A facile and practical synthesis of (-)-tasimelteon

Article abstract of DOI:10.3184/174751916X14758368248634

An efficient and practical route for the synthesis of (-)-tasimelteon from 2,3-bis(2-hydroxyethyl)phenol has been developed. The product was prepared in seven steps in overall 16.4% yield using highly stereoselective cyclopropanation reaction of the intermediate as the key step.

Full text of DOI:10.3184/174751916X14758368248634

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 NOVEMBER, 667–669
RESEARCH PAPER 667
A facile and practical synthesis of (−)-tasimelteon
a
a
b
a
Senyang Mi , Xinzhe Sun , Chaogang Wu and Xingxian Zhang *
a
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, P.R. China
Zhejiang Apeloa Medical Technology Co. Ltd, Dongyang, Zhejiang 322118, P.R. China
b
An efficient and practical route for the synthesis of (−)-tasimelteon from 2,3-bis(2-hydroxyethyl)phenol has been developed. The product
was prepared in seven steps in overall 16.4% yield using highly stereoselective cyclopropanation reaction of the intermediate as the
key step.
Keywords: 2,3-bis(2-hydroxyethyl)phenol, 4-vinyl-2,3-dihydrobenzofuran, tasimelteon, synthesis
Tasimelteon 1 is a new kind of oral melatonin receptor agonist.
Results and discussion
It was developed by the pharmaceutical company Vanda in
the United States. Tasimelteon appeared on the market in
The starting point for the synthetic route development is
outlined in Scheme 1. This approach involved the preparation
of 4-vinyl-2,3-dihydrobenzofuran 5 in a three-step sequence
from 2,3-bis(2-hydroxyethyl)phenol 2 as the starting material.
Compound 2 was dissolved in CH Cl and triethylamine, which
1
January 2014, and has a small dosage, strong efficacy and good
tolerability. Early in the synthesis of tasimelteon, 4-vinyl-2,3-
dihydrobenzofuran 5 was identified as a key intermediate,
allowing further manipulation at the vinyl group. It is prepared
from 2,3-bis(2-hydroxyethyl)phenol 2 (triol) as the starting
material because of its ready availability from the industrial
intermediate 5,8-dihydro-1-naphthol via ozonolysis and
2
2
was followed by dropwise addition of toluenesulfonyl chloride
in CH Cl . The unknown tosylated compound 3 was provided in
2
2
high yield (90%) and further utilised into the next step without
purification. The synthesis of 4-vinyl-2,3-dihydrobenzofuran
2
reduction. Therefore, an efficient synthesis of 4-vinyl-2,3-
5
is described in Scheme 1. Initially, compound 3 was treated
dihydrobenzofuran 5 became essential. A published method
for the synthesis of 5 involves the sulfonylation of 2,3-bis(2-
hydroxyethyl)phenol 2 with toluenesulfonyl chloride at −40
with 2.0 equiv. of tert-BuOK, which mainly gave intermediate
4 in anhydrous THF at −5–0 °C. Interestingly, we observed
that elimination of intermediate 4 was easily carried out and
subsequently converted into 4-vinyl-2,3-dihydrobenzofuran 5
by increasing the amounts of tert-BuOK. A one-pot reaction
of compound 3 treated with 5.0 equiv. of tert-BuOK gave
the key compound 5 in 85% yield. The sulfonate, compound
3, was susceptible to elimination, forming an irreversible
diene byproduct, and the intermediate product 4 could not be
obtained. We investigated a variety of bases, such as NaOMe,
EtONa, tert-BuOK, tert-BuONa and sodium tert-amyl alcohol.
Of the various screened bases, tert-BuOK was found to be the
best base in terms of yield and selectivity.
°
C using pyridine as the base, followed by intramolecular
cyclisation in the presence of potassium carbonate and then
elimination promoted by tert-BuOK to form the key intermediate
3
5
. Rao et. al. reported a two-step synthesis of 4-vinyl-2,3-
dihydrobenzofuran 5 from 2,3-bis(2-hydroxyethyl)phenol 2
with the Vilsmeier reagent via ring closure, chlorination and
2
dehydrohalogenation using a phase-transfer catalyst.
Jacobsen asymmetric epoxidation and Sharpless asymmetric
dihydroxylation of 4-vinyl-2,3-dihydrobenzofuran 5 were scaled
up to prepare large quantities of the chiral dihydrobenzofuran
4
epoxide. Singh’s group developed the cyclopropanation
With compound 5 in hand, it was first subjected to epoxidation
8
reaction of the chiral epoxide product with the anion of
using 30% hydrogen peroxide and 2,2,2-trifluoroacetophenone.
