Name: 151767-02-1|Sodium (R,E)-2-(1-(((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)thio)methyl)cyclopropyl)acetate|98%
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1
1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid R-(+)-α-methylbenzylamine salt [ No CAS ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium methylate; pyrographite; In toluene; at 25 - 30℃; for 1.5h;	The alpha-methyl benzyl amine salt (30 gm, 0.042mol) was dissolved in 240 ml toluene and to the resultant solution 2.4 gm of sodium methoxide (0.044mol) was added and the <n="17"/>contents stirred for 30 min at 25-30C followed by addition of 1.5 gm charcoal. The mass was stirred at 25-3O0C for 1 hr and filtered through celite. The clear filtrate was added drop-wise into 900 ml n-heptane. The product mass was stirred for an additional 10 min at 25-300C and filtered. The product was dried at 500C under vacuum to get 24 gm of montelukast sodium.Yield: 93% (of theory)Water content (by Karl Fisher): 1.3%Assay (by HPLC): 99.6%SOR: + 98.12 XRD: As per Fig-8

Reference： [1]Patent: WO2007/116240,2007,A1 .Location in patent: Page/Page column 15-16

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[ 1310-73-2 ]
[ 158966-92-8 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol; toluene at 20℃; for 1h;	5 Example 5: Preparation of Montelukast sodium 2.6 g of Montelukast acid were dissolved in 26 ml of toluene and 8.9 ml of 0.5M NaOH solution in methanol were added slowly at room temperature. The mixture was stirred for 1 hour and the solvent was removed under vacuum to obtain a residue. Then, heptane (24 ml) was added over 30 minutes to a well stirred solution of the residue in 4 ml of ethyl acetate at room temperature. Two hours after the addition, an off white solid was filtered off under a nitrogen atmosphere and washed with 5 ml of heptane. The wet product was dried under vacuum at 70-80 °C for 2 days to yield 2.7 g of Montelukast sodium (purity by HPLC: 99 area % ). Yield: 100%.
100%	In methanol; toluene at 2 - 20℃; for 0.75h;	28; 29 Example 28: Preparation of Montelukast sodium 2.6 g of Montelukast acid were dissolved in 26 ml of toluene and 8.9 ml of 0.5M NaOH solution in methanol were added slowly at room temperature. The mixture was stirred for 1 hour and the solvent was removed under vacuum to obtain a residue. Then, heptane (24 ml) was added over 30 minutes to a well stirred solution of the residue in 4 ml of ethyl acetate at room temperature. Two hours after the addition, an off white solid was filtered off under a nitrogen atmosphere and washed with 5 ml of heptane. The wet product was dried under vacuum at 70-80 °C for 2 days to yield 2.7 g of Montelukast sodium. Yield: 100%.Example 29: Preparation of Montelukast sodium 1.15 L of toluene were added to 115.2 g of Montelukast acid (e.e.: 99.9%). The mixture was cooled between 2 and 10 °C and 313.3 ml of 0.5M NaOH solution in methanol were added over 15 minutes. Then, the mixture was warmed to room temperature and stirred for 30 minutes. After this period of time, 1.5 L of the solvent were distilled off under reduced pressure at 30 °C. Then, 2.4 L of toluene were charged to the crude and the distillation was resumed to obtain a final volume of 300 ml. The solution of crude obtained was added over 1 hour to 1 L of heptane under stirring at room temperature. 18 hours after the addition, an off white solid was filtered off under a nitrogen atmosphere and washed with 500 ml of heptane. The wet product was dried under vacuum at 75 °C for 3 days to yield 120 g of Montelukast sodium. Yield: 100%. e.e.: 99.9%.
73%	In methanol at 20℃; for 1h;	6 Example 6: Preparation of Montelukast sodium 34.1 ml of 0.5M NaOH solution in methanol were added slowly at room temperature to 114.3 ml of the solution obtained in the Example 1. The mixture was stirred for 1 hour and the solvent was removed under vacuum to obtain a residue. Then, 90 ml of heptane were added over 30 minutes to a well stirred solution of the residue in 15 ml of ethyl acetate at room temperature. Two hours after the addition, an off white solid was filtered off under a nitrogen atmosphere and washed with 20 ml of heptane. The wet product was dried under vacuum at 70-80 °C for 2 days to yield 7.6 g of Montelukast sodium. Yield: 73%.

In methanol at 25 - 35℃; for 0.166667h;

25 EXAMPLE 25: PREPARATION OF MONTELUKAST SODIUM (FORMULA I)Sodium hydroxide pellets (1.69 g) and methanol (125 ml) were taken into a round bottom flask and stirred for about 15 minutes at 25 to 35 0C. A mixture of montelukast (25 g) in methanol (125 ml) was prepared and the solution of methanolic sodium hydroxide prepared above was added to it and stirred at 25 to 35 C for about 10 minutes. Activated carbon (2.5 g) was added to the solution and stirred for about 10 minutes at the same temperature. The mixture was then filtered over a celite bed and the bed was washed with methanol (50 ml). The combined filtrate was distilled under a vacuum of about 650 mm/Hg at a temperature of about 50 0C and the obtained solid was dried at about 70 °C for 7 hours to yield 24.5 g of the title compound. Purity By HPLC: 99.7% Chiral Purity: 99.9% Residual Solvents: Methanol: 545 ppm, All other solvents: Below LOD.

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1886997, 2008, A1 Location in patent: Page/Page column 8
[2]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1886998, 2008, A1 Location in patent: Page/Page column 10
[3]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1886997, 2008, A1 Location in patent: Page/Page column 8
[4]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2008/58118, 2008, A2 Location in patent: Page/Page column 43

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[ 158966-92-8 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In methanol; toluene; at 20℃; for 1h;	2.6 g of Montelukast free acid were dissolved in 26 ml of toluene and 8.9 ml of 0.5M NaOH solution in methanol were added slowly at room temperature. The mixture was stirred for 1 hour and the solvent was removed under vacuum to obtain a residue. Then, heptane (24 ml) was added over 30 min to a well stirred solution of the residue in 4 ml of ethyl acetate at room temperature. Two hours after the addition, an off white solid was filtered off under a nitrogen atmosphere and washed with 5 ml of heptane. The wet product was dried under vacuum at 70-80 C for 2 days to yield 2.7 g of amorphous solid form of Montelukast sodium. Yield: 100%. 1H NMR (400 MHz, DMSO-d6): 8.38 (1H, d, J: 8.6 Hz); 8.02-7.04 (14H, m); 5.19 (OH, s); 4.01 (1H, t, J: 7.2 Hz); 3.08 (1H, m); 2.72 (1H, m); 2.69 (1H, d, J: 12.4 Hz); 2.54 (1H, d, J: 12.4 Hz); 2.22 (1H, m); 2.10 (1H, d, J: 14.2 Hz); 2.10 (1H, m); 1.96 (1H, d, J: 14.2 Hz); 1.45 (3H, s); 1.44 (3H, s); 0.46-0.32 (2H, m); 0.28-0.15 (2H, m).
98%	With sodium hydroxide; In methanol; water; toluene; for 0.5h;Alkaline aqueous solution;Product distribution / selectivity;	5 g of l-(((l-(R)-(3-(2-(7-chloro-2-quinolidyl)ethenyl)phenyl)-3-(2- ( 1 -hydroxy- 1 -methyl-ethy l)pheny l)propy l)thio)methy l)cy clopropy lacetic acid obtained in step 2 was mixed with 10 ml of toluene, followed by removing the solvent under reduced pressure to remove the solvent. To the residue thus obtained, 14.5 ml of toluene and 13 ml of 0.5N NaOH/MeOH solution were sequentially added. The resulting mixture was stirred for 30min, followed by removing the solvent under reduced pressure. The residue was dissolved in 10 ml of toluene and 50 ml of n-hexane, and the product was recrystallized therefrom. The crystallized product was filtered to obtain 5.1 g (98%) of the title compound as a pale yellow solid.1H-NMR (300MHz, CD3OD) : delta 8.29 (IH, d), 7.99 (IH, s), 7.83-7.91 (3H ,m), 7.72 (IH ,s), 7.49-7.52 (2H, m), 7.38-7.44 (4H, m), 7.10-7.15 (3H, m), 4.04 (IH ,t), 3.08 (IH, m), 2.82 (IH, m), 2.66 (IH, d), 2.52 (IH, d), 2.43 (IH, d), 2.29 (IH, d), 2.16-2.24 (2H, m ), 1.52 (6H, s), 0.33-0.52 (4H, m)
98.70 - 98.79%	With sodium hydroxide; In methanol; at -5 - 35℃; for 1h;	To a stirred and cooled (0 to -5C) solution of sodium hydroxide (3.6 g, 0.09 mol.) inmethanol (250 ml), pure montelukast acid (VI) (50 g, 0.085 mol) was slowly added insmall lots. After stirring at 0 to -5C for 30 minutes, the temperature of the reactionmixture was raised to +25 to +35C and stirred for 30 minutes. Activated charcoal (1.25 g)was added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35C, themixture was filtered through a high-flow-bed and washed with methanol (50 ml).Methanol was thencarefully evaporated under vacuum < 40C and the residue was stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35C. The white solid was carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40C under vacuum toobtain Montelukast sodium (I) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. The powder XRD analysis of the sample indicated it to be amorphous (Figure 1) and XRD data is given below.

