediate for the synthesis of (S)-doxazosin, was prepared utilizing two approaches: (i) enzymatic resolution of ethyl 1,4-benzodioxan-2-carboxylate with an esterase (Serratia) followed by amide formation; (ii) direct resolution of 1,4-benzodioxan-2-carboxypiperazine 2 with D-tartaric acid. An efficient process for the conversion of (S)-2 to (S)-doxazosin mesylate was developed (80% yield, 99.9% e.e.).

Full text of DOI:10.1016/S0957-4166(01)00368-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2169–2174
Practical chemical and enzymatic technologies for
S)-1,4-benzodioxan-2-carboxypiperizine intermediate in the
synthesis of (S)-doxazosin mesylate
(
Q. Kevin Fang,* Paul Grover, Zhengxu Han, Fran X. McConville, Richard F. Rossi,
Damase J. Olsson, Donald W. Kessler, Stephen A. Wald and Chris H. Senanayake*
Chemical Process Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, MA 01752, USA
Received 24 July 2001; accepted 17 August 2001
Abstract—(S)-1,4-Benzodioxan-2-carboxypiperazine (S)-2, the key chiral intermediate for the synthesis of (S)-doxazosin, was
prepared utilizing two approaches: (i) enzymatic resolution of ethyl 1,4-benzodioxan-2-carboxylate with an esterase (Serratia)
followed by amide formation; (ii) direct resolution of 1,4-benzodioxan-2-carboxypiperazine 2 with
D-tartaric acid. An efficient
process for the conversion of (S)-2 to (S)-doxazosin mesylate was developed (80% yield, 99.9% e.e.). © 2001 Elsevier Science Ltd.
All rights reserved.
1
. Introduction
that the (S)-enantiomer of doxazosin would offer both
reduced side effects (e.g. asthenia, dizziness), and
improved efficacy over the racemate for the treatment
of BPH. As a result, (S)-doxazosin is being investigated
in clinical studies. Due to the importance and structural
similarity of these quinazolines (doxazosin, prazosin,
terazosin, and alfuzosin), a general synthetic strategy
®
(
±)-Doxazosin mesylate, marketed as CARDURA in
the US, is a newer member of the important quinazo-
line family of drugs and is indicated for the treatment
of hypertension. More recently, it has proven effective
in the treatment of benign prostatic hyperplasia
BPH). The mode of action of doxazosin is believed to
1
2
(
for this class of compounds has been well established.
be a selective inhibition of the a -subtype of the alpha
The last step in the synthesis usually involves the cou-
pling of chloro-quinazoline substrate 3 with an amine
1
adrenergic receptor. Pre-clinical studies have suggested
Scheme 1.
*
0
Corresponding authors. E-mail: kfang@sepracor.com; csenanay@sepracor.com
957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00368-8

2
170
Q. K. Fang et al. / Tetrahedron: Asymmetry 12 (2001) 2169–2174
derivative. Scheme 1 outlines the synthesis of (±)-doxa-
used enzymes, a microbial esterase derived from Serra-
tia marcescens was found to stereoselectively catalyze
3
5
zosin hydrochloride starting from the benzodioxane-2-
carboxylic acid 1 and quinazoline 3. The synthesis of
the hydrolysis of ethyl (S)-1,4-benzodioxan-2-carboxyl-
6
(
S)-1 was also reported by resolution with dehydroabi-
ate 4 with high activity (E value of 273) on 50 g scale.
4
etylamine in very low yield (ca 1%). In order to carry
out in vitro and in vivo efficacy and pharmacokinetic
studies of (S)-doxazosin, we required an efficient and
practical method for the synthesis (S)-2 and its conver-
sion to (S)-doxazosin mesylate.
(±)-4 was easily prepared in 93% yield by reaction of
catechol and ethyl dibromopropionate.
