Chapter-2 29

Chapter-2 30

2.1 INTRODUCTION

Zafirlukast 1 is an oral leukotriene receptor antagonist (LTRA) used

for the treatment of asthma. It acts by antagonizing one or more of the

arachidonic acid metabolites, such as leukotriene, which blocks the

action of cytochrome isozymes CYP 3A4 and CYP 2C9. Zafirlukast is

marketed with the brand name of accolate by Astra Zeneca.1

2.2 LITERATURE REVIEW

The literature survey revealed the following literature precedence for

the synthesis of zafirlukast 1. Bernstein et al.,2 have reported a process

for the synthesis of 1, which involves a linear synthesis starts from

3-methoxy-4-methyl benzoic acid 2. Esterification of compound 2 with

acetyl chloride in methanol followed by allylic bromination using bromine

in carbon tetrachloride provided compound 4. The resulted bromo

derivative 4 was reacted with 5-nitro indole 5 in the presence of silver

oxide to give condensed product 6. Compound 6 was subjected for

N-methylation using methyl iodide in the presence of NaH in tetra hydro

furan (THF) followed by reduction using palladium carbon (Pd/C) in

methanol to produce compound 8, which was treated with cyclopentyl

chloroformate (CPC) in the presence of N-methyl morpholine (NMM)

furnished compound 9.

Chapter-2 31

Scheme 2.1: Synthesis of zafirlukast 1 (product patent route)

Hydrolysis of compound 9 followed by condensation with o-toluene

sulfonamide (OTSA) using 1-[3-(dimethylamino)propyl]-3-ethyl

carbodiimide hydrochloride (DMAPEC) in the presence of DMAP resulted

zafirlukast 1 (scheme 2.1). A similar procedure was practiced by Matassa

and co-workers3 for the preparation of 1.

Chapter-2 32

Scheme 2.2: Synthesis of zafirlukast 1

Chapter-2 33

Gutman and co-workers4 also reported a similar process for synthesis

of 1. The major modification in this process isolation of pure sodium to

get the pure acid 12.

Hydrolysis of compound 6 with sodium hydroxide, acidification

followed by acid catalyzed esterification to furnish ester 7. In a similar

manner compound 13 was also isolated in pure form followed by

acidified to provide acid 10 (scheme 2.2). The requisite compound 6 was

synthesized form 3 by doing allylic bromination using N-bromo

succinimide (NBS) and dibenzoyl peroxide followed by condensation with

indole 5 in the presence of zinc bromide and DIEPA.

Scheme 2.3: Synthesis of zafirlukast

Chapter-2 34

Claire et al.,5 has reported an alternate process for synthesis of 1.

This involves hydrolysis of ester 7 to acid 14 with LiOH.H2O followed by

conversion into acid chloride 15 using SOCl2 in DMF. Condensation of

o-toluene sulfonamide (OTSA) and compound 15 resulted in compound

16, which was hydrogenated in presence of Pd/C and hydrogen to

furnish 17. The resulted compound 17 was condensed with cyclopentyl

chloroformate (CPC) to afford 1 (scheme 2.3). The starting material 7 was

achieved from condensation of 4 and 5 in the presence of Ag2CO3 in

toluene followed by N-methylation using methyl iodide (MeI) in the

presence of NaOH.

Scheme 2.4: Synthesis of zafirlukast

Chapter-2 35

Keesari and co-workers6 have synthesized 1 from compounds 18 and

19. Condensation of 18 and 19 using zinc bromide resulted nitro acid

20, which was subjected for reduction in the presence of Raney nickel to

furnish 21. This was underwent amidation with OTSA under DCC

coupling conditions to afford 22 followed by reaction with CPC in the

presence of N-methylmorpholine (NMM) resulted zafirlukast 1 (scheme

2.4). Compound 18 was synthesized from 2 by performing allylic

bromination with DBDMH and AIBN in chloroform.

The reported synthetic methods possess some disadvantages,

formation of N-alkylated products cannot be ruled out in the synthetic

routes as shown in schemes 2.1, 2.2 and 2.3. Since the condensation

reaction involves the utilization of unprotected indole.5 In addition to

this, selectivity of alkylation at C-3 position may decrease and leads to

formation of C-2 alkylated product also. The selectivity of alkylation at

C-3 position of indole depends on the substitution on nitrogen atom of

indole, this may be attributed to the steric hindrance at C-2 position due

to the N-substitution.7 Amide bond formation via acid chloride as shown

in scheme-2.3 is not preferable on large scale synthesis, as acid chloride

is unisolable intermediate and moisture sensitive, hence control of

impurities is not possible. Synthetic method (scheme 2.4) involves DCC

mediated coupling between acid and OTSA, but the amine group present

in the acid compound may also participates in the coupling reaction

(between 20 and 22) and leads to the formation of dimer impurity. Apart

Chapter-2 36

from these disadvantages, the reported processes involves usage of

unsafe chemicals, such as NaH, acetyl chloride, bromine, methyl iodide,

hydrazine hydrate and SOCl2, expensive reagent 1-[3-(dimethylamino)

propyl]-3-ethylcarbodiimide hydrochloride (DMAPEC) and column

chromatography purifications.