98.8%	With pyrographite; sodium sulfate; In tetrahydrofuran; at 8 - 15℃; for 2h;	4) To a 1000 mL three-necked flask, 30 g of montelukast acid, 300 mL of tetrahydrofuran were added successively, and 2.05 g1.5g of activated carbon, 4.5g of anhydrous sodium sulphate were added in succession, the temperature was controlled at 8-15 C for 2 hours, filtered, 150 mL of cyclohexane was added and the temperature was controlled at 2 to 10 C for 1 hour , Filtering and vacuum drying for 24 hours at 70 DEG C to obtain montelukast sodium, the yield is 98.8%, the purity is 99.9%, and the impurity content of styrene and sulfoxide is less than 0.02%.
98%	With sodium hydroxide; In methanol; at 20℃; for 0.5h;Darkness;	Room temperature, dark room,0.70 g of sodium hydroxide and 50 mL of methanol were placed in a round bottom flask,Stirred for 15 minutes, and then added to the lye dissolved l0gMontelukast acid in 50ml methanol,The reaction was stirred for 30 minutes,Then add activated carbon lg, stirring 30 minutes, and then filtered, the filtrate was concentrated to dry, vacuum drying the product 10. 2g, the yield was 98.0%, HPLC> 99.6%, isomer content <0 ? 1% .
95%	With sodium hydroxide; In methanol; at 20℃; for 0.5h;pH 9-10;	A solution of the compound of formula I '(9.8 g, 16.7 mmol)Dissolved in 60 mL of methanol,Methanol solution of sodium hydroxide was slowly added dropwise at room temperature,When the pH of the reaction solution is 9 to 10,Stop dropping, stirring 30min,The solvent was evaporated under reduced pressure and the residue was dissolved in 30 mL of toluene,Then 100 mL of n-heptane was slowly added dropwise,After the addition of 4h,Filtration, the solid at 50 ~ 60 vacuum drying 12h,That is, montelukast sodium 9.6g, the yield was 95%.
94%	With sodium hydroxide; In methanol;Inert atmosphere;	In a nitrogen atmosphere, 25 ml of methanol was added to 5.0 g of montelukast free acid and stirred A solution obtained by dissolving 0.35 g of sodium hydroxide in 10 ml of methanol Was added. After confirming that all of the solid was dissolved, the solvent was distilled off under reduced pressure to obtain an oily matter Crude montelukast sodium was obtained. 25 ml of isopropyl acetate was added to the obtained crude montelukast sodium, and the mixture was stirred and mixed , The obtained solution was added dropwise to 150 ml of heptane cooled to 0 C. and kept at the same temperature for 30 minutes . The precipitated solid was collected by filtration by pressure filtration, washed twice with 5 ml of heptane, and the obtained wet body Was dried at 80 C. under reduced pressure for 24 hours to obtain 4.9 g of amorphous montelukast sodium ( Purity 99.8%, isopropyl acetate residual amount 401 ppm, heptane residual amount 991 ppm) (Yield 94%). Amorphous of montelukast sodium obtained is white It was.
92.8 - 97.73%	With sodium hydroxide; In water; at 20℃;Product distribution / selectivity;	Step d) Preparation of sodium 1- [ [ [ (IR) -1- [3- [ (IE) -2- (7- chloroquinoline-2-yl) ethenyl]phenyl] -3- [2- (1-hydroxy-l- methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetate (Ib); Montelukast (Ia) obtained in the previous step was added on an aqueous solution containing 1 equivalent of NaOH. The resulting mixture was stirred at room temperature till a solution was obtained. The resulting solution was filtered and dried at the rotatory evaporator at 50 0C, resulting in the isolation of montelukast sodium (Ib) (92.8% yield, 98.78% purity by HPLC, Titration = 100.29%, Water content (Karl Fischer (K.F.)) = 2.90%); Example 5. Preparation of montelukast sodium (Ib) from a basic aqueous solution of the montelukast (Ia); 50.05 g (titration = 99.91%, 0.085 mols) of montelukast (Ia) (obtained following the same protocol as described in example 4) were added to a basic aqueous solution prepared by mixing 3.927 g (0.097 mols) of sodium hydroxide in 865.00 ml of water. The resulting suspension was stirred until a yellow solution was obtained, which was titrated with tetra n-butyl ammonium hydroxide to check that the salification was complete.The yellow solution was filtered to remove any particulates impurities, resulting in a clear solution, that was lyophilized in a LYOBETA 25 (cycle: 3.3Oh freezing at -45C and 17 h primary drying at -1O0C, 0.200 mbar)The process took one day, after which a yellow porous solid (Ib) was obtained (53.70 g, 97.73% yield, 97.38% purity by HPLC, assay 99.85%, water content (KF) = 5.76%, lod (loss on drying) = 3.47% (8O0C, 3 hours), [alpha] = +91.17, (c = 1%; D = Methanol; Ta = 200C) EPO <DP n="19"/>
87%	In methanol; ethanol; at 25 - 50℃; for 0.5h;Product distribution / selectivity;	Dissolved Montelukast free acid (100 g) in methanol (800 ml) by raised the temperature to 50 C., cooled the clear solution to 25 C.-30 C. and added 0.486 molar solution of 1% aqueous ethanol solution (352 ml) over 30 min. Maintained the mass at 25 C.-30 C. for 30 min. and treated the solution with activated carbon, Filtered off the carbon, distilled the solvents from filtrate at temperature below 40 C. under reduced pressure to get residue. Added toluene (100 ml) and again distilled off under reduced pressure to remove traces of methanol, Ethanol. Dissolved the residue in toluene (1000 ml), raised the temperature and maintained at 45 C.-50 C. Cooled the solution to 30 C.-35 C., added carbon, mixed for 15 min and filtered off the carbon. Added n-Heptane (3000 ml) slowly to the clear filtrate over 1 hr at temperature 25 C.-30 C. and maintained for 3 hrs. Filtered the product, washed with n-Heptane (50 ml) and dried at 80 C.-90 C. under vacuum till constant weight.Dry weight of Montelukast sodium is 90 g (87%)
87%	With sodium hydroxide; In methanol; ethanol; water; at 25 - 50℃;Product distribution / selectivity;	Example- 10: Preparation of Montelukast sodium from Montelukast free acid Dissolved Montelukast free acid (100 g) in methanol (800 ml) by raised the temperature to 50C, cooled the clear solution to 25C - 30C and added 0.486 molar solution of 1% aqueous ethanol solution (352 ml) over 30 min. Maintained the mass at 25C - 30C for 30 min. and treated the solution with activated carbon, Filtered off the carbon, distilled the solvents from filtrate at temperature below 40C under reduced pressure to get residue. Added toluene (100 ml) and again distilled off under reduced pressure to remove traces of methanol, Ethanol. Dissolved the residue in toluene (1000 ml), raised the temperature and maintained at 45C - 50C. Cooled the solution to 30C - 35C, added carbon, mixed for 15 min and filtered off the carbon. Added n-Heptane (3000 ml) slowly to the clear filtrate over 1 hr at temperature 25C - 30C and maintained for 3 hrs. Filtered the product, washed with n-Heptane (50 ml) and dried at 80C - 90C under vacuum till constant weight. Dry weight of Montelukast sodium is 90 g (87%) The product is identical with the Montelukast sodium obtained in the prior art methods.
80 - 90%	With sodium methylate; In methanol;pH 8.43;Product distribution / selectivity;	Example 6; Purified montelukast acid (85 mmol) was treated with 248 mL 0.31 N (77 mmol) sodium methoxide methanol solution (previously degassed), and additional 16.5 mL sodium methoxide was added until a pH of 8.43 was obtained. Most of the methanol was then removed under reduced pressure at less than 50 C. Water was added to the resulting crude oil, and the residual methanol was distilled off. Additional water was added to a final volume of 1,060 mL. The aqueous solution was then filtered, the residual methanol being 3.0% as determined by GC and the purity being 99.8% as determined by HPLC. The aqueous montelukast sodium was subjected to spray drying, and the results were listed in Table 6.
52.8%		Example - 1: Preparation of amorphous montelukast sodium; Montelukast free acid (70 g) is dissolved in methanol (210 ml), 0.486 molar solution of sodium hydroxide in ethanol (230 ml) is added, mixed for about 10-15 min, filtered the resultant reaction mass through hyflow bed, washed the bed with 35 ml methanol. The clear solution is spray dried with spray drier at inlet temperature of HO0C, outlet temperature of 730C to 750C, nitrogen flow rate of 40-50 mm, with a solution feed rate of 30%.Dry wt of the amorphous sodium is 62.0 g, (yield of 52.8%).
	With sodium hydroxide; In acetone; at 20℃; for 5h;Product distribution / selectivity;	EXAMPLE 5 Preparation of Montelukast Sodium in Acetone and Instant Drying Montelukast acid (3 g), NaOH powder (0.24 g, 1.2 eq), and acetone (9 mL) were added to a 100 mL flask equipped with a mechanical stirrer. The reaction was stirred at ambient temperature for 5 hours. The reaction mixture was slowly added dropwise into a 500 mL reactor under vacuum of 1 mm Hg and heated at 35 C. Every drop added was immediately evaporated before reaching the sides or bottom of the reactor. After the end of the addition, the mechanical stirrer was switched on to break the foam formed. The reactor was inverted to collect the powder produced.
	With sodium hydroxide; In methanol; at 20℃; for 2h;Product distribution / selectivity;	EXAMPLE 7 Preparation of Montelukast Sodium in MeOH and Instant Drying Montelukast acid (3 g), NaOH powder (0.24 g, 1.2 eq), and MeOH (15 mL) were added to a 100 mL flask equipped with a mechanical stirrer. The reaction was stirred at ambient temperature for 2 hours until a clear solution was obtained. The reaction mixture was slowly added dropwise into a 500 mL reactor under vacuum of 1 mm Hg and heated at 25 C. Every drop added immediately evaporated before reaching the sides or bottom of the reactor. After the end of the addition, the mechanical stirrer was switched on to break the foam formed. Then the reactor was inverted to collect the powder produced. The characterization of mupirocin calcium is carried out according to WO03/06595 (US 2004/024052).
	With sodium hydroxide; In ethanol;Product distribution / selectivity;	Step d) Preparation of sodium 1- [ [ [ (IR) -1- [3- [ (IE) -2- (7- chloroquinoline-2-yl) ethenyl]phenyl] -3- [2- (1-hydroxy-l- methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetate (Ib); One equivalent of IN NaOH is added to an ethanolic solution of montelukast (Ia) , obtained in the previous step c) . The solvent is evaporated and water is added to the resulting residue till a solution is obtained. The resulting solution is concentrated to dryness with a rotatory evaporator at 50 0C, resulting in the isolation of compound (Ib) .
	With sodium hydroxide; In tetrahydrofuran; water; at 20 - 25℃; for 0.5h;Product distribution / selectivity;	EXAMPLE 5 1-[1 (R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thiomethyl)-cyclopropaneacetic acid sodium salt (I) The solution of the acid from Example 4 was transferred into a 250 ml flask fitted with a mechanical stirrer and a thermometer. 1 equivalent of 1N NaOH was added and stirring of the mixture was continued at 20-25 C. for 30 minutes. The phases were separated and the aqueous phase was freeze-dried. 45 g of a light yellow solid were obtained in this manner (HPLC A%=99.5%). 1H-NMR(CDCl3): ppm 0.15-0.20 (d, 2H); 0.40 (d, 2H); 1.50 (s, 3H); 1.55 (s, 3H); 2.1-2.25 (m, 4H); 2.3-2.5 (dd, 2H); 2.70 (t, 1H); 3.25 (t, 1H); 4.5 (s, 1H) 6.95-8.0 (m, 15H).
		Example - 1: Preparation of amorphous montelukast sodiumMontelukast free acid (70 g) is dissolved in methanol (210 ml), 0.486 molar solution of sodium hydroxide in ethanol (230 ml) is added, mixed for about 10-15 min, filtered the resultant reaction mass through hyflow bed, washed the bed with 35 ml methanol. The clear solution is spray dried with spray drier at inlet temperature of HO0C, outlet temperature of 730C to 750C, nitrogen flow rate of 40-50 mm, with a solution feed rate of 30%.Dry wt of the amorphous sodium is 62.0 g, (yield of 52.8%). EPO <DP n="7"/>XRD is as shown in Fig.1.The various solvents used for dissolution of montelukast free acid and the parameters of Spray drier to obtain amorphous montelukast sodium is given in below (Table - 1)
		Example - 1: Preparation of amorphous montelukast sodiumMontelukast free acid (70 g) is dissolved in methanol (210 ml), 0.486 molar solution of sodium hydroxide in ethanol (230 ml) is added, mixed for about 10-15 min, filtered the resultant reaction mass through hyflow bed, washed the bed with 35 ml methanol. The clear solution is spray dried with spray drier at inlet temperature of HO0C, outlet temperature of 730C to 750C, nitrogen flow rate of 40-50 mm, with a solution feed rate of 30%.Dry wt of the amorphous sodium is 62.0 g, (yield of 52.8%). EPO <DP n="7"/>XRD is as shown in Fig.1.The various solvents used for dissolution of montelukast free acid and the parameters of Spray drier to obtain amorphous montelukast sodium is given in below (Table - 1)
		Example - 1: Preparation of amorphous montelukast sodiumMontelukast free acid (70 g) is dissolved in methanol (210 ml), 0.486 molar solution of sodium hydroxide in ethanol (230 ml) is added, mixed for about 10-15 min, filtered the resultant reaction mass through hyflow bed, washed the bed with 35 ml methanol. The clear solution is spray dried with spray drier at inlet temperature of HO0C, outlet temperature of 730C to 750C, nitrogen flow rate of 40-50 mm, with a solution feed rate of 30%.Dry wt of the amorphous sodium is 62.0 g, (yield of 52.8%). EPO <DP n="7"/>XRD is as shown in Fig.1.The various solvents used for dissolution of montelukast free acid and the parameters of Spray drier to obtain amorphous montelukast sodium is given in below (Table - 1)
		Example - 1: Preparation of amorphous montelukast sodiumMontelukast free acid (70 g) is dissolved in methanol (210 ml), 0.486 molar solution of sodium hydroxide in ethanol (230 ml) is added, mixed for about 10-15 min, filtered the resultant reaction mass through hyflow bed, washed the bed with 35 ml methanol. The clear solution is spray dried with spray drier at inlet temperature of HO0C, outlet temperature of 730C to 750C, nitrogen flow rate of 40-50 mm, with a solution feed rate of 30%.Dry wt of the amorphous sodium is 62.0 g, (yield of 52.8%). EPO <DP n="7"/>XRD is as shown in Fig.1.The various solvents used for dissolution of montelukast free acid and the parameters of Spray drier to obtain amorphous montelukast sodium is given in below (Table - 1)
		Example - 1: Preparation of amorphous montelukast sodiumMontelukast free acid (70 g) is dissolved in methanol (210 ml), 0.486 molar solution of sodium hydroxide in ethanol (230 ml) is added, mixed for about 10-15 min, filtered the resultant reaction mass through hyflow bed, washed the bed with 35 ml methanol. The clear solution is spray dried with spray drier at inlet temperature of HO0C, outlet temperature of 730C to 750C, nitrogen flow rate of 40-50 mm, with a solution feed rate of 30%.Dry wt of the amorphous sodium is 62.0 g, (yield of 52.8%). EPO <DP n="7"/>XRD is as shown in Fig.1.The various solvents used for dissolution of montelukast free acid and the parameters of Spray drier to obtain amorphous montelukast sodium is given in below (Table - 1)
		Example - 1: Preparation of amorphous montelukast sodiumMontelukast free acid (70 g) is dissolved in methanol (210 ml), 0.486 molar solution of sodium hydroxide in ethanol (230 ml) is added, mixed for about 10-15 min, filtered the resultant reaction mass through hyflow bed, washed the bed with 35 ml methanol. The clear solution is spray dried with spray drier at inlet temperature of HO0C, outlet temperature of 730C to 750C, nitrogen flow rate of 40-50 mm, with a solution feed rate of 30%.Dry wt of the amorphous sodium is 62.0 g, (yield of 52.8%). EPO <DP n="7"/>XRD is as shown in Fig.1.The various solvents used for dissolution of montelukast free acid and the parameters of Spray drier to obtain amorphous montelukast sodium is given in below (Table - 1)
		Example - 1: Preparation of amorphous montelukast sodiumMontelukast free acid (70 g) is dissolved in methanol (210 ml), 0.486 molar solution of sodium hydroxide in ethanol (230 ml) is added, mixed for about 10-15 min, filtered the resultant reaction mass through hyflow bed, washed the bed with 35 ml methanol. The clear solution is spray dried with spray drier at inlet temperature of HO0C, outlet temperature of 730C to 750C, nitrogen flow rate of 40-50 mm, with a solution feed rate of 30%.Dry wt of the amorphous sodium is 62.0 g, (yield of 52.8%). EPO <DP n="7"/>XRD is as shown in Fig.1.The various solvents used for dissolution of montelukast free acid and the parameters of Spray drier to obtain amorphous montelukast sodium is given in below (Table - 1)
	With sodium hydroxide; In methanol; water; toluene; at 25 - 50℃; for 0.833333h;	Example 16 - Montelukast sodium amorphous[0105] 2.0 g of Montelukast was dissolved in 5 ml of a toluene-methanol mixture (4: 1 v/v) at 500C. The turbid solution was cooled under stirring to 25C. Atthis temperature, 0.33 ml of aqueous NaOH solution (0.15 g, 3.75 mmol) was addeddropwise within 20 minutes. The solution was maintained at this temperature for 30minutes, 0.05 g of activated charcoal was added and the suspension was filteredthrough Celite filter. The Celite was washed with 2x2 ml of toluene. The combined solution was evaporated almost to dryness under reduced pressure at bath temperature38C . Yellow viscous oil was obtained.[0106] The oil was added dropwise into 10 ml of stirred n-heptane and stirredfor 15 minutes at 25C. White precipitate was formed. Then the mixture was stirred at250C for next 17 hours. The precipitate was filtered by suction, washed with 2x10 ml of n-heptane and dried at room temperature protected from light. Yield 1.85 g of whiteamorphous solid.
	With sodium hydroxide; In dichlorometnane; water; at 20℃;pH 10.5;	Another three-necked flask equipped with a thermometer, a nitrogen inlet and a magnetic stirrer was charged at room temperature with 6.7 g (0.0459 moles) of 1-(mercaptomethyl)cyclopropaneacetic acid and 48 ml of NMP under stirring and under nitrogen atmosphere to obtain a solution. 4.5 g of NaOH flakes (0.1125 moles) was added in one portion at room temperature followed by addition of 2.4 ml of water, and stirring was maintained for 1 hour to afford a suspension. The solution of compound (III) in about 50 ml THF, which was kept at 5 C., was added in portions at ambient temperature. After completing the addition, the mixture was stirred for 2 hours and reaction completion was checked by HPLC. 130 ml of toluene was added to the reaction mixture along with 130 ml of 5% sodium chloride solution, and the mixture was stirred for 20 minutes. Then, the layers were separated and the upper organic layer was washed with 130 ml of 5% sodium chloride solution, and the layers were separated. 84 ml of 0.5 M tartaric acid solution was added to the upper layer and the layers were separated. The upper layer was washed with 40 ml of water and again separated. The organic layer was distilled to dryness to afford an oily residue. 90 ml of toluene was added to the residue under stirring to obtain a solution. 3.1 ml of cyclooctylamine (0.0226 moles) was added and stirring was maintained for few minutes and the solution was seeded with crystalline montelukast acid cyclooctyl ammonium salt. Stirring was maintained at room temperature to afford a suspension, which was filtered off to obtain a cake. The cake was washed with toluene and dried at 40 C. in vacuum to afford 9.88 g of dry crude montelukast acid cyclooctyl ammonium salt in 70% yield, having 98% purity (according to HPLC). The crude montelukast cyclooctyl ammonium salt was crystallized from toluene containing about 2% of methanol to obtain a product having 99% purity (according to HPLC). 30 ml of dichloromethane was added followed by addition of 17 ml of 0.5M citric acid solution. The mixture was stirred at room temperature for half an hour to afford a two phase system. The layers were separated and the organic layer (containing the montelukast acid) was washed with 3×15 ml water, the layers were separated and the aqueous layer was removed. 20 ml of water was added under stirring followed by addition of 4 ml of 1M NaOH solution and stirring was maintained for about 5 minutes. The dichloromethane was distilled off at a temperature lower than 35 C. The pH was checked and 1 M NaOH solution was added drop-wise until the pH value was about 10.5. The aqueous layer (containing the desired end product) was freeze-dried to obtain 8.3 g of montelukast sodium in 99% yield having a purity of 99.8% (according to HPLC).
	With sodium methylate; In methanol; toluene; for 0.5h;	Example 2 - Preparation of (RVl-ri-(3-('2-(7-chloro-2-quinolinylVethenyl)-phenylV3-fr2-ri- hvdroxy-l-methylethvD-phenvD-propylVthioi-cyclopropaneacetic acid sodium salt, Montelukast Sodium (Compound 10, Scheme 2); To a stirred solution of the title compound of Example 1, montelukast free acid, (5.7 g), in dry toluene (4OmL), sodium methoxide (0.55g) in methanol was added. The resulting mixture was stirred for 30 minutes and diisopropyl ether (25OmL) was added dropwise over a period of 60 minutes. White solid started to precipitate. The white solid was then filtered off, washed with diisopropyl ether and dried under vacuum. The title compound, montelukast sodium, was obtained as an amorphous white solid (5.2g, 98.2 area%).
	With sodium hydroxide; In methanol; at 25 - 30℃; for 1h;	Example 16 : Preparation of Montelukast sodiumMontelukast -Isopropylamine salt (10 gm), methylene chloride (100 ml) and water (100 ml) was charged under nitrogen atmosphere and stirred for 10 minutes. The pH of the reaction mass was adjusted to 4.0-4.5 with 10% acetic acid solution, separated methylene chloride layer and extracted the aqueous layer with methylene chloride (50 ml), the combined methylene chloride layer was dried over sodium sulphate (5 gm) and distilled off methylene chloride completely under vacuum at 25-3O0C to residue. The residue was dissolved in methanol (60 ml), a solution of sodium hydroxide in methanol (0.68 gm in 30 ml of methanol) was added and stirred for 1 hour at 25-3O0C, clarified, distilled off methanol completely under vacuum at less than 350C, stripped off methanol with ethyl acetate (50 ml x 3) to residue, the residue was dissolved in toluene (30 ml), n-heptane (100 ml) was added dropwise under nitrogen atmosphere at 25-300C and stirred for 30 minutes, filtered the material so obtained was dried under vacuum at 70-800C for 24 hours to give Montelukast sodium (8.5 gm, 90% yield, 99% HPLC purity).
	With sodium hydroxide; In methanol; toluene; at 20℃; for 1h;Product distribution / selectivity;	Montelukast arginine salt (4.14 g) was dissolved in toluene (100 mL) . Acetic acid (1 mL) in water {100 mL) was added. The mixture was stirred at rt for 30 min, and layers separated. To organic layer, solution of sodium hydroxide (218 mg) in methanol (12 mL) was added, and stirred at rt for 1 hr . The solvent is completely disstiled off under vacuum at below 500C to afford the residue. The residue is dissolved in toluene (40 mL} and charcoal was added and stirred at 400C for 2 hrs . The reaction mixture was filtered, and concentrated under vacuum to -20 mL. The mixture was dropwise added to hexane (60 mL) and stirred under nitrogen 18 hrs. The product is filtered under nitrogen and washed with hexane (20 mL) , and dried under vacuum at 4O0C for 12 hrs to yield amorphous form of montelukast sodium (2.07 g) .; Example 171 Montelukast sodiumTo the solution of montelukast acid (2.5 g) prepared by the processes as disclosed in the previous examples or by any processes known from the prior art in toluene (50 mL) solution of sodium hydroxide (218 mg) in methanol (12 mL) was added, and stirred at rt for 1 hr. The solvent is completely disstiled off under vacuum at below 500C to afford the residue. The residue is dissolved in toluene (40 mL) and charcoal was added and stirred at 400C for 2 hrs. The reaction mixture was filtered, and concentrated under vacuum to -20 mL. The mixture was dropwise added to hexane (60 mL) and stirred under nitrogen 18 hrs. The product is filtered under nitrogen and washed with hexane (20 mL) , and dried under vacuum at 400C for 12 hrs to yield amorphous form of montelukast sodium (1.95 g) .
	With sodium hydroxide; In tetrahydrofuran; water;Product distribution / selectivity;	Example 5; Montelukast cyclohexylamine salt suspended in toluene (5 parts) was treated with aqueous acetic acid (5 parts) until a pH of 5.05.5 was reached. The organic phase was separated and washed with water (5 parts) twice, and the resulting organic layer was concentrated to provide a crude oil of montelukast acid. The montelukast acid (100.0 g, 170.2 mmol) thus obtained was dissolved in 500 mL THF, and then 78 mL of ca. 2N NaOH aqueous solution was added under nitrogen. After stirring for several minutes, the solvent was removed under reduced pressure at 30 C. to afford montelukast sodium as a crude oil. The crude oil was taken up in 2.5 L water and concentrated to remove the remaining THF until the total volume was about 2.7 L (THF remained as analyzed by GC was 1.7%). The aqueous solution of montelukast sodium was filtered, and its purity was determined by HPLC (99.7%). The filtered solution was subjected to spray drying at various conditions, and the results were listed in Table 5.
	With sodium hydroxide; In methanol; at 30℃; for 0.5h;	EXAMPLE 10: PREPARATION OF MONTELUKAST SODIUM (FORMULA I).; Sodium hydroxide pellets (0.34 g) were dissolved in methanol (25 mL) and stirred for about 30 minutes. Montelukast acid (5 g) obtained by the procedure of Example 2 was charged into a round bottom flask followed by addition of methanol (25 mL) and stirring for about 15 minutes. The sodium hydroxide and montelukast acid solutions were combined and stirred for about 30 minutes at 30+/-5C. Carbon (0.5 g) was charged and the mixture was filtered through a Hyflow bed and washed with methanol (10 mL). The filtrate was distilled completely under reduced pressure at a temperature of about 500C and the residue was dried at about 700C for 4 hours to yield the title compound. Yield 4.6 g, chemical purity by HPLC 99.7%, sulphoxide impurity 0.03%, stryrene impurity 0.057%, keto impurity 0.07%, chiral purity by HPLC 99.9%.
	With sodium hydroxide; In methanol; at 20 - 25℃; for 5h;	Example 6: Preparation of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt <n="17"/>; Sodium hydroxide (1.2 gm) was added to a solutin of [R- (E)]-l-[[[l-[3-[2-(7-chloro- 2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid (7 gm) in methanol ( 42 ml) at 25C. The resulting reaction mixture was stirred 5 hours at 20C to 25C and then concentrated under reduced pressure to get slurry. The slurry was treated with acetonitrile (40 ml) to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3 -[2-(I -hydroxy- 1- methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt. Yield: 6.2 gm
	With sodium hydroxide; In 4-methyl-2-pentanone; at 0 - 20℃; for 0.5h;Inert atmosphere;Product distribution / selectivity;	In a 5 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 100 g (0.1706 moles) montelukast acid was suspended in methyl isobutyl ketone (800 ml) under nitrogen atmosphere at room temperature, stir for 30 min and cool to 0-10 0C. Add 0.5 M NaOH solution in methanol (360 ml) at 0-10 0C and stir for 30 min. Charcoalise the product for 1 5 min. and filter through hyflo. Solvent was recovered under vacuum at 40-45 0C. Add methyl isobutyl ketone (100 ml) and recovery continued under vacuum. Remove traces of methyl isobutyl ketone under vacuum at 40-45 0C. Add n-Heptane ( 1 ltr.) to the product and stir for 4-6 hrs. Filter the product under nitrogen atmosphere and dry the material at 45-50 0C to get montelukast sodium (95 g, HPLC purity 99.4%)
	With sodium hydroxide; In Isopropyl acetate; water; at 20 - 25℃; for 0.5h;Product distribution / selectivity;	EXAMPLE 5 1-[1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thiomethyl)-cyclopropaneacetic acid sodium salt (I) The solution of the acid from Example 4 was transferred into a 250 ml flask fitted with a mechanical stirrer and a thermometer. 1 equivalent of IN NaOH was added and stirring of the mixture was continued at 20-25C for 30 minutes. The phases were separated and the aqueous phase was freeze-dried. 45 g of a light yellow solid were obtained in this manner (HPLC A% = 99.5%). 1H-NMR(CDCl3): ppm 0.15-0.20 (d, 2H); 0.40 (d, 2H); 1.50 (s, 3H); 1.55 (s, 3H); 2.1-2.25 (m, 4H); 2.3-2.5 (dd, 2H); 2.70 (t, 1H); 3.25 (t, 1H); 4.5 (s, 1H) 6.95-8.0 (m, 15H). EXAMPLE 8 1-[1 (R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thiomethyl)-cyclopropaneacetic acid sodium salt (I) The solution of the acid from Example 7 was transferred into a 250 ml flask fitted with a mechanical stirrer and a thermometer. 1 equivalent of IN NaOH was added and stirring of the mixture was continued at 20-25C for 30 minutes. The phases were separated and the aqueous phase was freeze-dried. 45 g of a light yellow solid were obtained in this manner (A% 99.5%).
	With sodium hydroxide; In ethanol; di-isopropyl ether; at 8 - 12℃; for 1.5h;	Montelukast free acid (100 gms.) is suspended in Di-isopropyl ether (700 ml) under Nitrogen at 25-300C. Stirred for 5 minutes and cooled at 8C under Nitrogen. 0.486- M Ethanolic NaOH solution (350ml) is slowly added at 8-12C under Nitrogen over 60 minutes. Stirred at 8-12C under Nitrogen for 30 minutes and treated with activated carbon at 8-120C. Filtered the carbon over hyflow bed and washed the bed with Diisopropyl ether (200 ml) at 10-150C. Filtrate is distilled off completely under vacuum at temperature below 400C and apply high vacuum for removing the traces to get white sticky material. n-Heptane (100ml) is charged to the sticky mass and distilled off solvent traces under vacuum at temperature below 400C to get sticky material. Again n-Heptane (2000 ml) is charged at 25-35C under Nitrogen. Stirred at 25-35C under Nitrogen for 8 hours. Precipitated product is filtered and washed with n-Heptane (200ml). Dried the product at 50-550C under high vacuum for 2 hours 700C / 6 hrs and at 85-95C for 3 hours. Out put: 90gms
		The reactor is charged with toluene (8.8 kg) and montelukast acid (0.6 kg, 1.024 mol) and the reactor is cooled to 0-5C. The ethanolic solution of sodium hydroxide (47 g of NaOH in 2.2 L of ethanol) is added dropwise to the solution of montelukast acid in toluene during 30 min, maintaining the temperature of solution below 5C. Thereafter, the reaction mixture is stirred at 20-30C for 2 hrs, than activated carbon is added and solution stirred at the same temperature for 2 hr. The reaction mixture is filtrated and activated charcoal is washed with the mixture of ethanol and toluene. Filtrate is concentrated to about 1/4 of the volume. To the crystallization reactor heptane (10 kg) is added and the solution of Montelukast sodium in toluene is added dropwise for 2 hrs (temperature is 15-25C), and after the addition, the reaction mixture is stirred for 2 hrs at the same temperature. The solution is transferred to the centrifuge, filtrated and crystalline product is washed with heptane. The material is transferred to a drier, and dried. The final product is amorphous montelukast sodium.
	With sodium hydroxide; In ethanol; toluene; at 0 - 30℃; for 2.5h;Industry scale;	The reactor is charged with toluene (8.8 kg) and monteiukast acid (0.6 kg, 1.024 mol) and the reactor is coo.ed to 0-5C. The ethanolic solution of sodium hydroxide (47 g of NaOH in 2.2 L of ethanol) is added dropwise to the solution of montelukast acid in toluene during 30 min, maintaining the temperature of solution below 5C. Thereafter, the reaction mixture is stirred at 20-30C for 2 hrs, than activated carbon is added and solution stirred at the same temperature for 2 hr. The reaction mixture is filtrated and activated charcoal is washed with the mixture of ethanol and toluene. Filtrate is concentrated to about ¼ of the volume. To the crystallization reactor heptane (10 kg) is added and the solution of Montelukast sodium in toluene is added dropwise for 2 hrs (temperature is 15-25C), and after the addition, the reaction mixture is stirred for 2 hrs at the same temperature. The solution is transferred to the centrifuge, filtrated and crystalline product is washed with heptane. The material is transferred to a drier, and dried.The final product is amorphous montelukast sodium.
	With methanol; sodium hydroxide; at -5 - 30℃; for 1h;	Step 2: preparation of montelukast sodium: Sodium hydroxide (3.6 g, 0.09 mol) was dissolved in methanol (250 ml) under an atmosphere of nitrogen gas at 25-30 C. After complete dissolution, the reaction mixture was cooled slowly to 0 to -5 C. Organic layer (as obtained in step I) was added to the resulting reaction mixture and at 0 to -5 C for 30 minutes. Reaction mixture was heated to 25-30 C and stirred for 30 minutes. Activated charcoal was added to the resulting solution and stirred for 1 hour at 25-30 C. Reaction mixture was filtered through a hyflo-bed and washed with methanol (50 ml). Solvent was evaporated under vacuum and n-heptane (500 ml) was added to the resulting residue. Mixture was stirred for 5 hours at 25-30 C. Solid thus precipitated was filtered, washed with n-heptane (100 ml) and dried at 35-40 C to give 50 g of the title compound as a very hygroscopic white powder having purity 99.70 % by HPLC.
	With sodium hydroxide; In methanol; at 0 - 30℃;pH 10.3 - 10.6;	Conversion of Montelukast (crude) to crude Montelukast sodium mixture: Methanolic sodium hydroxide 6.8 grams (0.17 mole in 100 ml methanol) was added slowly to (Crude) Montelukast 100 grams (0.17 mole) dissolved in 400 ml of methanol at 25-30 C., under stirring keeping the temperature at 0-5 C. to adjust the pH of the contents to 10.3-10.6. Stirring was continued for another 30 minutes at the temperature of 0-5 C. Temperature was then gradually increased to 25-30 C. to obtain a clear reaction solution. The clear reaction solution was charcolised by adding 10 grams activated charcoal and reaction solution was filtered through a 0.45 micron filter. The filter bed was washed with 100 ml methanol and filtrate was collected. Methanol was removed from the filtrate under reduced pressure at the temperature not exceeding 50-55 C. The resulting solids were further stripped with heptane (2×50 ml) to remove any remaining methanol. As a final step, 500 ml heptane was added under stirring and the stirring was continued for an hour at 25-30 C. The resulting precipitated crude Montelukast sodium mixture was further cooled to 10-15 C. and product was filtered off and dried under vacuum at 50-55 C. The yield of solid crude Montelukast sodium mixture was 101 grams.
	With sodium methylate; In methanol; ethyl acetate; toluene; at 20 - 25℃;Product distribution / selectivity;	Example 5Preparation of montelukast sodium (11)(19, amine = diisobutylamine)NaOMe(11 )40 g of montelukast diisobutylamine, 400 mL of AcOEt and a solution of 11.9 g of citric acid and 200 mL of H20 were mixed in a round bottom flask under nitrogen. After stirring during 15 minutes, the formed phases were separated and partially distilled under vacuum at 30-35C until the volume was reduced to 100 mL of AcOEt. 120 mL of toluene and 10.6 mL of NaOMe (30% in MeOH) were added to the distilled organic phase and the solution was stirred at 20-25C. Afterwards, 400 mg of activated charcoal was added to the solution and after stirring for 30 minutes at 50-55C, the mixture was filtered through celite and washed with 80 mL of toluene. The obtained filtrate was partially distilled off at atmospheric pressure under nitrogen until the volume was reduced to 120 mL. The distilled solution was added dropwise into 360 mL of cyclohexane. The product mass was stirred for 1 hour and 30 min. at 20-25C and filtered. The product was dried at 80C under vacuum to get 33.5 g of montelukast sodium (11) in amorphous form. Yield: 98%. Purity (HPLC): 99.55%.
	With sodium hydroxide; In methanol; for 1h;	30 ml of toluene and 15 ml of water were added to 3.0 g of montelukast dipropylamine salt crystals, stirred- mixed, and 0.30 g of acetic acid was added to the resulting solution, stirred for 30 minutes, and then the aqueous layer was removed and the obtained organic layer was cooled to 4 C, and the precipitated crystals were collected by filtration by pressure filtration and dried under reduced pressure to obtain crystals of montelukast free acid. To the solution of the montelukast free acid thus obtained was added 30 ml of methanol and stirred and mixed, and 0.15 g of sodium hydroxide was added and the mixture was stirred for 1 hour, then the solvent was distilled off and the precipitated crystals were collected by filtration by pressure filtration and dried under reduced pressure to obtain 2.9 g of montelukast sodium (montelukast sodium purity 99.9%, methylstyrene content 0.02%) (yield 93.2%).