The stereoselective hydrolysis of 4 was carried out in a
two-phase system of toluene and an aqueous solution
of sodium bicarbonate (Scheme 2). The pH of the
reaction mixture was maintained with an auto titrator
between pH 8.6 and 9.0 by the addition of aqueous
sodium hydroxide. The final conversion (45–46%) was
conveniently determined by the quantity of sodium
hydroxide consumed. (R)-4 remained in the toluene
phase and was removed by phase separation. The
recovered (R)-4 was racemized with a catalytic amount
of potassium tert-butoxide in toluene. The crude (S)-1
(41–43%, 95.6–98.4% e.e.) was isolated from the
aqueous phase by extraction with ethyl acetate after pH
adjustment of the aqueous phase to pH 0.3–1.0. Enan-
tiomerically pure (S)-1 (21–25% yield, 99.8% e.e.) was
obtained by crystallization of the crude product in
toluene on a 1–2 kg scale. The lower isolated yield
of the product (S)-1 compared to the conversion (45–
46%) was mainly due to the necessary enrichment by
crystallization during the isolation. Fig. 1 shows a
phase diagram of the acid 1 obtained by differential
scanning calorimetry (DSC). The conglomerate has an
Herein, we describe two new methods for the prepara-
tion of enantiomerically pure (S)-1,4-benzodioxan-2-
carboxypiperizine (S)-2. The first method involved
hydrolytic kinetic resolution of ethyl 1,4-benzodioxan-
2
-carboxylate 4 by an esterase enzyme, followed by
amide formation. The second employed the direct
chemical resolution of (±)-2 with -tartaric acid. In
D
addition, we report an efficient process for the conver-
sion of the key intermediate (S)-2 to (S)-doxazosin
mesylate in high chemical yield, chemical purity and
enantiomeric purity.
2
. Results and discussion
2.1. Enzymatic approach to (S)-1
Our first approach to (S)-1 involved the use of an
esterase enzyme. After screening a variety of commonly
Scheme 2.
Figure 1.

Q. K. Fang et al. / Tetrahedron: Asymmetry 12 (2001) 2169–2174
2171
unfavorable eutectic point, therefore, enrichment of
S)-1 is not efficient and recovery by crystallization was
screening a number of chiral acids (tartaric acid, ditolu-
oyl tartaric acid, dibenzoyl tartaric acid, and mandelic
acid), tartaric acid was found to be an excellent resolv-
ing agent for 2 (Scheme 4).
(
7
low.
2.2. Synthesis of (S)-2 from (S)-1
(
±)-2 was treated with 1 equiv. of
D-tartaric acid in
While a number of coupling reagents were explored for
acetonitrile/water (1:1) to give the diastereomerically
enriched salt in 39% yield (75–80% d.e.). Crystallization
of this salt in a mixture of solvents (acetonitrile,
methanol and water) gave the salt in 50% yield (99%
d.e.). After salt breakage, (S)-2 was isolated in 20%
overall yield after crystallization from toluene (e.e.=
the formation of (S)-2 from (S)-1, it was found that
8
racemization occurred during the reaction. Therefore,
the amination reaction was conducted utilizing the
3
available method with modification to minimize the
formation of diamide 5 as outlined in Scheme 3.
9
9.3%). In addition, (R)-2 was readily recovered from
(
S)-1 was converted to the corresponding acid chloride
the reaction mother liquors, racemized with potassium
10
by treatment with thionyl chloride. One equivalent of
acid chloride was then slowly added to excess piper-
azine monohydrochloride (3 equiv.) in water and
methanol over 4 h by sub-surface addition. Formation
of the highly insoluble by-product 5 was minimized to
about 10% and 5 could be readily removed by filtration
from the reaction mixture. The product (S)-2 was iso-
lated after extraction with dichloromethane and recrys-
tallization from toluene in 75–80% yield (99.94% e.e.,
tert-butoxide, and recycled. This direct, simple and
practical resolution procedure has been demonstrated
on 50 gram scale. Currently, this new resolution tech-
nology is under development for the multi-kilogram
production of (S)-2.