5
triethylphosphonoacetate. Furthermore, the asymmetric
Unfortunately, the epoxide 6 was not obtained. We succeeded
in epoxidising compound 5 using 30% hydrogen peroxide as
an oxidant in the presence of sodium bicarbonatein acetonitrile
cyclopropanation of 5 with ethyl diazoacetate in the presence of
6
a chiral catalyst has been investigated by Vanda. Subsequently,
9
the cyclopropanation product underwent hydrolysis,
aminoacylation and reduction to obtain the optical tasimelteon.
Catt’s group reported a novel method for the asymmetric
under mild conditions in 75% yield. Subsequently, we focused
on investigating the cyclopropanation of epoxide 6.
The reaction of epoxides with the anion of triethyl
synthesis of tasimelteon that involved 2,3-dihydrobenzofuran-
phosphonoacetate in the synthesis of cyclopropane derivatives
7
10,11
4
-carbaldehyde as a starting material.
has been known for over four decades.
Singh developed a
Owing to the lengthy synthetic routes, strict conditions, high cost
practical, safeandhigh-yieldingprocessforthecyclopropanation
and difficulties in large-scale preparation, an efficient and practical
synthetic method for optically active tasimelteon is desirable.
Herein, we report a convenient synthesis of tasimelteon in good
yields starting from 2,3-bis(2-hydroxyethyl)phenol 2 via a highly
selective cyclopropanation reaction of the key intermediate 5.
of a chiral epoxide such as 6 using triethyl phosphonoacetate
and tert-BuONa. Herein, we tried the cyclopropanation reaction
of epoxide 6 using diethyl cyanomethylphosphonate under
similar conditions, but a low yield was provided (Scheme 2).
To evaluate the scalability of this reaction, we systematically
6
OH
OTs
Ts
O
OH
OH
TsCl, TEA
CH Cl , r.t.
O
O
tert-BuOK
Ts
Ts
o
THF, -5-0 C
5%
O
2
2
8
O
2
90%
3
5
4
Scheme 1
*
Correspondent. E-mail: zhangxx@zjut.edu.cn

6
68 JOURNAL OF CHEMICAL RESEARCH 2016
O
O
O
sodium tert-amylate, (EtO)P(O)CH CN
CN
O
30% H O , NaHCO
3
2
2
2
o
o
MeCN, 40 C
5%
toluene, 110 C
6
7
7
83%
5
Scheme 2
(
2R)
O
O
CN
i ) NaBH -NiCl , EtOH, r.t., 85%
4
2
NH2
(
1R)
ii) (+)- Camphorsulfonic acid, EtOH, r.t., 42.5%
7
8
O
(2R)
O
CH CH COCl, Et N, CH Cl , r.t.
3
2
3
2
2
N
(1R)
H
95%
1
Scheme 3
studied the effect of base, solvent and temperature on the extent
of reaction completion. The results are listed in Table 1.
Initial experiments were carried out with sodium tert-amylate
Table 1 Optimisation of cyclopropanation reaction conditions of epoxide
a
6
with diethyl cyanomethylphosphonate
Product 7
Entry Base
Solvent
Temperature/°C Time/h
b
yield/%
(
STA) in different solvents and at different temperatures
1
2
3
4
5
6
7
8
9
STA
STA
STA
STA
STA
STA
STA
STA
STA
STA
STA
THF
DME
2-MeTHF
1,4-dioxane
DMF
65
85
80
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
2.0
5.0
5.0
5.0
5.0
5.0
–
–
–
because it is a very common and inexpensive base. By screening
various solvents, we found that toluene is the best solvent for
this reaction (Table 1, entry 9). Moderate yield was given in
DMSO (Table 1, entry 6). Low yields were given in dioxane
and DMF (Table 1, entries 4 and 5). No reactions were observed
in THF, DME and 2-MeTHF (Table 1, entries 1–3). It is worth
noting that the reaction temperature has an obvious effect on
the rate and conversion of the cyclopropanation reaction. The
reaction rate was considerably slow at temperatures below
101
125
127
90
100
110
110
110
110
110
110
110
110
14
47
60
24
31
83
65
60
25
41
38
50
15
DMSO
toluene
toluene
toluene
toluene
toluene
toluene
100 °C. It was efficiently conducted at 110 °C and good
10
yield was obtained (Table 1, entry 9). As the anion of TEPA
can be formed by almost any base (hydrides, alkoxides and
alkyllithiums), we screened several common bases in toluene.