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4
[ 151767-02-1 ]
[ 158966-92-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride; In water; at 20 - 25℃; for 1h;	Example 5; Production of amorphous form II of montelukast acid; The 1- (R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)-phenyl)-3-(2-(1-hydroxy-1- methylethyl) phenyl) propyl) thio) methyl) cyclopropane sodium salt (200 mg) was suspended in 1 M hydrochloric acid (3.5 ml) and stirred at 20-25 C for 1 hour. Amorphous form II of 1- (((1 (R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid was isolated by filtration, washed with water and dried on the air overnight with a resulting yield of 97%. This form was characterized by XRPD, DSC, and IR spectroscopy. The XRPD pattern is shown in Fig. 7, the IR spectrum is shown in Fig. 8, and the DSC is shown in Fig. 9.
97.9%	With hydrogenchloride; In water; at 20℃; for 1h;pH 6;	Crystallizing amorphous montelukast free acid <strong>[151767-02-1]Montelukast sodium</strong> (50 g) was dissolved in water (750 mL) and stirred at room temperature to form a solution. Hydrochloric acid (IN HCI, 0.85 eq, 70 mL) was added dropwise until the solution reached a pH of 6 and a precipitate started to form. Then, the solution was stirred at room temperature for 1 hour. The precipitate was recovered by filtration, washed with water (15 mL), and dried under reduced pressure, 10-50 mm Hg, at 50 C for 32 hours to obtain amorphous montelukast acid (47.2 g, 97.9% yield). The results are summarized in Table 1, below. Table 1: Results of crystallizing amorphous montelukast free acid Volume of solvent is in mL per gram of montelukast. Solvent Vol. Temp. Time XRD (19/ML) (OC) (hrs) Sample Form wet/dry Water 15 RT 2 d Amorphous
76%	With hydrogenchloride; citric buffer; In water; acetone; at 20 - 25℃; for 2h;	Example 2; Production of crystalline form of montelukast acid; The 1- ( ( (l (R)- (3- (2- (7-chloro-2-quinolinyl) ethenyl)-phenyl)-3- (2- (l-hydroxy-l- methylethyl) phenyl) propyl) thio) methyl) cyclopropane sodium salt (1 g) was dissolved in acetone (15 ml) and 1 % hydrochloric acid (7 ml) was added dropwise. The reaction mixture was stirred for 2 hours at 20-25 C. A yellow suspension was obtained and crystals of 1- ( ( ( 1 (R)- (3- (2- (7-chloro-2-quinolinyl) ethenyl)-phenyl)-3- (2- ( 1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid were isolated by filtration. The obtained yield was 76%. The new crystalline form of 1- ( ( (l (R)- (3- (2- (7-chloro-2-quinolinyl) ethenyl) -phenyl)-3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid was further characterized by XRPD, DSC and IR spectroscopy. The DSC, IR spectrum, and XRPD pattern were the same as the ones described in example 1.

