chapter – 2 application of ( r)-tert -butanesulfinamide in...
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40
CHAPTER – 2
Application of (R)-tert-butanesulfinamide in the asymmetric synthesis of (R)-5-(2-aminopropyl)-2-methoxy
benzene sulfonamide [Tamsulosin intermediate] LITERATURE BACKGROUND:
Numerous pharmaceutical agents, natural products, and synthetic
materials contain chiral amine functionality. For this reason, the
asymmetric synthesis of amines is of fundamental importance to many
synthetic applications.
In 1997 Ellman introduced a chiral ammonia equivalent [24],
enantiopure tert-butanesulfinamide(2-methyl-2-propanesulfinamide)(1)
which has been demonstrated to be a versatile chiral auxiliary [2, 3] and
has found extensive use in asymmetric synthesis of amine containing
compounds [59-62].
Direct condensation of aryl/alkyl aldehydes or ketones with 1
provides tert-butanesulfinyl imines (2), followed by the addition of
nucleophiles [viz. H, CH3 etc.] result with high diastereoselectivity and in
high yields to provide the desired amine product 4 after the cleavage of
the sulfinyl group. (Scheme 2.1)[49]
S
O
NH2
R2
R1O S
O
N
R2
R1
Nu- S
O
NH
R2
R1
NuHCl
MeOHCl.H3N
R2
R1
Nu
(1) (2) (3) (4) …..(Scheme 2.1)
41
Ellman et al. reported the preparation of 1 through the
intermediacy of tert-butyl tert-butanethio sulfinate (6) from tert-butyl
disulfide (5). (Scheme 2.2)[63]
Unfortunately the enantiomeric purity of the resulting sulfinamide
doesn’t exceed 91%.
SS
OHt-Bu
t-Bu
N OH
R R1H
VO(acac)2, H2O2
SS
O
LiNH2
NH3, THF,
-78°C
S
O
NH2
(5) (6) (1)
…..(Scheme 2.2)
Senanayeke et al. reported the preparation of 1 through the
intermediacy of (1R,2S)-1-amino-2-indanol-N-2,4,6-mesityl sulfo-
namide (8), (2R,4R,5S)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetra hydro-1-
oxa-2-thia-3-aza-cyclopenta[a]indene 2-oxide (9) & (S)-2-methyl-2-
propylsulfinic acid (1R,2S)-1-(2,4,6-mesitylsulfonylamino)-indan-2-yl
ester (10) from (1R, 2S)-1-amino-2-indanol (7) (Scheme 2.3) and (1S,
2R)-1-amino-2-indanol 7. (Scheme 2.4)[64]
42
NH2
OH
SO2Cl
SOCl2
2,4,6-CollidineNH
OH
SO
O
NH
O
SO
O
S
O
N
O
SO
O SO
ClMgLiNH2/NH3
S
O
H2N
+ NH
OH
SO
O
(7) (8) (9)
(10) (1) (8)
(R)-tert-butanesulfinamide
(1R,2S) (2R,4R,5S)
(1R,2S)(1R,2S)
…..(Scheme 2.3)
NH2
OH
SO2Cl
SOCl2
2,4,6-CollidineNH
OH
SO
O
NH
O
SO
O
S
O
N
O
SO
O SO
LiNH2/NH3S
O
H2N+ NH
OH
SO
O
(7) (8) (9)
(10) (1) (8)
(S)-tert-butanesulfinamide
(1S,2R)
(1S,2R)
(2S,4S,5R)
(1S,2R)
MgCl
…..(Scheme 2.4)
43