The cyclopropanation reaction did not work well in toluene
1
1
1
2
CH ONa
3
1
3
tert-BuONa toluene
tert-BuOK
NaH
1
4
toluene
toluene
toluene
at 110 °C with CH ONa, tert-BuONa, tert-BuOK, NaH and
3
15
16
LiHMDS as bases (Table 1, entries 12–16). In addition,
sufficient reaction time was necessary for conversion to the
desired product 7. With the improved reaction conditions in
hand, STA was selected for further scale-up work due to its ease
of handling, low hazards and low cost.
LiHMDS
a
The reaction was carried out by the condensation of epoxide 6 (10 mmol) and diethyl
cyanomethylphosphonate (15 mmol) in the presence of base (18 mmol) under the above
reaction conditions.
b
Isolated yield by silica gel flash column chromatography.
Treatment of cyano compound 7 with NaBH –NiCl in EtOH
4
2
provided the primary racemic amine. After completion, the
and nonhazardous reagents diethyl cyanomethylphosphonate
and sodium tert-amylate was developed as the key step.
(+)-10-Camphorsulfonic acid was selected as the optimal
resolving agent.
−1
reaction was quenched by 2 mol L HCl aqueous solution.
Ethyl acetate was added and the aqueous phase was separated.
−1
This aqueous was adjusted to pH = 12 using 2 mol L NaOH
aqueous and extracted with ethylacetate. The enantiomer
mixture was found to be efficiently separated as the salt or
complex with a resolving agent such as (+)-10-camphorsulfonic
acid. The most favourable separation was achieved when
Experimental
The purification of the products by flash column chromatography utilised
silica gel (200–300 mesh) and light petroleum ether (PE, b.p. 60–90 °C).
1
13
0
.5 equiv. of resolving agent is mixed with the enantiomer
mixture. The optical compound 8 was obtained in 42.5% yield
based on the racemic compound) with 95.6% e.e. Finally, the
H NMR and C NMR spectra were recorded on a Bruker Avance-500
spectrometer at 500 and 125 MHz, respectively, in CDCl solution using
3
(
Me Si as an internal standard. The reactions were monitored by TLC on
4
target product tasimelteon 1 was successfully obtained by the
acylation of compound 8 with propionyl chloride in the presence
of triethylamine at room temperature.
silica-gel polygram SILG/UV 254 plates. FTIR spectra were recorded on
a Bruker Tensor 27 spectrometer. EI-MS spectra were determined on a
Perkin Elmer spectrometer. HRMS(EI) was carried out on Waters GCT
Premier GC/TOF instrument. ESI-MS and HRMS(ESI) were determined
on a Therm LCQ TM Deca XP plus spectrometer. HPLC analysis was
conducted using an Agilent 1200, and an OJ-H chiral column was used for
chiral analysis. All compounds were identified by H NMR and the data
are in good agreement with those reported. Melting points were measured
on a BUCHI B-540 and are uncorrected.
Conclusion
The one-pot, two-step process for the synthesis of 4-vinyl-2,3-
dihydrobenzofuran 5 was fulfilled via compound 3, which
was not isolated. A practical, safe and high-yielding process
for the cyclopropanation of epoxide 6 using the inexpensive
1

JOURNAL OF CHEMICAL RESEARCH 2016 669
2
,3-Bis(2-tosyloxyethyl)phenyl 4-methylbenzenesulfonate (3)
To a stirred solution of 2,3-bis(2-hydroxyethyl)phenol 2 (1.82 g,
0.0 mmol) in CH Cl (10 mL) and triethylamine (5.53 mL, 40.0 mmol),
113.4 mmol) were added. The reaction mixture was stirred for 3 h at
room temperature. After concentration under reduced pressure, the
−1
1
aqueous was adjusted to pH = 3 by addition of 2 mol L HCl aqueous
(4 mL). After extraction with EtOAc (30 mL), the aqueous phase
2
2
a solution of p-toluenesulfonyl chloride (5.80 g, 30.5 mmol) in CH Cl
2
2
−1
(10 mL) was added dropwise at room temperature. The mixture was