	With acetic acid; In water; toluene; at 20℃; for 0.166667 - 0.25h;Product distribution / selectivity;	Example 1: Conversion of Montelukast Sodium into Crystalline Montelukast Acid; <strong>[151767-02-1]Montelukast sodium</strong> (0.5 g) was dissolved in a two-phase system containing 10 ml of water and 10 ml of toluene. To the well-stirred solution, 1.2 ml of 1 M acetic acid was added dropwise at room temperature. After 10 minutes, the stirring was stopped, and the mixture was transferred into a separation funnel. The aqueous layer was removed and the yellow organic phase was washed with 10 ml of water, dried with Na2S04, filtered, and evaporated to dryness. The yield was about 300 mg of a light yellow solid. The product was determined to be montelukast acid by'H-NMR. The melting range of the product was determined to be 148-153C. The product was also analyzed by IR. DSC indicated onset: 150. 7C ; peak: 153. 6C ; and-74. 6jug-1. The water content was determined to be 0.18 wt% by using a Karl Fisher apparatus. These results indicate that the product was crystalline montelukast acid.; Example 2: Conversion of Montelukast Sodium into Montelukast Acid; <strong>[151767-02-1]Montelukast sodium</strong> was converted to montelukast by the following scheme: <strong>[151767-02-1]Montelukast sodium</strong> H20/HAc/toluene/ (EtOAc) Montelukast acid The process involved the materials as shown in Table 1, below. In particular, 3.0 g of montelukast sodium was dissolved in 45 ml of water. After stirring for 5 minutes, 40 ml of toluene was added. To the well-stirred solution, 7.4 ml of 1 M acetic acid was added dropwise at room temperature. After 15 minutes, stirring was stopped and the mixture was transferred into a separation funnel. The aqueous layer was removed. To the yellow organic phase, 20 ml of ethyl acetate was added in order to dissolve some precipitated acid. The organic phase was washed with 50 ml water, dried with Na2S04, filtered, and evaporated to dryness, yielding a very intense yellow"foamy"solid. The material was dried overnight under vacuum at 40C. The product had a melting range as follows: 60C : melting starts; 70C : material (partially) molten; 103C : recrystallization starts; 125C : melting starts; 153C : material completely molten. The product was also analyzed by IR. The product had a DSC as follows: exotherm starts >60C (broad peak), followed by endotherm with onset: 142. 0C ; peak: 148. 3C ; -31. 3Jg-l. The melting range and DSC data indicate that the product was an amorphous material.
	With acetic acid; In water; at 20℃; for 0.333333h;Product distribution / selectivity;	Example 6: Conversion of Montelukast Sodium into Montelukast Acid; <strong>[151767-02-1]Montelukast sodium</strong> was converted to montelukast by the following scheme: <strong>[151767-02-1]Montelukast sodium</strong> H2O/HAc , Montelukast ac1d The process involved the materials as shown in Table 2, below. In particular, 5 g of montelukast sodium was dissolved in 100 ml of water. To this solution, 12.33 ml of 1 M acetic acid was added dropwise at room temperature. The suspension was stirred for 20 minutes. The acid was filtered off and washed with water. The resulting light yellow solid was dried overnight under vacuum at 40C. The yield was 4.6 g. The melting range of the material was rather broad with melting starting slightly at about 90C.; Example 9: Conversion of Montelukast Sodium into Montelukast Acid; <strong>[151767-02-1]Montelukast sodium</strong> (3 g) was dissolved in 50 ml of water. To this solution, 7.4 ml of 1 M acetic acid was added dropwise at room temperature. The resulting yellow suspension was stirred for 20 minutes. The acid was filtered off and washed with water. The resulting yellow solid was dried overnight under vacuum at 40C. The yield was 2.8 g. The product was determined to be montelukast acid by'H- NMR. The product had a broad melting range with melting starting already at 66C and was complete at 225C. TGA of the product indicated no weight loss. The product was also analyzed by IR and DSC. The product was determined to be amorphous montelukast acid.
	With citric buffer; In acetone; at 20℃; for 24h;pH 5;sonication;	Example 1; Production of the crystalline form of montelukast acid; The 1- ( ( (l (R)- (3- (2- (7-chloro-2-quinolinyl) ethenyl)-phenyl)-3- (2- (l-hydroxy-l- methylethyl) phenyl) propyl) thio) methyl) cyclopropane sodium salt (1 g) was suspended in acetone (100 ml) and citric buffer pH=5 (100 ml). The suspension was sonicated in ultrasound bath at a temperature of 20C for 3 minutes. The precipitant is formed after 24 h. The crystals were filtered off and dried at room temperature under atmospheric pressure to constant weight (0.85 g crystal form of 1- ( ( (I (R)- (3- (2- (7-chloro-2-quinolinyl) ethenyl) -phenyl)- 3- (2- (l-hydroxy-l-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid. A single crystal of the new crystalline form of 1- ( ( (l (R)- (3- (2- (7-chloro-2-quinolinyl) ethenyl) -phenyl)-3- (2- (l-hydroxy-l-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid was prepared, and single crystal X-ray diffraction data collected using a Bruker Nonius FR591/Kappa CCD diffractometer using CuKa radiation. Pertinent crystallographic data thus obtained are set forth in Table 1. The new crystalline form of 1- (((1(R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) -phenyl)-3- (2- (l-hydroxy-l-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid was further characterized by x-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), and Infrared (IR) spectroscopy. The resulting XRPD pattern is shown in Fig. 1 where characteristic diffraction peaks, designated by 2No. and expressed in degrees, are detected at 6. 50. 2, 10. 00. 2, 15. 5~0. 2, 18. 3~0. 2, 20. 40. 2 and 24. 60. 2. In the IR spectrum (see Fig. 2), characteristic bands are observed at 1715~5 cm'and 35735 cm-1. In the DSC (see Fig. 3), a characteristic endothermic peak in range from 120C to 180C is observed. TABLE 1. Crystallographic data for the new crystalline form of 1- ( ( (l (R)- (3- (2- (7-chloro- 2-quinolinyl) ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid Chemical formula (C35H35ClNO3S) 2 Empirical formula weight 585.15 Temperature 293 2K Crystal size 0. 06 x 0. 10 x 0. 25 mm Crystal system, space group Monoclinic, P 2, Unit cell dimension a = 7. 95 ~ 0.02A b = 21. 940. 02A c = 17. 950. 02A ss = 100. 030. 02 V 3082 2A' Z 2 Calculated density 1.26 0. 02g cm~3
	With citric buffer; silica gel; In dichloromethane; ethyl acetate;	Example 3; Production of the crystalline form of montelukast acid; The 1- ( ( (l (R)- (3- (2- (7-chloro-2-quinolinyl) ethenyl)-phenyl)-3- (2- (l-hydroxy-l- methylethyl) phenyl) propyl) thio) methyl) cyclopropane sodium salt (5.75 g) was dissolved in ethyl acetate/methylene chloride (4/1; v/v) mixture. The solution was accumulated on a preparative chromatography column with silica gel filling and was eluded from the column using ethyl acetate/methylene chloride (4/1 ; v/v) mixture. The fractions eluded between 300 ml and 900 ml were collected and combined. The solvent was removed at about 50 C under vacuum to dryness. This process produced free crystals of 1- ( ( (l (R)- (3- (2- (7-chloro-2- quinolinyl) ethenyl)-phenyl)-3- (2- (l-hydroxy-l-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid (5. 00g). The new crystalline form of 1- ( ( (l (R)- (3- (2- (7-chloro-2-quinolinyl) ethenyl) -phenyl)-3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid has been further characterized by XRPD, DSC, and IR spectroscopy. DSC, IR, XRPD were the same as the ones described in example 1.
	With acetic acid; In water; toluene;pH 4;Acidic aqueous solution;Product distribution / selectivity;	12 g of methyl l-(((l-(R)-(3-(2-(7-chloro-2-quinolidyl)ethenyl)phenyl)- 3-(2-( 1 -hydroxy- 1 -methyl-ethyl)phenyl)propyl)thio)methyl)cyclopropylacetate obtained in step 1 was dissolved in a mixture of 60 ml of tetrahydrofuran and 30 ml of methyl alcohol. After adjusting the temperature to 10 to 15 C , 24 g of 10% NaOH solution was slowly added to the resulting mixture. Then, the temperature was slowly increased to room temperature (24 to 27 C ), and the reaction mixture was stirred for 20 hrs. After reaction was completed, the organic layer was separated and dried, followed by removing the solvent under reduced pressure. The residue thus obtained was mixed with water layer again, and 120 ml of toluene was added thereto. Subsequently, the pH of the reaction product was adjusted to 4 by adding 300 ml of acetic acid. The organic layer was separated again and dried over sodium sulfate, followed by removing the solvent under reduced pressure. The residue thus obtained was dissolved in 96 ml of a mixture of isopropanol and distilled water (2: 1), and the product was recrystallized therefrom. The crystallized product was filtered to obtain 9.82 g (83%) of the title compound as a yellow solid.1H-NMR (300MHz, CD3OD) : delta 8.27 (IH, d), 7.98 (IH, s), 7.78 (2H, d), 7.73 (2H, d), 7.38-7.56 (6H, m), 7.07-7.14 (3H, m), 4.84 (IH, t), 3.30-3.33 (IH, m), 2.84-2.87 (IH, m), 2.52 (2H, s), 2.41 (2H, s), 2.18-2.23 (2H, m), 1.55 (6H, s), 0.37-0.52 (4H, m). <n="12"/>m.p. : 154 C , purity > 99%
	With acetic acid; In water;pH 5;Product distribution / selectivity;	Purification and drying of <strong>[151767-02-1]Montelukast sodium</strong>; Example 4; A crude oil of montelukast sodium was treated with 5% aqueous acetic acid to a pH of 5, and then extracted with toluene. The resulting toluene extract was washed with water. The organic layer containing montelukast acid was treated with cyclohexylamine (1.11.5 equiv.), and acetonitrile was added to effect precipitation. After stirring overnight, the salt was collected by filtration and washed with acetonitrile. The salt thus obtained was recrystallized over toluene/hexanes or toluene/acetonitrile until the desired purity was reached (see Table 4). The crystalline solid was analyzed by XRPD, and the spectrum is shown in FIG. 4. 1H NMR (600 MHz, CDCl3): delta 7.068.04 (15 H, Ar), 6.41 (bs, cy-NH3+), 3.96 (t, J=7.08 Hz, 1 H), 3.15 (m, 1 H), 2.772.87 (m, 2 H), 2.57 and 2.51 (ABq, 2J=11.1 Hz, 2 H), 2.31 and 2.27 (ABq, 2J=15.0 Hz, 2 H), 2.22 (m, 1 H), 2.12 (m, 1 H), 1.95 (d, J=10.6 Hz, 2 H), 1.68 (d, J=12.9 Hz, 2 H), 1.56 (s, 3 H), 1.54 (s, 3 H), 1.28 (m, 2 H), 1.14 (m, 2 H), 1.08 (m, 2 H), 0.49 (m, 1 H), 0.42 (m, 1 H), 0.34 (m, 1 H), 0.27 (m, 1 H). 13C NMR (150 MHz, CDCl3): delta 179.0 (CO2), 157.0, 148.7, 145.6, 144.1, 140.5, 136.6, 136.3, 135.7, 135.4, 131.7, 129.1, 128.8, 128.7, 128.6, 128.2, 127.2, 127.1, 127.0, 126.2, 125.8, 125.7, 125.6, 119.7 (olefinic), 73.7, 50.3, 50.2, 43.7, 40.3, 40.1, 32.5, 32.1, 32.0, 31.8, 25.1, 24.7, 17.7, 13.1, 12.4.
	With tartaric acid; In tetrahydrofuran; water;pH 3 - 4;Product distribution / selectivity;	Example 3: 3-(2-(1-hvdroxy-l-methylethyl)phenyl]propyllthio)methyl)cyclopropylacetic acid Isopropyammonium salt (MLK-IPAM): S-MKT (4 kg) is reacted with methanesulfonyl chloride (1.4 kg) in the presence ofDIPEA (2.2 Kg) in THF as solvent (20 liter) to yield the mesylate compound. During the reaction, the diisopropylethylamine hydrochloride (DIPEA'HCl) salt is formed. The salt is removed by filtration. The mother liquor, the THF solution of MKT-Mesylate, is then reacted with CYTAM (2.4 kg) in the presence of sodium hydroxide (2 kg) in a mixture ofTHF and DMA (4 L) to yield a solution of R-MLK-Me.After the isolation step, the reaction mixture is heated gradually to 400C and treated with an additional amount of sodium hydroxide (2 kg). The solution is mixed for about 4 hrs to induce the hydrolysis of R-MLK-Me and yield the R-MLK-Na. The DMA and the other side products are removed by twice washing the reaction mixture with a dilute NaCl solution (each washing is with 20 liters of 5% NaCl solution) to afford theTHF solution of crude MLK-Na. The reaction mixture is acidified with a dilute aqueous solution of tartaric acid (7.5%) until a pH of 3-4 is reached to yield MLK-H. The aqueous phase is separated to afford a THF solution of the crude MLK-H. The aqueous solution containing tartaric acid salts is discarded. The THF solvent is removed by distillation at 5O0C under vacuum until dry. The residue (a sticky foam) is dissolved in methyl-ethyl-ketone (MEK) and cooled to < 30C. 0.78 kg of i-Propylamine (IPAM) is added and after cooling a salt, MLK-IPAM5 precipitates from solution. The solid is filtered off, washed with MEK, and used in the next stage. Optionally depending on the purity the solid is recrystallized from MEK and optionally dried.