2.3 PRESENT WORK

2.3.1 Objective

To overcome the above mentioned disadvantages and develop robust

scalable process, we have re-looked into the process development of

zafirlukast. As per retro-synthesis (figure 2.1) zafirlukast preparation

involves majorly four reactions.

Figure 2.1: Retro-synthetic analysis of zafirlukast

(a) Formation of sulfonamide linkage.

(b) Formation of the carbamate linkage.

Chapter-2 37

(c) C-C Bond formation between indole moiety and benzyl moiety.

(d) N-Methylation (at the indole nitrogen).

Starting materials (a) Cyclopentyl chloroformate, (b) o-Toluene

sulfonamide, (c) 5-Nitro indole, (d) 3-Methoxy 4-methyl benzoic acid

obtained from the retro-synthesis are commercially available.

2.3.2 Result and discussion

In this regard, synthetic scheme (scheme 2.5) has been designed,

which starts from the readily available starting materials benzoic acid 2

and indole 5. The first step of the synthesis is esterification of 2 in the

presence of SOCl2 in methanol. In the reported process this reaction was

carried out using methanol and acetyl chloride and reaction time is

36 h.2 The major disadvantage of this process is longer reaction times.

By replacing the acetyl chloride with thionyl chloride, the reaction time

(3 h) was decreased significantly. Also simplified the isolation process by

quenching the reaction mass with water and the yield is comparable with

the reported yield. The purity of obtained ester 3 is more than 99 % by

HPLC.

The subsequent reaction is allylic bromination of compound 3. Same

protocol as mentioned in the literature6 was practiced for the allylic

bromination of 3, but cyclohexane was used instead of chloroform. This

modification was eliminated the laborious work up process and allowed

us to isolate the solid by simple cooling crystallization in 84 % yield with

99 % purity by HPLC. Formation of dibromo derivative 23 (figure 2.2)

Chapter-2 38

was minimized with lot wise addition of DBDMH. Esterification and

bromination reactions were carried out in one pot.

Scheme 2.5: Improved synthesis of zafirlukast

Chapter-2 39

Preparation of compound 19 involves N-methylation of 5-nitroindole 5

using dimethyl sulfate as a methylating agent in the presence of sodium

hydroxide in DMF medium, by using very mild reaction conditions with

99.0 % yield and more than 99.5 % purity by HPLC. Earlier, the same

methylation was conducted by using expensive reagents like dimethyl

carbonate, and methyl iodide, expensive catalysts like DABCO and

required harsh reaction conditions (90 oC) and longer reaction times.7

Preparation of compound 7 involves alkylation of 19 with 4. As

discussed above, N-methylated indole 19 was chosen to avoid the

formation of unwanted N-alkylated products (N1C2 and N1C3) and to

increase the selectivity at C-3 position during the alkylation reaction.

Previously Ag2O,2,3 Ag2CO35 and ZnBr2

4,6 were used for alkylation on

indole derivatives to synthesize zafirlukast. As per literature5 Ag2CO3 is

moderately selective reagent towards the alkylation of 5-nitro indole.

Along with the reported reagents, other reagents such as cuprous oxide

(Cu2O), cuprous chloride (CuCl), zinc oxide (ZnO), aluminum chloride

(AlCl3) and alumina (Al2O3) were also explored to check the selectivity of

alkylation (table 2.1). Experimental results shows that dialkylated (C-2

and C-3) product 25 (figure 2.2) is forming less, when cuprous oxide is

used. Another major impurity 24 (figure 2.2) also forming during the

alkylation reaction8 due to the presence of compound 23 (figure 2.2) in

compound 4.

Chapter-2 40

Figure 2.2: Chemical structures of 23, 24 and 25

Based on the experimental results cuprous oxide was found to be the

best reagent for the alkylation of indoles.