was adjusted to pH = 14 by addition of 2 mol L NaOH aqueous. The
aqueous was then extracted with EtOAc (3 × 40 mL) and concentrated
to give a colourless oil in 85% yield (2.6 g). This oil was dissolved
in 40 mL of ethanol. (+)-10-Camphorsulfonic acid (1.6 g, 6.9 mmol)
was added. The mixture was stirred for 2 h at room temperature,
and the precipitated crystals were filtered, rinsed with ethanol and
dried to give a white solid. To a stirred solution of this diastereomer
stirred for 8 h at room temperature and filtered. The organic phase
was washed with 2 mol L HCl, water and brine, and then dried over
anhydrous Na SO . After concentration, the residue was purified by flash
column chromatography on silica gel to give compound 3 as: Brown
viscous oil; yield 5.83 g (90%); R = 0.38 (PE:EtOAc, 3:1); FTIR (film) (ν
cm ): 759, 815, 965, 1096, 1175, 1359, 1456, 1598, 1737, 2892, 2925, 2961,
−1
2
4
f
−1
1
−1
3
067; H NMR (500 MHz, CDCl ): δ 2.43 (s, 3H), 2.44 (s, 3H), 2.48 (s,
complex in 20 mL water, 2 mol L NaOH aqueous was added to adjust
3
3
H), 2.82 (t, J = 7.2 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H), 4.04 (t, J = 7.2 Hz,
H), 4.10–4.15 (m, 2H), 6.94–6.99 (m, 2H), 7.09 (t, J = 8.0 Hz, 1H),
.28–7.32 (m, 4 H), 7.36 (d, J = 8.0 Hz, 2H), 7.65–7.69 (m, 4H), 7.73–7.75
to pH = 14. The suspension was stirred until it was clear, and then
extracted with EtOAc (3 × 40 mL). The organic phase was combined
and concentrated to obtain a chiral amine 8 as: Colourless oil; yield
1.1 g (42.5%) (based on the racemic compound) with 95.6% e.e.;
2
7
13
(
1
m, 2H); C NMR (125 MHz, CDCl ): δ 148.8, 145.8, 144.9, 144.7, 137.8,
3
−
1
30.0, 129.9, 129.8, 128.2, 128.0, 127.7, 127.6, 120.8, 69.6, 68.6, 32.0, 26.3,
[α] = −33.89° (c = 10.0 mg mL , MeOH); R = 0.35 (MeOH:EtOAc,
f
+
1
21.7, 21.6; MS (ESI) m/z (%): 667 (100) [M + Na] ; HRMS (ESI) m/z [M +
1:3); H NMR (500 MHz, CDCl ): δ 0.81–0.85 (m, 1H), 0.91–0.95 (m,
3
+
Na] calcd for C H NaO S : 667.1106; found: 667.1096.
31
32
9
3
1H), 1.27–1.30 (m, 1H), 1.60–1.64 (m, 1H), 1.92 (br s, 2H), 2.72–2.74
(m, 2H), 3.32 (t, J = 8.7 Hz, 2H), 4.57 (t, J = 8.7 Hz, 2H), 6.37 (d, J = 7.8
Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H).
4
4
-Vinyl-2,3-dihydrobenzofuran (5)
To a stirred solution of tert-BuOK (9.6 g, 86.1 mmol) in THF (20 mL)
under nitrogen, a solution of compound 4 (9.20 g, 14.3 mmol) in THF
(1R,2R)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl]methyl]
12
(
20 mL) was added dropwise over 0.5 h at −5–0 °C. After addition, the
propionamide (tasimelteon 1)
reaction mixture was stirred for 3 h at room temperature. The resulting
precipitate was filtered and washed with EtOAc (150 mL). The filtrate
was washed with water (3 × 30 mL) and then concentrated under
reduced pressure to give a brown liquid. The residue was purified
by flash column chromatography on silica gel to give compound
Compound 8 (1.00 g, 5.3 mmol) was dissolved in CH Cl (10 mL).
Triethylamine (0.95 mL, 6.9 mmol) was added, followed by addition
2
2
of propionyl chloride (0.54 g, 5.85 mmol) at 0 °C. The reaction
−1
mixture was stirred for 2 h and quenched with 2 mol L HCl (10 mL).
The organic phase was washed with saturated NaHCO3 aqueous
(3 × 10 mL), water (3 × 10 mL) and brine (2 × 10 mL). The organic
phase was dried over anhydrous Na SO and concentrated. The residue
5
as: Colourless oil; yield 1.77 g (85%); R = 0.62 (PE:EtOAc, 10:1);
f
1
H NMR (500 MHz, CDCl ): δ 3.28 (t, J = 8.7 Hz, 2H), 4.62 (t,
J = 8.7 Hz, 2H), 5.38 (d, J = 11.2 Hz, 1H), 5.74 (d, J = 17.7 Hz, 1H),
3
2
4
was purified by flash chromatography on silica gel to give tasimelteon
6
.72–6.78 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H).
