CHAPTER - 3 STUDIES IN THE SYNTHESIS OF ...shodhganga.inflibnet.ac.in/bitstream/10603/8272/11/11...STUDIES IN THE SYNTHESIS OF MONTELUKAST SODIUM 51 3.1 - INTRODUCTION The newer generation

50

CHAPTER - 3

STUDIES IN THE SYNTHESIS

OF

MONTELUKAST SODIUM

51

3.1 - INTRODUCTION

The newer generation of leukotriene antagonists, such as ICI 204,219

(or Accollate), the quinolones MK-571 and RG-12,525, ONO-1078

(prankulast) and SK&F 104,353 are more promising1 as enumerated in

introduction chapter-1.

Leukotrienes constitute a group of locally acting hormones produced

in living systems from arachidonic acid. Major leukotrienes are

Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4, and LTE4.

Biosynthesis of these leukotrienes begins with the action of 5-

lipoxygenase on arachidonic acid to produce the epoxide known as LTA4.

This is converted by further enzymatic transfermations to other

leukotrienes.24

A number of compounds of Formula (I) in which A represents

optionally substituted heterocycle, and pharmaceutically acceptable salts

thereof, have been disclosed as leukotriene antagonists and inhibitors of

leukotriene biosynthesis.24

The sodium salt of Montelukast (25) is a leukotriene receptor

antagonist (LTD4). It is useful in treatment of asthma, inflammation,

52

allergies, angina, cerebral spasm, glomerular nephritis, hepatitis,

endotoxemia, uveitis and allograft rejection.26

Bhupathy et al reported compounds of Formula (I) in which A

represents optionally substituted quinoline; more specifically disclosed is

the compound in which A represents 7-chloro-2-quinolinyl. U.S. Patent

document no. 5,270,324 reported two compounds of Formula (I) in which

A represents 6-fluoro- or 6,7-difluoro-2-quinolinyl. In the European

patent publication EP 0604,114 A1 there is disclosed compounds in

which A is halo-substituted thieno[2,3-b]pyridine, particularly 2,3-

dichlorothieno[2,3-b]pyridin-5-yl.27

Table-3.1: PRODUCT PROFILE OF MONTELUKAST SODIUM 26

Generic Name Montelukast sodium

Brand Name Singulair

Active Ingredient Montelukast

Innovator Merck & Co Inc

Marketed by Merck & Co Inc

Chemical Name [R]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)

ethenyl]phenyl]-3-[2-(1-hydroxy-1-methyl ethyl)-

phenyl]propyl]thio]methyl]cyclopropane acetic acid,

monosodium salt

Chemical C35H35ClNNaO3S

53

Formula

Molecular Weight 608.18

Chemical

Structure

CAS Registry No 151767-02-1

Physical

description

Hygroscopic, optically active, white to off-white

powder.

Solubility Freely soluble in ethanol, MeOH, and water; and

practically insoluble in acetonitrile.

3.2 – LITERATURE REVIEW

Many synthetic processes for preparation of Montelukast and its salts

are reported in literature. Some of them are discussed here under.

Belley et al 24 reported certain substituted quinoline compounds,

including (25), methods for their preparation, and methods of

pharmaceutical formulations using these compounds. The process

disclosed in Belley et al included preparation of (26), its reaction with

(27) in presence of hydrazine, cesium carbonate in acetonitrile as solvent

to provide (28). The protected compound (28) was reacted with

54

pyridinium p-toluene sulfonate in presence of NaOH in MeOH+THF to

afford (29) followed by its conversion to (25) (Scheme-3.1).

Scheme-3.1:

Cyclopropyl intermediate (27), which is used in scheme-3.1, was

prepared as per scheme-3.2.24

Scheme-3.2:

Bhupathy et al 27 reported a process for the preparation of (25) and

certain process intermediates. The process involved generation of

dilithium dianion of (36) followed by condensation with mesylate of (35)

to afford (29), which was further converted to (25) via dicyclohexyl amine

salt (37) (Scheme-3.3).

55

Scheme-3.3:

Shapiro et al 28, in one of the examples therein reported a process for

preparation of (25) by: (i) reacting a sodium salt of (38) with mesylate of

(35) in THF to give methyl ester of (29), (ii) hydrolysing with aqueous

NaOH in THF solvent to afford (29), (iii) converting it into (25) (Scheme-

3.4).

Scheme-3.4:

Many other modifications within scheme-3.4 were reported for the

preparation of (29) or (25). Most of these involved variation in the

56

functional group -COOH group present on cyclopropyl intermediate, such

as -COOCH3, amine salt of -COOH group instead of alkali metal salt etc.

Few other schemes involved other amine salts of (29) such as

adamentane salt etc.

Various other synthetic approaches were reported in literature.29-51

3.3 - PRESENT WORK

In view of the importance of (25) in drug therapy as enumerated above

and in chapter-1; and also in view of its market potential as evident from

its worldwide sales and worldwide consumption given in the abstract of

the thesis; though several synthetic processes for preparation of (25) are

reported in literature as discussed above, there is a continuing need for

new processes for the preparation of (29) and its salts more specifically

(25).

The objective of the present work is to study novel synthetic

approaches to provide cost effective, eco-friendly process for the

preparation of (25), which is well suited for commercial scale up.

57

3.4 – RESULTS AND DISCUSSION

In accordance with the above objective, two different synthetic

approaches for the preparation of (25) were developed.

3.4.1 - FIRST NOVEL SYNTHETIC APPROACH FOR THE

PREPARATION OF MONTELUKAST SODIUM OF THE PRESENT

WORK

The present work provides a first novel synthetic route for the

preparation of (29) and its salts, which was published as Reguri et al 52

and Chandra et al (ii) (Scheme-3.5).

Scheme-3.5:

58

In the process of developing the first novel synthetic approach, the

process was initially worked out by: (i) reducing (39) using (-)-DIP-Cl as a

chiral reducing reagent to provide corresponding hydroxyl ester, (ii)

mesylating the hydroxy ester with MsCl in presence of DIPEA, (iv)

reacting the resulting mesylate with disodium salt of (36) that is

prepared by treating it with sodium methoxide, to provide an ester, (v)

converting it into DCHA salt by treating with DCHA (42) in acetone to

provide dicyclohexyl amine salt of the ester, (vi) reacting the ester with

methyl magnesium chloride under Grignard’s reaction conditions until

the starting material is substantially consumed as observed by TLC to

provide the corresponding tertiary alcohol, which was expected to be

(25).

All the reactions were monitored by TLC and the final compound was

analyzed by High performance liquid chromatography (HPLC) using

chiral column to check the optical purity of the compound. It was

observed from the chromatograph that the retention time of the major

component was not matching with the retention of the (25) working

standard available at the time of development of the process. It rather

matched with the retention time of (65), the unwanted S-isomer of (25),

while the required isomer was R-isomer. When the reasons for this result

were investigated, the following facts were identified.

59

It was observed from many reported synthetic schemes discussed

before in this chapter that the reaction of S-isomer of mesylate with

mercaptan must happen in SN2 (substitution nucleophilic bi-molecular)

fashion, thereby it under goes inversion in configuration i.e., S- to R-

whereby the resulting compound after reaction would be R-isomer. But

in the instant case, though the starting hydroxy ester was an S-isomer,

the final compound was found to be having S-configuration as its

retention time matched with the retention time of unwanted isomer (65)

by chiral HPLC. This was further confirmed by its SR of –980 (c=1 in

chloroform). Whereas (25) has a SR of +1030 (c=1 in chloroform).

From the above discussion, it was evident that when S-isomer of

hydroxy ester (60) was used, the final product of the process was (65)

i.e., S-isomer and not the required R-isomer (25). The reason for this

could be due to anchiemeric affect of neighbouring carbomethoxy group

participation Hence, the synthetic scheme was modified to start from R-

isomer of hydroxy ester (40) to get required R-isomer (25).

Therefore, the process was developed by: (i) reducing (39) using (+)-

DIP-Cl as a chiral reducing reagent in DCM solvent followed by

quenching the reaction mixture with aqueous ammonia and isolating the

resulting precipitate, (ii) purifying it in a mixture of MeOH and water to

provide pure R-isomer (40), (iii) mesylating the resulting purified hydroxy

60

ester (40) with MsCl in presence of DIPEA in DCM solvent to provide the

mesylate (41), (iv) reacting the mesylate (41) with disodium salt of (36)

that is prepared by treating it with sodium methoxide, in a mixture of

DCM and DMF to provide an ester analog of (29), (v) converting it into

dicyclohexyl amine salt by treating with DCHA (42) in acetone solvent to

provide (43), (vi) reacting the free acid of (43) with methyl magnesium

chloride in THF under Grignard’s reaction conditions in toluene solvent

to get (29).