Reference： [1]Patent: WO2005/73194,2005,A2 .Location in patent: Page/Page column 16
[2]Patent: WO2005/74935,2005,A1 .Location in patent: Page/Page column 13; 14
[3]Patent: WO2005/73194,2005,A2 .Location in patent: Page/Page column 15
[4]Patent: WO2005/40123,2005,A1 .Location in patent: Page/Page column 19-20
[5]Patent: WO2005/40123,2005,A1 .Location in patent: Page/Page column 22-24
[6]Patent: WO2005/73194,2005,A2 .Location in patent: Page/Page column 13; 14
[7]Patent: WO2005/73194,2005,A2 .Location in patent: Page/Page column 15
[8]Patent: WO2008/72872,2008,A1 .Location in patent: Page/Page column 10
[9]Patent: US2008/97104,2008,A1 .Location in patent: Page/Page column 4
[10]Patent: WO2007/5965,2007,A1 .Location in patent: Page/Page column 18-19

5
[ 151767-02-1 ]
[ 1178966-47-6 ]
[ 158966-92-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In water; isopropyl alcohol at 20℃; for 0.916667h;	10 Montelukast sodium (200 mg) was dissolved in 40 ml of i-propanol. To this solution, 0.24 ml of 5-6 N hydrochloric acid in i-propanol was added dropwise at room temperature. The color of the clear solution changed from colorless to very intense yellow, and the reaction was exothermic. After 10 minutes, a precipitate formed. After 45 minutes of stirring, the suspension was filtered, and the residue was washed with i-propanol. The resulting intense yellow solid was dried overnight under vacuum at 40°C. The yellow solid was analyzed by IR, DSC, and TGA. The solid could not be analyzed by NMR because part of the material was insoluble in CDCl3. While not wishing to be bound by theory, the yellow solid may be a mixture of montelukast acid and HCl salt (with nitrogen in the quinoline-part of molecule).

Reference： [1]Current Patent Assignee: BC PARTNERS LLP - WO2005/40123, 2005, A1 Location in patent: Page/Page column 24

6
[ 880769-26-6 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
92%		To 2 g of montelukast free acid crystals obtained in Example 1, 10 ml of methanol was added and mixed with stirring, 0.14 g of sodium hydroxide was added and after stirring for 1 hour, the solvent was distilled off, the precipitated crystals were added Filtration by pressure filtration, drying under reduced pressure,1.9 g (99.9% purity) of montelukast sodium was obtained (yield 92%).
67.8%		Suspended Montelukast DPA salt (100 g, 0.146 mole) in a mixture of methylene chloride (2000 ml), water (1500 ml) and mixed for 15 min. Added 6% acetic acid (216 ml) at temperature of 250 C.-35 C., mixed for 30 min, allowed to settle and separated the layers. Extracted the aqueous layer with methylene chloride (1000 ml) and combined the organic. layers. Washed the combined organic layer with water (1500 ml), dried over sodium sulphate and treated with carbon for 15 min. at 25 C.-30 C. Filtered off the carbon and added 0.486 molar sodium hydroxide solution in ethanol (275 ml) at 25 C.-30 C. over 30 min. Maintained for 30 min at 250 C.-30 C. and distilled methylene chloride at temperature below 40 C. till to get residue under reduced pressure. Added toluene (200 ml) and distilled under vacuum at temperature below 40 C. to get residue. Added toluene (800 ml) to the residue mixed for 15 min and treated with activated carbon at 25 C.-35 C. for 20 min. Filtered off the carbon and washed the carbon bed with toluene (200 ml). Poured the clear filtrate slowly into n-Heptane (3000 ml) over 1 hr at 25 C.-35 C. under nitrogen. Maintained at 25 C.-30 C. for 2 hrs, filtered the product, washed with n-Heptane (100 ml) and dried at 90 C.-95 C. under vacuum till constant weight.Dry weight of Montelukast sodium is 60 g (yield: 67.8%)
67.8%		Example-11: Preparation of Montelukast sodium from Montelukast DPA salt Suspended Montelukast DPA salt (100 g, 0.146 mole) in a mixture of methylene chloride (2000 ml), water (1500 ml) and mixed for 15 min. Added 6% acetic acid (216 ml) at temperature of 25C - 35C, mixed for 30 min, allowed to settle and separated the layers. Extracted the aqueous layer with methylene chloride (1000 ml) and combined the organic layers. Washed the combined organic layer with water (1500 ml), dried over sodium sulphate and treated with carbon for 15 min. at 25C - 30C. Filtered off the carbon and added 0.486 molar sodium hydroxide solution in ethanol (275 ml) at 25C - 30C over 30 min. Maintained for 30 min at 25C - 30C and distilled methylene chloride at temperature below 40C till to get residue under reduced pressure. Added toluene (200 ml) and distilled under vacuum at temperature below 40C to get residue. Added toluene (800 ml) to the residue mixed for 15 min and treated with activated carbon at 25C - 35C for 20 min. Filtered off the carbon and washed the carbon bed with toluene (200 ml). Poured the clear filtrate slowly into n-Heptane (3000 ml) over 1 hr at 25C - 35C under nitrogen. Maintained at 25C - 30C for 2 hrs, filtered the product, washed with n-Heptane (100 ml) and dried at 90C - 95C under vacuum till constant weight. Dry weight of Montelukast sodium is 60 g (yield: 67.8 %)

	With sodium t-butanolate; In n-heptane; toluene; at 20 - 40℃; for 2h;Product distribution / selectivity;	Example 4; The preparation of [R-(E)]-1-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic sodium salt According to U.S. application Ser. No. 11/481,877 A 500 ml flask equipped with mechanic stirrer was charged with toluene (225 ml) and montelukast di-n-propylamine salt (45 g). The suspension was stirred at ambient temperature for 30 minutes. Sodium tert-butoxide (6.5 g) was added to the suspension, and the reaction mixture was stirred at 30-40 C. for 30 minutes. Active carbon (2 g) was added, and the solution was filtered over active carbon. The mixture was added portionwise to a flask containing heptane (630 ml) to form a precipitate, and the mixture was further stirred at ambient temperature for 1 hour. The montelukast sodium salt crystals were collected by filtration, washed with heptane, and dried at 45 C. under reduced pressure. Montelukast sodium (32 g) was obtained as an amorphous material containing greater than 1% water. The amount of [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-propenyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid (?MLK-D?) was reduced to an undetectable level.
	With sodium t-butanolate; In toluene; at 30 - 40℃; for 0.5h;Product distribution / selectivity;	Example 7: The preparation of (R-(E))-1-(((3-[2-(7-chloro-2-quinolinyl)ethenyl) phenyl)-3-[2-(l-hvdroxy-l-methylethyl)phenyl)propyl) thio)methyl)cvclopropaneacetic sodium salt: A 500 ml flask equipped with mechanic stirrer was charged with toluene (225 ml) and montelukast di-n-propylamine salt (45 g). The suspension was stirred at ambient temperature for 30 minutes. Sodium tert-butoxide (6.5 g) was added to the suspension, and the reaction mixture was stirred at 30-40C for 30 minutes. Active carbon (2 g) was added, and the solution was filtered over active carbon.The mixture was added portionwise to a flask containing heptane (630 ml) to form a precipitate, and the mixture was further stirred at ambient temperature for 1 hour. The montelukast sodium salt crystals were collected by filtration, washed with heptane, and dried at 45C under reduced pressure. Montelukast sodium (32 g) was obtained as an amorphous material containing greater than 1% water. The amount ofMLK-D was reduced to an undetectable level.
6.05 g	With sodium hydroxide; In water; toluene; at 20 - 40℃; for 2h;Inert atmosphere;	In a nitrogen gas atmosphere, montelukast dipropylamine salt (5.0 g) was added to toluene (25.0 mL) at room temperature and stirred. There,10% aqueous sodium hydroxide solution (3.06 g, 1.05 eq) was added, heated to 40 C.,And the mixture was stirred for 2 hours.Sodium chloride (0.69 g) was added to the solution after the reaction and the mixture was stirred and then cooled to 25 C.,Stirring was stopped at 25 C. Two layers are formed, the aqueous layer is pulled out,To the obtained organic layer,48% aqueous sodium hydroxide solution (5.0 g) was added and stirred at 25 C.After stopping stirring at 25 C., two layers were formed and the aqueous layer was removed. The obtained organic layer was concentrated under reduced pressure at 50 C. until the concentration of the concentrate reached about 20 mL. Toluene (10 mL) was added to the obtained concentrate, and the mixture was again concentrated under reduced pressure at 50 C. until the concentration of the concentrate reached about 20 mL.The resulting concentrate was filtered while the vessel was washed with toluene (2.5 mL), the washings were also filtered,A toluene solution of montelukast sodium was obtained.In a nitrogen gas atmosphere, the above montelukast sodium toluene solution was added dropwise to heptane (75 mL).The vessel was washed with toluene (2.5 mL), and washing solution was also added dropwise.After the dropwise addition, the mixture was stirred at room temperature for 5 hours, filtered, and cake washed with heptane (15 mL) to obtain montelukast sodium (6.05 g) containing moisture.