Table 2.1: Alkylation of compound 19 using different reagents

S. No. Reagent Yield (%) 7 (%) 24 (%) 25 (%) 19 (%)

1 Ag2O 65 51.4 5.6 16.8 1.2

2 CuCl 30 33.4 4.1 7.5 38.3

3 ZnO 60 49.1 41.1 4.3 1.8

4 Al2O3 95 6.7 ND ND 35.0

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

6 ZnBr2 62 53.2 18.2 9.5 4.8

7 Cu2O 85 85.3 8.2 3.6 1.0

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

Further, to check the impact of solvent on yield and quality of the

product, toluene, acetonitrile (ACN), methyl ethyl ketone (MEK), methyl

isobutyl ketone (MIBK), ethyl acetate (EA), dichloromethane (DCM), tert-

butyl acetate (TBA), tetrahydrofuran (THF) and 1,4-dioxane were

examined. Reaction with 1,4-dioxane as a solvent furnished the product

Chapter-2 41

in highest yield (85 %) and purity (85 %) (table 2.2). Attempts were made

to eliminate the impurities 24 and 25 from 7 by doing purification using

different solvents, but did not succeed. Therefore, proceeded for next

stage with crude 7 and observed impurities 26 and 27 (figure 2.3) in

compound 8 respectively.

Table 2.2: Alkylation of indole with compound 7 in different solvents

S. No. solvent yield (%) 7 (%) 24 (%) 25 (%) 19 (%)

1 toluene 95 49.2 44.3 3.3 1.2

2 ACN 65 50.6 4.8 2.8 2.1

3 MEK 93 51.5 24.3 13.7 5.3

4 MIBK 54 81.5 8.2 3.6 1.0

5 EA 86 52.3 33.2 3.0 8.0

6 DCM* --- --- --- --- ---

7 TBA 58 77.8 9.7 4.8 1.3

8 1,4-dioxane 85 85.3 8.2 3.6 1.0

9 THF 55 39.6 5.5 5.6 42.8

* indicates product formation not observed

In the reported literature Pd/C and Raney nickel were used for the

reduction of nitro group to amine. Cost, recovery and reuse point of view

Raney nickel is preferable in large scale synthesis. In view of this Raney

nickel was selected for this study. Compound 7 having

85 % purity was subjected for reduction using Raney nickel in ethyl

acetate and water medium. The crude amine 8 was converted to

Chapter-2 42

hydrochloride salt in mixture of ethyl acetate and water, thus obtained

solid was purified by doing slurry in mixture of dichloromethane and

water (table 2.3). The free base 8 was liberated from its hydrochloride

salt by neutralizing with 10 % aqueous sodium carbonate solution.

Further, the obtained amine 8 was purified by doing slurry in methanol

(table 2.3) for elimination of compounds 26 and 27. Finally, amine 8 was

obtained in 45 % yield with 99.5 % purity.

Figure 2.3: Chemical structures of impurities 26 and 27

Table 2.3: Impurity levels in 8 at each stage of isolation

S. No. Purification stage 8 (%) 26 (%) 27 (%) 7 (%)

1 reaction medium 64.7 8.0 12.5 ND

2 after isolation from mixture 97.7 1.6 0.3 ND

of EA and water

3 DCM and water 99.2 0.6 0.1 ND

4 free base 99.3 0.6 0.1 ND

5 methanol 99.5 0.3 0.05 ND

ND: Not detected

Chapter-2 43

An advantageous process was developed over the reported for the

condensation of cyclopentyl chloroformate and amine 8. In this process

the condensed compound 9 was obtained in quantitative yield (98 %)

with 99.7 % purity (HPLC). The reaction was carried out in the presence

of N-methyl morpholine in toluene medium at room temperature for 60

min. The N-methyl morpholine content in 9 was found to be less than

0.10 %.

Having developed an efficient process for 9, our attention was turned

towards the hydrolysis of 9. The reported processes involved the usage of

lithium hydroxide monohydrate and sodium hydroxide in the mixture of

THF & methanol and water & methanol, respectively. It was found that

lithium hydroxide monohydrate is the suitable base for hydrolysis of 9

with respect to yield and quality. Acid 10 was obtained in 98 % yield and

99.2 % purity with lithium hydroxide monohydrate in aqueous methanol.

The reaction time is very less (2 h at 65 °C) compare to the reported

processes.

