CHAPTER-5A AN IMPROVED PROCESS FOR THE PREPARATION...

176 Chapter-5

CHAPTER-5A

AN IMPROVED PROCESS FOR THE PREPARATION OF

ZAFIRLUKAST - AN ANTI ASTHMA DRUG

177 Chapter-5

AN IMPROVED PROCESS FOR THE PREPARATION OF

ZAFIRLUKAST: AN ANTI ASTHMA DRUG

5. 1.1 INTRODUCTION

Asthma is a disease that causes swelling and narrowing the

airways of the lungs. Airways are air carriers to and from lungs. Swollen

and narrower airways affect the air flow to and from the lungs and this

lead to tightness of chest, wheezing, shortness of breath and cough.

These symptoms are often occurs in early morning and in night. Asthma

is caused by genetic and environmental factors, it was not curable

completely but this can be controlled with good medical care.

Leukotriene antagonists also known as leukast are the

medicaments that are used to reduce leukotrienes, which are produced

by several types of cells and causes inflammation in asthma and

bronchitis. Leukotriene antagonists that are available in market are

Montelukast, Zafirlukast and Pranlukast. Zafirlukast is the first leukast

compound approved for management of Asthma. US FDA approved

zafirlukast in the form of 10 mg and 20 mg tablet with the brand name

of Accolate®.1 Subsequently this was approved and launched by

innovator in few other countries.

Importance of Leukotriene antagonists for treating asthma are

motivated us to develop an improved and cost effective process for the

preparation of Zafirlukast.

178 Chapter-5

5. 1.1.1 PRODUCT PROFILE

1. Generic name : Zafirlukast

2. Chemical structure :

3. Chemical name : [3-[[2-Methoxy-4-[[[(2-methylphenyl)

sulfonyl] amino] carbonyl] phenyl]

methyl]-1- methyl-1H-indole-5-yl]

carbamic acid cyclopentyl ester

4. Molecular formula : C31H33N3O6S

5. Molecular weight : 575.69

6. CAS No : 107753-78-6

7. Therapeutic category : Anti asthmatic

5. 1.1.2 PHYSICAL CHARACTERISTICS

1. Description : Off white to pale yellow powder

2. Solubility : Tetrahydrofuran (Rx-list)

3. Melting piont : 137 – 140°C

5. 1.1.3 MARKET INFORMATION

1. Applicant : AstraZeneca

2. Patentee : ICI

3. Brand name : ACCOLATE

179 Chapter-5

5. 1.2 LITERATURE REVIEW

There are many synthetic routes for the preparation of Zafirlukast 4 is

well documented in literature. Some of the key approaches are discussed

here under. Scientists from ICI Americas Inc2 have reported process for

the synthesis of 4, which starts with esterification of

3-methoxy-4-methyl benzoic acid 53 using methanol in presence of

acetyl chloride (Scheme 5.1).

OCH3

OCH3

H3C

O

OCH3

OCH3

O

Br

OH

OCH3

H3C

O

NH

O2N

NH

O2N

53 54 55

124

125

Acetyl chloride

Methanol

OCH3

O

OCH3

N

O2N

57

OCH3

O

OCH3

CH3

N

H2N

58

OCH3

O

OCH3

CH3

N

HN

59

OCH3

O

OCH3

CH3

O

O

N

HN

60

OCH3

O

OH

CH3

O

O

N

HN

4

OCH3

O

NH

CH3

O

O

S

O O CH3

Bromine

1,4-dioxane

Silver oxide

NaH, CH3I

Tetrahydro furan

Pd/C, H2

Methanol

CPC, NMM Lithium hydroxide

THF, Methanol

OTSA, DMAPEC

CCl4

DMAP

Scheme 5.1: Synthesis of zafirlukast 4 (product patent route)

180 Chapter-5

Allylic bromination of methyl ester 54 using bromine in presence

of CCl4 resulted bromo compound 55, which was reacted with 5-nitro

indole 124 using silver oxide as catalyst to obtain condensed compound

125. N-methylation of 125 utilizing methyl iodide in presence of NaH

afforded N-methyl indole derivative 57. Thus obtained 57 was subjected

to reduction using palladium carbon (Pd/C) in methanol followed by

reacted with cyclopentyl chloroformate to obtain compound 59.

Hydrolysis of 59 using LiOH.H2O subsequently reaction with o-toluene

sulfonamide (OTSA) in presence of 1-[3-(dimethylamino)propyl]-3-ethyl

carbodiimide hydrochloride (DMAPEC) and DMAP furnished zafirlukast

4. Matassa et al3 also reported similar procedure for the synthesis of

Zafirlukast 4.

Gutman et al4 reported process for synthesis of zafirlukast 4

commenced with hydrolysis of 125 as depicted in Scheme 5.2. Basic

hydrolysis of 125 using NaOH provided 126 in the form of sodium salt,

which was converted into acid 127 by treating 126 in aqueous HCl.

Simultaneous N-methylation and methyl esterification of acid 127 using

dimethyl sulfate followed by reduction of nitro compound 57 in presence

of 10% Pd/C provided amine 58. The resulted 58 was reacted with

cyclopentyl chloro formate to obtain cyclopentyl carbamate 59, which

was subjected to hydrolysis under basic conditions (NaOH) to obtain

acid compound in the form of its sodium salt 128. Thus obtained 128

181 Chapter-5

was isolated and further treated with HCl to get acid 60. Reaction of 60

with OTSA in presence of DMAPEC and DMAP furnished Zafirlukast 4.