As is well known, the Grignard’s reaction of a carboxylic acid ester

involves a two step conversion. The first step of reaction involves

conversion of ester group into the corresponding methyl ketone with one

mole of Grignard’s reagent. The second step of reaction involves

conversion of the methyl ketone obtained in the first step into the

corresponding tertiary alcohol with another mole of Grignard’s reagent.

In the present case also there was conversion of an ester group into the

corresponding tertiary alcohol by Grignard’s reaction. However, it was

observed that the rate of first step of conversion of ester group into the

corresponding methyl ketone was faster whereas the rate of second step

of conversion of the methyl ketone into the corresponding tertiary alcohol

was slower when it was carried out within in the same reaction mixture

either by using excess moles of Grignard’s reagent from the beginning or

by using excess moles during the course of reaction in the conversion of

61

(43) to (29). During the reaction, three spots were observed in TLC

corresponding to ester, ketone and alcohol respectively. The reaction was

stopped after disappearance of ester by TLC and was quenched with aq.

acetic acid, layers were separated and the organic layer was washed aq.

sodium bicarbonate solution followed by washing with water. After

removing water azeotropically, the resulting solution containing ketone

and alcohol was reacted with Grignard’s reagent once again to consume

the ketone. Quenched with aq. acetic acid, layers were separated, organic

layer was washed with aq. sodium bicarbonate solution followed by

water. Solvent was removed by distillation under reduced pressure. The

resulting crude (29) had a purity of about 96% as measured by HPLC. It

was purified by repeated recrystallizations from toluene to get pure

crystalline (29). The purity of the crystalline (29) after 5th

recrystallization was about 98% by HPLC. It was observed that the purity

though increased after repeated recrystallizations, in order to achieve a

purity of about 99% or more, it was required to convert (29) into (44).

Therefore, the pure crystalline (29) was treated with TBA (45) in a

mixture of acetone and IPA; and its purification by repeated

recrystallization from a mixture of acetone and IPA gave a pure

crystalline (44). The said (44) was then suspended in DCM, treated with

aq. acetic acid, stirred to get a clear biphasic medium wherein all the

solids were dissolved. Organic layer was separated and washed with

62

water to get a solution of (29) in DCM, followed by treatment with

methanolic NaOH solution to get a solution of (25) in a mixture of DCM

and MeOH. The solvent was distilled completely under reduced pressure

and the resulting crude was dissolved in minimum quantity of toluene,

the solution was added to n-heptane and stirred to get a precipitate. The

solid precipitate was filtered, washed with n-heptane and dried under

reduced pressure to provide (25). The resulting (25) had a purity of

about 99% as measured by HPLC and an optical purity of about 99.8%

as measured by chiral HPLC method. It had a SR of +1030 (c=1 in

chloroform).

3.4.2 - SECOND NOVEL SYNTHETIC APPROACH FOR THE

PREPARATION OF MONTELUKAST SODIUM OF THE PRESENT

WORK

The present work further provides a second novel synthetic approach

for the preparation of (29) and its salts published as Sundaram et al 53

and Chandra et al. (iii)

In the second novel synthetic approach for the preparation of (25) of

the present work, (10) was one of the key starting materials from which

further process steps were evolved. Another key intermediate involved

was (50).

The process of the second novel synthetic approach for the

preparation of (25) involved: (i) mesylation of (35) using MsCl in presence

63

of DIPEA in acetonitrile solvent; (ii) condensation of the resulting

mesylate in a mixture acetonitrile and DMF with lithium salt of (46) that

was prepared by treating it with n-butyl lithium to provide (47); (iii)

hydrolysis of the resulting compound with aqueous NaOH to provide

(29); (iv) converting it into (44) by treating with TBA (45) in acetone and

purifying the isolated (29) by recrystallization from acetone; (v)

converting the purified (44) into (25) (Scheme-3.6).

Scheme-3.6:

When a mixture of (46) and (49) was used, the resulting product in

step-1 of scheme-3.6 would be a mixture of (47) and (50) (Scheme-3.7).

64

Scheme-3.7:

NCl

OH

OH

CN

SH

n-BuLiCH3CNDMF

NCl

S

OHCN

MsClDIPEADCM

(46)

(35)

(49)

NCl

OSO2Me

OH

(48)

NCl

OSO2Me

OH

(48)+ +

CONH2

SH

(47)(50)

+ NCl

S

OHCONH2

3.4.3 - STUDIES IN THE SYNTHESIS OF STARTING MATERIALS OF

THE FIRST AND SECOND NOVEL SYNTHETIC APPROACHES FOR

THE PREPARATION MONTELUKAST SODIUM OF THE PRESENT

WORK

(39) and (36) were the key starting materials in the process of first

novel synthetic approach of the present work; and (35) and {(46) or a

mixture of (46) and (49)} were the key starting materials in the process of

the second novel synthetic approach of the present work. The synthetic

processes for the preparation compounds (39), (36), (35), {(46) or a

mixture of (46) and (49)} were broadly selected based on the respective

synthetic processes disclosed in Belley et al.

65

It is also the objective of the present work to provide an improved

process for the preparation of compounds (39), (36), (35), {(46) or a

mixture of (46) and (49)}.

3.4.3.1 - Improved process for the preparation of (39) and an

improved process for the preparation of (35) from (39):

Synthetic processes disclosed in Belley et al and few other prior art

references were taken as the basis for preparation of different

intermediates of (39) and incorporated various improvements such as

avoiding hazardous reagents, costly raw materials and solvents,

simplifying reaction and work up procedures, purifying the intermediates

thereby providing cost effective, eco-friendly and commercially viable

process for each of the intermediate.

The sequence of steps for the preparation of (39) (scheme-3.8) started

from reaction of (51) with (52) in presence of Ac2O in toluene solvent. In

this reaction the major by-product was a dimer (66), which was formed

due to reaction of the required product of the reaction (53) with one more

mole of (51). In Tung et al 32, the process for preparation of (53) involved

1.5 molar equivalents of (52) per mole of (51) in excess Ac2O in xylene

solvent. In an objective to minimize the quantity of Ac2O whose excess

usage was not preferable on a commercial scale, the process was

optimized with 1.2 molar equivalents of (52) and just 1.9 molar

equivalents of Ac2O per mole of (51) in toluene solvent at reflux

66

condition. Reaction was monitored by TLC (mobile phase: Ethyl acetate :

Hexanes – 1:4). After completion of reaction, the isolated wet compound

containing (53) and the dimer (66) was suspended in ethyl acetate and

heated to reflux. The mixture was filtered, filtrate containing pure (53)

was concentrated, cooled to room temperature and added hexanes to

precipitate out the compound completely. The resulting yield was

improved with good quality.

The next step was Grignard’s reaction of (53) with methyl magnesium

chloride in THF in toluene, precipitation of compound by adding aqueous

NH4Cl solution to provide the alcohol (54). The improvement in this step

was the replacement of expensive methyl magnesium bromide and

aqueous acetic acid reported in Balley et al for this reaction with

comparatively inexpensive methyl magnesium chloride and aqueous

NH4Cl respectively, which improved the yield to about 80% with good

quality and was void of extraction and void of column chromatography

for purification.

The next step was oxidation of the alcohol (54) to provide the

corresponding methyl ketone (55). The oxidizing agent used was

manganese (IV) dioxide. Initially, when the process reported in Belley et

al was reproduced exactly, the reaction did not go to completion as

monitored by TLC (mobile phase: Ethyl acetate : Hexanes – 1: 4). To

complete the reaction, the solvent was changed from ethyl acetate to

67

DCM but there was not much improvement. Then it was thought that the

activity of manganese (IV) dioxide must be playing a role in the reaction

and hence, tried with activated manganese (IV) dioxide. Though there

was slight improvement in the reactivity, still the problem was not

resolved completely as various commercial lots of manganese (IV) dioxide

lots had varying activity and therefore the activity of given lot to be used

for a given experiment had become highly unpredictable, which was not

a preferable situation to make the process commercially viable.

Therefore, it was thought to work on the temperature of the reaction by

the right solvent choice as the reaction medium. In the reported

processes, reaction was conducted at room temperature and the reaction

time used run through several hours such as 20 or more hours

depending on the activity of the manganese (IV) dioxide lot used. To

overcome this problem, the reaction was conducted by using manganese

(IV) dioxide of a randomly chosen commercial lot by not taking its activity

into consideration in toluene as solvent at reflux temperature. The

reaction completed within about 5 hours. The reaction mixture was

filtered hot to remove reduced manganese dioxide, the filtrate was

concentrated and the solid was isolated to provide the methyl ketone (55)

in quantitative yield with good quality.