2.4. Synthesis of (S)-doxazosin mesylate
99.90% chemical purity).
Coupling of 3 with (S)-2 proceeded smoothly to give
(
S)-doxazosin hydrochloride in a 95% yield (99.9%
3
The enzymatic route was successfully used to prepare
multi-kilogram quantities of (S)-2. However, the over-
all isolated yield of enantiomerically pure (S)-2 (99.94%
e.e.) from (±)-4 is low, primarily due to the unfavorable
eutectic point of the conglomerate in the upgrade of the
e.e. of (S)-1 to >99.50%. In addition, amination of
e.e.). both the hydrochloride salt, and the free amine
were insoluble in common solvents (e.g. water, DMSO,
EtOAc, toluene), which made it impractical to use a
neutralization and extraction protocol to obtain the
free base. It was found that when the HCl salt was
suspended in DMF/water and treated with concen-
trated sodium hydroxide (1.1 equiv.), followed by dilu-
tion with water, the free base precipitated from the
aqueous phase and was isolated in 95% yield and high
chemical purity. To our surprise, the doxazosin free
base was partially racemized (90% e.e.) due to the high
pH. To avoid racemization, weaker bases were evalu-
ated. When potassium carbonate (1.2 equiv.) was used
under similar conditions, the free amine precipitated
without racemization, and was easily collected by filtra-
tion. The free amine was in turn treated with methane-
sulfonic acid in methanol to give the mesylate salt in
85–90% overall yield, as outlined in Scheme 5.
(
S)-1 by (S)-2 produced 10% of undesired 5. To cir-
cumvent these problems, our attention turned to devel-
oping a direct resolution method for the preparation of
(
S)-2.
2.3. Resolution approach to (S)-2
Recently, a number of practical methods for the prepa-
9
ration of (±)-2 have been developed. In particular,
9
a
Chou described the high yielding and direct coupling
of piperazine with 4 (94%), making (±)-2 a readily
available and attractive candidate for resolution. After
Scheme 3.
Scheme 4.

2
172
Q. K. Fang et al. / Tetrahedron: Asymmetry 12 (2001) 2169–2174
Scheme 5.
3. Conclusion
4.3. (S)-1,4-Benzodioxan-2-carboxylic acid (S)-1
In conclusion, complementary enzymatic and chemical
resolution methods for the preparation of the key inter-
mediate (S)-2 were developed. The direct resolution of
readily available (±)-2 with tartaric acid provided the
most practical and economical solution. In addition, an
efficient, practical and non-epimerizable protocol for
the conversion of (S)-2 to (S)-doxazosin mesylate (>
To a 60 L Buchi reactor equipped with mechanical
stirrer, and pH meter auto-titrator was charged with
aqueous NaHCO (0.1N, 12 L, pH 8.6), and 4 (4.0 kg)
3
in toluene. The mixture was stirred for 5 min at 25°C.
Serratia enzyme (180 mL) was added. The pH of the
reaction mixture was maintained between 8.5 and 9.0
by addition of 2N NaOH. After 6.5 h (25% conver-
sion), stirring was stopped and the aqueous phase was
99.9% e.e., 99.8% chemical purity) was developed.
Work is continuing on the direct resolution of (±)-2 for
separated and stored. Additional NaHCO (0.1N, 6 L)
3
further process optimization.
was added to the organic phase, followed by additional
Serratia (60 mL). The pH of the reaction mixture was
maintained between 8.5 and 9.0 for an additional 13 h.
