chapter – 2 application of ( r)-tert -butanesulfinamide in...

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

+


(22) (R,R)(22) (S,R)

…..(Scheme 2.15)

H2NO2S

H3CO

NH2.HCl


H2NO2S

H3CO

NH2

.HCl+


(22) (R,R)(22) (S,R)

H2NO2S

H3CO

NH2


H2NO2S

H3CO

NH2 +


(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


H2NO2S

H3CO

NH2.HCl+


(22)(S)

H2NO2S

H3CO

NH2


H2NO2S

H3CO

NH2

+


(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





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



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.

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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%.

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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%).


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


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).


The results are similar with (S)-isomer also.

chapter – 2 application of ( r)-tert -butanesulfinamide in...

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