The next step involved conversion of the methyl ketone (55) into the β-

keto ester (56) by condensation with dimethyl carbonate. Reported

68

procedure involved sodium hydride base and THF solvent. As both base

and solvent were not preferable on commercial scale, they were replaced

by sodium methoxide powder and 1,4-dioxan respectively, both of which

are safe to handle on large scale and inexpensive. After completion of the

reaction (monitored by TLC; Mobile phase: Ethyl acetate : Hexanes – 1:

4), the reaction mixture was cooled to room temperature and was

quenched with slow addition of water. The separated solid was filtered

and the wet solid was washed with MeOH with stirring to provide the β-

keto ester (56) with quantitative yield and good quality.

The next step was the condensation of the β-keto ester (56) with (57)

to get a diester (58). The reported procedure involves NaH base and THF

solvent. As both base and solvent are not preferable on commercial scale,

they were replaced by K2CO3 and DMF respectively, as both of which are

safe to handle on large scale and inexpensive. The reaction proceeded

very smoothly with good conversion rate. However, as observed by TLC

(mobile phase: Ethyl acetate : Hexanes – 1: 4), three product spots were

observed, which corresponded to the diester (58), the keto acid (59) and

the keto ester (39) respectively. The reaction mixture after substantial

disappearance of β-keto ester (56), was quenched with aqueous sodium

acetate and the resulting compound was filtered and washed with MeOH

with stirring to provide diester (58) with quantitative yield and good

quality.

69

In the next step, the diester (58) was hydrolyzed with a mixture of

acetic acid and aqueous HCl to provide the corresponding keto acid (59).

Reaction was monitored by TLC (mobile phase: Ethyl acetate : Hexanes –

1: 4) only for substantial disappearance of the diester (58). In this step

two product spots were observed corresponding to the keto acid (59) and

the keto ester (39) respectively, with the major spot being keto ester (39),

which infers that the major reaction in this step is decarboxylation of

carboxylic group attached to aliphatic chain alone with the retention of

the ester group attached to aromatic ring with a minor reaction of

decarboxylation and hydrolysis to lead to the keto acid (59) as the minor

product. The resulting isolated wet compound was stirred in MeOH to get

keto acid (59) with quantitative yield and good quality.

In the next step, the keto acid (59) containing the keto ester (39) as

the major component was converted to the keto ester (39) by

esterification. Reported procedure involved the said conversion with

methyl iodide in presence of potassium carbonate in acetone solvent. The

reaction mixture after completion of reaction (monitored by TLC; mobile

phase: Ethyl acetate : Hexanes – 1: 4) was filtered to remove potassium

carbonate. Acetone from the filtrate was distilled completely. The

resulting mass was dissolved in minimum quantity of chloroform and

keto ester (39) was isolated in quantitative yield and good quality. The

70

said keto ester (39) was used as the starting material in the first novel

synthetic approach of the present work.

Next step (scheme-3.9) was the chiral reduction of the keto ester (39)

with (-)-DIP-Cl to get the hydroxy ester (60), which was the S-isomer of

(40). Reported procedure involved THF as solvent and diethanolamine

was used for quenching the reaction mixture. The reaction temperature

in the reported procedure was -250C. The process was simplified by

replacing the THF solvent with DCM, using aqueous ammonia in place of

diethanolamine for quenching the reaction mixture and optimizing the

reaction temperature to -5 to 00C. Reaction was monitored by TLC

(mobile phase: Ethyl acetate : Hexanes – 1 : 4 and one drop of aq.

ammonia). The resulting hydroxy ester (60) carried α-pinene as the side

product of the reaction that was the starting material for the preparation

of (-)-DIP-Cl. Due to the presence of α-pinene along with the obtained

hydroxy ester (60), it was denatured with gumminess. To get a pure

hydroxy ester (60), it was purified by suspending the gummy solid in

MeOH whereby the gummy insoluble solid separated out, the mixture

was filtered, water was added to the clear filtrate to provide the pure

hydroxy ester (60) in quantitative yield and good quality.

Next step was the Grignard’s reaction of the hydroxy ester (60) to get

the diol (35). The reported procedure involved usage of methyl

magnesium bromide and a mixture of Toluene and THF as reaction

71

medium. The reaction conditions were simplified by replacing expensive

methyl magnesium bromide with inexpensive methyl magnesium

chloride and by using only toluene as the solvent without using

additional THF. That means THF associated with methyl magnesium

chloride was sufficient for the required polarity for the reaction. Reaction

was monitored by TLC (mobile phase: Ethyl acetate : Hexanes – 1 : 4 and

one drop of aq. ammonia). The resulting diol (35) was purified by

recrystallization from toluene.

Hydroxy ester (40) i.e., R-isomer was the required intermediate in the

first novel synthetic approach of the present work rather than hydroxy

ester (60) to get Montelukast having R-configuration, which was the

required isomer rather than S-isomer (65). Hydroxy ester (40) was

prepared by following substantially the similar procedure as that of

hydroxy ester (60) discussed above except that (+)-DIP-Cl was used

instead of (-)-DIP-Cl as the required isomer of hydroxy ester is the R-

isomer.

Scheme-3.8:

72

Scheme-3.9:

The process for preparation of hydroxy ester (40) from keto ester (39)

according to the present work is given in Scheme-3.10.

Scheme-3.10:

NCl

O COOCH3

(+)-DIP chlorideDCM

NCl

OH COOCH3

(39)

(40)

3.4.3.2 - Improved process for the preparation of (46) and a mixture

of (46) and (49):

(46) was prepared from (61) by hydrolysis with methanolic NaOH at a

temperature of -15 to -120C (Scheme-3.11).

73

A mixture of (46) and (49) was prepared by hydrolysis of (61) with

potassium hydroxide in a mixture of MeOH and water at a temperature

of 500C (Scheme-3.11).

Scheme-3.11:

3.4.4 - RESULTS AND DISCUSSION ON IMPURITIES OF

MONTELUKAST SODIUM OBTAINED THE PRESENT WORK AND ITS

INTERMEDIATES

The following impurities were identified in (25) and its intermediates

by LC-MS method or by spiking method by HPLC. The said impurities

were prepared by the procedures described here under in the

experimental section for the preparation of impurities of (25) and were

characterized.

74

Table-3.2 - Impurities of Montelukast sodium from First Novel

process

S.

No.

Com

poun

d

Structure of impurity Chemical name

1. 40

(R)-E-methyl 2-(3-(3-(2-(7-

chloronaphthalen-2-

yl)vinyl)phenyl)-3-

hydroxypropyl)benzoate

2. 43

acid

(R)-E-2-(1-(((1-(3-(2-(7-

chloroquinolin-2-yl)vinyl)phenyl)-3-

(2-

(methoxycarbonyl)phenyl)propyl)thi

o)methyl)cyclopropyl)acetic acid

3. 62

2-(1-(((R)-((R)-1-(3-(2-(7-

chloroquinolin-2-yl)ethyl)phenyl)-3-

(2-(2-hydroxypropan-2-

yl)phenyl)propyl)sulfinyl)methyl)cyc

lopropyl)acetic acid

4. 63

(R)-E-2-(1-(((3-(2-acetylphenyl)-1-

(3-(2-(7-chloroquinolin-2-

yl)vinyl)phenyl)propyl)thio)methyl)c

yclopropyl)acetic acid

5. 64

(R)-E-2-(1-(((1-(3-(2-(7-


(2-(prop-1-en-2-

yl)phenyl)propyl)thio)methyl)cyclopr

75

opyl)acetic acid

6. 65

(S)-E-2-(1-(((1-(3-(2-(7-




opyl)acetic acid

Table-3.3 - Impurities of Montelukast sodium from Second Novel

process

S.

No.

Com

poun

d

Structure of impurity Chemical name

1. 35

(S)-E-1-(3-(2-(7-chloroquinolin-2-

yl)vinyl)phenyl)-3-(2-(2-

hydroxypropan-2-yl)phenyl)propan-

1-ol

2. 62

2-(1-(((R)-((R)-1-(3-(2-(7-

chloroquinolin-2-yl)ethyl)phenyl)-3-


yl)phenyl)propyl)sulfinyl)methyl)cyc

lopropyl)acetic acid

3. 63

(R)-E-2-(1-(((3-(2-acetylphenyl)-1-

(3-(2-(7-chloroquinolin-2-

yl)vinyl)phenyl)propyl)thio)methyl)c

yclopropyl)acetic acid

76

4. 64

(R)-E-2-(1-(((1-(3-(2-(7-


(2-(prop-1-en-2-


opyl)acetic acid

5. 65

(S)-E-2-(1-(((1-(3-(2-(7-




opyl)acetic acid

6. 47

(R)-E-2-(1-(((1-(3-(2-(7-




opyl)acetonitrile

Table-3.4 - Impurities of intermediates of Montelukast sodium

S.