Reference： [1]Patent: JP2015/7000,2015,A .Location in patent: Paragraph 0057; 0063
[2]Patent: US2009/143590,2009,A1 .Location in patent: Page/Page column 10
[3]Patent: EP1812394,2011,B1 .Location in patent: Page/Page column 12
[4]Patent: US2007/161796,2007,A1 .Location in patent: Page/Page column 7
[5]Patent: WO2007/5965,2007,A1 .Location in patent: Page/Page column 20
[6]Patent: EP1812394,2011,B1
[7]Patent: JP2016/20320,2016,A .Location in patent: Paragraph 0022

7
[ 123-03-5 ]
[ 151767-02-1 ]
[ 934545-03-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water;	Solution A (containing 5% montelukast sodium in DI water) and solution B (containing 10% of Cetyl-pyridinium chloride in DI water) were prepared. 0.6 mL of solution A was mixed with 0.177 mL of solution B and allowed to sit. The salt of montelukast cetyl-pyridinium was obtained through centrifugation. The process to generate Montelukast Cetyl-pyridinium is: [C21H38N+]Cl-+C34H35ClNSCOONa?[C21H38N+]C34H35Cl NSCOO-+NaCl Montelukast cetyl-pyridinium shows a solubility of 1.1 mg/mL in human serum, calculated as Montelukast sodium. It was measured by an HPLC method.

Reference： [1]Patent: US2007/154546,2007,A1 .Location in patent: Page/Page column 9

8
[ 942303-96-0 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium methylate; In toluene; at 25 - 30℃; for 0.5h;	Montelukast sodium saltThe above N-methyl morpholine salt (10 gm, 0.014) was dissolved in 80 ml toluene and to the resultant solution 0.86 gm of sodium methoxide (0.016mol) was added and the contents stirred for 30 min at 25-300C followed by addition of 0.5 gm charcoal. The mass was stirredat 25-3O0C for 1 hr and filtered through celite. The clear filtrate was added drop-wise into 300ml n-heptane. The product mass was stirred for an additional 10 min at 25-300C and filtered.The product was dried at 5O0C under vacuum to get 7.95 gm of montelukast sodium.Water content (by Karl Fisher) = 1.8%; Chemical assay (by HPLC) 99.2%; Yield = 90% (of theory); SOR: + 79.12

Reference： [1]Patent: WO2007/72114,2007,A1 .Location in patent: Page/Page column 11

9
[ 577953-88-9 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
99%		lOg of montelukast amine salt obtained from Comparative Example 4 was dissolved in 100ml of methylene chloride, and 10% acetic acid was dropped into it so as to adjust thepH to a range of 4 to 4.5. Then, the resultant product was washed with distilled water twice. The organic layer was concentrated and dissolved in 100ml of methanol. Then, 0.54g of NaOH dissolved in 1.7mL of distilled water was introduced, and lg of activated carbon was added, followed by stirring for 1 hour and filtration. After vacuum-concentration of the solvent, the resultant product was dissolved in 20ml of water and freeze-dried so as to provide 7.8g of montelukast sodium salt, (yield: 99%, purity: 97.9, HPLC wavelength: 238nm, Phenyl column, 4.6X250mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20min at a flow rate 1.5mL/min).
99%		Comparative Example 8 Preparation of sodium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate 10 g of montelukast amine salt obtained from Comparative Example 4 was dissolved in 100 ml of methylene chloride, and 10% acetic acid was dropped into it so as to adjust the pH to a range of 4 to 4.5. Then, the resultant product was washed with distilled water twice. The organic layer was concentrated and dissolved in 100 ml of methanol. Then, 0.54 g of NaOH dissolved in 1.7 mL of distilled water was introduced, and 1 g of activated carbon was added, followed by stirring for 1 hour and filtration. After vacuum-concentration of the solvent, the resultant product was dissolved in 20 ml of water and freeze-dried so as to provide 7.8 g of montelukast sodium salt. (yield: 99%, purity: 97.9, HPLC wavelength: 238 nm, Phenyl column, 4.6*250 mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20 min at a flow rate 1.5 mL/min).
94%		Add 844 g (1.05 mol) of compound III refined product and 10 L of toluene to a 50 L reaction vessel.Purified water 4.5L, cooled to 20 C,A solution of 100 g (1.70 mol) of glacial acetic acid and 1.1 L of purified water was added dropwise, and the mixture was stirred for about 10 minutes.Completely dissolved, separated, the aqueous phase was extracted once with 2 L of toluene, the organic phase was combined, washed with 5 L of purified water, and the organic phase was concentrated under reduced pressure at 50 C to remove toluene, and then cooled to 20 C.A solution of 45.8 g (1.14 mol) of sodium hydroxide and 500 ml of methanol was added dropwise, and stirred at 20-25 C for 2 hours.Add 50g of activated carbon and stir for 1 hour.Filtration, the filtrate was added to the rapidly stirred n-heptane 10L, controlled at 20-25 C, and stirred for 1 h after the completion of the dropwise addition.Filtered, the solid was washed with n-heptane and dried at 45 C vacuo.It was obtained from montugat sodium 610 g in a yield of 94.0%.The whole process is protected by nitrogen.

87%		2.00 g (0.00284 mol) Montelukast DCHA salt (IX) was dissolved in a mixture of 50 cm3 of dichloromethane and 40 cm (0.0258 mol) of 1 M potassium-dihydrogen-phosphate solution. The mixture was stirred for 15 minutes at room temperature, and then the layers were separated. To organic layers was added 40 cm3 (0.04 mol) of 1M sodium hydroxide and the layers was stirred for 15 minutes, and then separated. The organic layer was dried over sodium sulfate. The drying agent was filtered, washed with 10 cm of dichloromethane and the filtrate was evaporated in vacuum.The obtained 1.8 g evaporation residue was diluted with 5.6 cm of toluene and 22.4 cm of n- heptane was slowly added under the stirring. The crystalline product was filtered, washed with 2x4 cm3n-heptane. The product was dried in vacuum at 40 C.Yield: 1.51 g of white powder (87%)1H NMR DMSO-d6) delta 0.15-0.30 (m, 2H), 0.33-0.48 (m, 2H), 1.44 + 1.45 (2 s, 2 3H, Me2C), 2.05-2.17 + 2.17-2.28 (2 x m, 2 x 1H, CH2CS), 2.01 + 2.14 (2 d, 2 x 1H, Jgem = 14.3 Hz, CH2CO), 2.55 + 2.71 (2 x d, 2 x 1H, Jgem = 12.6 Hz, CH2S), 2.70-2.81 + 3.03-3.15 (2 x m, 2 x 1H, CH2Ar), 3.99-4.07 (m, CHS), 5.14 (br, 1H, OH), 7.03-7.16 (m, 3H), 7.33-7.45 (m, 3H), 7.51 (d, 1H, Jtrans = 16.3 Hz), 7.59 (dd, 1H, J= 8.7 Hz, J= 2.1 Hz), 7.63 (dm, 1H, J = 6.9 Hz), 7.71-7.76 (m, 1H), 7.90 (d, 1H, Jtrans = 16.3 Hz), 7.95 (d, 1H, J = 8.6 Hz), 8.00 (d, 1H, J= 8.7 Hz), 8.04 (d, 1H, J= 2.1 Hz), 8.41 (d, 1H, J= 8.6 Hz) ppm.
	With sodium methylate; In methanol; at 25 - 35℃; for 1h;Product distribution / selectivity;	Added dicyclohexyl amine salt of [R-(E)-1[[[1-[3-[2-[7-chloro-2-quinolinyl]ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid compound of formula (IV) (100 gr) prepared as per the procedures given in examples 1, 2, 4, 5 & 6 to a solution of sodium methoxide (23 gr) and methanol (210 ml) at 25-35 C. Stirred for 60 minutes at 25-35 C. Washed the reaction mixture with hexanes. Distilled the solvent completely under reduced pressure at below 55 C. Added toluene to the crude and slowly added the toluene layer to heptane at 25-35 C. under nitrogen atmosphere. Stirred the mass for 45 minutes under nitrogen atmosphere. Separated the solid by filtration and washed with heptane. Dried the compound at 60-70 C. under reduced pressure to get title compound. Yield 70 gr.
	With sodium methylate; In methanol; at 25 - 35℃; for 1h;Product distribution / selectivity;	Added dicyclohexyl amine salt of [R-(E)-I [[[l-[3-[2-[7-chloro-2- quinolinyl] ethenyl]phenyl] -3 - [2-( 1 -hydroxy- 1 - methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid compound of formula (IV) (100 gr) prepared as per the procedures given in examples 1,2,4,5 & 6 to a solution of sodium methoxide (23 gr) and methanol (210 ml) at 25-350C. Stirred for 60 minutes at 25-35C. Washed the reaction mixture with hexanes. Distilled the solvent completely under reduced pressure at below 550C. Added toluene to the crude and slowly added the toluene layer to heptane at 25-35C under nitrogen atmosphere. Stirred the mass for 45 minutes under nitrogen atmosphere. Separated the solid by filtration and washed with heptane. Dried the compound at 60-700C under reduced pressure to get title compound. Yield 70 gr.
		To a suspension of 5 gms of l-(((l(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)- phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)- propyl)thio)methyl)cyclopropaneacetic acid dicyclohexylamine salt in 50 ml water add 5 ml of 10% tartaric acid solution. Stir for 1 hr and extract with 20 ml of ethyl acetate. Wash the combined organic layers with 2 x 20 ml portions of water. The solvent from the organic layer is distilled under vacuum at 5O0C to yield viscous oil. Add 20 ml of methanol to dissolve the viscous oil and then add 7 ml of 1 N methanolic NaOH. Stir for 1 hr. Distil the solvent under vacuum at 4O0C to yield viscous oil. Add 7.5 ml of water and stir to get a clear solution. Add 0.05 gms of charcoal and stir for 1 hr. Filter through hyflo bed and 0. 45mu membrane filter. Filtrate is freeze dried to yield 3.79 gm of the title compound.
		Method G: To a stirred suspension of montelukast DCHA salt (80 g) in methyl tert-butyl ether (800 ml) and DM water (400 ml) at 10-15C, acetic acid (10% solution, 160 ml) was charged over a period of 30 minutes and reaction mixture was stirred for 15 minutes at 10-15C. The temperature was slowly raised to 25-30C and stirred for 1 hr, methyl tert-butyl ether layer was separated and successively washed with cold (10-15C, 2 % aqueous solution of sodium bicarbonate (400 ml) and water (2 x 800 ml). The organic layer was stirred with activated charcoal and anhydrous sodium sulfate for 15 minutes and filtered through hyflo-bed. Methyl tert- butyl ether was completely distilled off under vacuum and anhydrous methanol (160 ml ) was added to it . Methanol was distilled off under vacuum to remove traces of methyl tert-butyl ether. To the resulting reaction mass, methanol ( 400 ml) was added and cooled to 0 to -5C . To this cold solution, a solution of methanol (300 ml) and sodium hydroxide (4.42 g, 0.1 1 mol), prepared separately, was added at 0 to -5C. After stirring at 0 to -5C for 30 minutes, temperature of reaction mixture was raised to 35-40C and stirred for 30 minutes. Activated charcoal was added to clear pale yellow solution and after stirring for 1 hr at 35-40C, the mixture was filtered through a hyflo-bed and washed with methanol (50ml). Methanol was evaporated under vacuum <40C to get a residue .To the residue n-heptane (400ml) was added and the suspension was stirred for 1 hr at 25-30C. The solid was filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at 35-40C under vacuum to afford 62.2 g of pure montelukast sodium as white to almost white, a very hygroscopic powder, having purity 99.62% by HPLC.

Reference： [1]Patent: WO2012/15255,2012,A2 .Location in patent: Page/Page column 19
[2]Patent: US2013/184464,2013,A1 .Location in patent: Paragraph 0089
[3]Patent: CN109503476,2019,A .Location in patent: Paragraph 0053-0057
[4]Patent: WO2012/20271,2012,A1 .Location in patent: Page/Page column 22
[5]Patent: US2009/171092,2009,A1 .Location in patent: Page/Page column 8-9
[6]Patent: WO2007/69261,2007,A1 .Location in patent: Page/Page column 10-12; 23
[7]Patent: WO2008/23044,2008,A1 .Location in patent: Page/Page column 3; 10
[8]Patent: WO2012/77133,2012,A1 .Location in patent: Page/Page column 29-30

10
[ 1310-73-2 ]
[ 577953-88-9 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
98%		Step 3: Preparation of montelukast sodium. A reaction vessel equipped with a thermometer, a nitrogen inlet, and stirrer was charged with toluene (1 L) and water (950 mL). The mixture was stirred, then montelukast dicyclohexylamine salt (63.0 g, 0.0821 moles) was added via a powder funnel. Toluene (260 mL) was used to rinse in the remaining solid. To the well stirred suspension, a 2M aqueous acetic acid solution (62 mL, 0.124 moles) was added at room temperature, i.e., 20-250C. After 10 minutes, the stirring was stopped to afford two clear phases. The upper yellow organic layer was separated and water (950 mL) was added. The resulting mixture was stirred for 10 minutes. Stirring was stopped, and the layers were separated. To the upper toluene layer (1270 mL) containing the montelukast acid was added a titrated solution of sodium hydroxide in 1% aqueous ethanol containing 3.29 g sodium hydroxide (169 mL, 0.0821 moles), in portions, over 10 minutes at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 minutes, then filtered to afford a clear filtrate, which was transferred to a clean reaction vessel equipped with a thermometer, a nitrogen inlet, and a stirrer. The solution was concentrated under vacuum at a temperature lower than 400C to a volume of about 400 mL. Acetonitrile (400 mL) was added in portions, over 20 minutes, to the concentrate at 400C. The clear solution was seeded with montelukast sodium, and the mixture was stirred for 1.5 hours at 4O0C. To the resulting suspension, acetonitrile (400 mL) was added slowly over 20 minutes at 400C. The suspension was stirred at 400C for 1 hour and again acetonitrile (400 mL) was added slowly over 20 minutes. The resulting suspension was stirred for 12 hours at 4O0C, then for 1 hour at room temperature. The product was filtered under nitrogen and washed with acetonitrile (400 mL). After drying at 4O0C under vacuum with nitrogen bleed, montelukast sodium salt (49 g) was obtained in 98% yield having >99.7% ee and HPLC purity >99.5%.