NH

O2N

125

OCH3

O

OCH3

N

O2N

57

OCH3

O

OCH3

CH3

N

H2N

58

OCH3

O

OCH3

CH3

N

HN

59

OCH3

O

OCH3

CH3

O

O

N

HN

60

OCH3

O

OH

CH3

O

O

N

HN

4

OCH3

O

NH

CH3

O

O

S

O O CH3

DMAP, DCM

OTSA, DMAPEC

NH

O2N

126

OCH3

O

ONa

NH

O2N

127

OCH3

O

OH

N

HN

128

OCH3

O

ONa

CH3

O

O

NaOH

Methanol

Water

DMS, K2CO3

2-Butanone

NH2-NH2. H2O

10% Pd/C

Ethanol

CPC, NMM

DCM

NaOH

Methanol

HCl

Water

MeOH

Scheme 5.2: Synthesis of zafirlukast 4

Claire and co-workers5 have reported an alternate synthesis for

preparation of 4, which starts with hydrolysis of ester 57 as described in

Scheme 5.3. Hydrolysis of 57 in presence of hydrochloric acid provided

acid 129, which was converted into acid chloride 130 by treating with

thionyl chloride followed by reacted with o-toluene sulfonamide in

presence of DMAP to obtain amide 131. Thus obtained amide 131 was

182 Chapter-5

subjected to reduction using Pd/C followed by reacted with cyclopentyl

chloroformate to obtain Zafirlukast 4.

N

HNO

O

O

NH

S

CH3OO

CH3

4

57 129130

131132

N

O2N

O

OCH3

CH3

N

O2N

O

OH

CH3

N

O2N

O

Cl

CH3

N

O2N

O

NH

S

CH3OO

CH3

N

H2N

O

NH

S

CH3OO

CH3

Water, HCl Thionyl chloride

DMF

OTSA

DMAP

Pd/C, H2

NaOH

NaOH

OCH3 OCH3 OCH3

OCH3 OCH3

OCH3

Cyclopentyl chloroformate

Scheme 5.3: Synthesis of zafirlukast 4

Keesari et al6 have reported synthesis of 4 from benzoic acid

derivative 133 and N-methyl nitro indole 56 as described in Scheme 5.4.

Reaction of 133 with 56 in presence of ZnBr2 offered nitro acid 129,

which was hydrogenated using Raney nickel to obtain amine 134. The

resulted amine 134 was treated with OTSA in presence DCC as coupling

agent followed by reaction with cyclopentyl chloroformate in presence of

NMM furnished zafirlukast 4.

183 Chapter-5

OH

OCH3

O

Br N

O2N

+

CH3

N

HNO

O

O

NH

S

CH3OO

CH3

4

N

O2N

O

OH

CH3

N

H2N

O

OH

CH3

N

H2N

O

NH

S

CH3OO

CH3

135

ZnBr2

1,4-Dioxane

Raney nickel, H2

THF

OTSA, DCC

DMAP

133 56 129

134

CPC, NMM

DCM

OCH3

OCH3OCH3

OCH3

Scheme 5.4: Synthesis of zafirlukast

The reported synthetic routes for preparation of zafirlukast have

certain disadvantages, (i) possibility for formation of N-alkylated by-

products are high when unprotected indole compound was used for the

condensation reaction (synthetic routes 5.1, 5.2 and 5.3),5 (ii) selectivity

of alkylation at C-3 position depends on the substitutients on indole

nitrogen atom. Usage of unsubstituted indole for condensation reaction

leads to formation of C-2 alkylated by product rather than alkylation at

C-3 position, 7 (iii) formation of amide linkage via acid chloride is not

suitable for commercial level since acid chloride intermediate is non

solid, unstable and moister sensitive intermediates (scheme 5.3), (iv)

preparation of sulfonamide 135 via DCC mediated coupling reaction

184 Chapter-5

leads to formation of dimer compounds because unprotected primary

amine 134 underwent intermolecular coupling with acid group and (v)

removal of dicyclohexyl urea (obtained as by product in DCC mediated

coupling reactions) from the sulfonamide compounds needed

purification, which makes process expensive.

Apart from these drawbacks, the reported synthetic processes for

preparation of zafirlukast 4 involves usage of commercially unsafe

reagents, such as sodium hydride, acetyl chloride, Br2, CH3I and

hydrazine hydrate, expensive reagents palladium carbon, 1-[3-

(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (DMAPEC)

and usage of column chromatography techniques purifications of crude

compounds.

5. 1.3 PRESENT WORK

5. 1.3.1 OBJECTIVE

The drawbacks associated with the reported processes motivated us

to develop an efficient, cost-effective and large-scale process for the

synthesis of zafirlukast. As per retro-synthetic path way, synthesis of

zafirlukast involves majorly four reactions (Figure 5.1).

(i) Sulfonamide linkage.

(ii) Carbamate linkage.

(iii) C-C bond formation.

(iv) N-Methylation.

185 Chapter-5

Figure 5.1: Retro-synthetic analysis of zafirlukast

All the raw materials resulted from retero-synthetic path way are

commercially available.

