CHAPTER - 3 STUDIES IN THE SYNTHESIS

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 promising 1 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 Brand Name Active Ingredient Innovator Marketed by Chemical Name Montelukast sodium Singulair Montelukast Merck & Co Inc Merck & Co Inc [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 C 35 H 35 ClNNaO 3 S

53 Formula Molecular Weight 608.18 Chemical Structure CAS Registry No 151767-02-1 Physical description Solubility Hygroscopic, optically active, white to off-white powder. 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 -COOCH 3, 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 S N 2 (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 98 0 (c=1 in chloroform). Whereas (25) has a SR of +103 0 (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 5 th 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 +103 0 (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: Cl N (35) OH OH OH MsCl DIPEA DCM Cl N (48) OSO 2 Me OH OSO 2 Me Cl N (48) CN + + SH (46) (49) CONH 2 SH n-buli CH 3 CN DMF Cl N (47) CN S OH + N Cl (50) CONH 2 S OH 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 Ac 2 O 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 Ac 2 O in xylene solvent. In an objective to minimize the quantity of Ac 2 O 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 Ac 2 O 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 NH 4 Cl 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 NH 4 Cl 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 K 2 CO 3 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 -25 0 C. 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 0 0 C. 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: O Cl N COOCH 3 (+)-DIP chloride DCM OH COOCH 3 (39) Cl N (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 -12 0 C (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 50 0 C (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. Com Structure of impurity Chemical name No. poun d 2. 43 acid 1. 40 (R)-E-methyl 2-(3-(3-(2-(7- chloronaphthalen-2- yl)vinyl)phenyl)-3- hydroxypropyl)benzoate (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- chloroquinolin-2-yl)vinyl)phenyl)-3- (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- chloroquinolin-2-yl)vinyl)phenyl)-3- (2-(2-hydroxypropan-2- yl)phenyl)propyl)thio)methyl)cyclopr opyl)acetic acid Table-3.3 - Impurities of Montelukast sodium from Second Novel process S. Com Structure of impurity Chemical name No. poun d 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- (2-(2-hydroxypropan-2- 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- chloroquinolin-2-yl)vinyl)phenyl)-3- (2-(prop-1-en-2- yl)phenyl)propyl)thio)methyl)cyclopr opyl)acetic acid 5. 65 (S)-E-2-(1-(((1-(3-(2-(7- chloroquinolin-2-yl)vinyl)phenyl)-3- (2-(2-hydroxypropan-2- yl)phenyl)propyl)thio)methyl)cyclopr opyl)acetic acid 6. 47 (R)-E-2-(1-(((1-(3-(2-(7- chloroquinolin-2-yl)vinyl)phenyl)-3- (2-(2-hydroxypropan-2- yl)phenyl)propyl)thio)methyl)cyclopr 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- Preparation of (53) yl)vinyl)styryl)quinoline

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 -5 0 C with stirring. Above (39) solution in DCM was added to (+)-DIP-Cl in DCM at -5 to 0 0 C slowly drop wise. After addition, the reaction mixture was aged at -5 to 0 0 C for 10 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 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 50 0 C to yield 80 grams (yield: 80%) of (40). (Purity by HPLC: 98%). SR: of +34 0 (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 1 H-NMR spectrum of (40) (CDCl 3, 400 MHz): (δ ppm) 2.1 (m, 4H, CH 2 -CH 2 ); 3.1 (s, 1H, OH); 3.9 (s, 3H, CH 3 ); 4.7 (m, 1H, CH-OH); 7.3-8.3 (m, 15H, Ar-H & vinyl CH). Fig. 3.3

80 13 C-NMR spectrum of (40) (CDCl 3, 200 MHz): (δ ppm) 41 (CH 2 -CH 2 ); 51 (OCH 3 ); 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 50 0 C 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 0-5 0 C. 57.5 ml (0.328 mol) of DIPEA were added at once to the stirred mixture; and the reaction mass was stirred at 0-5 0 C for 15-30 minutes. 22 ml (0.284 mol) of MsCl were added dropwise at 0-5 0 C with stirring. After the addition was completed, the cooling was discontinued, and the reaction mass was maintained at 25-35 0 C 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 50 0 C. The resulting residue was re-dissolved in toluene (200 ml), which was again distilled off under reduced pressure at 45-50 0 C 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 25-35 0 C 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 25-35 0 C. 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 45-50 0 C. The obtained residue was dissolved in 200 ml acetone; and acetone was