No.

Com

poun

d

Structure of impurity Chemical name Source of

the

impurity

1. 66

2-methyl-7-((E)-3-((E)-2-(7-

methylquinolin-2-

yl)vinyl)styryl)quinoline

Preparation

of (53)

77

3.5 – EXPERIMENTAL SECTION

3.5.1 - Experimental Section For The First Novel Process For The

Preparation Of Montelukast Sodium (25):

Preparation of (40) {R (+)-hydroxy ester}:

100 grams (0.219 mol) of (39) was dissolved in 500 ml of DCM. 180

ml of (+)-DIP-Cl (0.346 mol, 1.6 equivalents) was taken separately in 500

ml of DCM and cooled to -50C with stirring. Above (39) solution in DCM

was added to (+)-DIP-Cl in DCM at -5 to 00C slowly drop wise. After

addition, the reaction mixture was aged at -5 to 00C for 10 hours.


1:4 and one drop of aq. ammonia). After the completion of reaction, the

reaction mixture was quenched with aqueous ammonia and stirred 60

minutes. Aqueous sodium chloride solution was added and stirred for 30

minutes. Layers were separated and the organic layer was washed with

aqueous sodium chloride solution. DCM was distilled from the organic

layer.

Purification of (40):

The resulting crude (40) obtained above was dissolved in 1200 ml of

MeOH and filtered the insoluble solids. 50 ml water was added slowly

drop wise to the filtrate and continued stirring for 2 hours. The separated

solid was filtered, washed with a mixture of MeOH and water and dried

78

at 500C to yield 80 grams (yield: 80%) of (40). (Purity by HPLC: 98%). SR:

of +340 (c=1 in chloroform).

Characterization of (40):

Other than SR, the following characterization data confirmed the

structure of (40).

IR spectrum of (40):

(cm-1) 3148 (OH str); 1716 {C=O str (ester)}; absence of peak for C=O

str (Ketone); 1600 (vinylic C=C str) and 1492 (Ar C=C str).

Fig. 3.1

79

Mass spectrum of (40) (ESI):

m/z 458 (M++1).

Fig. 3.2

1H-NMR spectrum of (40) (CDCl3, 400 MHz):

(δ ppm) 2.1 (m, 4H, CH2-CH2); 3.1 (s, 1H, OH); 3.9 (s, 3H, CH3); 4.7

(m, 1H, CH-OH); 7.3-8.3 (m, 15H, Ar-H & vinyl CH).

Fig. 3.3

80

13C-NMR spectrum of (40) (CDCl3, 200 MHz):

(δ ppm) 41 (CH2-CH2); 51 (OCH3); 120-158 (23 carbons-Ar & vinyl

CH); 167 (COO of ester).

Fig. 3.4

DEPT spectrum of (40):

Methyl and methyne groups as positive peaks and methylene groups

as negative peaks.

81

Fig. 3.5

Preparation of (43):

A stirred mixture of 100 grams (0.219 mol) of (40) and 500 ml of

toluene was heated to reflux and water was removed by azeotropic

distillation using Dean-Stark apparatus. The mixture was cooled to 500C

and the remaining solvent was distilled under reduced pressure. The

residue was re-dissolved in 200 ml of DCM at ambient temperature and

the solvent was distilled again under reduced pressure. The residue was

re-dissolved in 1000 ml of DCM and the mixture was cooled to 0-50C.

57.5 ml (0.328 mol) of DIPEA were added at once to the stirred

mixture; and the reaction mass was stirred at 0-50C for 15-30 minutes.

22 ml (0.284 mol) of MsCl were added dropwise at 0-50C with stirring.

After the addition was completed, the cooling was discontinued, and the

reaction mass was maintained at 25-350C until reaction completion. 600

ml of water was added and the mass was stirred for another 30 minutes.

82

The organic and aqueous layers were separated, and the aqueous

layer was extracted with 200 ml of DCM. The combined organic layers

were washed with water (3 X 600 ml). DCM was distilled off

atmospherically, followed by distillation under reduced pressure at a

temperature of below 500C. The resulting residue was re-dissolved in

toluene (200 ml), which was again distilled off under reduced pressure at

45-500C to obtain a residue of the mesylate (41).

38.3 grams (0.262 mol) of (36) and 450 ml of MeOH were stirred until

clear dissolution at 25-350C for 60 minutes. Added 29.34 grams (0.524

mol) of NaOMe powder slowly. A mixture of the crude mesylate (41)

obtained above, DCM and DMF (450 ml) were added to this disodium salt

of (36), and the resulting reaction mass was stirred for clear dissolution

at 25-350C. The reaction mass was heated and maintained at reflux

temperature for 2-3 hours. 450 ml of water was charged to the reaction

mixture and continued stirring for 15 minutes. The organic and aqueous

layers were separated; the aqueous layer extracted with 200 ml of DCM.

The combined organic layer was washed with a mixture of NaCl (37.5

grams) and water (400 ml) solution, then washed with a solution of acetic

acid (45 ml) in water (400 ml), followed by a water wash (4 X 400 ml).

The solvents were distilled off under atmospherically from the organic

layer; followed by distillation under reduced pressure at 45-500C. The

obtained residue was dissolved in 200 ml acetone; and acetone was

83

distilled off under reduced pressure at 45-500C. Thus obtained residual

crude product was re-dissolved in 500 ml acetone at 25-350C. 52 ml

(0.262 mol) of DCHA (42) were added to the solution of the crude residue

at 25-350C; and the mass was stirred at 25-350C until a solid separated.

Solid was filtered, the wet compound was taken into 400 ml of acetone,

and heated to reflux. The mass was maintained at reflux for 1-2 hours

and then cooled to 25-350C; stirring continued for 4-5 hours. The

resulting solid was filtered and washed with 50 ml of acetone. The solid

was dried in an oven at 45-500C to afford the 49.7 grams of (43).


49 grams (0.0639 mol) of (43) and 490 ml of acetone were charged

into a round bottomed flask, and the mixture was heated to reflux. The

mass was maintained at reflux for 1-2 hours, cooled to 25-350C slowly

under stirring, and maintained at 25-350C for another 4-5 hours. The

separated solid was filtered; washed with acetone (49 ml) and dried at

50-550C to afford 44.7 grams of purified (43).



(cm-1) 3431 (N-H str); 2668, 2530, 2380 (+N-H str); 3056 (Ar C-H str);

2926 & 2854 (aliphatic C-H str); 1721 (C=O str); 1605 (-COO- Asymm.

Str); 1533 (C=C str); 1496 (Ar C=C str); 697 (C-S str).

84

NCl

COOCH3

COO

S

H2N

Fig. 3.6

Mass spectrum of (43) (ES-MS):

m/z 767.8 (DCHA salt).

Fig. 3.7

85

1H-NMR spectrum of (43) (DMSO-D6, 400 MHz):

(δ ppm) 0.3-0.5 (m, 4H, two CH2 of cyclopropyl ring); 1.0-1.8 (two

multiplets, 10H, CH2 of cyclohexyl rings); 2.1 (m, 2H, CH2 adjacent to C-

S); 2.3 (m, 2H, CH2 adjacent to COO-); 2.50-2.54 (m, 2H, CH2 ajdacent to

S); 2.57 (m, 2H, CH of cyclohexyl rings); 2.8-2.9 (m, 2H, S-CH-CH2-CH2);

3.7 (s, 3H, COOCH3); 3.9 (t, 1H, CH-S); 7.3-8.0 (m, 15H, Ar-H, vinyl CH);

8.4 (m, 2H, +NH2).

Fig. 3.8

13C-NMR spectrum of (43) (DMSO-D6, 100 MHz):

(δ ppm) 11.8 & 12.1 (CH2 of cyclopropyl ring); 17.2 (C of cyclopropyl

ring); 31.9 & 25 (CH2 of dicyclohexyl); 41.4 & 40.1 (CH2 attached to

cyclorpropyl ring); 49 (C-S); 51.6 (CH of cyclohexyl); 51.7 (OCH3); 120-

156 (Ar and vinyl CH); 167 (COOCH3); 174 (COO-).