The final step is condensation of 10 with o-toluene sulfonamide in the

presence of DCC and DMAP to give the crude zafirlukast 1. The

unwanted compound, dicyclohexylurea (DCU) was effectively eliminated

from the product by treating with methanol. An unknown impurity

(impurity-A) was observed in the crude zafirlukast 1 at a range of 0.15 to

0.6 %, whose mass number is m/z 867.4 (LC-MS). The description of the

crude 1 not meeting the specification.9

Chapter-2 44

Table 2.4: Results of crude zafirlukast 1

S. No. 1 (%) 9 (%) Imp-A (%)

1 96.53 1.01 0.42

2 97.47 0.73 0.43

3 97.68 0.75 0.60

4 98.43* 0.66 0.15

5 97.62* 0.63 0.49

* indicates laboratory experiments

Attempts were made to purify the crude 1 by recrystallizing in

different solvents, but unsuccessful. Finally, we achieved the desired

purity by doing slurry of dichloromethane solution of zafirlukast and

silica gel. Impurities were absorbed on silica gel, there by removed from

the solution by filtration. The dichloromethane was distilled completely

and solid was isolated using acetonitrile. The description of zafirlukast,

which was obtained after treatment with silica gel is meeting with

description as mentioned in the RX list.9 The purity of the zafirlukast

obtained from this process at scale-up level is more than 99.5 % (by

HPLC) impurity-A and all other impurities are less than 0.10 %. The

results are summarized in table 2.5.

Powdered X-ray diffraction (PXRD) and differential scanning

calorimetric (DSC), thermal gravity analysis (TGA) study of zafirlukast

isolated from acetonitrile showed a crystalline polymorph (figure 2.4 and

2.5), which is different polymorphic form from the reported

Chapter-2 45

polymorphs,10-12 amorphous (form-A), anhydrous (form-X) and

monohydrate (form-B) of zafirlukast (figure 2.6).

Table 2.5: Purification of zafirlukast by silica gel

S. No. 1 (%) 9 (%) Imp-A (%)

1 99.65 0.06 0.05

2 99.57 0.07 0.07

3 99.63 0.05 0.04

4 99.72 0.09 0.02

5 99.85a 0.06 0.04

a = laboratory experiments

Figure 3: X-ray diffractogram of acetonitrile solvate form

Figure 2.4: XRD of acetonitrile solvate form

The thermo gravimetric analysis showed a weight loss of

5.75 % (figure 2.7), this is clearly indicating that the crystalline form is

acetonitrile solvate form. To demonstrate our claim, the acetonitrile

Chapter-2 46

content was estimated by GC and it was found that 55,275 ppm present

in the solid.

Figure 2.5: DSC of acetonitrile solvate form

Figure 2.6: Overlay of acetonitrile solvate form and other reported

polymorphic forms

Chapter-2 47

Figure 2.7: TGA of acetonitrile solvate form

The XRD analysis revealed the presence of amorphous form in the

innovator tablet (Accolate), hence it was targeted to synthesize the

amorphous form. In view of this our attention was drawn towards the

process development for amorphous form. In this context, many solvents

such as dichloromethane (DCM), tetrahydrofuran (THF), acetone,

dimethyl sulphoxide (DMSO), ethyl acetate (EA), n-heptane, cyclohexane

and water were screened by solvent and anti-solvent technique. All the

eight combinations were unsuccessful with respect to residual solvents

(OVI) and polymorph (table 2.6). These results are clearly indicating that

the precipitative crystallization is not suitable for the preparation of

amorphous form.

Chapter-2 48

Table 2.6: Preparation of amorphous zafirlukast by solvent and anti-

solvent technique

S. No. Solvent/anti-solvent XRD Solvent Anti-solvent

(ppm)

1 DCM/n-heptane Form-A ND 139003

2 DCM/cyclohexane Form-A 144 297883

3 THF/n-heptane Form-A ND 7366

4 THF/cyclohexane Form-A 1860 140297

5 acetone/cyclohexane Form-B --- ---

6 acetone/water Form-B --- ---

7 DMSO/water Form-B --- ---

8 Ethyl acetate/n-heptane Form-X --- ---

Another technique, evaporative crystallization was studied using

dichloromethane, acetone and ethyl acetate. Pink color compound was

observed using ethyl acetate and higher amounts of mesityl oxide

(961 ppm) and diacetone alcohol (32620 ppm) contents were observed in

the acetone process. Dichloromethane (DCM) was found to be the

suitable solvent, since no disadvantages were observed (table 2.7).

Table 2.7: Preparation of amorphous zafirlukast by evaporative

crystallization using different solvents

S. No. Solvent XRD Solvent (ppm)

1 DCM amorphous 709

2 acetone amorphous 87

3 ethyl acetate amorphous 22

Chapter-2 49

Evaporative crystallization was achieved in two different ways. In the

first approach, the solution obtained from the dissolution of zafirlukast

in 20 volumes of dichloromethane was subjected for complete distillation

of solvent at 50 °C under vacuum in the rotary evaporator (figure 2.8). In

the second approach, the solution was pumped into spray drier (figure

2.8) and allowed to evaporate the solvent completely at 50 °C.

