Selective synthesis of methyl dithienyl-glycolates

Article abstract of DOI:10.24820/ark.5550190.p010.717

An efficient selective synthesis of methyl dithienyl-glycolates has been developed. The interest of this two steps protocol resides in the possibility of synthesized either methyl 2,2-dithienyl glycolate – the target intermediate for the preparation of an

Full text of DOI:10.24820/ark.5550190.p010.717

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Arkivoc 2018, part vii, 0-0
Selective synthesis of methyl dithienyl-glycolates
a
a
b
b
Francesca Foschi, Elisa Bonandi, Andrea Mereu, Barbara Pacchetti,
b
a
Davide Gozzini, and Daniele Passarella*
a
Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, Milano 20133, Italy
b
LINNEA SA, Via Cantonale, 6595 Riazzino (TI), Switzerland
Email: daniele.passarella@unimi.it
Received 08-06-2018
Accepted 10-26-2018
Published on line 12-01-2018
Abstract
An efficient selective synthesis of methyl dithienyl-glycolates has been developed. The interest of this two
steps protocol resides in the possibility of synthesized either methyl 2,2-dithienyl glycolate – the target
intermediate for the preparation of anticholinergic agents – or its regio-isomer methyl 2,3-dithienyl glycolate –
the most critical precursor of anticholinergic drug impurity.
Keywords: Bromothiophene lithiation, dithienyl glycolate, muscarinic antagonist, COPD
DOI: https://doi.org/10.24820/ark.5550190.p010.717
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Introduction
Methyl 2,2-DiThienylGlycolate (1a, Figure 1) is a key intermediate for the preparation of a wide range of
anticholinergic agents, as muscarinic receptor antagonists, used in the treatment of ‘Chronic Obstructive
Pulmonary Disease’ (COPD). In particular, condensation of 1a with scopine or 3-quinuclidinol derivatives under
basic conditions, followed by quaternization of the tertiary amino moiety to increase their lipophilicity, is a
classical pharmaceutical process to obtain tiotropium bromide (Scheme 1; marketed as SPIRIVA®
1-7
8
9-18
HANDIHALER®), aclidinium bromide (trade name: TUDORZA® PRESSAIR®), and their analogues.
Scheme 1. Synthesis of tiotropium bromide and aclidinium bromide starting from 1a.
In general, synthesis of 1a is carried out via either Friedel—Crafts acylation of thiophene,19-29 or Grignard
reactions.30 In our hands, reaction of the Grignard reagent derived from 2a with dimethyl oxalate 3 in diethyl
ether at reflux afforded 1a in 54% yield, but in inseparable mixture with an impurity identified as the regio-
isomer 1b (12% yield, Scheme 2); 1b probably derived by equilibration of the initial 2-thienylmagnesium
bromide.
Reaction conditions: 2a (2.0 mmol), 3 (1.0 mmol), Mg (2.1 mmol), solvent (10 mL).
[a]
Scheme 2. Reported synthesis of dithienylglycolate 1a-b .
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Results and Discussion
The difficult separation of 1a and 1b leads to pollute drugs, due to the formation of pharmacological regio-
isomer impurities.3 Thus, to find an alternative method to selectively obtain either 1a or 1b, we decided to
modulate the reactivity of the thienyl anion species by changing the nature of the counter cation. To that aim
1
2- thienyl lithium and 3- thienyl lithium (derived, respectively, from lithiation of 2-bromothiophene 2a and 3-
bromothiophene 2b), were reacted with oxalate 3 to obtain methyl 2-oxo-2-(thiophen-2-yl)acetate 4a and
methyl 2-oxo-2-(thiophen-3-yl)acetate 4b. The latter compounds are intermediates for methyl dithienyl-
glycolate 1a and 1b production. Preliminary runs (entries 1–2, Table 1), evidenced that a mixture of regio-
isomers 4a and 4b could be obtained when oxalate 3 was added to 3-thienyl lithium: in according to the anion
equilibration, the longer the metalation time of 2b, the higher the yield of 4a.
Table 1. Reactivity of bromothiophene 2b a
Entry
Base
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
LDA
solvent Base addition
4a%b
35
61
--
4b%b
24
--
1
2
3
4
5
6
7
THF
THF
THF
THF
A
B
C
48
66
35
22
--
D
D
D
D
--
2
Et O
--
Toluene
THF
--
<5
a
b
Reaction conditions: 3 (1.5 mmol), 2b (1 mmol), Base (0.95 mmol), solvent (10 mL). Isolated yields.