Reference： [1]Patent: WO2008/135966,2008,A1 .Location in patent: Page/Page column 9

11
[ 110-04-3 ]
[ 151767-02-1 ]
montelukast 1,2-ethanedisulfonic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol at 20 - 25℃; for 18h;	2 Sodium salt 3 (608 mg) and 1 ,2-ethanedisulfonic acid monohydrate (416.4 mg) were added to ethanol (25 ml). The mixture was aged at 20-25 0C for 18 h during which time a precipitate formed. The solids were collected by filtration and dried to yield 598 mg of salt 4. 1H NMR (400 MHz, DMSO): δ 8.53 (d, 1 H), 8.06 (m, 3 H), 7.97 (d, 1 H), 7.73 (s, 1 H), 7.66 (m, 2 H), 7.51 (d, 1 H), 7.44-7.33 (m, 3 H), 7.12-7.06 (m, 3 H), 3.99 (t, 1 H), 3.03 (td, 1 H), 2.73 (td, 1 H), 2.63 (s, 4 H), 2.30 (s, 2 H), 2.14 (m, 2 H), 1.42 (s, 6 H), 0.46-0.32 (m, 4 H); 13C NMR (IOl MHz, DMSO): 5173.56, 156.11, 148.50, 147.20, 144.38, 140.23, 136.60, 135.57, 136.02, 131.54, 130.75, 129.87, 129.66, 128.34, 127.72, 126.91, 126.84, 126.19, 125.85, 125.73, 120.60, 72.11, 49.78, 48.50, 40.62, 40.41, 39.87, 38.98, 32.34, 32.16, 32.13, 17.18, 12.63, 12.41.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2009/52625, 2009, A1 Location in patent: Page/Page column 15

12
[ 162515-68-6 ]
[ 151767-02-1 ]
[ 1187586-61-3 ]
[ 1187586-58-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium t-butanolate; PEG-600 In toluene Inert atmosphere; Stage #2: Montelukast sodium In tetrahydrofuran; toluene at 20℃; Inert atmosphere;	12 EXAMPLE 12 (Preparation of the standards of 2-[(R)-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)- (S)- 1 -( { [ 1 -(carboxymethyl)cyclopropyl]methyl} thio)ethyl]phenyl]-3-[2-( 1 -hydroxy- 1 - methylethyl)phenyl]-propyl]thio]methyl]cyclopropane]acetic acid and 2-[(R)-l-[[[l-[3-[2-(7- chloro-2-quinolinyl)-(R)-l-([l-(carboxymethyl)cyclopropyl]-methyl}thio)ethyl]phenyl]-3-[2- (l-hydroxy-l-methyl-ethyl)phenyl]propyl]thio]methyl]cyclopropane]acetic acid)To [l-(mercaptomethyl)cyclopropyl] acetic acid (0.7 g) toluene (20 ml), sodium tert-butoxide (0.85 g) and a solution of 2.6 g of PEG-600 in 3 ml of toluene were added under argon atmosphere. Then, a solution of montelukast sodium (2.72 g) in 15 ml of tetrahydrofuran was added dropwise to the stirred mixture. The obtained mixture was stirred at the laboratory temperature and under argon atmosphere for 30 days. Then, toluene (100 ml) was added and 45 ml of the liquid was removed by vacuum distillation. The residue was washed with a solution of tartaric acid and water. The organic phase was dried over sodium sulfate and concentrated to the volume of 30 ml after filtration of the desiccant. To the concentrated residue 3 ml of acetonitrile, 0.5 ml of isopropylamine and gradually 30 ml of heptane were added. The separated suspension of the salt of montelukast with isopropylamine was filtered off and the filtered mother liquor was concentrated in vacuum. 0.4 g of an oily product were obtained, which, according to HPLC, contained 70% of a mixture of montelukast diastereoisomers I and II. The standards of both the diastereoisomers in the form of free acids were obtained in the quantities of approx. 80 mg with the use of the Waters auto-purification system (description - see analytic methods).Montelukast diastereoisomer I:1H NMR (500 MHz, CDCl3), δ (ppm): 0.38 (m, 2H) ; 0.41-0.48 (m, 4H); 0.56(m, 2H); 1.60(s, 3H); 1.61(s, 3H); 2.00(d, IH); 2.40(d, IH); 2.16(q,2H); 2.33(d, IH); 2.43(d, IH); 2.35(d, IH); 2.55(d, IH); 2.37(d, IH); 2.49(d, IH); 2.97(q, 2H); 3.37(dd, IH); 3.62(dd, IH); 3.93(t, IH); 4.29(dd, IH); 7.1 l(m, IH); 7.17(m, 2H); 7.23(m, IH); 7.24(m, IH); 7.28(m, IH); 7.30(m, IH); 7.38(d, IH); 7.4(dd, lH);7.70(d, IH); 8.08(d, IH); 8.1 l(d, IH). 13C NMR (500 MHz, CDCl3), δ (ppm): 12.2; 12.5; 12.6; 17.1; 17.7; 31.6; 31.8; 32.4; 38.1; 39.2; 39.3; 40.0; 41.2; 45.4; 50.7; 51.2; 123.2; 125.4; 125.5; 126.1; 126.2; 126.8; 127.3; 127.5; 128.2; 128.8; 129.4; 131.8; 135.9; 139.7; 140.7; 142.3; 142.6; 144.6; 147.2; 161.0; 175.7; 175.9. MS: 432,2586 (M+l)+.Montelukast diastereoisomer II:1H NMR (500 MHz, CDCl3), δ (ppm): 0.36-,62(m, 8H); 1.56(s, 3H); 1.57(s, 3H); 1.98(m, IH);2.13(m, IH); 2.00(m, IH); 2.46(m, IH); 2.20(d, IH); 2.65(d, IH); 2.36(d, IH); 2.48(d, IH); 2.77(m, IH); 2.96(m, IH); 3.29(dd, IH); 3.68(dd, IH); 3.95(t, IH) 4.36(dd, IH); 7.09(m, IH);7.10(m, IH);; 7.16(dd, IH); 7.18(dd, IH); 7.27(m, IH); 7.28(m, IH); 7.30(m, IH);; 7.35(m,IH); 7.36(m, IH); 7.40 (dd, IH); 7.61(d, IH); 8.02(d, IH); 8.09(d, IH).13C NMR (500 MHz, CDCl3), δ (ppm): 12.1; 12.3; 12.5; 12.8; 16.6; 17.0; 31.6; 31.7; 32.1;38.8; 39.1 ; 40.0; 40.5; 45.7; 50.3; 51.0; 74.3; 123.3; 125.3; 125.4; 125.6; 125.9; 126.8; 127.1; 127.2; 127.4; 128.2; 129.1; 131.7; 135.9; 136.7; 140.4; 142.4; 142.7; 144.8; 147.3; 161.0;175.9; 176.2.MS: 432,2591 (M+l)+.

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2009/111998, 2009, A2 Location in patent: Page/Page column 25-26

13
[ 169954-93-2 ]
[ 162515-68-6 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium t-butanolate; PEG-600 In toluene at -10℃; Inert atmosphere; Stage #2: 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethyl)phenyl)-3-(methanesulfonyl-1-oxy)methylethyl)phenyl)-2-propanol In tetrahydrofuran; toluene at -10 - 20℃;	1 EXAMPLE 1 (synthesis, crude montelukast sodium)In 200 ml of toluene [l-(mercaptomethyl)cyclopropyl] acetic acid (6.62 g), a base (sodium tert- butoxide, 8.50 g) and PEG-600 (26 ml in 30 ml of toluene) were mixed together, the mixture was stirred under argon and cooled to ca. -10 °C. To the obtained slurry a solution of 2-(3-(S)- (3-(2-(7-chloroquinolinyl)-ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl-2-propanol (26 g) in 120 ml of tetrahydrofuran was subsequently added. The reaction mixture was gradually stirred at from -10 0C to the laboratory temperature for 1 hour. The stirring was continued at the laboratory temperature for a number of hours. The reaction mixture was continuously analyzed by means of HPLC (isocratic mode). At the end of monitoring the reaction mixture contained 85.7% of montelukast.
	With sodium t-butanolate In tetrahydrofuran; toluene; PEG-600 at -10 - 21℃; Inert atmosphere;	1 In 200 ml of toluene, [1-(mercaptomethyl)cyclopropyl]acetic acid (6.62 g), a base (sodium tert-butoxide, 8.50 g) and PEG-600 (26 ml in 30 ml of toluene) were mixed; the mixture was stirred in an argon atmosphere and cooled to ca. -10° C. Then, a solution of 2-(3-(S)-(3-(2-(7-chloroquinolinyl)-ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl-2-propanol (26 g) in 120 ml tetrahydrofuran was added to the obtained slurry. The reaction mixture was stirred gradually from -10° C. up to the laboratory temperature for 1 hour. It was further stirred at the laboratory temperature (about 21° C.) for several hours. The reaction mixture was continuously analyzed by means of HPLC: At the end of the monitoring the reaction mixture contained 85.7% of Montelukast.

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2009/111998, 2009, A2 Location in patent: Page/Page column 18
[2]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - US2010/267958, 2010, A1 Location in patent: Page/Page column 3; 6

14
[ 1100021-00-8 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium t-butanolate; In toluene; at 30℃;	15 ml of toluene were added to 2.11 g of the crystalline salt of Montelukast with n-propylamine obtained in accordance with Example 8, the suspension was stirred for 20 minutes, then, sodium tert-butoxide (0.34 g) was added and the suspension was further stirred at the temperature of approximately 30 C. for 45 minutes. Then, filtration was performed and the clear yellow filtrate was injected to 35 ml of intensively stirred heptane with a syringe. The obtained suspension was further stirred for one hour, after that filtration and vacuum drying was carried out. 1.63 g of a powder was obtained. Yield 82%, HPLC 99.6%.

Reference： [1]Patent: US2010/267958,2010,A1 .Location in patent: Page/Page column 7

15
[ 162515-68-6 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / -5 - 0 °C / Inert atmosphere 1.2: 20 - 45 °C 2.1: dichloromethane; water 2.2: 25 - 35 °C 3.1: cerium(III) chloride / tetrahydrofuran / -5 - 65 °C / Inert atmosphere 4.1: sodium hydroxide / ethanol; water; methanol / 25 - 50 °C
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran / -15 - -10 °C / Inert atmosphere 1.2: -15 - 20 °C 2.1: toluene; acetonitrile / 30 - 50 °C / Inert atmosphere 3.1: acetic acid / dichloromethane; water / pH 7 / Inert atmosphere 3.2: 1 h / Activated carbon
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran / -15 - -10 °C / Inert atmosphere 1.2: -15 - 20 °C 2.1: toluene; acetonitrile / 30 - 50 °C / Inert atmosphere 3.1: acetic acid / dichloromethane; water / 15 - 20 °C / pH 7 / Inert atmosphere 3.2: 32 °C

	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -15 - -10 °C 2.1: tetrahydrofuran; hexane / 10 h / -15 - 5 °C 2.2: 24 h / 25 - 35 °C 3.1: acetic acid / dichloromethane; water / 25 - 30 °C / pH 4 - 4.5 3.2: 0.5 h
	Multi-step reaction with 3 steps 1.1: sodium methylate / N,N-dimethyl-formamide; methanol / 2 h / -5 - 0 °C 2.1: N,N-dimethyl-formamide; methanol / 12 h / -5 - 5 °C 2.2: 12 h / 25 - 35 °C 3.1: acetic acid / dichloromethane; water / 25 - 30 °C / pH 4 - 4.5 3.2: 0.5 h

Reference： [1]Current Patent Assignee: VIATRIS INC - EP1812394, 2011, B1
[2]Current Patent Assignee: PARTNERS GROUP HOLDING AG - WO2011/76237, 2011, A1
[3]Current Patent Assignee: PARTNERS GROUP HOLDING AG - US2012/259121, 2012, A1
[4]Current Patent Assignee: LAURUS LABS LIMITED - WO2014/1860, 2014, A1
[5]Current Patent Assignee: LAURUS LABS LIMITED - WO2014/1860, 2014, A1

16
[ 807638-71-7 ]
[ 162515-68-6 ]
C₂₉H₂₆ClNO [ No CAS ]
2-[2-((E)-3-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-allyl)-phenyl]-propan-2-ol [ No CAS ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
1: 53.9 %Chromat. 2: 20.6 %Chromat. 3: 8.1 %Chromat.	With sodium t-butanolate In tetrahydrofuran; toluene at -10 - 20℃; Inert atmosphere; Large scale reaction;

Reference： [1]Location in patent: body text Halama, Ales; Jirman, Josef; Bouskova, Olga; Gibala, Petr; Jarrah, A. Kamal [Organic Process Research and Development, 2010, vol. 14, # 2, p. 425 - 431]

17
[ 807638-71-7 ]
[ 162515-68-6 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
85.7 %Chromat.	With sodium t-butanolate In tetrahydrofuran; toluene at -10 - 21℃; Inert atmosphere; Large scale reaction;

Reference： [1]Location in patent: experimental part Halama, Ales; Jirman, Josef; Bouskova, Olga; Gibala, Petr; Jarrah, A. Kamal [Organic Process Research and Development, 2010, vol. 14, # 2, p. 425 - 431]

18
[ 162515-68-6 ]
[ 151767-02-1 ]
2-[(R)-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)-(R)-1-([1-(carboxymethyl)cyclopropyl]methyl}thio)ethyl]phenyl]-3-[2-(1-hydroxy-1-methyethyl)phenyl]propyl]thio]methyl]cyclopropane]acetic acid [ No CAS ]
2-[(R)-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)-(S)-1-([1-(carboxymethyl)cyclopropyl]methyl}thio)ethyl]phenyl]-3-[2-(1-hydroxy-1-methyethyl)phenyl]propyl]thio]methyl]cyclopropane]acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 80 mg 2: 80 mg	With sodium t-butanolate In tetrahydrofuran; toluene at 20℃; for 720h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Halama, Ales; Jirman, Josef; Bouskova, Olga; Gibala, Petr; Jarrah, A. Kamal [Organic Process Research and Development, 2010, vol. 14, # 2, p. 425 - 431]

19
[ 142569-70-8 ]
[ 151767-02-1 ]

Reference： [1]Patent: US2011/166356,2011,A1
[2]Patent: WO2014/118796,2014,A1
[3]Patent: CN105294556,2016,A

20
[ 1100021-03-1 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
99%		Comparative Example 6 Preparation of sodium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate 10 g of montelukast amine salt obtained from Comparative Example 2 was dissolved in 100 ml of methylene chloride, and 10% acetic acid was dropped into it so as to adjust the pH to a range of 4 to 4.5. Then, the resultant product was washed with distilled water twice. The organic layer was concentrated and dissolved in 100 ml of methanol. Then, 0.54 g of NaOH dissolved in 1.7 mL of distilled water was introduced, and 1 g of activated carbon was added, followed by stirring for 1 hour and filtration. After vacuum-concentration of the solvent, the resultant product was dissolved in 20 ml of water and freeze-dried so as to provide 8.7 g of montelukast sodium salt (yield: 99%, purity: 94.5%, HPLC wavelength: 238 nm, Phenyl column, 4.6×250 mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20 min at a flow rate 1.5 mL/min).
		lOg of montelukast amine salt obtained from Comparative Example 2 was dissolved in 100ml of methylene chloride, and 10% acetic acid was dropped into it so as to adjust the pH toa range of 4 to 4.5. Then, the resultant product was washed with distilled water twice. The organic layer was concentrated and dissolved in 100ml of methanol. Then, 0.54g of NaOH dissolved in 1.7mL of distilled water was introduced, and lg of activated carbon was added, followed by stirring for 1 hour and filtration. After vacuum-concentration of the solvent, the resultant product was dissolved in 20ml of water and freeze-dried so as to provide 8.7g of montelukast sodium salt (yield: 99%, purity: 94.5%, HPLC wavelength: 238nm, Phenyl column, 4.6X250mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20min at a flow rate 1.5mL/min).