They have also reported the synthesis of 1 through the
intermediacy of (1S,2R)-N-(2-hydroxy-1-phenyl-propyl)-2,4,6-
mesitylsulfonamide (12), (2S,4S,5R)-5-methyl-4-phenyl-3-(2,4,6-
mesitylsulfonyl)-[1,2,3]oxathiazolidine 2-oxide (13) &
(S)-2-Methyl-2-propylsulfinic acid (1S,2R)-1-methyl-2-phenyl-2-
(2,4,6mesitylsulfonylamino)-ethyl ester (14) from (1S, 2R)-1-amino-1-
phenyl-2-propanol 11. (Scheme 2.5)
OH
NH2.HCl
SO2Cl
Et3N/
CH2Cl2
OH
NH
SO O 2,4,6-Collidine
THF/ -45°C
O
NS
O
SO O
SOCl2
MgCl
THF/-78°C
O
HNS
S (CH3)3
O
O O
LiNH2/NH3
-45°C
OH
NH
SO O
+S
O
H2N
(11) (12) (13)
(14) (1) (12)(S)-tert-butanesulfinamide
…..(Scheme 2.5)
and through the intermediacy of (1S,2R)-N-(1-hydroxy-2-methyl-1phenyl
ethyl)-4-toluene sulfonamide (16), (2R,4R,5S)-4-methyl-5-phenyl-3-(4
toluenesulfonyl)-[2,3]oxathiazolidine 2-oxide (17), (R)-2-methyl-2-
propylsulfinic acid (1S,2R)-1-phenyl-2-(4-toluenesulfonylamino)propyl
ester (18) from (1S, 2R)-norephedrine 15. (Scheme 2.6)
44
OH
NH2
SO2Cl
Et3N / CH2Cl2
OH
NHS
O O
O
NS
SO O
OSOCl22,4,6-Collidine
THF / -45°C
MgCl
THF / -78°C
O
NH
S(CH3)3
O
SO
O
LiNH2 / NH3
-45°C
S
O
H2N +
OH
NHS
O O
(15) (16) (17)
(18) (1) (16)(R)-tert-butanesulfinamide
…..(Scheme 2.6)
Recently Ellman et al. reported the recovery and recycling of tert-
butanesufinyl group in the synthesis of amines using tert-
butanesulfinamide. (Scheme 2.7)[65]
S
O
NH2
R2
R1O
S
O
N
R2
R1
Nu- S
O
NH
R2
R1
NuHCl
Cl.H3NR2
R1
Nu
(1) (2) (3) (4)
CPME23°C, 1 h
S Cl
O
(19)
Quinidine (10mol%),EtOH (5 equiv),proton sponge (1.5 equi)
CPME-50°C, 20 h
S
O
OEt
(20)
1. Na (5 equiv), NH3,
Fe(NO3)3.9H2O (cat),
-48°C, 1 h
2. Purification
S
O
NH2
(1)
(R)-tert-butanesulfinamide
S
O
NH
R2
R1
Nu
(3)
…..(Scheme 2.7)
45
Tamsulosin Hydrochloride i.e. (R)-(-)-5-{2-[2-(2-ethoxyphenoxy)
ethyl amino)propyl)-2-methoxy benzene sulfonamide Hydrochloride (21)
[66] is an antihypertensive drug also used in the treatment of benign
prostatic hyperplasia, was invented by Yamanouchi and co-developed by
Boehringer Ingelheim in the United States and CSL Pharma in Australia.
H3CO
H2NO2S NH
CH3
O
O
(21)
The key intermediate in the preparation of 21 is the amine, an
amphetamine derivative (R)-2-(4-methoxy-3-aminosulfonyl-phenyl)-1-
methylethylamine (22).
H3CO
H2NO2S
CH3
NH2
(22)
Tamsulosin is a chiral drug; so, many synthetic approaches have
been followed in the development of single enantiomer that exhibits
amine functionality at the chiral center.
The known methods of synthesis for this amine are..