86

Fig. 3.9

DEPT spectrum of (43) (DMSO-D6; 400 MHz):


as negative peaks.

Fig. 3.10

87


100 grams (0.13 mol) of (43) and 1000 ml of toluene were charged to

a round bottomed flask, and stirred for about 5 minutes. A mixture of

acetic acid (15 ml) and water (500 ml) was added, and the mass was

stirred for another 30 minutes. The organic and aqueous layers were

separated. Organic layer was dried over anhydrous Na2SO4 after washing

with water (3 X 500 ml). The solvent was removed under reduced

pressure at a temperature below 500C. The resulting crude residue was

dissolved in a mixture of toluene (760 ml) and THF (760 ml); the solution

was transferred into a round bottomed flask and cooled to 00C under

nitrogen atmosphere. 261 ml of 3 M solution of methyl magnesium

chloride in THF were added dropwise during 2-3 hours at 0-50C. The

reaction mass was maintained at 0-50C for 6-7 hours, and cooled to 00C.

A mixture of acetic acid (90 ml) and water (750 ml) was slowly added at

below 150C for about one hour. The reaction mass was stirred at 25-350C

for another one hour until clear dissolution. The organic and aqueous

layers were separated. Organic layer was washed with 5% sodium

bicarbonate solution (2 X 750 ml), followed by a water wash (2 X 750 ml)

and dried over anhydrous Na2SO4. The solvent from the organic layer

was removed under reduced pressure. The resulting residue was treated

with additional amount of methyl magnesium chloride (50 ml) followed

by work-up in the same procedure.

88

The crude product was dissolved in toluene (100 ml) and stirred at

25-350C to separate a solid. The separated solid was filtered and washed

with toluene (30 ml). The wet solid and toluene (90 ml) were charged into

a round-bottomed flask, heated to 900C, and stirred for 30 minutes until

complete dissolution, cooled to 25-350C, and maintained for 6-10 hours.

The solid was filtered and washed with toluene (22 ml). The re-

precipitation process was repeated four to five times. The solid was dried

to afford about 17.4 grams of the purified (29).


8.6 grams (0.0147 mol) of (29), 155 ml of acetone and 17 ml of IPA

were charged into a round bottomed flask and stirred at 25-350C until

clear dissolution. 2.3 ml (0.022 mol) of TBA (45) was added and the mass

was stirred at 25-350C. The separated solid was filtered, washed with

acetone (20 ml) and dried at 40-500C. The dried residue was re-

precipitated from a mixture of acetone (225 ml) and IPA (25 ml), affording

6 grams of (44). Characterization data of (44) is substantially in

accordance with the data discussed for (44) under experimental section

for second novel process for preparation of Montelukast sodium (25).


(44) obtained above and 50 ml of DCM were mixed at 25-350C. A

mixture of 0.5 ml of acetic acid and 25 ml of water was added to the

mass, and stirred at 25-350C for 15 minutes. The organic and aqueous

89

layers were separated; the organic layer was washed with water (4 X 25

ml) and dried over Na2SO4. The solvent was removed under reduced

pressure at a temperature below 450C. 10 ml of MeOH were added to the

residue. The solvent was removed again under reduced pressure at a

temperature of below 450C. A mixture of 0.307 grams of freshly prepared

sodium pellets and 50 ml of MeOH was added to the residue at 25-350C.

0.5 grams of carbon were added and the mass was stirred for about 30

minutes at 25-350C. The carbon was filtered and washed with MeOH.

The filtrates were combined and the solvent was removed under reduced

pressure at a temperature below 450C. The residue was re-dissolved in

toluene (25 ml) and the solvent was removed again under reduced

pressure at a temperature below 450C. The residue was re-dissolved in

toluene (5 ml) and added to a pre-filtered n-heptane under nitrogen

atmosphere at 25-350C. The mixture was stirred at 25-350C for about 1

hour to form a precipitate, which was filtered and washed with n-heptane

(25 ml) under nitrogen atmosphere. The resulting solid was dried at 800C

to afford 3.2 grams of (25).


Characterization data given here under for (25) obtained in the first

novel process is in agreement with the data discussed for (25) under

experimental section for second novel process for preparation of (25).

90


(cm-1) 3350 (OH str); 1629 (C=O str); 2624 & 2536 (+N-H str); 1612

(C=C str); 1496 (aromatic C=C str); 697 (C-S str).


m/z 586 corresponding to (29).

1H-NMR spectrum of (25):

(δ ppm) 0.4 (m, 4H, two CH2 groups of cyclopropyl ring); 1.3 (s, 6H,

CH3); 2.0-3.2 (m, 8H, all CH2 groups excluding CH2 groups of cyclopropyl

ring); 3.9 (t, 1H, CH-S); 5.2 (s, 1H, OH); 7.0-8.3 (m, 15H, Ar-H & vinyl

CH).

13C-NMR spectrum of (25):

(δ ppm) 12.2 (CH2 of cyclopropyl ring); 17.8 (C of cyclopropyl ring); 31

(CH3); 43 & 39 (CH2 attached to cyclorpropyl ring); 49 (C-S); 72 (t-C of t-

alcohol); 122-157 (Ar and vinyl CH); 174 (COO).

DEPT spectrum of (25):


as negative peaks.

91

3.5.2 - Experimental Section For The Second Novel Process For The

Preparation Of Montelukast Sodium (25):


10 grams (0.0218 mol) of (35) was added in 50 ml of toluene, and the

mixture was heated to reflux. Reaction mixture was concentrated by

simultaneous azeotropic removal of water. 90 ml of acetonitrile was

added after room temperature was attained by the resulting mass and

was stirred at 50 600C for 30-45 minutes. Resulting mass was further

cooled to -10 to -150C. and 5.33 ml of DIPEA was added and was stirred

for about 30 minutes. 9.3 ml of MsCl was added and seeded with

mesylate of (35) and reaction mass was aged at -10 to -150C. for about 8

9 hours. The reaction mass was filtered and washed with acetonitrile

followed by hexanes to provide 10.0 g of mesylate of (35).

3.23 g (0.0254 mol) of (46) was dissolved in 40 ml of DMF and the

mixture was cooled to -10 to -150C. 31.75 ml of 3.4 M n-Butyl lithium

was added drop wise in reaction mass. 8 g of above obtained mesylate of

(35) was added to the reaction mass at -10 to -150C and the reaction

mass was aged at -10 to -150C. for about 6 8 hours. 50 ml of 15%

sodium chloride solution was added followed by 80 ml of toluene and the

reaction mass was stirred for about 30 minutes. Organic layer and

aqueous layer were separated. Aqueoues layer was extracted with

toluene. Water was added to combined organic layers and the pH was

92

adjusted to 5.0 using 5 ml of acetic acid and the reaction mass was

stirred at 25 350C for 30-40 minutes. Organic layer was washed with 64

ml of 5% NaHCO3 solution followed by water. 1 gm of carbon and Na2SO4

were added to the organic layer and stirred for 30 minutes. It was filtered

and washed with toluene followed by removal of solvent under reduced

pressure below 500C to afford 8 g of (47).



(cm-1) 3418 (O-H str); 2247 (C=N str); 3062 (Ar C-H str); 2957

(aliphatic C-H); 1635 (C=C str).

Fig. 3.11

93

Mass spectrum of (47) CI mode (+ve): m/z 567.

Fig. 3.12



CH3); 2.0-3.2 (m, 8H, all CH2 groups excluding CH2 groups of cyclopropyl

ring); 3.2 (s, 1H, OH); 3.9 (m, 1H, CH-S); 7.0-8.3 (m, 15H, Ar-H & vinyl

CH).

Fig. 3.13

94


Method A:

65 g (0.114 mol) of (47) and 325 ml of caustic lye was added into

round bottom flask and further stirred and heated to reflux at 118-1220C

for 6 to 8 hours. 130 ml of water and 650 ml of toluene were added to the

reaction mass below 900C and stirred for 30 minutes. Separated the

layers and the aqueous layer was extracted with 325 ml of toluene at 60

- 700C. Combined organic layers were distilled under reduced pressure

below 500C and washed with 720 ml of n-heptane at 25-350C. 300 ml of

water and 200 ml of DCM were added to the reaction mass the pH was

adjusted to 5 with acetic acid. Layers were separated and the aqueous

layer was extracted with 200 ml of DCM. Combined organic layer was

washed with 1300 ml of water and distilled off solvent from organic layer

at atmospheric pressure followed by distillation under reduced pressure

below 500C to afford (29). 500 ml of acetone was added to the above

obtained crude and distilled of acetone under reduced pressure below

500C to remove the traces of DCM. 21 gm (0.287 mol) of TBA (45) was

added to the above reaction mass slowly at 25 - 300C and seeded. The

reaction mass was stirred till thick solid separation at 25-350C for 8 - 10

hours. The separated solid was filtered and washed with acetone. It was

then dried at 50 - 550C to afford 40 gm of (44).