83 distilled off under reduced pressure at 45-50 0 C. Thus obtained residual crude product was re-dissolved in 500 ml acetone at 25-35 0 C. 52 ml (0.262 mol) of DCHA (42) were added to the solution of the crude residue at 25-35 0 C; and the mass was stirred at 25-35 0 C 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 25-35 0 C; 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 45-50 0 C to afford the 49.7 grams of (43). Purification 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 25-35 0 C slowly under stirring, and maintained at 25-35 0 C for another 4-5 hours. The separated solid was filtered; washed with acetone (49 ml) and dried at 50-55 0 C to afford 44.7 grams of purified (43). Characterization of (43): IR spectrum of (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 COO S H 2 N COOCH 3 Cl N Fig. 3.6 Mass spectrum of (43) (ES-MS): m/z 767.8 (DCHA salt). Fig. 3.7

85 1 H-NMR spectrum of (43) (DMSO-D6, 400 MHz): (δ ppm) 0.3-0.5 (m, 4H, two CH 2 of cyclopropyl ring); 1.0-1.8 (two multiplets, 10H, CH 2 of cyclohexyl rings); 2.1 (m, 2H, CH 2 adjacent to C- S); 2.3 (m, 2H, CH 2 adjacent to COO - ); 2.50-2.54 (m, 2H, CH 2 ajdacent to S); 2.57 (m, 2H, CH of cyclohexyl rings); 2.8-2.9 (m, 2H, S-CH-CH 2 -CH 2 ); 3.7 (s, 3H, COOCH 3 ); 3.9 (t, 1H, CH-S); 7.3-8.0 (m, 15H, Ar-H, vinyl CH); 8.4 (m, 2H, + NH 2 ). Fig. 3.8 13 C-NMR spectrum of (43) (DMSO-D6, 100 MHz): (δ ppm) 11.8 & 12.1 (CH 2 of cyclopropyl ring); 17.2 (C of cyclopropyl ring); 31.9 & 25 (CH 2 of dicyclohexyl); 41.4 & 40.1 (CH 2 attached to cyclorpropyl ring); 49 (C-S); 51.6 (CH of cyclohexyl); 51.7 (OCH 3 ); 120-156 (Ar and vinyl CH); 167 (COOCH 3 ); 174 (COO - ).

86 Fig. 3.9 DEPT spectrum of (43) (DMSO-D6; 400 MHz): Methyl and methyne groups as positive peaks and methylene groups as negative peaks. Fig. 3.10

87 Preparation of (29): 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 Na 2 SO 4 after washing with water (3 X 500 ml). The solvent was removed under reduced pressure at a temperature below 50 0 C. 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 0 0 C under nitrogen atmosphere. 261 ml of 3 M solution of methyl magnesium chloride in THF were added dropwise during 2-3 hours at 0-5 0 C. The reaction mass was maintained at 0-5 0 C for 6-7 hours, and cooled to 0 0 C. A mixture of acetic acid (90 ml) and water (750 ml) was slowly added at below 15 0 C for about one hour. The reaction mass was stirred at 25-35 0 C 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 Na 2 SO 4. 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 25-35 0 C 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 90 0 C, and stirred for 30 minutes until complete dissolution, cooled to 25-35 0 C, and maintained for 6-10 hours. The solid was filtered and washed with toluene (22 ml). The reprecipitation process was repeated four to five times. The solid was dried to afford about 17.4 grams of the purified (29). Preparation of (44): 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 25-35 0 C until clear dissolution. 2.3 ml (0.022 mol) of TBA (45) was added and the mass was stirred at 25-35 0 C. The separated solid was filtered, washed with acetone (20 ml) and dried at 40-50 0 C. The dried residue was reprecipitated 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). Preparation of (25): (44) obtained above and 50 ml of DCM were mixed at 25-35 0 C. A mixture of 0.5 ml of acetic acid and 25 ml of water was added to the mass, and stirred at 25-35 0 C 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 Na 2 SO 4. The solvent was removed under reduced pressure at a temperature below 45 0 C. 10 ml of MeOH were added to the residue. The solvent was removed again under reduced pressure at a temperature of below 45 0 C. A mixture of 0.307 grams of freshly prepared sodium pellets and 50 ml of MeOH was added to the residue at 25-35 0 C. 0.5 grams of carbon were added and the mass was stirred for about 30 minutes at 25-35 0 C. The carbon was filtered and washed with MeOH. The filtrates were combined and the solvent was removed under reduced pressure at a temperature below 45 0 C. The residue was re-dissolved in toluene (25 ml) and the solvent was removed again under reduced pressure at a temperature below 45 0 C. The residue was re-dissolved in toluene (5 ml) and added to a pre-filtered n-heptane under nitrogen atmosphere at 25-35 0 C. The mixture was stirred at 25-35 0 C 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 80 0 C to afford 3.2 grams of (25). Characterization 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 IR spectrum of (25): (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). Mass spectrum of (25) (ES-MS): m/z 586 corresponding to (29). 1 H-NMR spectrum of (25): (δ ppm) 0.4 (m, 4H, two CH 2 groups of cyclopropyl ring); 1.3 (s, 6H, CH 3 ); 2.0-3.2 (m, 8H, all CH 2 groups excluding CH 2 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). 13 C-NMR spectrum of (25): (δ ppm) 12.2 (CH 2 of cyclopropyl ring); 17.8 (C of cyclopropyl ring); 31 (CH 3 ); 43 & 39 (CH 2 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): Methyl and methyne groups as positive peaks and methylene groups as negative peaks.