46
(i) Dubey et al. reported the conventional resolution technology of the
dl-amine 22 with (D) –tartaric acid. They did the purification number of
times to get the optically pure (>99%) amine 22. (Scheme 2.8)[67]
MeO
H2NO2S O
NH3
H2/Pd
MeO
H2NO2S NH2
Resolution
Tartaric acid
(23) (22)(d,l)
22 (R)
…..(Scheme 2.8)
(ii) Okada et al. Yamanouchi Pharmaceutical Co., Ltd. did the
asymmetric synthesis using (R)-Phenyl ethylamine (24). The optical
purity they achieved is 94.5% and they purified it four times to get the
optical purity of >99%. (Scheme 2.9)[68]
MeO
H2NO2S OH2N
MeO
H2NO2S N
[H2]
MeO
H2NO2S NH
Pd-catalystMeO
H2NO2S NH2
(23) (24) (25)
(26) (22)
…..(Scheme 2.9)
(iii) Kumar et al. reported the transformation of 22 through the
intermediacy of 27, 22(R,S) & 28. The chiral purity they have achieved is
more than 99% after many recrystallizations of the tartarate salt with
over all yield of 33-35% only. (Scheme 2.10)[69]
47
MeO
H2NO2S O
MeO
H2NO2S N
Reduction
OH
MeO
H2NO2S NH2
D-(-)-Tartaric acid
Opticalresolution
MeO
H2NO2S NH2
Alkali treatment MeO
H2NO2S NH2
optical purity > 99%
(23) (27) (22)(R,S)
(28) (22)(R)
NH2OH.HCl
.tartarate
…..(Scheme 2.10)
(iv) Mohar from Novartis Pharma [USA] synthesized 22 in a new and
straightforward process starting from D-alanine (29) and
methoxybenzene (32) via a Friedel-Crafts reaction. (Scheme 2.11)[70]
HO
O
H2N
HO
O
HN CF3
O
Cl
O
HN CF3
O
OMe
MeO
O
HN CF3
OMeO
HN CF3
O
(29) (30) (31) (32)
(33) (34) (35)
(22)
+
H3CO
H2NO2S
CH3
NH2
H3CO
H2NO2S
CH3
NH
CF3
O
…..(Scheme 2.11) (v) Dambrin et al. synthesized the Tamsulosin intermediate (42) in a
new route through the intermediacy of 37, 38, 39, 40 & 41 starting from
(L)-tyrosine (36). (Scheme 2.12)[71]
48
Ac2O
H2O
CH3I
DMF
K2CO3
LiBH4 , MeOH
THF
Tf2O
MTBEHeptane
LiCl
NMP
ClSO3H
NH3
(36) (37) (38)
(39) (40)
(41) (42)
H3CO
H2NO2S
NHAc
Cl
H3CONHAc
Cl
H3CONHAc
OCOCF3
H3CONHAc
OH
H3CONHAc
CO2CH3
HONHAc
CO2H
HONH2
CO2H
…..(Scheme 2.12)
PRESENT WORK:
It is obvious from the references cited above that a good number of
researchers have synthesized and resolved 21 and its key intermediates.
Therefore, in the present investigation, it was considered worthwhile to
study the synthesis of Tamsulosin and/or its key intermediate, the
amine, an amphetamine derivative 22, using Ellman reagent (i.e. (R) or
(S)-tert-butanesulfinamide) 1 under different conditions. The present
chapter deals with the synthesis of (R)-2-(4-methoxy-3-aminosulfonyl-
phenyl)-1-methylethylamine by reaction of 5-acetonyl-2
methoxybenzenesulfonamide (23) with (R)-tert-butanesulfinamide using
the conditions of Ellman reaction [49].
49
RESULTS AND DISCUSSION:
5-Acetonyl-2-methoxybenzenesulfonamide 23 can be produced
through Darzens glycidic ester condensation from 4-methoxy
benzaldehyde (43), which was a commercially available intermediate
(Scheme 2.13).
Cl
CO2Et
NaOEt
1. ClSO3H
2. ammonia
(43) (44) (45)
(23)
CHO
MeO MeO
OCO2Et
MeO
O
MeO
H2NO2S O
…..(Scheme 2.13) Melting Point = 196° - 199° C
23 on condensation with (R) 1 in the presence of titanium tetra
isopropoxide in tetrahydrofuran at 65-70°C for 3-4 hours gave an imine
intermediate 46, followed by reduction with sodium borohydride at -53°
to -48° C gave a product different from the starting material and
homogeneous on TLC. It was assigned 2-methoxy-5-[2-(2-methyl-
propane-2-sulfinylamino)-propyl]benzenesulfonamide structure (47)
based on its analytical and spectral data (Scheme 2.14). Thus, its IR in
KBr (cm-1) (fig. 2.1) showed characteristic absorption peaks at 3290
(strong, sharp due to –NH of sulfinamide) and 3473 (strong band due to –
NH2 of sulfonamide). Its 1HNMR (CDCl3/TMS) spectrum (fig. 2.2) showed
50
signals at δ1.14 (d, 3H, -CH3), 1.16 (s, 9H, -C(CH3)3, 2.81 (m, 2H, -CH2),
3.60 (p, 1H, -CH), 3.99 (s, 3H, -OCH3), 5.30 (s, 1H, -NH), 5.49 (broad
s, 2H, -NH2), 6.98 (d, 1H, aryl protons), 7.39 (dd, 1H, aryl protons),
7.72 (d, 2H, aryl protons). Its 13CNMR (CDCl3/TMS) spectrum (fig. 2.3)
showed signals at δ 154.72, 135.21, 130.11, 130.0, 129.13, 128.92,
112.38, 56.46, 55.69, 52.28, 43.45, 22.57, 20.73.