95


30 gm of (44) was dissolved in 360 ml of acetone and heated to reflux

for 1 to 2 hours. Cooled to 250C and the reaction mixture was

maintained at the same temmperature for 10 hours. Solid was filtered,

washed with acetone and dried at 600C to afford 23.8 gm of purified (44).

Method B:

13.5 g (0.0238 mol) of (47), 94.5 ml of diethyleneglycol and a solution

of 10.7 g (0.19 mol) of KOH in 40 ml of water were added and refluxed for

24 hours. The reaction mass was cooled to room temperature and

washed with 325 ml of toluene. After addition of water (54 ml), the

product was extracted into ethyl acetate (472.5 ml). Organic layer was

washed with aqueous acetic acid and then with 50 ml of 5% of aqueous

NaHCO3 solution. The solvent was evaporated from the organic layer to

afford 7.5 g of (29). The obtained (29) was added into 45 ml of acetone. 2

ml of TBA (45) was added to reaction mass and stirred for about 10

hours. The separated solid was filtered and washed with acetone followed

by hexanes to get 4.3 g of (44).

(44) could be purified by recrystallization from solvents like ethyl

acetate, a mixture of IPA and acetonitrile or a mixture of MeOH and

acetonitrile as described above.

96

Method C:

The mixture of (47) and (50) was hydrolyzed by following the

procedure described above to afford (44).



(cm-1) 3360 (OH str); 1631 (C=O str); 2635 & 2554 (+N-H str); 1608

(C=C str); 1498 (Ar C=C str); 697 (C-S str).

Fig. 3.14


m/z 586 correponding to (29).

97

Fig. 3.15



CH3 of t-BuNH2); 1.6 (s, 6H, CH3 of ter-alcohol); 2.2-3.2 (m, 8H, all CH2

groups excluding CH2 groups of cyclopropyl ring); 3.5 (s, 1H, OH); 4.0 (t,

1H, CH-S); 5.1 (s, 3H, +NH3); 7.0-8.2 (m, 15H, Ar-H & vinyl CH).

Fig. 3.16

98


20.0 g (0.0303 mol) of (44) and DCM (50 ml) were added into round

bottom flask at 25 - 350C. Acetic acid (2.62 ml) and water (100 ml) were

added to the reaction mass and was stirred at 25 - 350C for 60 minutes.

Layers were separated and the aqueous layer was extracted with DCM

(40 ml). Organic layer was washed with water (4 X 25 ml); dried over

anhydrous sodium sulphate. Distilled off solvent completely from organic

layer under reduced pressure below 500C. Residual mass was dissolved

in MeOH (200 ml) and distilled off solvent completely under reduced

pressure below 500C. Residual mass was dissolved in 100 ml of MeOH.

Freshly prepared solution of NaOH (1.21 grams, 0.0303) pellets in MeOH

(100 ml) was added to the residual mass at 25 - 350C under nitrogen

blanketting and stirred for 30 minutes at 25-350C. Carbon (0.5 grams)

was added to reaction mass and stirred for 30 minutes at 25 - 350C.

Carbon was filtered and cake was washed with 25 ml of MeOH. Solvent

was distilled off completely under reduced pressure below 500C; the

obtained crude was dissolved in toluene (40 ml) and distilled off solvent

completely under reduced pressure below 500C. Finally crude was

dissolved in toluene (30 ml) and added to 200 ml of n-heptane under

nitrogen atmosphere at 25 - 350C. The reaction mass was maintained at

25 - 350C for 1 to 2 hours. The compound was filtered and washed with

99

n-heptane (40 ml) under nitrogen atmosphere and dried at 70 - 750C for

5 hours to afford 16.8 grams of (25) in amorphous form.



(cm-1) 3360 (OH str); 1631 (C=O str); 1608 (C=C str); 1498 (Ar C=C

str); 697 (C-S str).

Fig. 3.17


m/z 608 (25) and m/z 586 (29).

100

Fig. 3.18

1H-NMR spectrum of (25) (DMSO, 400 MHz):

(δ ppm) 0.2-0.4 (m, 4H, two CH2 groups of cyclopropyl ring); 1.4 (s,

6H, CH3); 1.9-3.1 (m, 8H, all CH2 groups excluding CH2 groups of

cyclopropyl ring); 3.4 (s, 1H, t-OH); 4.0 (t, 1H, CH-S); 7.1-8.4 (m, 15H,

Ar-H & vinyl CH).

Fig. 3.19

101

13C-NMR spectrum of (25) (DMSO-D6, 50 MHz):

(δ ppm) 175.9 (COO); 120-156 (Ar-C & vinyl CH); 71.6 (to t-C of t-

alcohol); 49.5 (C-S); 44 & 39.5 (CH2 attached to cyclorpropyl ring); 31.7

(CH3); 18.1 (C of cyclopropyl ring); 12.4 & 12.1 (CH2 of cyclopropyl ring).

Fig. 3.20

DEPT spectrum of (25) (DMSO-D6):


as negative peaks.

102

Fig. 3.21

Preparation of a mixture of (47) and (50):

Taken 240 mg of about 3:2 mixture of (46) and (49) in 20 ml of DMF,

the mixture is cooled to below 00C, 1 ml of 1.6 M n-Butyl lithium in

hexanes was added drop wise and stirred for about 20 minutes. 450 mg

of mesylate of (35) prepared above below 00C and the reaction mass was

aged below 00C for about 5 hours. After subsequent work up as

described above afforded 400 mg of about 3:2 mixture of (47) and (50).


51.0 g (0.302 mol) of (61) (prepared as per the procedure described in

Bhupathy et al) was dissolved in 500 ml of MeOH and it was allowed to

cool to -15 to -120C. 24.4 g (0.452 mol) of NaOMe was dissolved in 127.5

ml of MeOH and transferred this solution to above reaction mass at -15

to -120C and stirred at -15 to -120C. 484.5 ml of water was added to the

103

reaction mass under stirring below 00C and the resulting aqueous mass

was washed with 1020 ml of heptane. Aqueous layer was acidified with

65.3 ml of acetic acid and stirred the reaction mixture below 00C for 30

minutes. Layers were separated and the aqueous layer was extracted

with 204 ml of DCM. Organic layer was washed with 102 ml of 5%

sodium bicarbonate followed by 459 ml of water. 5.1 gm of carbon and

sodium sulphate were added to combine organic layer and stirred for 30

minutes. Reaction mass was filtered over hyflow bed and washed with 51

ml of DCM followed by removal of solvent completely from organic layer

under reduced pressure below 500C afforded 27.0 g of (46).

Characterization of (46)


(cm-1) 2923 (aliphatic C-H str); 2566 (S-H str) and 2248 (C N str).

Fig. 3.22

104

Mass spectrum of (46):

m/z 127 by GC-MS.


(δ ppm) 0.6-0.7 (m, 4H, two CH2 groups of cyclopropyl ring); 1.4 (t,

1H, SH); 2.6-2.9 (m, 4H, CH2).

Fig. 3.23

Preparation of a mixture of (46) and (49):

2.5 g (0.0147 mol) of (61) (prepared as per the procedure described in

Bhupathy et al) was dissolved in 25 ml of MeOH and stirred at ambient

temperature. 2.5 g of KOH was dissolved in 10.0 ml of water and

transferred this solution to above reaction mass. The reaction mass was

then aged below 500C temperature until reaction was substantially

105

complete. Then 40 ml of water was added to reaction mass and washed

with 120 ml of hexanes. Aqueous phase was extracted with 160 ml of

ethyl acetate. Organic layer was then washed with aqueous acetic acid

followed by 5% sodium bicarbonate solution and then with water.

Evaporated the solvent from the organic layer to afford 600 mg of about

3:2 mixture of (46) and (49).

3.5.3 - Experimental Section For The Starting material (10):


100 grams (0.219 mol) of (39) was dissolved in 500 ml of DCM. 180

ml of (-)-DIP-Cl (0.346 mol, 1.6 equivalents) was taken separately in 500

ml of DCM and cooled to -50C with stirring. Above (39) solution in DCM

was added to (-)-DIP-Cl in DCM at -5 to 00C slowly drop wise. After

addition, the reaction mixture was aged at -5 to 00C for 10 hours.