A: Base was dropped in 5 min to a solution of 2b and stirred for 15 min before addition of a solution of 3; B:
Base was dropped in 5 min to a solution of 2b and stirred for 30 min before addition of a solution of 3; C: 2b
was added to a solution of BuLi and 3 in THF; D: Base was added to a solution of 2b and 3.
In fact, a complete regio-selectivity in favor of 4b was reached by adding 2b to a cold mixture of base (n-
BuLi) and 3 (entry 4). Furthermore, the best yield of 4b (66%, entry 4) was achieved by adding the strong, non-
hindered base n-BuLi at – 78 °C, to a mixture of 2b and a slightly excess of 3 in THF as the solvent. Other
solvents (entries 5–6), gave worst results while, the use of non-nucleophilic base LDA, resulted in the
formation of a series of by-products (entry 7). Similarly, LDA induced on 2a a base catalyzed halogen-dance
reaction, forming, as the main reactive intermediate, the 2- thienyl anion specie bearing the bromine atom in
32-36
the C-3 position.
This latter, in turn, evolves in the 4c product in presence of 3 (entry 1, Table 2).
Furthermore, 1a reacted under the best reaction conditions found for 1b, giving 4a in good yield (entry 2); we
were able to increase the yield of 4a by generating the stable lithium anion at the thiophene C-2 position and
then adding oxalate 3 to the reaction mixture (entry 3).
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Table 2. Reactivity of bromothiophene 2a.a
Entry
Base solvent Base addition
4a%b
--
4c%b
36
--
1
2
3
LDA
BuLi
BuLi
THF
THF
THF
A
A
B
67
73
--
a
b
Reaction conditions: 3 (1.5 mmol), 2b (1 mmol), Base (0.95 mmol), solvent (10 mL). Isolated yields. A: Base
was added to the mixture of 2a and 3; B: Base was dropped in 5 min to a solution of 2a and stirred for 30 min
before addition of a solution of 3.
Similar behavior (Scheme 3) was found when the 2-thienyl anion specie, generated by metalation of 2a at
low temperature, was then trapped using as electrophiles 4a or 4b: under these reaction conditions,
compounds 1a (derived from intermediate 4a, path a.) and 1b (derived from 4b, path b.) were isolated as pure
isomers and fully characterized.
a
Reaction conditions: 2 (1.0 mmol), 4 (1.0 mmol), Base (0.95 mmol), solvent (10 mL), reaction time: 30 min. b
Isolated yields.
path A and B: BuLi was dropped in 5 min to 2a and the mixture was stirred for 30 min before addition of 4;
path C: Base was added to the mixture of 2b and 4.
Scheme 3. Synthesis of 1a and 1b.a
On the contrary, our attempts to isolate 1b or its regio-isomer methyl 3,3-dithienylglycolate by 3-
bromothiophene 2b lithium halogen exchange in the presence of either oxo-acetate 4b or 4a, gave a mixture
1
of degradation compounds (path c.). Comparison between H NMR spectra of compounds 1a and 1b (Table 3),
exhibited a slightly highfield chemical shifts for almost all 1a signals (only 1a and 1b H
together at ~7.19 ppm); furthermore, 1b H NMR showed two additional signals at 7.39 ppm (H
3
protons resonate
) and 7.10
1
7
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ppm (H
arise in the presence on substrate 1b of both the isolated signal at 142.5 ppm (C
9
). Even for 13C NMR spectra, all the peaks of 1a and b are quite good shifted; the major difference
) and 123.2 ppm (C ).