To check the consistency, three consecutive experiments were carried

out by doing evaporative crystallization of dichloromethane (DCM) and

zafirlukast solution, which was provided the desired polymorph

(figure 2.9 and 2.10) that meets the quality requirements13 (table 2.8).

Figure 2.8: Rotary evaporator and spray drier

Chapter-2 50

Figure 2.9 : XRD of amorphous form

Figure 2.9: XRD of amorphous form

Figure 2.10: TGA of amorphous form

Table 2.8: Quality data of amorphous zafirlukast 1

S. No. XRD DCM (ppm) ACN (ppm) Purity (%)

1 amorphous 339 43 99.6

2 amorphous 122 79 99.5

3 amorphous ND 59 99.7

ND = not detected

Chapter-2 51

Zafirlukast obtained by this process was confirmed by spectral data

and it is in complete agreement with the reported data.

Figure 2.11: Mass spectrum of zafirlukast 1

The elctrospray ionization (ESI) mass spectrum of 1 exhibited (figure

2.11), the protonated molecular ion peak at m/z 576 and ammonium

adduct as a base peak at m/z 593 in positive ion mode.

In the FT–IR spectrum (figure 2.12), absorption at 1690 cm–1 for

carbonyl group and absorptions at 1340 and 1161 cm–1 for sulfonyl

group were observed.

Chapter-2 52

Figure 2.12: IR spectrum of compound 1

Figure 2.13: 1H NMR spectrum of compound 1

In the 1H NMR (figure 2.13), three singlets due to O-methyl, N-

methyl and aromatic methyl group displayed at δ 3.82, 3.68 and 2.68,

Chapter-2 53

respectively. Also, a singlet at δ 4.0 correspoding to two benzylic protons

and all the aromatic protons obseved in their respective regions and

account for compound 1.

Figure 2.14: 13C NMR spectrum of compound 1

In the 13C NMR spectrum, signals observed at δ 55.2 and 77.5 for

OCH3 and OCH, respectively (figure 2.14). The peaks at δ 164.7 and

157.1 for carbonyl carbon further confirmed the assigned structure 1.

The complete spectral data was furnished in the experimental section

2.5.6.9.

2.4 CONCLUSION

In conclusion, an improved and scalable manufacturing process was

developed for zafirlukast 1 and stable amprphous and new acetonitrile

solvate polymorh. The amorphous product obtained by this process

conforms to all the regulatory requirements.

Chapter-2 54

In next continuation chapter (Chapter-3), we concentrate for the

identification of impurities for zafirlukast, including synthesis,

characterization and root cause of their formation of these impurities.

2.5 EXPERIMENTAL SECTION

2.5.1 Gas Chromatography (GC)

Solvent contents are estimated by GC using AT-1 (30 m x 0.32 mm

5.0 µm) column, 160°C injector temperature, 275 °C (FID) detector

temperature, 50 mg/ml sample concentration and benzyl alcohol as

diluent.

2.5.2 X-ray Powder Diffraction (XRD)

Powder X-Ray diffraction patterns were recorded on a D8 ADVANCE

BRUKER axes model differentiometer equipped with vertical goniometer

the sample was scanned between 3 and 45° 2θ.

2.5.3 Differential scanning calorimetry (DSC)

The thermal analysis was carried out on TA Q1000. The thermo gram

was recorded from 40 to 250 °C under the nitrogen flow of 50 mL/min at

a heating rate of 10 °C/min.

2.5.4 Thermal gravity analysis (TGA)

The thermal analysis was performed on TGA, Q500 of TA

instruments. The thermo gram was recorded from 25 to 250 °C under the

nitrogen gas purge at a flow of 40 mL/min for balance and 60 mL/min

for sample at a heating rate of 10 °C/min.

Chapter-2 55

2.5.5 High Performance Liquid Chromatography HPLC)

A Waters Model Alliance 2690-separation module equipped with a

waters 996-photo diode array detector was used. The analysis was

carried out on zodiac 100, C18 columns, 250 mm × 4.6 mm, 5 µ.m

particle size with a mobile phase consisting of A: (degassed buffer) 7.27 g

of KH2PO4 1.0 g of 1-decanesulphonicacid sodium salt in 1000 ml of

milli-Q water and pH adjusted to 4.0 with diluted phosphoric acid (1.0 g

in 10.0 ml water) and methanol in the ratio of 85:15. B: acetonitrile,

methanol and water in the ratio of 850:100:50, sample dissolve in

diluent (acetonitrile : water in the ratio of 8:2) and injection load is 20 µl,

program gradient elution (T (min)/ A (v/v)/ B (v/v) = 0/60/40, 5/60/40,

17/38/62, 33/38/62, 35/40/60, 45/26/74, 55/26/74, 60/14/86,

65/7/93, 75/60/40, 85/60/40) was used with UV detection at 220 nm

at a flow rate of 0.8 ml/min. The column temperature was maintained at

27 °C. The data was recorded using Waters Millennium software. This LC

method was able to detect all the isomers and impurities ranged from

0.05 % to 0.10 % in the presence of parent compound.