1:4 and one drop of aq. ammonia). After the completion of reaction, the

reaction mixture was quenched with aqueous ammonia and stirred 60

minutes. Aqueous sodium chloride solution was added and stirred for 30

minutes. Layers were separated and the organic layer was washed with

aqueous sodium chloride solution. DCM was distilled from the organic

layer. The resulting crude was dissolved in 1200 ml of MeOH and filtered

to remove insoluble solids. To the filtrate 50 ml water was added slowly

drop wise and stirring was continued for 2 hours. The separated solid

106

was filtered, washed with a mixture of MeOH and water and dried at

500C to yield 80 grams (yield: 80%) of (60). (Purity by HPLC: 97%). SR:

of –32.90 (c=1 in chloroform).


Apart from SR the following characterization data confirms the

structure of (60).


(cm-1) 3148 (OH str); 1716 {C=O str (ester)}; absence of peak for C=O

str (Ketone); 1600 (vinylic C=C str) and 1492 (Ar C=C str).

Fig. 3.24


m/z 458 (M++1).

107

Fig. 3.25


(δ ppm) 2.1 (m, 4H, CH2-CH2); 3.1 (s, 1H, OH); 3.9 (s, 3H, CH3); 4.7

(m, 1H, CH-OH); 7.3-8.3 (m, 15H, Ar-H & vinyl CH).

Fig. 3.26


100 grams (0.22 mol) of (60) was taken in 1500 ml of toluene and

heated with stirring. Water was removed by azeotropic distillation. The

resulting solution was cooled to -50C and added 280 ml (0.88 mol, 4

108

equivalents) of methyl magnesium chloride in THF slowly at a

temperature of -5 to 00C. After addition was complete, the reaction

mixture was aged at -5 to 00C for 4 hours. Reaction was monitored by

TLC (mobile phase: Ethyl acetate : Hexanes – 1:4 and one drop of aq.

ammonia). After the completion of reaction, the reaction mixture was

quenched with aq. acetic acid and stirred one hour. Layers were

separated and the organic layer was washed with aq. sodium bicarbonate

solution followed by water. Water was removed from the organic phase by

azeotropic distillation. Concentrated the organic layer and cooled the

resulting solution to room temperature and stirred for 4 hours.

Separated solid was filtered and recrystallized from toluene to yield 70

grams (yield: 80%) of (35). (Purity by HPLC: 98%). SR: of –22.60 (c=1

in chloroform).



(cm-1) 3307 (OH str); absence of peak for C=O str (ester); 1607 (vinylic

C=C str); 1595 (OH bend); and 1492 (Ar C=C str).

109

Fig. 3.27


m/z 458.

Fig. 3.28

110


(δ ppm) 1.4 (s, 6H, CH3 of t-alcohol); 2.0 (m, 2H, CH2-CH2); 3.0 (m,

2H, CH2-CH2); 4.7 (m, 1H, CH-OH); 4.9 (s, 1H, OH of t-OH); 5.3 (s, 1H,

OH of CH-OH); 7.1-8.4 (m, 15H, Ar-H & vinyl CH).

Fig. 3.29

3.5.4 - EXPERIMENTAL SECTION FOR THE PREPARATION OF

IMPURITIES:

The impurities of (25) and its intermediates as given above in Tables-

3.3, 3.4 and 3.5 were prepared as described here under.

Preparation of impurities according to Table-3.3:

(40) & (43) are intermediates in the first novel process for the

preparation of (25). Their characterization data is in agreement with the

data for the same discussed herein above.

111


(62) was prepared by oxidation of Montelukast using hydrogen

peroxide according to the procedure of Saravanan et al. 54

2.0 grams of Montelukast (29) was taken in 50 ml of MeOH and

added 3 ml of hydrogen peroxide and the reaction mixture was aged at

ambient temperature for 3 hours. Reaction mixture was quenched with

water and the compound was extracted into DCM. DCM was distilled

completely and the resulting residue was triturated with hexanes to

afford 1.7 grams of (62).



(cm-1) 3402 (OH str); 1713 (C=O str); 1220 (S=O str); 697 (C-S str).

Fig. 3.30

112


m/z 602.

Fig. 3.31


(δ ppm) 0.3-0.6 (m, 4H, two CH2 groups of cyclopropyl ring); 12

(COOH); 1.4 (s, 6H, CH3); 2.0-2.9 (m, 8H, all CH2 groups excluding CH2

groups of cyclopropyl ring); 4.0 (t, 1H, CH-S); 4.9 (s, 1H, OH of t-alcohol);

7.1-8.4 (m, 15H, Ar-H & vinyl CH).

113

Fig. 3.32


(63) as its DCHA salt was prepared according to the following

synthetic scheme.

Cl

OH COOCH3

(40)Cl

OH COCH3

(67)

Cl

H3CO2SO COCH3

(68)

COOH

SH (36)

NCl

COCH3

COOS

(63 DCHA salt)

H2N

A stirred mixture of 5.0 gram (0.0109 mol) of (40) was taken 100 ml of

toluene and heated to reflux. Water was removed by azeotropic

114

distillation and resulting mixture was cooled to -50C. 3.2 gram (0.0329, 3

molar equivalents) was added and stirred for 30 minutes. 3.8 ml of 1 M

ethyl magnesium bromide in THF (0.0285 mol, 2.6 molar equivalents)

was added drop wise. The reaction mixture was aged at -50C for 3 hours.

Reaction mixture was quenched with saturated aqueous ammonium

chloride solution and stirred for 30 minutes. Layers were separated.

Organic layer was washed with water and dried over anhyd.Na2SO4.

Toluene was distilled off completely and the resulting residue was

dissolved in 50 ml of THF and cooled to -50C. Added 36 ml of 1.5 M

methyl magnesium bromide in THF drop wise. Temperature was raised to

250C and was aged at that temperature for 3 hours. Reaction mixture

was quenched with aqueous NH4Cl solution and stirred at ambient

temperature for 30 minutes. Layers were separated and the aqueous

layer was extracted with toluene and the combined organic phases was

washed with water and dried over anhydrous Na2SO4. Solvents were

distilled completely to afford 4.5 grams of (67).

Above obtained (67) was mesylated using the procedure of (41) to

afford the corresponding mesylated (68), which was then converted to

(63) DCHA salt using the procedure of (43) given above in the

experimental section 3.5.1 except for using sodium methoxide powder

(1.2 molar equivalents to 41) in place of n-butyl lithium. The resulting

115

(63) in its free acid form was converted to DCHA salt by treating with

DCHA (42) in acetone to afford 1 gram of DCHA salt of (63).



(cm-1) 3421 (N-H str); 3057 (Ar C-H str); 2924 (aliphatic C-H str); 1706

(C=O str); 1608 (-COO- asymm. Str); 1560 (C=C str); 1498 (Ar C=C str);

697 (C-S str).

Fig. 3.33


m/z 570 (63 acid).

116

Fig. 3.34


(δ ppm) 0.3 (m, 4H, two CH2 groups of cyclopropyl ring); 1.3-3.0 (m,

33H, all CH2 groups excluding CH2 groups of cyclopropyl ring & CH

groups of dicyclohexyl and CH3); 3.9 (t, 1H, CH-S); 7.2-8.1 (m, 15H, Ar-H

& vinyl CH); 8.2 (m, 2H, +NH2).

Fig. 3.35

117


5.0 grams of Montelukast acid was dissolved in 200 ml of chloroform

and added 0.8 ml of conc.H2SO4. Reaction mixture was aged at 500C for

6 hours. Reaction mixture was cooled to room temperature and

quenched with ice cooled water. Layers were separated and the organic

layer was washed with water followed by aqueous sodium bi-carbonate

solution. Chloroform was distilled completely to afford 4.6 grams of (64).



(cm-1) 3429 (OH str); 1713 (C=O str); 1608 (C=C str); 1499 (Ar C=C

str); 697 (C-S str).

Fig. 3.36


m/z 568.

118

Fig. 3.37


(δ ppm) 0.4 (m, 4H, two CH2 groups of cyclopropyl ring); 1.9-2.5 (m,

11H, all CH2 groups excluding CH2 groups of cyclopropyl ring & methyl);

3.9 (t, 1H, CH-S); 5.1 & 4.7 (2 singlets, 2H, =CH2 of styrene); 7.1-8.4 (m,

15H, Ar-H & vinyl CH).

Fig. 3.38

119


(65) is an enantiomer (S-isomer) of (29). It was prepared starting from

10 grams of (39) according to scheme-3.5 except using (-)-DIP-Cl in place

of (+)-DIP-Cl by following the procedure for Montelukast given in

experimental section 3.5.1 to afford 1.2 grams of (65) (Purity by HPLC –

98%). It has a SR of -980 (c=1 in chloroform).