5. 1.3.2 RESULT AND DISCUSSION

In this context, an improved synthetic approach (scheme 2.5) for

preparation of 4 has been designed, which commenced with the

esterification of commercially available benzoic acid 53. The major

drawback associated with the esterification reaction is longer reaction

time (about 36 hours). At our end after screening the key reaction

parameters, reaction time was significantly reduced to 3 hours from 36

hours by replacing the earlier reported acetyl chloride2 with thiony

chloride. This modification is allowed us to isolate ester 54 with about

98% yield and more than 99 % of purity. Further, workup and isolation

process was simplified by quenching the reaction mixture with water.

186 Chapter-5

Modification of solvent system (chloroform with cyclohexane) in

subsequent allylic bromination reaction is avoided the tedious workup

process. Targeted bromo compound 55 was isolated with about 85%

yield and more than 99% purity by adopted simple crystallization at

lower temperature (about 4 ºC). In addition to the above modifications

both esterfication reaction and allylic bromination reactions were

performed in one pot.

To enhance the selectivity at indole C-3 position and to reduce the

formation of N-alkylated by products, N-Methyl indole 56 was chosen for

condensation reaction at indole C-3 position. N-Methyl indole 56 was

synthesized with about 99.0 % yield and more than 99.5 % purity by

reacting 5-nitroindole 124 with dimethyl sulfate (DMS) in presence of

NaOH and DMF, where as similar reaction was performed earlier using

expensive catalysts and reagents such as DABCO, CH3I and (CH3)2CO3

at elevated temperature (90 oC).7

Expensive reagents like Ag2CO3, ZnBr2 and Ag2O are previously

used2-6 for the reaction of N-methyl indole 56 and bromo compound 55.

In order to improve the process efficiency and to reduce the

manufacturing cost, commercially available and less expensive reagents

such as Cu2O, CuCl, ZnO, AlCl3 and Al2O3 are examined along with the

reported reagents for synthesis of 57.

Table 5.1: Alkylation of compound 56 using different reagents

187 Chapter-5

S. No. Reagent Yield (%) 57 (%) 136 (%) 56 (%)

1 Ag2O 65 51.4 16.8 1.2

2 CuCl 30 33.4 7.5 38.3

3 ZnO 60 49.1 4.3 1.8

4 Al2O3 95 6.7 ND 35.0

5 AlCl3* --- --- --- ---

6 ZnBr2 62 53.2 9.5 4.8

7 Cu2O 85 85.3 3.6 1.0

* indicates product formation not observed; ND = not detected.

Experimental results are indicated that lower amount of

dialkylated (C-2 and C-3) compound 136 (figure 5.4) and better yield

and purity was observed in Cu2O (Table 5.1, entry 7) when compared

with other reagents.

N

O2N O

OCH3

CH3

OOCH3

136

H3CO

Figure 5.2: Chemical structures of 136

The resulted crude compound 57 was subjected to purification for

removal of the related substances. Various purification techniques and

different solvents were screened for the purification of 57, but did not

188 Chapter-5

succeed. Hence it was decided to proceed to subsequent stage rather

than the purification of crude compound 57. In subsequent step,

previously reported expensive and pyrophoric reducing reagents like

Raney nickel and Pd/C for reduction of 57 was replaced with plant-

friendly and low toxic reducing agent sodium dithionite.

OCH3

OCH3

H3C

O

OCH3

OCH3

O

Br

OH

OCH3

H3C

O

N

O2N

53 54 55

56

Methanol

N

O2N

57

OCH3

O

OCH3

CH3

N

H2N

58

OCH3

O

OCH3

CH3

N

HN

59

OCH3

O

OCH3

CH3

O

O

N

HN

60

OCH3

O

OH

CH3

O

O

N

HN

4

OCH3

O

NH

CH3

O

O

S

O O CH3

3 h, 98 % 84 %

85 %

1,4-dioxane

Cu2O

Sodium dithionate

Methanol, water

45 %

CPC, NMM

Toluene, 97 %

LiOH. H2O

Methanol

98 %

OTSA

DCM

CH3

SOCl2 DBDMH, AIBN

Cyclohexane

T3P, DMAP

86 %

Scheme 5.5: Improved synthesis of zafirlukast

The resulted amine 58 was subjected to purification for

elimination of related compounds. After screening the various

189 Chapter-5

purification techniques, purity of the 58 was significantly improved

(more than 99.5%) by converting crude compound 58 as its HCl salt.

Having developed advantageous process for synthesis of 58, our focus

was moved towards subsequent reactions. Reaction of amine 58 with

cyclopentyl chloroformate using N-Methyl morpholine as base in toluene

medium afforded carbamate 59 with 98 % yield and about 99.7 %

purity. Thereafter, 59 was converted into 60 using lithium hydroxide

monohydrate as base in mixture of methanol and water with 98% yield

and more than 99% of purity. These processes are advantageous over

the processes reported in literature with respect to yield, cycle time and

purity.

Good number of references available in literature for the

condensation of acid 60 with o-toluene sulfonamide and these processes

involves the usage dicyclocarbodiimide (DCC) as coupling agent. Usage

of DCC as coupling reagent for formation of amide linkage facilitates

formation of dicyclohexylurea (DCU) as by-product. As per the ICH

guidelines limit of DCU in final drug compound is less than or

equivalent to 0.1%. To meet the regulatory requirement, DCU present in

crude zafirlukast 4 need to be removed by employing purification.