Chapter-2 56

2.5.6 Process description

2.5.6.1 Methyl 4-bromomethyl-3-methoxybenzoate (4)

To a solution of 2 (5 kg, 30.12 mol) in methanol (7.5 L) was slowly

added thionyl chloride (2.5 L, 33.90 mol) over a period of 2 h. The

reaction mixture was heated to 55-60 °C and stirred for 2-3 h, then

quenched with chilled water at below 20 °C. The precipitated solid was

filtered and washed with 10 % aqueous sodium carbonate solution (10 L)

to furnish 5.4 Kg of compound 3 (2.20 % water content). DBDMH (4 kg,

17.48 mol) and AIBN (30 g, 0.18 mol) were charged into the solution of

compound 3 in cyclohexane (30 L). The resultant reaction mass was

refluxed (78-82 °C) for 3-4 h and charged DBDMH (1.0 kg, 4.37 mol) and

AIBN (10 g, 0.06 mol) at room temperature. Heated the reaction mixture

to reflux and stirred for 1-2 h. To the reaction mass added water (20 L)

and stirred for 45-60 min at 55-60 °C. The organic layer was separated

at the same temperature, cooled to 10-15 °C and stirred for 45-60 min.

The precipitated solid was filtered, washed with cyclohexane (5 L) and

dried under vacuum at 45-50 °C for 3-4 h to afford 6.5 kg (84 %) of title

compound 4 with 99.1 % HPLC purity.

Mp: 84-88 °C.

Chapter-2 57

IR (KBr, cm–1): 1717 (C═O, ester), 2951 (Ali, CH), 1276 (OCH3).

1H NMR (200 MHz, CDCl3): δ 7.60 (d, J ═ 7.8 Hz, 1H), 7.54 (s, 1H), 7.39

(d, J ═ 7.8 Hz, 1H), 4.55 (s, 2H), 3.95 (s, 3H), 3.92 (s, 3H).

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

2.5.6.2 1-Methyl-5-nitro-1H-indole (19)

To a suspension of sodium hydroxide (2.6 kg, 65.0 mol),

dimethylformamide (20 L) and compound 5 (5 kg, 30.86 mol) and was

slowly added dimethyl sulfate (4.55 kg, 36.11 mol) and stirred for 2-4 h

at 25-35 °C. To the reaction mass charged water (50 L) and stirred for

45–60 min. The obtained solid was filtered, washed with water (25 L),

and dried under vacuum at 50-60 °C for 3-4 h to furnish 5.36 kg (99 %)

of title compound 19 with 99.63 % HPLC purity.

Mp: 173-178 °C.

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

1H NMR (200 MHz, CDCl3): δ 8.56 (d, J ═ 2.4 Hz, 1H), 8.10 (dd, J ═ 2.4,

9.0 Hz, 1H), 7.32 (d, J ═ 9.2 Hz, 1H), 7.20 (d, J ═ 3.2 Hz, 1H), 6.66 (dd, J

═ 0.8, 3.2 Hz, 1H), 3.85 (s, 3H).

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

Chapter-2 58

2.5.6. 3 Methyl 3-methoxy-4-(1-methyl-5-nitro-1H-indol-3-yl

methyl) benzoate (7)

A suspension of compound 4 (3.82 kg, 14.75 mol), compound 19 (2

kg, 11.36 mol) and cuprous oxide (4.88 kg, 34.12 mol) in 1,4-dioxane (14

L) was heated to 95-100 °C and stirred for 24-30 h. The resulted reaction

mixture was filtered through hyflow bed and washed with 1,4-dioxane (4

L). Thus obtained filtrate was concentrated, added methanol (18 L) and

ethyl acetate (2 L). Subsequently, heated to reflux and maintained for 60

min, cooled to 25-35 °C and stirred for 3-4 h. The obtained solid was

filtered and dried at 50-55 °C to provide 3.42 kg (85 %) of title compound

7 with 85.3 % purity by HPLC.