H2NO2S
H3CO
O+ S
O
H2N
Ti(OPr)4
THF H2NO2S
H3CO
NS
O
NaBH4
MeOH H2NO2S
H3CO
NH
S
O
(23) (1) (46)
(R)-tert-butanesulfinamide >99% ee
H2NO2S
H3CO
NH
S
O+
88% in chiral HPLC Purity11% in chiral HPLC Purity
65° - 75°C
- 48°C (47) (R,R)(47) (S,R)
…..(Scheme 2.14)
Mechanism:
H2NO2S
H3CO
O
S
O
H2N
Ti(OEt)4
H2NO2S
H3COH2N
O
S
O
H2NO2S
H3COHN
OH
S
O
H
H2NO2S
H3COHN
OH2
S
O
-H2O
H2NO2S
H3CO
NH
S
O
H2NO2S
H3CO
NS
O NaBH4
51
O
SN
HTi
OCH3H2NO2S
H2NO2S
H3CO
NH
S
O
Hydrolysis of 47 with methanolic hydrochloride gave a mixture of 3-
(4-methoxy-3-sulfonamido-phenyl)-2-amino propane hydrochloride in the
ratio of 88.7% (R) and 11% (S) isomers (ee is only 77%) (Scheme 2.15).
So, to improve the chiral purity from basic reaction the reduction of the
imine intermediate was carried out with different reducing agents at
different temperature conditions. For details, please see (Table 2.1).
[Chiral purity (fig. 2.4) was checked on a Daicel chiral pak AD-H, 250 x
4.6mm with eluent 1 ml diethyl amine in 1.0L of ethanol and wavelength
at 226 nm. Flow rate was 1.0 ml / min] 22 structure was confirmed
based on its analytical and spectral data. Thus, its IR in KBr (cm-1) (fig.
2.5) showed characteristic absorption peaks at 3328 (weak band due to
aliphatic secondary amine), 3202 (strong, sharp peak due to –NH2 of
sulfonamide) and 1326 (strong, sharp peak due to and SO2 of
sulfonamide). Its 1HNMR (CD3OD/TMS) spectrum (fig. 2.6) showed
signals at δ1.24 (d, 3H, -CH3), 2.98 (m, 2H, -CH2), 3.29 (m, 1H, -CH),
3.97 (s, 3H, -OCH3), 7.20 (d, 1H, phenyl), 7.48 (dd, 1H, phenyl), 7.73 (d,
1H, phenyl). Its 13CNMR (CDCl3/TMS) spectrum (fig. 2.7) showed signals
at δ 154.62, 134.59, 131.95, 131.15, 128.32, 112.79, 56.37, 48.69,
52
45.28 and 23.54. Its mass spectrum (fig. 2.8) showed the molecular ion
peak at m/z 245 corresponding to a molecular mass of 244 when
recorded in the Q+1 mode and Specific rotation of –4.3° (C=1.0% in
MeOH) at a wavelength of 589nm and Melting point of 266 – 267°C
(decompose).
H2NO2S
H3CO
NH
S
OMeOH.HCl
H2NO2S
H3CO
NH
S
O+
88% in chiral HPLC Purity11% in chiral HPLC Purity
(47) (R,R)(47) (S,R)
H2NO2S
H3CO
NH2.HCl
88% in chiral HPLC Purity
H2NO2S
H3CO
NH2
.HCl
+
11% in chiral HPLC Purity
(22) (R,R)(22) (S,R)
…..(Scheme 2.15)
H2NO2S
H3CO
NH2.HCl
88% in chiral HPLC Purity
H2NO2S
H3CO
NH2
.HCl+
11% in chiral HPLC Purity
(22) (R,R)(22) (S,R)
H2NO2S
H3CO
NH2
88% in chiral HPLC Purity
H2NO2S
H3CO
NH2 +
11% in chiral HPLC Purity
(22) (R,R)(22) (S,R)
K2CO3
H2O
…..(Scheme 2.16)
53
Treatment of 22 hydrochloride salt with aqueous potassium
carbonate afforded 22 base (Scheme 2.16). Purification of the
diastereomers was carried out with Dibenzoyl-D(+)-tartaric acid (48)
(Scheme 2.17), (fig. 2.9) and (Table 2.2), Di-p-tolyl-D(+)-tartaric acid
(50) (Scheme 2.18), (fig. 2.10) and (Table 2.3), D(+)-tartaric acid and
other acid derivatives (Table 2.4). Among these Dibenzoyl-D(+)-tartaric
acid gave good result and Di-p-tolyl-D(+)-tartaric acid gave only
satisfactory result.