25
(
1) as: Colourless oil; yield 1.23 g (95%) with 96% e.e.; [α] = −37.08
D
−1
5
(c = 10.0 mg mL , CHCl ); R = 0.39 (PE:EtOAc, 1:1); FTIR (film)
ν cm ): 985, 1230, 1459, 1590, 1647 (C=O), 2926, 2974, 3070;
H NMR (500 MHz, CDCl ): δ 0.91–0.94 (m, 1H), 0.95–1.00 (m, 1H),
4
-(Oxiran-2-yl)-2,3-dihydrobenzofuran (6)
3 f
−1
(
1
4
-Vinyl-2,3-dihydrobenzofuran 5 (10.0 g, 68.5 mmol) was dissolved in
acetonitrile (50 mL). 30% hydrogen peroxide (125 mL, 411 mmol) and
3
1
.18 (t, J = 7.6 Hz, 3H), 1.32–1.36 (m, 1H), 1.73–1.76 (m, 1H), 2.22 (q,
J = 7.6 Hz, 2H), 3.22–3.26 (m, 2H), 3.28–3.37 (m, 2H), 4.60 (t, J = 8.7
Hz, 2H), 5.72 (br s, 1H), 6.35 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 7.9 Hz,
NaHCO (23.0 g, 274 mmol) was added. After stirring for 24 h at 40 °C,
3
the mixture was filtered and the filtrate was extracted with EtOAc
(
2 × 100 mL). The organic layer was washed with saturated NaHSO3
13
1H), 7.03 (t, J = 7.9 Hz, 1H); C NMR (125 MHz, CDCl ): δ 173.8,
aqueous, water and brine. After concentration, the residue was purified
3
1
59.6, 138.9, 128.2, 126.0, 115.7, 106.8, 71.0, 43.5, 29.7, 28.6, 21.7, 19.7,
by flash column chromatography on silica gel to give compound 6 as:
+
1
13.4, 9.9; MS (ESI) m/z (%) = 246 (100) [M + H] .
Colourless oil; yield 8.3 g (75%); R = 0.32 (PE:EtOAc, 10:1); H NMR
f
(
5
500 MHz, CDCl ): δ 2.84 (dd, J = 2.6, 5.6 Hz, 1H), 3.14 (dd, J = 4.2,
3
Acknowledgement
.6 Hz, 1H), 3.27 (t, J = 8.7 Hz, 2H), 3.85 (dd, J = 2.8, 4.0, 1H), 4.60 (t,
J = 8.8 Hz, 2H), 6.71–6.76 (m, 2H), 7.12 (t, J = 7.9 Hz, 1H).
We are grateful to the National Natural Science Foundation of
China (No. 21372203 and 21272076).
2
-(2,3-dihydrobenzofuran-4-yl)cyclopropane-1-carbonitrile (7)
To a solution of the epoxide compound 6 (14.0 g, 86.4 mmol) in toluene
150 mL), diethyl cyanomethylphosphonate (22.9 g, 129.4 mmol) and
Received 14 August 2016; accepted 3 September 2016
Paper 1604258 doi: 10.3184/174751916X14758368248634
Published online: 24 October 2016
(
sodium tert-amylate (17.1 g, 155.5 mmol) were added. The reaction
mixture was refluxed at 110 °C under nitrogen for 5 h. After cooling to
room temperature, water (100 mL) and EtOAc (300 mL) were added.
The organic phase was separated and concentrated under reduced
pressure to give a yellow oil. The residue was purified by flash column
chromatography on silica gel to give compound 7 as: White solid; m.p.
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1
2
3
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4
7.3–47.8 °C; yield 13.3 g (83%); R = 0.20 (PE:EtOAc, 10:1); FTIR
f
−1
(
2
KBr) (ν cm ): 773, 985, 1237, 1457, 1478, 1592, 1612, 2237, 2898,
970; H NMR (500 MHz, CDCl ): δ 1.46–1.49 (m, 1H), 1.54–1.58 (m,
4
5
1
3
1H), 1.60–1.64 (m, 1H), 2.52–2.56 (m, 1H), 3.27–3.31 (m, 2H), 4.63 (t,
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1
3
6
7
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(
1
1
t, J = 8.0 Hz, 1H); C NMR (125 MHz, CDCl ): δ 160.0, 134.1, 128.4,
3
26.8, 120.9, 115.9, 108.3, 71.0, 28.3, 22.7, 14.3, 5.4; MS (EI) m/z (%):
85 (100) [M] ; HRMS (EI) m/z [M] calcd for C H NO: 185.0841;
+
+
12
11
8
9
found: 185.0826.
1
0
12
(
1R, 2R)-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl]methanamine (8)
To a stirred solution of white solid 7 (3.0 g, 16.2 mmol) in
0 mL ethanol, nickel chloride (2.2 g, 13 mmol) and NaBH (4.3 g,
11
12 Y.Z. Liu, H.C. Zhang and J. Liu, C.N. Patent: 102675268, issued date 19
September 2012.
8
4