Mp: 142-146 °C.

IR (KBr, cm–1): 2949 (Ali, CH), 1709 (C═O, ester), 1579 & 1324 (NO2,

asym. and sym.), 1291 (OCH3).

1H NMR (200 MHz, CDCl3): δ 8.60 (s, 1H), 8.10 (d, J ═ 9.0 Hz, 1H),

7.62−7.55 (m, 2H), 7.30 (d, J ═ 7.8 Hz, 1H), 7.18 (d, J ═ 7.8 Hz, 1H), 6.93

(s, 1H), 4.16 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 3.80 (s, 3H).

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

Chapter-2 59

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

methoxy benzoate (8)

A suspension of compound 7 (10 kg, 28.24 mol) and Raney nickel (3.0

kg) in ethyl acetate (50 L) and water (10 L) was stirred under hydrogen

pressure (5-6 kg/cm2 ) for 3-4 h at 25–35 °C. Filtered the Raney nickel

through hyflow bed and washed with ethyl acetate (50 L). Thus obtained

filtrate was acidified to pH 1-2 with a solution of conc HCl (5 L) and water

(5 L), stirred for 30-45 min. The precipitated solid was filtered and

charged into a mixture of water (50 L) and dichloromethane (50 L) and

stirred for 3-4 h at room temperature and filtered the wet compound. The

wet compound was charged into water (50 L) and basified to pH 7-8 with

10 % aqueous sodium carbonate solution. The precipitated solid was

filtered and purified in methanol (10 L) to give 4.01 kg (44 %) of title

compound 8 with 99.5 % HPLC purity.

Mp: 110-113 °C.

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

1297 (OCH3).

Chapter-2 60

1H NMR (200 MHz, CDCl3): δ 7.56-7.50 (m, 2H), 7.12 (t, J ═ 7.8 Hz, 2H),

6.80 (s, 1H), 6.72-6.68 (m, 2H), 4.07 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H),

3.66 (s, 3H), 3.10 (s, 2 H).

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

2.5.6.5 4-(5-Cyclopentyloxycarbonylamino-1-methyl-1H-indol-3-yl

methyl)-3-methoxybenzoicacid methyl ester (9)

Cyclopentyl chloroformate (9.66 kg, 65.05 mol) was slowly added to

the solution of compound 8 (14 kg, 43.20 mol) and N-methyl morpholine

(5.29 kg, 52.37 mol) in toluene (70 L) at 25-35 °C. The resulted reaction

mixture was stirred for 45-60 min at room temperature and distilled the

solvent completely. Charged methanol (70 L), filtered the precipitated

solid. Wet solid was washed with methanol (14 L) and dried for 2-3 h at

50-55 °C to provide 18.5 kg (98 %) of title compound 9 with 99.7 % HPLC

purity.

Mp: 128-132 °C.

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

1232 (OCH3).

Chapter-2 61

1H NMR (400 MHz, DMSO–d6): δ 9.18 (bs, 1H), 7.60 (s, 1H), 7.48 (s, 1H),

7.45 (d, J ═ 7.6 Hz, 1H), 7.26 (d, J ═ 7.6 Hz, 1H), 7.16 (d, J ═ 7.4 Hz,

2H), 7.03 (s, 1H), 5.08-5.01 (m, 1H), 3.98 (s, 2H), 3.95 (s, 3H), 3.92 (s,

3H), 3.69 (s, 3H), 1.90-1.56 (m, 8H).

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

2.5.6.6 [4-(5-Cyclopentyloxycarbonylmethyl-1-methyl-1H-indol-3-

ylmethyl)-3-methoxybenzoic acid (10)

To the mixture of compound 9 (16 kg, 36.69 mol) in methanol (96 L)

was added a solution of lithium hydroxide monohydrate (2.4 kg, 57.14

mol) in water (24 L) and heated to 60-65 °C. The resultant reaction

mixture was stirred for 1-2 h, cooled to 25-35 °C and acidified to pH

1.0-2.0 with diluted HCl. The reaction mixture was stirred for 1-2 h,

filtered the precipitated solid and washed with water. The wet solid was

dried under vacuum at 70-75 °C to afford 15.2 kg (98 %) of title

compound 10 with 99.2 % of HPLC purity.

Mp: 178-182 °C

IR (KBr, cm–1): 3288 (NH), 2957 (OH), 1696 (C═O, acid), 1646 (C═O,

carbamate), 1264 (OCH3).

Chapter-2 62

1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.56–7.52 (m, 2H), 7.41 (s,

1H), 7.38 (s, 1H), 7.20-7.13 (m, 3H), 6.79 (s, 1H), 5.22-5.10 (m, 1H), 4.06

(s, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 1.91-1.56 (m, 8H).