(cm-1) 3367 (OH str); 1637 (C=O str); 1607 (C=C str); 1498 (Ar C=C str); 697 (C-S str).

Fig. 3.39

Mass spectrum of (65) (ESI): m/z 586.

120

Fig. 3.40


(δ ppm) 0.2 & 0.4 (2 m, 4H, two CH2 groups of cyclopropyl ring); 2.1-

3.2 (m, 8H, all CH2 groups excluding CH2 groups of cyclopropyl ring); 3.0

(s, OH, t-OH); 1.5 (m, 6H, CH3); 3.9 (t, 1H, CH-S); 7.0-8.0 (m, 15H, Ar-H

& vinyl CH).

Fig. 3.41

121


(35) was an intermediate of the second novel process for the

preparation of Montelukast sodium its characterization data was in

agreement with the data given for this compound herein above.

Process for preparation of (63), (64), (66) and (67) are described

above under the heading preparation of impurities according to Table-

3.3.


(66) was the dimer impurity that was formed during preparation of

(53) when a mole of 7-chloro-2-methyl quinoline reacts with (53). It was

isolated by filtering the hot suspension obtained during purification of

(53) from ethyl acetate as described in the experimental section 3.5.3 for

the preparation of intermediates of (25). The filtered solid is (66).



(cm-1) 2253 (C=N str); 1590 (vinylic C=C str); 1492 (Ar C=C str).

122

Fig. 3.42


m/z 413 (M++1).

Fig. 3.43

123

3.6 - STUDY ON POLYMORPHISM OF MONTELUKAST AND ITS

SALTS

X-ray diffractometry is the most widely used analytical tool for the

determination of polymorphic forms of solids. Therefore, as part of the

present work, the polymorphic forms were determined using powder X-

ray diffraction pattern.

Definition of amorphous solid

Amorphous solids are the solids wherein the molecules are arranged

randomly in a three dimensional space. It is a non crystalline solid with

no well defined ordered structure. That means it lacks long range order

as a crystalline solid.

Hence, there would not be seen any sharp well defined peaks in a

typical X-ray diffraction pattern of an amorphous solid.

Definition of crystalline solid

Crystalline solids are the solids wherein the molecules are arranged in

a regular fashion in a three dimensional space. It will have long range

order. It will have well defined ordered three dimensional structures.

There would be seen sharp well defined peaks in a typical X-ray

diffraction pattern of a crystalline solid.

124

Study on polymorphic nature of Montelukast sodium (25) of the

present work:

(25) obtained in the process of the present work was confirmed to be

amorphous in nature as observed by its powder X-ray diffraction pattern

(Fig. 3.44), which did not have any well defined peaks. It was observed

as a hollow pattern without any sharp peaks.

Fig. 3.44

Study on polymorphic form of (44) of the present work:

(44) obtained in the process of the present work was confirmed to be

crystalline in nature as observed by its powder X-ray diffraction pattern

(Fig. 3.45).

Further, polymorphic form of (44) was studied by different isolation

methods as follows:

125

(i) By crystallization from the solvents or their mixtures, the resulting

solid had the similar X-ray powder diffraction pattern, which

substantially matches with (Fig. 3.45).

(ii) Dissolving in a solvent and isolation by adding an anti-solvent

(solvent is the one in which the solid is freely soluble whereas anti-

solvent is the one in which the solid is poorly soluble) lead to the

polymorph, which substantially matches with (Fig. 3.45).

Fig. 3.45

Study on polymorphic forms of (29) of the present work:

The X-ray powder diffraction pattern of (29) obtained after

recrystallization from toluene in the process of present work had well

defined sharp peaks (Fig. 3.46) and therefore it is crystalline.

Further, polymorphic forms of (29) were studied by different isolation

methods as follows:

126

(i) After crystallization from most of the solvents or their mixtures, the

resulting solid had the similar X-ray powder diffraction pattern in

all cases, which substantially matched with (Fig. 3.46). Following

procedure was followed.

Taken 2 grams of (29) in 50 ml of MeOH and heated to dissolve.

After complete dissolution the solution was filtered at hot condition

and the filtrate was cooled to ambient temperature and aged for 10

hours. Separated solid was filtered and dried at 700C to afford (29)

whose X-ray powder diffraction pattern substantially matched with

(Fig. 3.46). Similarly, crystallization from the following solvents

was carried out and the X-ray powder diffraction pattern of the

resulting (29) substantially matched with (Fig. 3.46).

Table-3.5

Run Solvent XRPD

1. 2-Propanol (50 ml) Fig. 3.46


3. 1-Butanol (50 ml) Fig. 3.46

4. Ethyl acetate (50 ml) Fig. 3.46

5. Acetone (30 ml) Fig. 3.46

6. Acetonitrile (30 ml) Fig. 3.46

7. THF (20 ml) Fig. 3.46

127

(ii) Dissolving in a solvent and isolation by adding an anti-solvent

(solvent is the one in which the solid is freely soluble whereas anti-

solvent is the one in which the solid is poorly soluble) lead to the

same polymorph (Fig. 3.46).

Taken 2 grams of (29) in 10 ml of DCM and stirring started. The

mixture was heated to 450C to dissolve (29) completely. The

solution was cooled to 300C and added 50 ml of hexanes drop wise.

The resulting mixture was aged for 12 hours at ambient

temperature. Separated solid was filtered and dried at 600C to

afford (29) whose X-ray powder diffraction pattern substantially

matched with (Fig. 3.46). Similarly, crystallization from the

following solvents was carried out and the X-ray powder diffraction

pattern of the resulting (29) substantially matched with (Fig.

3.46).

Table-3.6

Run Solvent Anti-solvent XRPD

1. Chloroform (30 ml) Hexanes (90 ml) Fig. 3.46

2. DCM (30 ml) n-Heptane (90 ml) Fig. 3.46

3. DCM (30 ml) Cyclohexane (90 ml) Fig. 3.46

4. Ethyl acetate (50 ml) Hexanes (100 ml) Fig. 3.46

5. THF (30 ml) Hexanes (90 ml) Fig. 3.46

128

(iii) Distilling off solvent completely under reduced pressure from a

solution of (29) in water miscible solvents such as alcohols,

acetonitrile and acetone lead the same polymorph (Fig. 3.46).

Taken 2 grams of (29) in 100 ml of MeOH and heated to reflux.

After complete dissolution, the solution was filtered at hot

condition and solvent was distilled off completely from the filtrate

under reduced pressure. The resulting solid was dried at 700C to

afford (29) whose X-ray powder diffraction pattern substantially

matched with (Fig. 3.46). Similar procedure was repeated with the

following solvents and the X-ray powder diffraction pattern of the

resulting (29) substantially matched with (Fig. 3.46).

Table-3.7

Run Solvent XRPD



3. Toluene (100 ml) Fig. 3.46

4. DCM (100 ml) Fig. 3.46

5. Chloroform (100 ml) Fig. 3.46

6. Ethyl acetate (100 ml) Fig. 3.46

7. THF (100 ml) Fig. 3.46

129

Fig. 3.46

3.7 – CONCLUSION

The processes described herein for the preparation of Montelukast

sodium (25) towards the objective of the present work avoided

disadvantages of the reported processes viz. series of protection-de-

protection steps resulting in a lengthy synthetic scheme rendering the

process expensive and hence leading to a commercially unviable process.

Reported processes involved undesirable hazardous and costly raw

materials such as ter-butyl dimethyl silane, dihydropyran, hydrazine,

pyridinium p-toluenesulfonate, cesium carbonate; and undesirable

130

reaction conditions such as low temperatures of -250C. The reported

processes involved tedious workups resulting in longer time cycle

rendering the process expensive and less eco friendly. Thus the

processes were not amenable for commercial scale up.

The objective of the present work was achieved by providing cost

effective, eco-friendly process, which was well suited for commercial scale

up. Montelukast sodium obtained in the present novel process had

>99.0% enantiomeric excess purity as determined by chiral HPLC and

resulted in amorphous form as characterized by X-ray powder diffraction.

Montelukast sodium obtained in the present process is free flowing and

non-solvated solid; and therefore it is well suited for pharmaceutical

applications. The process of the present work is cost effective, eco-

friendly and amenable for scale up.

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CHAPTER - 3 STUDIES IN THE SYNTHESIS OF ...shodhganga.inflibnet.ac.in/bitstream/10603/8272/11/11...STUDIES IN THE SYNTHESIS OF MONTELUKAST SODIUM 51 3.1 - INTRODUCTION The newer generation