Multiple purifications lead to loss of yield and this makes process

expensive. In view of this, DCC is replaced with non toxic and

commercially available coupling reagent propylphosphonic anhydride

also known as T3P®. By-products obtained during the T3P mediated

190 Chapter-5

amide formation are water soluble and these can be removed with simple

water washings. By implement all the process improvements, zafirlukast

was obtained with more than 99.5% purity and all other known and

unknown impurities are less than 0.1%.

An improved synthetic method depicted in Scheme 5.5 for the

preparation of Zafirlukast 4 has certain advantages over the earlier

reported processes that are mentioned below.

(i) Time cycle for esterification reaction was reduced from 36 hours to

3 hours.

(ii) Tedious work-up processes were avoided.

(iii) Formation of N-alkylated by products was controlled by using N-

methyl indole 56 as starting material for alkylation reaction.

(iv) Formation of dialkylated compound 136 during alkylation reaction

is significantly reduced to below 4.0%.

(v) Expensive and pyrophoric reducing reagents like Raney nickel and

Pd/C are replaced with plant-friendly and low toxic reducing agent

like sodium dithionite.

(vi) Purifications for removal of DCU (obtained as by-product in DCC

mediated coupling reactions) in crude Zafirlukast 4 is avoided using

commercially available less toxic coupling reagent T3P® instead of

DCC.

(vii) Usage of toxic reagents like bromine and acetyl chloride is avoided.

191 Chapter-5

5. 1. 4 CONCLUSION

In conclusion, an efficient, robust and large scale manufacturing

process for zafirlukast 4 was developed. The product obtained by this

process fulfills all the regulatory needs.

5. 1. 5 EXPERIMENTAL SECTION

5. 1. 5.1 Process description

5. 1.5.1.1 Methyl 4-bromomethyl-3-methoxybenzoate (55)

Thionyl chloride (50 mL, 0.689 mol) was slowly added to the

stirring solution of acid 53 (100 g, 0.602 mol) & methanol (150 mL).

Reaction mass was heated to 60 °C and stirred at same temperature for

3 hours, quenched with precooled water at below 15 °C. Separated solid

was filtered, washed with 10 % aqueous Na2CO3 solution (200 mL) to

afford 108 g of ester compound 54. To the stirring solution of ester 54 in

cyclohexane (600 mL), DBDMH (80 g, 0.28 mol) and AIBN (0.6 g, 3.6

mmol) were charged and the resultant reaction mixture was heated to 80

°C and stirred for 4 hours. AIBN (0.1 g, 0.601 mmol) and DBDMH (20 g,

0.072 mol) charged into reaction mixture at ambient temperature then

heated to 80 °C and stirred for 2 hours. Reaction mass was quenched

with water (400 mL) at 55 °C and stirred for 45–60 min. Organic phase

192 Chapter-5

and aqueous phase was separated at about 55 °C, organic phase was

cooled to 10 °C and stirred at same temperature for 1 hour. The

separated solid was collected by filtration, washed with cyclohexane (50

mL) and dried under reduced pressure 50 °C for 4 hours to give 84 %

(130 g) of title compound 55 with 99.1 % purity.

IR (KBr, cm–1): 2951 (Ali, CH),1717 (ester, C═O), 1276 (Ether, C-O-C).

1H NMR (200 MHz, CDCl3): δ 7.60 (d, 1H, Ar-H), 7.54 (s, 1H, Ar-H),

7.39 (d, 1H, Ar-H), 4.55 (s, 2H, CH2), 3.95 (s, 3H, CH3), 3.92 (s, 3H,

CH3).

MS (m/z): 283.2 (M+ + Na).

5. 1.5.1. 2 1-Methyl-5-nitro-1H-indole (56)

N

CH3

O2N

Dimethyl sulfate (91 g, 0.722 mol) was slowly added to the

suspension of NaOH (52 g, 1.3 mol), DMF (400 mL) and indole

compound 124 (100 g, 0.617 mol) and stirred at 28 °C for 4 hours.

Water (1.0 L) was added to the reaction mass and stirred for 1 hour. The

separated solid was filtered, washed with water (500 mL) and dried

under reduced pressure at 55 °C for 4 hours to afford 99 % of title

compound 56 with 99.6 % purity.

IR (KBr, cm–1): 1579 & 1397 (NO2, asym. and sym.).

193 Chapter-5

1H NMR (200 MHz, CDCl3): δ 8.56 (d, 1H, Ar-H), 8.10 (dd, 1H, Ar-H),

7.32 (d, 1H, Ar-H), 7.20 (d, 1H, Ar-H), 6.66 (dd, 1H, Ar-H), 3.85 (s, 3H,

CH3).

MS (m/z): 177.0 (M+ + H).