H2NO2S
H3CO
NH2
+
HOOC
OHOOC
O C
C
O
O
H2NO2S
H3CO
NH2
COOH
O
HOOC
O
CC OO
.
1. EtOH, DMF
(88%(R):11%(S)
(48)
(49)
K2CO3
H2O
H2NO2S
H3CO
NH2
>99.5% ee
S-(R*,R*)]-2,3-Bis(benzoyloxy)succinic acid
(22)
+
H2NO2S
H3CO
NH2
COOH
O
HOOC
O
CC OO
.
[R, R] >99.5% ee [R, S] <0.5% ee
(49)
H2NO2S
H3CO
NH2
(22)[S]
<0.5% ee
2. Purification in MeOH
+
(22) [R]
54
…..(Scheme 2.17)
H2NO2S
H3CO
NH2
+
Acetone
DMF
(88%(R):11%(S)
(50)(22)
(+)-O,O'-Di-p-toluoyl-D-tartaric acid
O
O
O
OHO
OHO
O
H2NO2S
H3CO
NH2.
(51)
K2CO3
H2O
H2NO2S
H3CO
NH2
>99.2% ee
+
H2NO2S
H3CO
NH2.
[R, R] >99.2% ee [R, S] <0.7% ee(51)
H2NO2S
H3CO
NH2
(22)(S)
<0.7% ee
OO
O OHO
OH
O
O
OO
O OHO
OH
O
O
+
(22)(R)
…..(Scheme 2.18)
(S)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide was also
synthesized in the same manner by using (S)-tert-butanesulfinamide
(Scheme 2.19). For chiral purity of (S)-isomer, see (fig. 2.11) and (fig.
55
2.12). In this case the (R)-isomer was completely removed in purification
of Dibenzoyl-D-tartarate salt.
H2NO2S
H3CO
O+ S
O
H2NTi(OPr)4
THF H2NO2S
H3CO
NS
O
NaBH4
MeOH H2NO2S
H3CO
NH
S
O
(23) (1) (46)(S)-tert-butanesulfinamide
H2NO2S
H3CO
NH
S
O
+
88% in chiral HPLC Purity 11% in chiral HPLC Purity
65° - 75°C
- 48°C(47)(S,R) (47)(R,R)
MeOH.HCl
H2NO2S
H3CO
NH2.HCl
88% in chiral HPLC Purity
H2NO2S
H3CO
NH2.HCl+
11% in chiral HPLC Purity
(22)(S)
H2NO2S
H3CO
NH2
88% in chiral HPLC Purity
H2NO2S
H3CO
NH2
+
11% in chiral HPLC Purity
(22)(S)
K2CO3
H2O
(22)(R)
(22)(R)
56
H2NO2S
H3CO
NH2
+
HOOC
OHOOC
O C
C
O
O
1. EtOH,DMF
(88%(S):11%(R)
(48)
K2CO3
H2O
S-(R*,R*)]-2,3-Bis(benzoyloxy)succinic acid
(22)
H2NO2S
H3CO
NH2
COOH
O
HOOC
O
CC OO
.
(49)(S) 100%
H2NO2S
H3CO
NH2
(22)(S) 100%
2. Purification in MeOH
…..(Scheme 2.19)
57
Table 2.1: Reduction of imine 46 with different reducing agents
S.No Temperature Reducing agent
Optical purity
Comments
01 - 48°C to -25°C NaBH4 88% No improvement in optical purity
02 -70°C NaBH4 85% Still no improvement in optical purity
03 55°-60°C & RT Raney nickel
-- No reaction
04 RT NaBH(OAc)3 -- No reaction
05 - 40°C Vitride -- No reaction
06 - 40°C DIBAL -- Only 25% conversion.