6
7
1
13
Table 3. H and C assignment for 1a and 1b
1H
13C
position
1H
13C
1H
13C
-Acetone
126.1
CDCl
3
CDCl
3
d
6
7.32
7.00
7.19
126.0
126.1
126.8
145.7
76.6
1
2
7.28
6.97
7.18
– –
125.8
126.7
7.41
7.00
7.12
– –
127.1
126.2
147.9
77.5
3
125.9
146.0
77.5
–
–
–
4
–
5
– –
– –
4
.68
– –
OH
CO
4.47
– –
– –
5.76
– –
– –
–
–
172.8
54.2
173.4
53.9
173.3
53.3
3.92
OCH
3
3.87
– –
3.83
– –
6
7
8
9
142.5
123.2
125.8
126.8
144.7
123.2
126.0
127.6
7.39
7.28
7.10
7.47
7.44
7.22
Conclusions
We have described a complete regio-selective protocol for methyl 2,2-dithienylglycolate 1a and methyl 2,3-
dithienylglycolate 1b synthesis. Depending on both the nature of the bromothiophene derivative used and the
condensation conditions, it was possible to obtain either 1a - the key starting material in the preparation of
important anticholinergic agents - or 1b, precursor of pharmacological impurities. By this way 1b was fully
characterized, giving the characteristic signals that permit its differentiation for the target compound.
Experimental Section
General. All available chemicals and solvents were purchased from commercial sources and were used
without any further purification. Thin layer chromatography (TLC) was performed using 0.25 mm silica gel
precoated plates Si 60-F254 (Merck) visualized by UV-254 light and CAM staining. Purification by flash column
chromatography (FCC) was conducted by using silica gel Si 60, 230-400 mesh, 0.040-0.063 mm (Merck).
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Melting points were determined on a Büchi B450 apparatus and are corrected. H and 13C NMR spectra were
1
1
13
recorded on a Bruker Fourier 300 (recorded at: 300.13 MHz for H; 75.00 MHz for C) or Bruker Avance
Spectrometer (recorded at: 400.13 MHz for H; 100.62 MHz for 13C); chemical shifts are indicated in ppm
1
downfield from TMS, using the residual proton (CHCl
3
7.28 ppm; acetone 2.05 ppm) and carbon (CDCl 77.0
3
ppm; acetone 207.1 and 30.9 ppm) solvent resonances as internal reference. Coupling constants values J are
given in Hz.
Preparation of methyl 2-oxo-2-(thiophen-3-yl)acetate (4b). In a flame-dried round flask, BuLi [1.6] (0.60 mL,
0
.95 mmol) was added by syringe under N
bromothiophene (193 mg, 1.0 mmol) in anhydrous THF (25 mL) at -80 °C. The reaction mixture was stirred at -
0 °C until completion [30 min, TLC analysis - AcOEt/hexane (1:9)], then was quenched with saturated NH Cl
solution (5 mL). After extraction with AcOEt (2×20 mL), the collected organic phases were washed with brine
1×10 mL), dried over Na SO and, after evaporation of the solvent in vacuum, the crude was purified by FCC -
AcOEt/hexane (1:9) - on silica gel to afford the pure compound 4b (112 mg, 66%) as a slightly yellow waxy
2
to a solution of dimethyl oxalate (177 mg, 1.5 mmol) and 3-
8
4
(
2
4
1
13
solid; H NMR (400 MHz, Acetone-d
75 MHz, Acetone-d ) δ 179.3, 164.0, 138.7, 138.2, 128.3, 127.7, 52.9. Anal. Calcd. for C
.55. Found: C, 49.01; H, 3.48.
6
) δ 8.67 (dd, 1H, J 2.7, 1.5 Hz), 7.67 – 7.65 (m, 2H), 3.96 (s, 3H); C NMR
(
3
6
7 6 3
H O S: C, 49.40; H,
Lithiation of 2-Bromothiophene: preparation of oxo-acetate (4a,c) and glycolates (1a,b). In a flame-dried
round flask, organolithium reagent (0.95 mmol) was added dropwise to a solution of 2-bromothiophene 1b
(
193 mg, 1.0 mmol) in anhydrous THF (15 mL) under N
oxalate 3 or oxo-acetate 4a−c was added. After the disappearing of the starting thiophene, the reaction was
quenched by saturated aqueous NH Cl and extracted with AcOEt (2×20 mL); the collected organic phases were
washed with brine (1×10 mL), dried over Na SO and the solvent was evaporated under vacuum (RV). The
2
at -80 °C. After 20 min, a THF (5.0 mL) solution of
4
2
4
resulting crude was purified by FCC - AcOEt/hexane (1:9) - on silica gel. Yield, physical, spectroscopic and
analytical data of products 4a,c, 1a,b are as follows.