5. 1.5.1. 3 Methyl 3-methoxy-4-(1-methyl-5-nitro-1H-indol-3-yl

methyl) benzoate (57)

A suspension of bromo derivative 55 (95.5 g, 0.368 mol), N-methyl

indole compound 56 (50 g, 0.284 mol), Cu2O (12.2 g, 0.853 mol) and

1,4-dioxane (350 mL) was heated to 95 °C and stirred at same

temperature for 27 hours. Thus obtained reaction mass was filtered

through celite bed and washed with 1, 4-dioxane (100 mL). Solvent from

the filtrate was evaporated, methanol (450 mL) and ethyl acetate (50 mL)

was added. The resultant reaction mixture was heated to 65 °C and

stirred for 1 hour, then cooled to ambient temperature and stirred for 4

hours. The separated solid was collected by filtration and dried at 55 °C

to give 85 % of title compound 57 with 85 % purity.

IR (KBr, cm–1): 2949 (Ali, CH), 1709 (ester, C═O), 1579 & 1324 (asym.

and sym., NO2), 1291 (ether, C-O-C).

194 Chapter-5

1H NMR (200 MHz, CDCl3): δ 6.9-8.6 (m, 1H, Ar-H), 3.98 (s, 3H, CH3),

3.94 (s, 3H, CH3) and 3.80 (s, 2H, CH2).

MS (m/z): 377 (M+ + Na).

5. 1.5.1.4 Methyl 4-(5-amino-1-methyl-1H-indole-3-yl-methyl)-3

methoxybenzoate (58)

To the stirring suspension of compound 57 (100 g, 0.282 mol),

dichloromethane (500 mL), triethylamine (78.7 mL, O.565 mol) and

sodium dithionite (98.3 g, 0.565 mol) was added slowly water (100 mL)

at 28 °C and stirred for 4 hours. Thus obtained reaction mass was

acidified with 50% aqueous hydrochloride solution (100 mL) at 27 °C

and stirred for 45 minutes. The separated compound was filtered and

washed with water (50 mL). Wet compound, water (500 mL) and

dichloromethane (500 mL) was stirred at 28 °C for 4 hours. The obtained

solid was filtered, water (500 mL) was added to the resulted wet

compound and pH of the reaction mixture was adjusted to 7-8 with 10%

Na2CO3 solution. The precipitated solid was filtered to give 44 % of title

compound 58 with 99.5 % HPLC purity.

195 Chapter-5

IR (KBr, cm–1): 3442 & 3360 (Amine, NH2), 2937 (Ali, CH), 1703 (ester,

C═O), 1297 (ether, C-O-C).

1H NMR (200 MHz, CDCl3): δ 6.7−7.50 (m, 7H, Ar-H) 4.07 (s, 2H, CH2),

3.93 (s, 3H, CH3), 3.90 (s, 3H, CH3), 3.66 (s, 3H, CH3).

MS (m/z): 325 (M+ + H).

5. 1.5.1.5 4-(5-Cyclopentyloxycarbonylamino-1-methyl-1H-indol-3-

yl methyl)-3-methoxybenzoicacid methyl ester (59)

To a stirring solution of amine 58 (70 g, 0.216 mol), toluene (350

mL) and N-methyl morpholine (27 g, 0.267 mol) was slowly added

cyclopentyl chloroformate (50 g, 0.337 mol) at ambient temperature and

stirred at same temperature for 1 hour. Solvent from the resulted

reaction mixture was evaporated completely, methanol (350 mL) was

charged to the obtained crude and stirred for 30 minutes. Separated

solid was filtered, washed with methanol (70 mL) and dried at 55 °C for

3 hours to afford 98 % of title compound with more than 99.6 % purity.

IR (KBr, cm–1): 3247 (amine, NH), 1719 (ester, C═O), 1692 (carbamate,

C═O), 1232 (ether, C-O-C).

196 Chapter-5

1H NMR (400 MHz, DMSO–d6): δ 9.18 (bs, 1H, NH), 7.0-7.60 (s, 7H, Ar-

H) 5.0−5.1 (m, 1H, CH), 4.0 (s, 2H, CH2), 3.9 (s, 3H, CH3), 3.8 (s, 3H,

CH3), 3.7 (s, 3H, CH3), 1.6−1.9 (m, 8H, CH2).

MS (m/z): 437.4 (M+ + H).

5. 1.5.1.6 [4-(5-Cyclopentyloxycarbonylmethyl-1-methyl-1H-indol-

3-ylmethyl)-3-methoxybenzoic acid (60)

Mixture of carbamate compound 59 (50 g, 0.115 mol), methanol

(300 mL), LiOH.H2O (7.5 g, 0.178 mol) and water (75 mL) was heated to

65 °C and the stirred at same temperature for 2 hours. The resulted

reaction mass pH was adjusted to 1.0-2.0 with diluted hydrochloric acid

at 28 °C and stirred for 2 hours. Separated solid was filtered, washed

with water (100 mL) and dried under reduced pressure at 75 °C to

provide 98 % of title compound 60 with more than 99 % of purity.

IR (KBr, cm–1): 3288 (amine, NH), 2957 (hydroxyl, OH), 1696 (acid,

C═O), 1646 (carbamate, C═O), 1264 (ether, C-O-C).

1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.1–7.6 (m, 7H, Ar-H), 6.8 (s,

1H, CH), 5.1−5.2 (m, 1H, CH), 4.1 (s, 2H, CH2), 3.9 (s, 3H, CH3), 3.7 (s,

3H, CH3), 1.6−1.9 (m, 8H, CH2).

197 Chapter-5

MS (m/z): 423.3 (M+ + H).