Based on consumption of the 2N NaOH solution, the
overall conversion was 45%. The aqueous phase was
separated and combined. The combined aqueous
phases were acidified with concentrated HCl to pH 1,
then saturated with NaCl (2.5 kg), and extracted with
EtOAc (30 L). The extract was washed with water (2 L)
and concentrated to give crude (S)-1 as a solid (1.5 kg)
with e.e. of 96.5% determined by HPLC analysis (Chi-
ralpak OD, 10 mm, 4.6 mm×25 cm, 90% hexane/10%
IPA/0.1% TFA, 1.0 mL/min (S)-1: 7.9 min (R)-1: 9.3
min). Crystallization of the crude product from toluene
4. Experimental
4.1. General
Solvents and reagents were commercial grade. All lab-
scale reactions were carried out in oven-dried glassware
under an argon atmosphere. All kilo-scale reactions
were performed using a 60 L Buchi under an argon
1
13
atmosphere. H and C NMR were performed on a
00 MHz Varian instrument. HPLC analysis was per-
3
1
gave (S)-1 (808 g, 24% yield, >99.94% e.e.); H NMR
formed on a Waters system, using a Waters m-Bonda-
(
(
CDCl ): l 4.30–4.50 (m, 2H), 4.90 (m, 1H), 6.80–6.95
m, 3H), 7.00 (m, 1H), 8.20 (br s, 1H).
pak C18 300×3.9 mm column, ChiralPak OD, 10 mm,
3
4
.6 mm×25 cm, ChiralPak AD, 10 mm, 4.6 mm×25 cm,
or ChiralPak OD-R, 10 mm, 4.6 mm×25 cm.
3
4
.4. (S)-1,4-Benzodioxan-2-carbonyl chloride
4.2. Ethyl 1,4-benzodioxan-2-carboxylate 4
To a 1 L round bottom flask was charged (S)-1 (400 g,
.2 mol) and SOCl (33 mL). DMF (0.80 mL) was
2
2
A 60 L Buchi reactor was charged with catechol (2.5
kg), potassium carbonate (anhydrous powder, 6.8 kg)
and acetone (23 kg). The reactor was heated to reflux,
and to it was added ethyl 2,3-dibromopropionate (5.8
kg) over a 1.5 h period. After the addition, the reaction
mixture was heated under reflux for 4 h and the reac-
tion volume was reduced by distillation to 10 L. To the
residue was added toluene (17 L) to give a suspension,
which was distilled to remove residual acetone. The
toluene suspension was washed with water (10 L),
NaOH (0.1N, 6 L), water (6 L), and then concentrated
to give a solution of 4 in toluene (16 kg). The chemical
purity of 4 solution was 95% by HPLC analysis (Waters
m-Bondapak C18 300×3.9 mm, 50% acetonitrile/50%
buffer (0.05 M NaHClO ·H O, pH 2.0), 1.0 mL/min).
added to the flask, and the reaction was heated to 84°C
for 1.5 h. The reaction was allowed to cool to 30°C.
The excess thionyl chloride was carefully distilled at a
temperature not exceeding 50°C. The solution was
again cooled to 25°C. With agitation, EtOAc (0.8 kg)
was added, and the mixture was used in the next
reaction.
4.5. (S)-N-(1,4-Benzodioxan-2-carbonyl)piperazine (S)-
3
2
To a 60 L Buchi reactor equipped with mechanical
stirrer and a pH meter auto-titrator was charged piper-
azine (2.6 kg, 30.1 mol) and water (6.0 kg). The reactor
was charged with methanol (6.3 kg). With agitation, the
slurry was cooled to 0°C. To the reactor was slowly
added concentrated hydrochloric acid (3.9 kg) while
4
2
A total of 4.3 kg (92%) of 4 was produced. This
solution was used in the next step without purification.

Q. K. Fang et al. / Tetrahedron: Asymmetry 12 (2001) 2169–2174
2173
1
maintaining the reaction at a temperature below 30°C.