58
Table 2.2: Preparation of Di-Benzoyl-D(+)-Tartarate salt of 22 (88(R):11(S)
S.No Input (22)
Crude base
[moles]
HPLC chiral purity
DBT acid
Input [moles]
Solvent mixture [no. of times on wt.of
22]
Time
[Hrs]
Practical
Yield
Theoretical
Yield
HPLC chiral purity
% of impurity
Remarks
01 1.0 82.92% 1.1 MeOH: DMF [10:2] 1 2.5 2.6 91.47% 8.53% No satisfactory result
02 1.0 82.92% 1.1 Acetone: DMF [10:2] 1 2.2 2.6 90.77% 8.66% No satisfactory result
03 1.0 82.92% 1.1 Acetone: DMF: MeOH [10:1:0.5]
2 1.8 2.6 93.0% 6.77% No satisfactory result
04 1.0 82.92% 1.1 Acetone: DMF: MeOH [10:1:1]
2 1.5 2.6 92.68% 7.32% No satisfactory result
05 1.0 82.92% 1.1 MeOH: DMF [10:2] 5 2.0 2.6 93.98% 6.02% No satisfactory result
06 1.0 82.92% 1.1 Acetone: DMF [9:2] 3 1.5 2.6 90.79% 9.21% No satisfactory result
07 1.0 82.92% 1.1 MeOH: DMF [10:2] 10 1.4 2.6 94.95% 5.05% No satisfactory result
08 1.0 82.92% 1.1 Acetone: DMF [8:3] 1 1.3 2.6 91.87% 8.09% No satisfactory result
09 1.0 82.92% 1.1 MeOH: DMF [10:2] 5 0.7 2.6 97.78% 2.22% Satisfactory result
10 1.0 82.92% 1.1 EtOH: DMF [10:2] 5 1.36 2.6 98.56% 1.44% Good result
11 1.0 85.83% 1.1 ACN: DMF [10:2] 2 0.7 2.6 92.24% 6.83% No satisfactory result
12 1.0 85.83% 1.1 MeOH: DMF [10:2] 2 2.0 2.6 92.13% 7.87% No satisfactory result
13 1.0 85.83% 1.1 MeOH: DMF [10:2] 6 1.25 2.6 96.94% 3.06% No satisfactory result
14 1.0 85.83% 1.1 EtOH: DMF [10:2] 6 1.2 2.6 99.54% 0.46% Good result
59
Table 2.3: Preparation of Di-p-toluolyl-D-Tartarate salt of 22 (88(R):11(S)
S.No Input (22)
Crude base
[moles]
HPLC chiral purity
DpTT acid
Input [moles]
Solvent mixture [no. of times on wt.of 22]
Time
[Hrs]
Practical Yield
Theoretical Yield
HPLC chiral purity
Remarks
01 1.0 85.83% 1.1 MeOH: DMF [10:2] 2 0.32 2.74 98.96% Satisfactory result, but very less yield
02 1.0 85.83% 1.1 Acetone [22.5] 2 2.1 2.74 88.64% No satisfactory result
03 1.0 85.83% 1.1 Acetone: MeOH [12.5:1.5]
2 2.0 2.74 89.18% No satisfactory result
04 1.0 85.83% 1.1 EtOH: MeOH [17.5:3.5] 2 2.7 2.74 87.87% No satisfactory result
05 1.0 85.83% 1.1 Acetone: DMF [10:2] 2 2.44 2.74 93.33% No satisfactory result
06 1.0 85.83% 1.1 EtoAc: DMF [10:2] 2 2.6 2.74 86.83% No satisfactory result
07 1.0 85.83% 1.1 MeOH: DMF [5:1] 2 1.86 2.74 89.93% No satisfactory result
08 1.0 85.83% 1.1 Acetone: DMF [10:1] 2 2.6 2.74 89.66% No satisfactory result
09 1.0 85.83% 1.1 MeOH: DMF [3:2] 2 1.9 2.74 89.63% No satisfactory result
10 1.0 85.83% 1.1 Acetone: DMF [6:3] 2 0.6 2.74 99.23% Satisfactory result, less yield
60
And also prepared Tartaric acid salt, Mandelic acid salt and Malic acid salt and the results were summarized in Table – 2.4 Table 2.4: Resolution of 22 with different tartarate and other acid derivatives
S.No Input (22)
Crude base
[moles]
HPLC chiral purity (before)
Acid used Solvent mixture [no. of times on wt.of
22]
Practical Yield
Theoretical Yield
HPLC chiral purity (after)
Remarks
01 1.0 85.5% R- (-)-Mandelic acid EtoAc: DMF [15:2.5] -- 1.62 88.35% No salt formation
02 1.0 85.5% D-Malic acid EtoAc: MeOH [10:2] -- 1.55 88.38% No salt formation
03 1.0 85.5% D-Tartaric acid MeOH: DMF [10:2] 1.5 1.6 95.43% No satisfactory result even after 4
crystallizations
04 1.0 85.5% Di-p-toluolyl-D-tartaric acid
Acetone: DMF [6:3] 0.4 2.74 99.23% Satisfactory result
05 1.0 85.5% Di-benzoyl-D(+)-tartaric acid
EtOH: DMF [10:2] 1.2 2.6 99.54% Satisfactory result
Conclusion:
• Thus, different tartaric acid salts were prepared to get high optical purity.