5. 1.5.1.7 {3-[2-Methoxy-4-(toluene-2-sulfonylaminocarbonyl)

benzyl]-1-methyl-1H-indol-5-yl} acetic acid cyclopentyl ester (4)

Propylphosphonic anhydride in dichloromethane solution (170

mL, 0.355 mol) was slowly added to the stirring suspension of

compound 60 (50 g, 0.118 mol), diisopropyl ethylamine (41.3 mL, 0.236

mol), o-toluene sulfonamide (24.2 g, 0.141 mol) and dichloromethane

(400 mL) at 28 °C and stirred at same temperature for 4 hours. The

resultant reaction mixture was quenched with water (500 mL), organic

phase and aqueous phase was separated. Solvent from organic phase

was evaporated; acetonitrile (200 mL) was added to the crude compound

and stirred at 27 °C for 45 minutes. Separated solid was filtered,

washed with methanol (50 mL) and dried under reduced pressure at 75

°C to afford 85 % of crude 4. Suspension of crude zafirlukast (20 g),

silica gel (40 g) and DCM (300 mL) were stirred at ambient temperature

for I hour and filtered the reaction mixture. Filtrate solvent was

evaporated, acetonitrile (240 mL) charged into crude compound and

stirred at 80 °C for 45 minutes. The resultant reaction mass was cooled

198 Chapter-5

to 28 °C and stirred at same temperature for 45 minutes. Separated

solid was filtered, washed with acetonitrile (60 mL) and dried under

reduced pressure at 75 °C to afford pure zafirlukast with more than

99.5% purity.

IR (KBr, cm–1): 3371 (amine, NH), 2960 (Ali, CH), 1690 (amide, C═O),

1340 & 1162 (asym. and sym, SO2).

1H NMR (400 MHz, CDCl3): δ 9.35 (br, 1H), 7.0-8.2 (m, 11H, Ar-H), 6.7

(s, 1H), 6.5 (s, 1H), 5.1−5.2 (m, 1H), 4.00 (s, 2H, CH2), 3.8 (s, 3H, CH3),

3.68 (s, 3H, CH3), 2.7 (s, 3H, CH3), 1.5−1.9 (m, 8H, CH2).

13C NMR (100 MHz, CDCl3): δC 20.0, 23.4, 23.4, 24.8, 32.3, 32.5, 55.2,

77.5, 109.1, 109.4, 109.7, 111.7, 115.2, 119.8, 126.0, 127.7, 128.0,

129.4, 129.7, 131.1, 132.1, 133.5, 134.0, 136.0, 136.7, 137.4, 154.3,

157.1, 164.8.

MS (m/z): 576 (M+ + H).

199 Chapter-5

5.7 REFERENCES

1. Phipatanakul, W.; Eggleston, P. A.; Conover-Walker, M. K.;

Kesavanathan, J.; Sweitzer, D.; Wood, R. A. Journal of Allergy and

Clinical Immunol., 2000, 105 (4), 704–710.

2. Bernstein, P. R.; Brown, F. J.; Matassa, V. G.; Yee, Y. K. US

4859692, 1989.

3. Matassa, V. G.; Thomas, P. M,; Jr., Howard, S.; Shapiro, Barrie,

H.; David, W. S.; David, A.; Robert, D. K.; Richard, A. K. J. Med.

Chem., 1990, 33, 1781–1790.

4. Arie, G.; Genndy, N.; Igor, Z.; Victor, P.; Maxim, S. WO 02/46153

A2, 2002.

5. Claire, L. A.; Ian, D.; Jonathan, D. M.; Jeffery, A. S. Org. Proc. Res.

& Dev., 2004, 8, 808–813.

6. Srinivas, K.; Srinivasan, N.; Krishna, M. R.; Reddy, C. R.;

Muthulingam. A.; Lalitha, R.; Reddy, K. S. R.; Reddy, B. S.; Reddy,

G. M.; Reddy, P. P.; Kumar, M. K.; Reddy M. S. N. Org. Proc. Res.

& Dev., 2004, 8, 952–954.

7. (a). Jiang, X.; Tiwari, A.; Thompson, M.; Chen, Z.; Cleary, T. P.;

Lee, T. B. K. Org. Process Res. Dev., 2001, 5, 604–608; (b). Laurila,

L. N.; Magnus, A. N.; Staszak, A. M.; Org. Process Res. Dev., 2009,

13, 1199–1201.

8. Anu, M.; Howard, S.; Mario, G.; John, C. M.; Tetrahedron Lett.,

2003, 44, 4589–4591.

200 Chapter-5

9. http://www.Rxlist.com

10. Robert, J.; Timko, R. J.; Bradway, A. C. US 5993859, 1999.

11. James, J. Holohan, I. J.; Edwards, R. J.; Timko, R. J.; Bradway, A.

C. US 5482963, 1996.

12. Holohan, J. J.; Edwards, I. J. US 5319097, 1994.

13. International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human Use

(ICH). Q3C (R3): Impurities: Guideline for Residual Solvents,

1997.