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

2.5.6.7 {3-[2-Methoxy-4-(toluene-2-sulfonylaminocarbonyl) benzyl]-

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

A mixture of compound 10 (8.0 kg, 18.95 mol), DMAP (2.85 kg, 23.33

mol), DCC (4.45 kg, 21.56 mol), o-toluene sulfonamide (3.88 kg, 22.53

mol) in dichloromethane (80 L) was stirred at 25-35 °C for 3-4 h. The

unwanted solid (DCU) was filtered and washed with dichloromethane

(13.7 L). Filtrate was washed with diluted HCl (2.4 L of conc. HCl and 2.4

L of water), water (40 L) and distilled the solvent completely under

vacuum below 45 °C. The crude solid was isolated from acetonitrile and

slurred in methanol (96 L) for 45 min at 25-35 °C. Filtered the solid,

washed with methanol (8 L) and dried under vacuum at 70-75 °C to

furnish 9.25 kg (86 %) of crude 1 with 98.6 % HPLC purity.

Chapter-2 63

2.5.6.8 Purification of crude zafirlukast (1)

To a solution of crude zafirlukast 1 (7.0 kg) in dichloromethane (112

L) was charged silica gel (14 kg) and stirred for 60 min at 25-30 °C.

Filtered the silica gel and washed with dichloromethane (2 x 70 L). The

filtrate was distilled completely under vacuum below 45 °C, cooled to

25 °C and charged acetonitrile (84 L). The resultant mixture was heated

to 80 °C for 40 min, cooled to 30 °C and stirred for about 50 min. The

precipitated solid was filtered and washed with acetonitrile (21 L). This

process was repeated one more time and the wet solid was dried at 75 °C

under vacuum for 4 h to afford 4.1 kg (58 %) of pure zafirlukast 1 with

99.5 % HPLC purity.

Mp: 142-145 °C.

IR (KBr, cm–1): 3291, (NH), 1682 (C═O, amide), 1341 & 1163 (SO2, asym.

and sym.)

XRD: Solvate form.

TGA: 5.752 % w/w.

Acetonitrile content by GC: 55,275 ppm

2.5.6.9 Preparation of amorphous form of zafirlukast 1

A mixture of pure zafirlukast 1 (800 g) in dichloromethane (12 L) was

heated to about 40 °C and stirred for about 30 min for complete

dissolution. The resultant clear solution was filtered through a micro

filter and washed with dichloromethane (1.6 L). The combined filtrate

was pumped into a spray drier through nitrogen pressure at 50 °C and

Chapter-2 64

evaporated the solvent completely. The resultant solid was dried under

vacuum at 70–75 °C for about 10-12 h to afford the 720 g (90 %) of the

amorphous zafirlukast 1 with 99.6 % HPLC purity.

Mp: 115-120 °C.

IR (KBr, cm–1): 3371 (NH), 2960 (Ali, CH), 1690 (C═O, amide), 1340 &

1162 (SO2, asym. and sym.).

1H NMR (400 MHz, CDCl3): δ 9.35 (br, 1H), 8.24 (d, J ═ 7.8 Hz, 1H),

7.49 (t, J ═ 7.6 Hz, 2H), 7.38 (t, J ═ 7.6 Hz, 1H), 7.30 (s, 1H), 7.27 (d, J ═

7.6 Hz, 1H), 7.26 (s,1H), 7.18 (d, J ═ 8.8 Hz, 2H), 7.10 (d, J ═ 7.6 Hz,

1H), 7.06 (d, J ═ 7.6 Hz, 1H), 6.74 (s, 1H), 6.54 (s, 1H), 5.22-5.18 (m,

1H), 4.00 (s, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 2.68 (s, 3H), 1.90-1.53 (m,

8H).

13C NMR (100 MHz, CDCl3): δC 164.7, 157.1, 154.3, 137.4, 136.7,

136.0, 134.0, 133.5, 132.1, 131.1, 129.7, 129.4, 128.0, 127.7, 126.0,

119.8, 115.2, 111.7, 109.7, 109.4, 109.1, 77.5, 76.6, 55.2, 32.5, 32.5,

24.8, 23.4, 20.0.

MS (m/z): 576.4 (M+ + H), 593.4 (M+ + NH3).

TGA: 0.2653 % w/w.

XRD: Amorphous form.

2.6 REFERENCES

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Chapter-2 65

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

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

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

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(ICH). Q3C (R3): Impurities: Guideline for Residual Solvents, 1997.