91 3.5.2 - Experimental Section For The Second Novel Process For The Preparation Of Montelukast Sodium (25): Preparation of (47): 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 60 0 C for 30-45 minutes. Resulting mass was further cooled to -10 to -15 0 C. 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 -15 0 C. 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 -15 0 C. 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 -15 0 C and the reaction mass was aged at -10 to -15 0 C. 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 35 0 C for 30-40 minutes. Organic layer was washed with 64 ml of 5% NaHCO 3 solution followed by water. 1 gm of carbon and Na 2 SO 4 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 50 0 C to afford 8 g of (47). Characterization of (47): IR spectrum 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 1 H-NMR spectrum of (47) (CDCl 3, 400 MHz): (δ ppm) 0.4 (m, 4H, two CH 2 groups of cyclopropyl ring); 1.3 (s, 6H, CH 3 ); 2.0-3.2 (m, 8H, all CH 2 groups excluding CH 2 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 Preparation of (44): 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 118-122 0 C for 6 to 8 hours. 130 ml of water and 650 ml of toluene were added to the reaction mass below 90 0 C and stirred for 30 minutes. Separated the layers and the aqueous layer was extracted with 325 ml of toluene at 60-70 0 C. Combined organic layers were distilled under reduced pressure below 50 0 C and washed with 720 ml of n-heptane at 25-35 0 C. 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 50 0 C to afford (29). 500 ml of acetone was added to the above obtained crude and distilled of acetone under reduced pressure below 50 0 C to remove the traces of DCM. 21 gm (0.287 mol) of TBA (45) was added to the above reaction mass slowly at 25-30 0 C and seeded. The reaction mass was stirred till thick solid separation at 25-35 0 C for 8-10 hours. The separated solid was filtered and washed with acetone. It was then dried at 50-55 0 C to afford 40 gm of (44).

95 Purification of (44): 30 gm of (44) was dissolved in 360 ml of acetone and heated to reflux for 1 to 2 hours. Cooled to 25 0 C and the reaction mixture was maintained at the same temmperature for 10 hours. Solid was filtered, washed with acetone and dried at 60 0 C 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 NaHCO 3 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). Characterization of (44): IR spectrum of (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 Mass spectrum of (44) (ESI): m/z 586 correponding to (29).

97 Fig. 3.15 1 H-NMR spectrum of (44) (CDCl 3, 400 MHz): (δ ppm) 0.4 (m, 4H, two CH 2 groups of cyclopropyl ring); 1.2 (s, 9H, CH 3 of t-bunh 2 ); 1.6 (s, 6H, CH 3 of ter-alcohol); 2.2-3.2 (m, 8H, all CH 2 groups excluding CH 2 groups of cyclopropyl ring); 3.5 (s, 1H, OH); 4.0 (t, 1H, CH-S); 5.1 (s, 3H, + NH 3 ); 7.0-8.2 (m, 15H, Ar-H & vinyl CH). Fig. 3.16