• Tartaric acid salt, as reported didn’t give the best quality even after two crystallizations. (only 98.2% ee)
• The ditoluoyl tartarate also didn’t yield the required quality of product in two crystallizations. [99.2%ee]
• Only the dibenzoyl tartaric acid salt when prepared and with two crystallizations, the optical purity was improved to >99.55%ee. This amine was further converted to Tamsulosin and confirmed in all respects.
61
Experimental Section:
2.1) Preparation of 22 from 23 & (R) - 1 (General Procedure):
(R)- 1 (41.6gm, 1 equiv.) was added to a 0.5M solution of Titanium
tetra isopropoxide (187.7gm, 2 equiv.) and 23 (100.0gm, 1.2 equiv.) in
tetrahydrofuran under N2 atmosphere and the mixture was heated to 65°
to 70°C for 3-4 hours. Upon completion, as determined by TLC, the
mixture was cooled to room temperature first and then to –48°C to -52°C
with a dry ice/acetone bath. NaBH4 (23.3gm, 4 equiv.) was added portion
wise at –48°C to -52°C, and the mixture was stirred at –48°C until the
reduction was complete. Then methanol was added drop wise until gas
no longer evolved. The resulting mixture was poured into an equal
volume of brine with rapid stirring. The resulting suspension was filtered
through celite, and the bed washed with ethyl acetate. The filtrate was
extracted with ethyl acetate. The combined organic portions were dried
over Na2SO4, filtered, and concentrated to obtain the crude product 47.
The crude product thus obtained was hydrolyzed and purified by making
hydrochloride salt with 20% Methanolic hydrochloride solution (75.0 ml),
followed by base preparation using aqueous potassium carbonate. Chiral
ratio of the crude product is 88.7(R): 11(S).
Yield 60.0 g (60%); M. P. 170.8-172.5° C; [α]D23 (C= 1.07, MeOH) –15.0°;
HPLC Chiral Purity 88.7% R-isomer and 11.0% S-isomer; IR, ν max
(KBr): 3328 cm-1 (s, w, -NH2), 3202 cm-1 (s, s, -NH2 of sulfonamide), 1326
cm-1 (s, s, SO2); 1H NMR (CD3OD/TMS): δ1.24 (d, 3H, -CH3), 2.98 (m, 2H,
62
-CH2), 3.29 (m, 1H, -CH), 3.97 (s, 3H, -OCH3), 7.20 (d, 1H, aryl proton),
7.48 (dd, 1H, aryl proton), 7.73 (d, 1H, aryl proton); 13C NMR
(CD3OD/TMS): δ 23.54, 45.28, 48.69, 56.37, 112.79, 128.32, 131.15,
131.95, 134.59 and 154.62; MS (m/z): 245.3 [Q+1]+.
2.2) Preparation of 49 from 22:
The above crude (88% (R): 11%(S) 22 (25.0g) was dissolved in a
solvent mixture of Ethanol (250.0 ml) and N, N-dimethylformamide (50.0
ml) with heating. 48 (40.0g) was added at 75° to 80°C temperature, and
then stirred for 6 hours. The crystals formed were collected by filtration
and washed with Ethanol (25.0 ml), affording Dibenzoyl-D (+)-Tartarate
salt of (R) -5-(2-Aminopropyl)-2-methoxybenzene sulfonamide 49.