At 30–35°C, an EtOAc solution of the acid chloride
give the (S)-2 as free base (>99.3% e.e.); H NMR
(CDCl ): l 1.80 (s, 1H), 2.80–2.96 (m, 4H), 3.48–3.78
3
(
10.0 mol, from 1.79 kg (S)-1) was slowly added to the
(m, 4H), 4.26–4.40 (m, 1H), 4.46–4.51 (m, 1H), 4.80–
4.84 (m, 1H), 6.85–6.92 (m, 4H).
reactor over a 4 h period. The reaction mixture was
stirred for an additional 30 min, and was then vacuum
distilled to a final volume of 15 L while maintaining the
reactor temperature at <50°C. After cooling the reactor
to 25°C, water (23 kg) was charged. The solids 5 were
filtered through a B u¨ chner funnel, and washed with
water (1.7 kg). The filtrate was charged with aqueous
3
4.8. Synthesis of (S)-doxazosin·HCl
4-Amino-2-chloro-6,7-dimethoxyqunizoline (1.27 kg)
and N-(1,4-benzodioxan-2-carbonyl)piperazine (S)-2
(1.4 kg) were suspended in n-butanol (30 L). The
mixture was heated under reflux for 4 h. The reaction
mixture was cooled to 60°C. The slurry was collected
by filtration. The wet cake was washed with ethyl
acetate (500 mL) and dried at 50°C under vacuum to
give product (2.5 kg, 99.2% chemical purity, and
99.80% e.e. as determined by chiral HPLC [Chiralcel
NH OH (5.0 kg) maintaining the temperature at 22±
5
4
°C, and dichloromethane (14.3 kg) was added. After
mixing for 10 min, the phases were separated. The
aqueous phase was extracted further with dichloro-
methane (2×7.6 kg). The combined dichloromethane
phases were washed with water (7.77 kg). The phases
were separated and the dichloromethane solution was
concentrated to leave a volume of 4.32 L. toluene (10.8
kg) was charged to the reactor and the solution was
distilled to leave a volume of 7.9 L. The reactor was
heated until all of the solids had dissolved, without
exceeding 120°C. The reaction was slowly allowed to
cool to 25°C, and allowed to stir for 1 h. The solids
were collected filtration via B u¨ chner funnel and washed
with toluene (2×0.5 kg). Additional (S)-2 (170 g) was
obtained from the mother liquor. The solids were com-
bined and dried in vacuo to provide (S)-2 (1.86 kg,
OD-R, 10 mm, 4.6×25 cm, 0.5 M NaClO /acetonitrile
4
(55:45), (R)-isomer: 17.4 min, (S)-isomer: 19.6 min].
4.9. Synthesis of (S)-doxazosin free base
(S)-Doxazosin·HCl (2.5 kg) was suspended in a mixture
of DMF (7 kg) and water (3.6 kg) at 15–35°C and
treated with K CO (40% aq. 1.8 kg) to give a clear
2
3
solution. The solution was diluted with water (30 kg)
while (S)-doxazosin free base precipitated from the
solution. The free base was collected by filtration and
dried under vacuum to afford the title product (2.1 kg,
2
2
1
7
5%, 99.90% e.e.); [h] +85.4 (c 1, MeOH); H NMR
D
2
2
(CDCl ): l 1.76 (s, 1H), 2.83–2.96 (m, 4H), 3.43–3.55
95%, 99.90% e.e., 99.7% chemical purity); [h] +25.4 (c
3
D
1
(
m, 2H), 3.64–3.78 (m, 2H), 4.32 (m, 1H), 4.50 (m, 1H),
1, DMSO); H NMR (DMSO-d ): l 3.66 (m, 8H), 3.79
6
1
3
4
4
1
.90 (m, 1H), 6.86 (m, 4H); C NMR: l 43.2, 45.8,
6.4, 47.1, 65.2, 70.5, 117.2, 117.3, 121.5, 122.2, 142.5,
43.2, 164.8. E.e. was determined by HPLC (Chiralpak
(s, 3H), 3.83 (s, 3H), 4.21 (m, 1H), 4.41 (d, J=11.6 Hz,
1H), 5.24 (m, 1H), 6.84 (m, 5H), 7.17 (s, 2H), 7.44 (s,
13
1H); C NMR: l 41.57, 43.38, 43.99, 45.14, 55.44,
55.84, 64.79, 69.52, 103.04, 103.67, 105.28, 116.90,
117.10, 121.40, 121.51, 142.89, 143.08, 145.09, 148.77,
154.26, 158.29, 161.20, 164.91.