201 Summary & Conclusions

SUMMARY & CONCLUSIONS

CHAPTER-1

We have described importance of: (i) novel anti-diabetic agent

pioglitazone hydrochloride 1 (ii) antianginal drug Ranolazine 2, (iii)

anti- thrombotic drug clopidogrel bisulfate 3 (iv) anti-asthma drug

zafirlukast 4 and PDE5 inhibitor tadalafil 5. We further discussed

significance of impurity profile (Related substances) in the process

development.

CHAPTER-2

An efficient, new and robust synthetic method (two alternative

routes) for the preparation of pioglitazone 1 is developed and these are

more compatible on commercial scale. Our new synthetic methods to 1

are schematically described in Scheme 1 and scheme 2.

Scheme-1:

N

EtOH

TEA, TolueneN

EtOMs

K2CO3, Toluene

OHC

OH

N

Et

O

CHO

S

HNO O

Piperidine

MethanolN

Et

OS

NH

O

O

MeOH, DMF

5% NaOHN

Et

OS

NH

O

O

MsCl

7

8

9

10

11 1

100% 83%

75%

NaBH4, DMG

Co(NO3)2 . 6H2O

HCl

WaterN

Et

OS

NH . HCl

O

O

1.HCl

6

98%

90%


Scheme-2:

N

EtOH

TEA, TolueneN

EtOMs

K2CO3, Toluene

OHC

OH

N

Et

O

CHO

S

HNO O

N

Et

OS

NH

O

O

MsCl

7

8

9

10

1

100% 83%

HCl

Water N

Et

OS

NH . HCl

O

O

1.HCl

6

NaBH4

MeOHN

Et

O

12

OH

N

Et

O

13

ClHCl

DCMLiAlH4, THF

Possible potential impurities generated during the synthesis of

pioglitazone 1 and its key intermediate 11 are identified, synthesized

and controlled in pioglitazone 1. Structures of these impurities are

depicted in Figure 1.

Figure-1:

N

Et

N

Et

OS

NH

O

O

HOS

NH

O

O

HOS

NH

O

ON

Et

OH

OH

N

Et

OS

N

O

O

N

Et

O

CHO

9

14

11

15 16

18

17

19

N

Et

N

Et

OS

N

O

O N

Et


CHAPTER-3

An efficient, commercially viable and greener process for the

synthesis of ranolazine 2 has been disclosed in this chapter.

Additionally, comprehensive study on impurity profile of crude

ranolazine and its key intermediates including identification, synthesis

and characterization is presented in this chapter.

Synthesis of ranolazine 2 started from the commercially available

starting materials 2, 6-dimethyl aniline 20 and 2-methoxy phenol 25 as

described in Scheme 3.

Scheme-3:

O

OHOCl+

O

O

NaOHWater

O

Methanol

NH

HN

24

25 26

22

NH2

ClCl

O

+

TEADCM

HN

Cl

O

2

20 21

Methanol80%

N

NO

HN O

O

OH

27

HN

N

O NH

23

96%

97%77%

Based on the molecular weight obtained from LC-MS data,

reaction conditions and reagents/reactants used for reactions,

impurities generated during synthesis of 2 and its key intermediates

(Figure 2) were identified and characterized with spectral data. All these


impurities were controlled to below 0.05% level in final ranolazine 2 and

root causes for the formation of these impurities were discussed.

Figure 2:

O

O Cl

OH O

O OH

OHO

O O

OH O

28 29 30

HN

N

O NNH

O

HN

Cl

O

Cl

31 32

O

HO

O

N

NH

O

HO

O

N

N

O

OH

O

33

34

HN

N

O N N

OH N

HN

O

HN

N

O NOH

OHN

N

O NOH

OO

O

35

36 37

CHAPTER-4

Whilst there are many synthetic routes to clopidogrel bisulfate 3,

we focused on two which have potential for industrial manufacturing

with some limitations that are addressed in this chapter. Our efficient

and large scale processes to 3 are described in Scheme 4 and Scheme 5.


Scheme-4:

+

3.0 vol. toluene

1.65 eq. TEA. HCl

N

Cl

CO2CH3

. H2SO4S

HN

Cl

CO2CH3

S

OTs

S

OH

S

SO2Cl

CH3

38 40 42

3

41

1.5 vol. toluene

3.0 eq. K2HPO4

100-110 oC, 18 h

HCl, 67%

1. HCHO

25-35 0 C, 22 h

DCM

2. Acetone

0.92 eq. H2SO4

H2N

Cl

CO2CH3

39

Scheme-5:

S

N

CN

Cl

S

NH.HClOHC

Cl

S

N

CONH2

Cl

1.0 eq.NaCN

Water

3.0 eq. KOH,

t-Butanol

DMS, H2SO4

Methanol

+

60-65 °C, 2 h

100%

67%

water, Acetone. CSA

(S)-(+)-CSA. H2O

S

N

COOCH3

Cl

NaHCO3

DCM

H2SO4

2-Butanol

.H2SO4

S

N

COOCH3

Cl

43 44 45

46 47(±) 3

80-85 °C, 3h

92%

Acetone

.H2SO4S

N

COOCH3

Cl

3

Additionally, two unknown impurities generated during the

synthesis of 3 were identified, synthesized and characterized by spectral

data. Further, synthetic process for the preparation of the three USP

listed impurities along with the two new impurities (Figure 3) is

presented in this chapter.