Yield 26.0 g (42%); HPLC chiral purity 98.0%.
2.3) Purification of 49:
49 98% (R):2%(S) (26.0 gm) and methanol (26.0 ml) was stirred for
15 minutes to become a clear solution. Absolute alcohol (260.0 ml) was
added to the clear solution and heated to reflux temperature, which was
stirred for 1 hour. The reaction mixture was cooled to 28 to 30°C,
filtered, and washed with alcohol. The solid was dried at 50- 55°C to a
constant weight to give pure dibenzoyl-D-tartarate salt of 22(R).
Yield 24.0 g (92%); HPLC Chiral Purity 99.5%.
63
2.4) Preparation of 22 from 49:
Aqueous potassium carbonate (16.0 gm of K2CO3 in 72.0 ml Water)
was added to the above pure 49 (24.0 gm). The solution was stirred for 1
hour at room temperature. The isolated solid was filtered, washed with
water, and dried at 60-65°C to a constant weight to give pure (R) - 22.
Yield 8.0 g (82.5%); HPLC Chiral Purity 99.54%; [α]D23 (C=1.07,
methanol) –17.1°; M. P. 166-167°C.
Preparation of (S)-isomer:
2.5) Preparation of 22 from 23 & (S)-1:
(S)- 1 (41.6gm, 1 equiv.) was added to a 0.5M solution of Titanium
tetra isopropoxide (187.7gm, 2 equiv.) and 23 (100.0gm, 1.2 equiv.) in
tetrahydrofuran under N2 atmosphere and the mixture was heated to 65°
to 70°C temperature for 3-4 hours. Upon completion, as determined by
TLC, the mixture was cooled to room temperature first and then to –48°C
with a dry ice/acetone bath. NaBH4 (23.3gm, 4 equiv.) was added portion
wise at –48°C, and the mixture was stirred at –48°C until the reduction
was complete. Then methanol was added drop wise until gas no longer
evolved. The resulting mixture was poured into an equal volume of brine
with rapid stirring. The resulting suspension was filtered through celite,
and the bed washed with ethyl acetate. The filtrate was extracted with
ethyl acetate. The combined organic portions were dried over Na2SO4,
64
filtered, and concentrated to obtain the crude product 47. The crude
product thus obtained was hydrolyzed and purified by making
hydrochloride salt with 20% Methanolic hydrochloride solution (75.0 ml),
followed by base preparation using aqueous potassium carbonate. Chiral
ratio of the crude product is 88(S): 11(R).
Yield 62.0 g (62%).
2.6) Preparation of 49 from 22:
22 (88%(S):11%(R) (25.0g) was dissolved in a solvent mixture of Ethanol
(250.0 ml) and N, N-dimethylformamide (50.0 ml) with heating. 48
(40.0g) was added at 75° to 80°C temperature, and then stirred for 6
hours. The crystals formed were collected by filtration and washed with
Ethanol (25.0 ml), affording Dibenzoyl-D-Tartarate salt of (S) -5-(2-
Aminopropyl)-2-methoxybenzene sulfonamide 49.
Yield 25.0 g (41%); HPLC chiral purity 98%.
7) Purification of 49:
49 98%(S):2%(R) (25.0 gm) and methanol (25.0 ml) was stirred for
15 minutes to become a clear solution. Absolute alcohol (250.0 ml) was
added to the clear solution and heated to reflux temperature, which was
stirred for 1 hour. The reaction mixture was cooled to 28 to 30°C,
filtered, and washed with alcohol (25.0 ml). The solid was dried at 50-
55°C to a constant weight to give pure dibenzoyl-D(+)-tartarate salt of
49(S) .
65
Yield 23.0 g (92%); HPLC Chiral Purity 100.0%.
2.8) Preparation of (S)- 22 from 49:
Aqueous potassium carbonate (16.0 gm of K2CO3 in 72.0 ml Water)
was added to the above pure 49 (S) (23.0 gm). The solution was stirred
for 1 hour at room temperature. The isolated solid was filtered, washed
with water, and dried at 60-65°C to a constant weight to give pure 22 (S).
Yield 7.5 g (81%); HPLC Chiral Purity 100.0%.
The results are similar with (S)-isomer also.