AD, 10 mm, 4.6 mm×25 cm, 80% hexane/10% EtOH/
0% MeOH, 1.0 mL/min (S)-2: 15.5 min (R)-2: 18.9
min).
1
4
.6. (S)-2-
D
-Tartrate
4.10. Synthesis of (S)-doxazosin mesylate
(
±)-N-(1,4-Benzodioxan-2-carbonyl)piperazine
(±)-2
(S)-Doxazosin free base (2.1 kg) was suspended in
MeOH (10 kg) at 25°C and treated with methanesul-
fonic acid (500 g). The reaction mixture was heated to
55°C for 30 min. The solution was slowly cooled to
25°C for 5 h to give (S)-doxazosin mesylate as a slurry.
The (S)-doxazosin mesylate was collected by filtration
and dried under vacuum to give the product (2.33 kg,
(
50.0 g) was dissolved in acetonitrile (1130 mL) and
methanol (97.5 mL) and treated at rt with a solution of
-tartaric acid (35.0 g) in water (227 mL). The reaction
D
mixture was heated to 80°C, cooled to rt over 30 min
and stirred at rt for 3 h. The precipitate was collected
by filtration and washed with acetonitrile (150 mL), and
2
2
dried to give 2-
stereomeric ratio of the salt was determined by HPLC
Chiralpak AD column (4.6×250 mm) and a mixture of
D
-tartrate (31.3 g, 39%). The dia-
90%, 99.90% e.e., 99.7–99.8% chemical purity); [h]
D
1
+69.6 (c 1, DMSO); H NMR (DMSO-d ): l 2.46 (s,
6
(
3H), 3.70 (m, 8H), 3.82 (s, 3H), 3.88 (s, 3H), 4.20 (dd,
J=11.7, 6.3 Hz, 1H), 4.47 (dd, J=11.7, 2.4 Hz, 1H),
5.32 (m, 1H), 6.84 (bs, 3H), 6.90 (m, 1H), 7.25 (s, 1H),
hexane/ethanol/methanol (9:1:1)) to be S:R=87:13).
This wet cake (24.0 g) was further crystallized in a
mixture of solvents (MeCN (318 mL); water (107 mL),
and MeOH (64 mL)) to give the pure salt (12.0 g, 50%
recovery); [h]D −9.0 (c. 0.3, H O); H NMR (DMSO-
d6): l 3.02–3.08 (m, 4H), 3.65 (m, 2H), 3.77 (m, 2H),
13
7.60 (s, 1H), 8.68 (s, 1H), 8.80 (s, 1H); C NMR: l
40.82, 44.09, 44.44, 56.15, 64.69, 69.47, 99.00, 101.54,
104.62, 116.92, 117.04, 121.44, 135.84, 142.86, 143.08,
146.82, 151.24, 155.32, 161.24, 165.29.
2
2
1
2
4
1
.06 (s, 2H), 4.20 (m, 1H), 4.41 (m, 1H), 5.23–5.26 (m,
H), 6.91 (m, 4H), 6.0–7.5 (br s, 6H).
Acknowledgements
4.7. (S)-2 from (S)-2-D-tartrate
The above salt was treated with aqueous K CO and
extracted with dichloromethane. The organic phase was
then separated and washed with brine, concentrated to
We would like to thank Dr. Hal Butler, Dr. Paul Byers,
Mr. Robert E. Malone, and Mr. Hui Li for their
analytical support.
2
3

2
174
Q. K. Fang et al. / Tetrahedron: Asymmetry 12 (2001) 2169–2174
5. Serratia marcescens enzyme was supplied by Tanabe
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4
10. Treatment of (R)-2 (>99% e.e.) with a 20 mol% solution
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