Figure-3:

S

N

Cl

CO2CH3

S N

Cl

CO2CH3

S

N

Cl

CO2CH3

HO

S

N

Cl

CO2H

S

HN

Cl

CO2CH3

S

N

Cl

CO2CH3

48 49 50

51 42 52

CHAPTER-5

This chapter divided into two parts. In the first part (part-A) an

improved process for the synthesis for zafirlukast 4 is described. In the

second part (part B) an alternative synthetic approach for the

preparation of PDE5 inhibitor tadalafil 5 is presented.

Part A:

An improved process for the synthesis of zafirlukast 4 is

developed. This process is commenced with the commercially available

key raw material 3-methoxy-4-methyl benzoic acid 53 and N-methyl 5-

nitro indole 56 as described in Scheme 6. Usage of expensive and

pyrophoric reducing reagents like Raney nickel and Pd/C are replaced

with plant-friendly and low toxic reducing agent like sodium dithionite.

Purifications for removal of DCU (obtained as by-product in DCC

mediated coupling reactions) in crude Zafirlukast 4 is avoided using

commercially available less toxic coupling reagent T3P® instead of DCC.


Scheme-6:

OCH3

OCH3

H3C

O

OCH3

OCH3

O

Br

OH

OCH3

H3C

O

N

O2N

53 54 55

56

Methanol

N

O2N

57

OCH3

O

OCH3

CH3

N

H2N

58

OCH3

O

OCH3

CH3

N

HN

59

OCH3

O

OCH3

CH3

O

O

N

HN

60

OCH3

O

OH

CH3

O

O

N

HN

4

OCH3

O

NH

CH3

O

O

S

O O CH3

3 h, 98 % 84 %

85 %

1,4-dioxane

Cu2O

Sodium dithionate

Methanol, water

45 %

CPC, NMM

Toluene, 97 %

LiOH. H2O

Methanol

98 %

OTSA

DCM

CH3

SOCl2 DBDMH, AIBN

Cyclohexane

T3P, DMAP

86 %

Part B:

An alternative synthesis of tadalafil 5 starts with the coupling of

commercially available amino acid, D-tryptophan 61 and piperonal 62.

Coupling of D-tryptophan 61 with piperonal 62 under Pictet–Spengler

reaction conditions furnished β-carboline derivative 63 with the

diastereomeric mixture ratio 70(cis):30(trans), which was treated with

aqueous hydrochloric acid to get optically pure β-carboline derivative 64.


Diimidation of 64 with sarcosine ethyl ester hydrochloride under DCC

and HOBt conditions provided tadalafil 5 (scheme 7).

Scheme-7:

NH

O

OOHC Trifluoro acetic acid NH

NH

OO

CO2H

DCC, HOBt, TEA

85 %

61

5

NH

N

OO

N

O

O

CH3

+

62

63 (dr= 7:3)

Sarcosine ethyl ester HCl

NH2

O

OH

90 %

NH

NH

OO

CO2H

64

.HCl

Water, 1N HCl

Dichloromethane

209 Publications

LIST OF PUBLICATIONS

1. An Improved Process for Pioglitazone and Its Pharmaceutically

Acceptable Salt.

Lokeswara Rao Madivada, Raghupathi Reddy Anumala,

Goverdhan Gilla, Sampath Alla, Kavitha Charagondla, Mukkanti

Khagga, Apurba Bhattacharya and Rakeshwar Bandichhor.

Organic Process Research & Development 2009, 13, 1190–

1194.

2. An efficient synthesis of 1-(2-methoxyphenoxy)-2, 3-epoxypropane:

Key intermediate of β-blockers.


Goverdhan Gilla, Mukkanti Khagga and Rakeshwar Bandichhor.

Organic Process Research & Development 2012, 16,

1660−1664.

3. Alternative Synthesis of Tadalafil: PDE-5 Inhibitor.

Raghupathi Reddy Anumula, Lokeswara Rao Madivada,

Goverdhan Gilla, V. V. N. K. Prasad Raju, Mukkanti Khagga, Padi

Pratap Reddy, Apurba Bhattacharya and Rakeshwar Bandichhor.

Synthetic communications, 2008, 38, 4265-4271

4. An efficient and large scale synthesis of Clopidogrel: Antiplatelet

drug

210 Publications


Goverdhan Gilla, Mukkanti Khagga and Rakeshwar Bandichhor.

Der Pharma Chemica, 2012, 4 (1): 479-488.

5. An efficient and greener synthesis of Zafirlukast: Anti Asthma

drug.

Lokeswara Rao Madivada, Goverdhan Gilla, Mukkanti Khagga

and Rakeshwar Bandichhor.

Manuscript is ready for communication

6. An efficient and high-yielding synthesis of Ranolazine: Antianginal

drug

Lokeswara Rao Madivada, Mukkanti Khagga, and Rakeshwar

Bandichhor.

Presented in National seminar on recent advances in heterocyclic

chemistry (NSRACH 2011) organized by department of chemistry,

JNTUH college of engineering during November 4th and 5th, 2011.

7. An efficient and large scale synthesis of Clopidogrel: Antiplatelet

drug

Lokeswara Rao Madivada, Mukkanti Khagga and Rakeshwar

Bandichhor.

Presented in National seminar on recent research trends in chemical

sciences (RRTCS 2011) held on 23rd December, 2011 at Sri

Venkateswara University, Tirupati.

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