98 Preparation of (25): 20.0 g (0.0303 mol) of (44) and DCM (50 ml) were added into round bottom flask at 25-35 0 C. Acetic acid (2.62 ml) and water (100 ml) were added to the reaction mass and was stirred at 25-35 0 C 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 50 0 C. Residual mass was dissolved in MeOH (200 ml) and distilled off solvent completely under reduced pressure below 50 0 C. 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 25-35 0 C under nitrogen blanketting and stirred for 30 minutes at 25-35 0 C. Carbon (0.5 grams) was added to reaction mass and stirred for 30 minutes at 25-35 0 C. Carbon was filtered and cake was washed with 25 ml of MeOH. Solvent was distilled off completely under reduced pressure below 50 0 C; the obtained crude was dissolved in toluene (40 ml) and distilled off solvent completely under reduced pressure below 50 0 C. Finally crude was dissolved in toluene (30 ml) and added to 200 ml of n-heptane under nitrogen atmosphere at 25-35 0 C. The reaction mass was maintained at 25-35 0 C for 1 to 2 hours. The compound was filtered and washed with

99 n-heptane (40 ml) under nitrogen atmosphere and dried at 70-75 0 C for 5 hours to afford 16.8 grams of (25) in amorphous form. Characterization of (25): IR spectrum of (25): (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 Mass spectrum of (25) (ESI): m/z 608 (25) and m/z 586 (29).

100 Fig. 3.18 1 H-NMR spectrum of (25) (DMSO, 400 MHz): (δ ppm) 0.2-0.4 (m, 4H, two CH 2 groups of cyclopropyl ring); 1.4 (s, 6H, CH 3 ); 1.9-3.1 (m, 8H, all CH 2 groups excluding CH 2 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 13 C-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 (CH 2 attached to cyclorpropyl ring); 31.7 (CH 3 ); 18.1 (C of cyclopropyl ring); 12.4 & 12.1 (CH 2 of cyclopropyl ring). Fig. 3.20 DEPT spectrum of (25) (DMSO-D6): Methyl and methyne groups as positive peaks and methylene groups 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 0 0 C, 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 0 0 C and the reaction mass was aged below 0 0 C for about 5 hours. After subsequent work up as described above afforded 400 mg of about 3:2 mixture of (47) and (50). Preparation of (46): 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 -12 0 C. 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 -12 0 C and stirred at -15 to -12 0 C. 484.5 ml of water was added to the

103 reaction mass under stirring below 0 0 C 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 0 0 C 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 50 0 C afforded 27.0 g of (46). Characterization of (46) IR spectrum 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. 1 H-NMR spectrum of (46) (CDCl 3, 200 MHz): (δ ppm) 0.6-0.7 (m, 4H, two CH 2 groups of cyclopropyl ring); 1.4 (t, 1H, SH); 2.6-2.9 (m, 4H, CH 2 ). 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 50 0 C 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): Preparation of (60): 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 -5 0 C with stirring. Above (39) solution in DCM was added to (-)-DIP-Cl in DCM at -5 to 0 0 C slowly drop wise. After addition, the reaction mixture was aged at -5 to 0 0 C for 10 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 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 50 0 C to yield 80 grams (yield: 80%) of (60). (Purity by HPLC: 97%). SR: of 32.9 0 (c=1 in chloroform). Characterization of (60): Apart from SR the following characterization data confirms the structure of (60). IR spectrum 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 Mass spectrum of (60) (ESI): m/z 458 (M + +1).

107 Fig. 3.25 1 H-NMR spectrum of (60) (CDCl 3, 200 MHz): (δ ppm) 2.1 (m, 4H, CH 2 -CH 2 ); 3.1 (s, 1H, OH); 3.9 (s, 3H, CH 3 ); 4.7 (m, 1H, CH-OH); 7.3-8.3 (m, 15H, Ar-H & vinyl CH). Fig. 3.26 Preparation of (35): 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 -5 0 C and added 280 ml (0.88 mol, 4

108 equivalents) of methyl magnesium chloride in THF slowly at a temperature of -5 to 0 0 C. After addition was complete, the reaction mixture was aged at -5 to 0 0 C 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 22.6 0 (c=1 in chloroform). Characterization of (35): IR spectrum of (35): (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 Mass spectrum of (35) (ESI): m/z 458. Fig. 3.28

110 1 H-NMR spectrum of (35) (DMSO-D6, 200 MHz): (δ ppm) 1.4 (s, 6H, CH 3 of t-alcohol); 2.0 (m, 2H, CH 2 -CH 2 ); 3.0 (m, 2H, CH 2 -CH 2 ); 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 Preparation of (62): (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). Characterization of (62): IR spectrum of (62): (cm -1 ) 3402 (OH str); 1713 (C=O str); 1220 (S=O str); 697 (C-S str). Fig. 3.30