Methyl 2-oxo-2-(thiophen-3-yl)acetate 4a. BuLi [1.6] (0.6 mL), dimethyl oxalate 3 (177 mg, 1.5 mmol). 4a (124
1
mg, 73%, 40 min); slightly yellow waxy solid. H NMR (300 MHz, CDCl
3
) δ 8.18 (dd, 1H, J 3.9, 1.1 Hz), 7.84 (dd,
) δ 175.9, 162.0, 139.0,
S: C, 49.40; H, 3.55. Found: C, 49.01; H, 3.51.
1
1
H, J 4.9, 1.1 Hz), 7.22 (dd, 1H, J 4.9, 3.9 Hz), 3.99 (s, 3H); 13C NMR (75 MHz, CDCl
37.6, 137.4, 128.7, 53.2. Anal. Calcd. for C
3
7
H
O
6 3
Methyl 2-(3-bromothiophen-2-yl)-2-oxoacetate (4c). LDA [1.0] (0.95 mL), dimethyl oxalate 2 (177 mg, 1.5
1
mmol). 4c (90 mg, 36%, 30 min); yellow solid. H NMR (300 MHz, CDCl
3
) δ 7.94 (d, 1H, J 4.2 Hz), 7.19 (d, 1H, J
13
4.2 Hz), 3.99 (s, 3H); C NMR (75 MHz, CDCl
3
) δ 174.1, 161.4, 139.8, 137.6, 131.8, 127.4, 53.4. Anal. Calcd. for
C
7
H
5
BrO S: C, 33.75; H, 2.02. Found: C, 33.39; H, 1.99.
3
Methyl 2-hydroxy-2-(thiophen-2-yl)-2-(thiophen-2-yl)acetate (1a). BuLi [1.6] (0.6 mL), oxo acetate 4a (187
1
mg, 1.1 mmol). 1a (191 mg, 75%, 30 min), whitish solid, mp 94 – 95 °C. H NMR (300 MHz, CDCl
3
) δ 7.32 (d, 2H,
) δ
72.3, 145.7 (2CAr), 126.8 (2CHAr), 126.0 (2CHAr), 125.9 (2CHAr), 76.4, 54.3. HPLC analyses were carried out on a
J 4.9 Hz), 7.20 – 7.18 (m, 2H), 7.00 (dd, 2H, J 5.1, 3.6 Hz), 4.68 (s, 1H), 3.92 (s, 3H); 13C NMR (75 MHz, CDCl
3
1
Zorbax Rx-C8 column (5 μm, 4.6 × 150 mm) by using as eluent a mixture of solvents [solvent A H O (with 1%
2
trimethylamine and adjusting pH to 3.0 with perchloric acid) and solvent B CH
5 (isocratic); 20 − 36 min, % B 51 (gradient); 36 – 36.1 min, % B 25 (gradient). Flow rate 2 mL/min, T=25°C; UV
detector λ 254 nm. Retention times: 1b, 13.20 min; 1a, 14.51 min. Anal. Calcd. for C11 : C, 51.95; H,
.96. Found: C, 51.71; H, 3.89.
3
CN]. Gradient: 0 – 20 min, % B
2
10
H O
S
3 2
3
Methyl 2-hydroxy-2-(thiophen-2-yl)-2-(thiophen-3-yl)acetate (1b). BuLi [1.6] (0.6 mL), oxo acetate 4b (187
1
mg, 1.1 mmol). 1b (173 mg, 68%, 30 min), greyish waxy solid, mp 90 – 92 °C. H NMR (400 MHz, Acetone- d
6
) δ
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7
3
1
.47 (s, 1H), 7.44 (dd, 1H, J 5.1, 3.2 Hz), 7.41 (dd, 1H, J 5.2, 1.2 Hz), 7.22 (dd, 1H, J 5.0, 1.4 Hz), 7.12 (dd, 1H, J
13
.6, 1.2 Hz), 7.00 (dd, 1H, J 5.1, 3.6 Hz), 5.76 (bs, 1H), 3.83 (s, 3H); C NMR (101 MHz, Acetone-d
6
) δ 173.3,
47.9, 144.7, 127.6, 127.1, 126.2, 126.1, 126.0, 123.2, 77.5, 53.3. Anal. Calcd. for C11 : C, 51.95; H, 3.96.
10
H O
S
3 2
Found: C, 51.55; H, 3.90.
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