Reference： [1]Patent: US2013/184464,2013,A1 .Location in patent: Paragraph 0087
[2]Patent: WO2012/15255,2012,A2 .Location in patent: Page/Page column 18

21
[ 1254938-23-2 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
99%		lOg of montelukast amine salt obtained from Example 4 was dissolved in 100ml of methylene chloride, and 10% acetic acid was dropped into it so as to adjustthe pH to a range of 4 to 4.5. Then, the resultant product was washed with distilled water twice. The organic layer was concentrated and dissolved in 100ml of methanol. Then, 0.54g of NaOH dissolved in 1.7mLof distilled water was introduced, and lg of activated carbon was added, followed by stirring for 1 hour and filtration. After vacuum-concentration of the solvent, the resultant product was dissolved in 20ml of water and freeze- dried so as to provide 8.3g of montelukast sodium salt (yield: 99%, purity: 99.6%, chiral purity: 99.9% ee, HPLC wavelength: 238nm, Phenyl column, 4.6X250mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20min at a flow rate 1.5mL/min).<i27> H-NMR(300MHz, CDC13) delta (ppm) : 7.98(d, 1H), 7.94(d, 1H), 7.62~7.47(m, 4H) ,7.40~6.96(m, 9H) , 3.93(t, 1H), 3.19~3.33(m, 1H) , 2.65~2.79(m, 1H) , 2.48~2.35(m, 2H), 2.27-2. ll(m, 4H), 1.55(d, 6H), 0.38-0.14(m, 4H)
99%		Example 5 Preparation of sodium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate 10 g of montelukast amine salt obtained from Example 4 was dissolved in 100 ml of methylene chloride, and 10% acetic acid was dropped into it so as to adjust the pH to a range of 4 to 4.5. Then, the resultant product was washed with distilled water twice. The organic layer was concentrated and dissolved in 100 ml of methanol. Then, 0.54 g of NaOH dissolved in 1.7 mL of distilled water was introduced, and 1 g of activated carbon was added, followed by stirring for 1 hour and filtration. After vacuum-concentration of the solvent, the resultant product was dissolved in 20 ml of water and freeze-dried so as to provide 8.3 g of montelukast sodium salt (yield: 99%, purity: 99.6%, chiral purity: 99.9% ee, HPLC wavelength: 238 nm, Phenyl column, 4.6×250 mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20 min at a flow rate 1.5 mL/min). 1H-NMR (300 MHz, CDCl3) delta (ppm): 7.98 (d, 1H), 7.94 (d, 1H), 7.627.47 (m, 4H), 7.406.96 (m, 9H), 3.93 (t, 1H), 3.193.33 (m, 1H), 2.652.79 (m, 1H), 2.482.35 (m, 2H), 2.272.11 (m, 4H), 1.55 (d, 6H), 0.380.14 (m, 4H)

Reference： [1]Patent: WO2012/15255,2012,A2 .Location in patent: Page/Page column 14-15
[2]Patent: US2013/184464,2013,A1 .Location in patent: Paragraph 0072; 0073

22
[ 1254938-26-5 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
98%		lOg of montelukast amine salt obtained from Example 3 was dissolved in 100ml of methylene chloride, and 10% acetic acid was dropped into it so as to adjust thepH to a range of 4 to 4.5. Then, the resultant product was washed with distilled water twice. The organic layer was concentrated and dissolved in 100ml of methanol. Then, 0.54g of NaOH dissolved in 1.7mL of distilled water was introduced, and lg of activated carbon was added, followed by stirring for 1 hour and filtration. After vacuum-concentration of the solvent, the resultant product was crystallized using toluene and normal heptane so as to provide 8.2g of montelukast sodium salt (yield: 98%, purity: 99.7%, chiral purity: 99.9% ee, HPLC wavelength: 238nm, Phenyl column, 4.6X250mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20min at a flow rate 1.5mL/min).<132>

Reference： [1]Patent: WO2012/15255,2012,A2 .Location in patent: Page/Page column 15
[2]Patent: US2013/184464,2013,A1 .Location in patent: Paragraph 0074

23
[ 149968-10-5 ]
[ 151767-02-1 ]

Reference： [1]Patent: WO2012/20271,2012,A1

24
[ 1312993-47-7 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
86.8%		EXAMPLE 3 Preparation of Montelukast Sodium In a 3L 4-neck r.b. flask, 1500 ml Dichloromethane and 150 g (0.199 mol) Montelukast salt are charged under inert gas. The reaction mass is cooled to temperature from about 15 to 20 C. and extracted twice with about 395 ml Acetic acid 5% w/v aq. solution and washed with 5*667 ml de-mineral water till pH 7. The organic layer is distilled off at temperature below about 32 C. under vacuum and the residue is diluted in 236 ml Methanol and a solution of 8.78 g (0.21 mol) NaOH in 118 ml Methanol is added slowly. Activated carbon of 2.01 g is charged to the flask, while maintaining the stirring for about 1 hour. The reaction mass is filtered through hyflow bed and washed with 118 ml Methanol. The solvent is distilled off completely at temperature below 45 C. and the residue is stripped with 219 ml Cyclohexane. To the residue 1010 ml Cyclohexane is added and the reaction mixture is stirred for about 1 to 2 hours at temperature from about 25 to 30 C. The obtained material is filtered on Buchner funnel and washed twice with 100 ml Cyclohexane. The wet cake is charged in 2L Rotavapor flask, followed by 220 ml Methanol. Stirring is maintained for about 15 min and methanol is distilled off completely at temperature below 45 C. under vacuum. The wet material is unloaded and dried under vacuum at temperature from about 65 to 70 C. Montelukast sodium is obtained, i.e. a yield of 86.3% to 86.8%. The present invention describes a large-scale manufacture process for the preparation of Montelukast sodium with improved yield and purity at relative low production cost in comparison to the prior art processes for producing similar products. In summary, according to the present invention a one-pot process for the preparation of crude Montelukast free acid is provided, wherein the protection/de-protection steps used in the prior art processes are obviated without sacrificing the yield and quality of the product. In addition, the use of optically pure L-ephedrine according to the present invention results in a process for the purification of Montelukast free acid, wherein Montelukast-L-ephedrine salt has improved yield with increased chemical and optical purity. Also the present invention has provided a process for the preparation of Montelukast sodium in improved yield with increased chemical and optical purity from the corresponding Montelukast-L-ephedrine salt.

Reference： [1]Patent: US2012/259121,2012,A1 .Location in patent: Page/Page column 5-6

25
[ 59394-27-3 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / 0 - 5 °C 1.2: 4 h / 0 - 15 °C 2.1: palladium diacetate; triphenylphosphine; triethylamine / N,N-dimethyl-formamide / 110 °C 3.1: caustic lye / 12 h / 120 °C 4.1: sodium hydroxide / methanol / 1 h / 25 °C

Reference： [1]Saravanan; Satyanarayana; Reddy, P. Pratap [Synthetic Communications, 2013, vol. 43, # 15, p. 2050 - 2056]

26
[ 142522-28-9 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide; In methanol; at 20℃; for 0.5h;Inert atmosphere;	The compound of formula I (40g, 0 · 068piomicron1) was dissolved in 200mL of methanol, 2 g of activated carbon was added, stirred at room temperature30min, filtered, room temperature and a solution of sodium hydroxide to the filtrate under inert gas in methanol (2. 73g NaOH solutionIn 95mL of methanol) and stirred for 30min, the solvent was distilled off under reduced pressure, the residue was dissolved in 100mL of toluene and stirred for 15min, againThe solvent was distilled off under reduced pressure, the residue was dissolved in 120mL of toluene and 400mL of n-heptane was slowly added dropwise, with stirring after completion of the dropwise addition2h, filtered and solid at 80-85 C under vacuum drying 12h, to obtain Montelukast sodium 38. 2g, molar yield 92%

Reference： [1]Patent: CN105294556,2016,A .Location in patent: Paragraph 0045; 0046

27
[ 143418-49-9 ]
[ 151767-02-1 ]
C₄₁H₃₈F₃NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With O4P(3-)3K(1+)5H2O; tris(1-adamantyl)phosphine; {2-[((acetyl-kappaO)amino)phenyl-kappaC](tri-1-adamantylphosphine)palladium}(p-toluenesulfonate); In tetrahydrofuran; at 100℃; for 5h;Inert atmosphere;	To a mixture of montelukast sodium salt (152 mg, 0.25 mmol, 1 equiv), 3,4,5- trifluorophenyl boronic acid (53 mg, 0.30 mmol, 1.2 equiv), and K3P045 H20 (0.18 g, 0.60 mmol, 2.4 equiv) was added THF (2 mL) then a THF stock solution of 3 and PAd3 (1 mL, 2.5jtmol of Pd/PAd3). The mixture was stirred at 100 C for 5 h. The reaction mixture was diluted with ethyl acetate then extracted with saturated ammonium chloride then water. The combine organic layers were evaporated and the crude product was purified by flash chromatography. After drying, 152 mg (89 %) of 14 was obtained as yellow solid.H NMR (500 MHz, CDC13) 6 8.18 (d, J 1.8 Hz, 1H), 8.10 (d, J 8.5 Hz, 1H), 7.82 (d, J 8.4Hz, 1H), 7.74 (d, J- 1.9 Hz, 1H), 7.67 (d, J 8.6 Hz, 1H), 7.62 (dd, J- 5.0, 1.8 Hz, 1H), 7.59(d, J= 17.1 Hz, 1H), 7.48 (d, J= 17.1 Hz, TH), 7.40 (m, 1H), 7.37-7.28 (m, 5H), 7.18 -7.13(m, 2H), 7.10 (ddd, J= 7.6, 5.8, 3.0 Hz, 1H),5.29 (s, 1H),4.01 (t, J 7.2 Hz, 1H), 3.17 (ddd, J13.5, 11.2, 5.1 Hz, 1H), 2.90 (ddd, J- 13.5, 11.2, 5.4 Hz, 1H), 2.65 (d, J= 13.1 Hz, 1H), 2.57 (d,J= 16.2 Hz, 1H), 2.45 (d, J= 13.1 Hz, 1H), 2.38 (d, J= 16.1 Hz, 111), 2.28-2.09 (m, 2H), 1.60(d, J 4.9 Hz, 6H), 0.71 - 0.24 (m, 4H).C{H} NMR (126 MHz, CDC13) 176.3, 156.9, 151.5 (ddd, J= 249.9, 10.0, 4.2 Hz), 147.7,145.2, 143.6, 140.2, 139.7 (dt, J= 253.3, 15.4 Hz),139.4, 136.5, 136.4, 136.3 (m), 135.4, 131.5,129.0, 128.6, 128.5, 128.4, 127.1, 126.9, 126.5, 126.5, 126.4, 125.6, 125.4, 125.0, 119.4, 111.4(dd, J 12.6, 5.0 Hz), 73.8, 50.3, 40.3, 40.0, 38.9, 32.3, 31.8, 16.8, 12.7, 12,4.HRMS (ESI) m/z calculated for C41H38F3N03S (M+1) 682.2597, found 682.2598.

Reference： [1]Patent: WO2017/75581,2017,A1 .Location in patent: Page/Page column 18; 19

28
1-(((1-(R)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropylacetate 2-amino-1-butanol [ No CAS ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
97.2%		C. To a 1000 mL three-necked flask were successively added 50 g of montelukast acid 2-amino-1-butanol salt, 400 mL of methylene chloride, and an aqueous solution of acetic acid (10 mL of acetic acid diluted with 100 mL of purified water)Stirring was continued for 15 min after the addition was completed. The phases were separated and the organic phase was washed with 100 mL of water and dried over 30 g of anhydrous sodium sulfate for 1 hour. The mixture was concentrated under reduced pressure to give montelukast acid. The yield was 97.4% and the purity was 99.9%.D. To 1000mL three-necked flask followed by adding 30g montelukast acid, 300mL of anhydrous methanol, was slowly added 2.05g of sodium hydroxide,After the clarification, 1.5g of activated carbon and 4.5g of anhydrous sodium sulfate are sequentially added, and the temperature is controlled at 15 to 25 DEG C for 1 hour,Filtered, concentrated, 150mL of n-heptane was added, the temperature was controlled at 5-15 C for 1 hour, filtered and vacuum dried at 70 C for 24 hours to obtain montelukast sodium,Yield 97.2%, purity 99.9%, styrene, sulfoxide impurities less than 0.03%.

Reference： [1]Patent: CN105924392,2016,A .Location in patent: Paragraph 0037-0038; 0042-0048; 0052-0058

29
C₃₅H₃₁ClNO₅P [ No CAS ]
[ 162515-68-6 ]
[ 151767-02-1 ]

Yield	Reaction Conditions	Operation in experiment
57.17 g	Stage #1: C₃₅H₃₁ClNO₅P; 1-(sulfanylmethyl)cyclopropaneacetic acid With 2,6-dimethylpyridine; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -20 - -15℃; Inert atmosphere; Stage #2: With sodium hydroxide In methanol at 10 - 20℃; Inert atmosphere;	1-5; 1 Under the protection of nitrogen, in a 1000 mL three-neck flask with mechanical stirring, add 61.20 g of the compound of formula (II), 428 mL of tetrahydrofuran, 20.64 g of N,N-diisopropylethylamine, and 8.56 g of 2,6-lutidine , Stir and cool to -20-15, add dropwise a mixed solution of 17.52g compound of formula (III) and 80mL tetrahydrofuran under stirring. After the addition is complete, stir and react at -20-15 for 34 hours; slowly; To room temperature,TLC detects the progress of the reaction.After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was added with 150mL purified water and 350mL chloroform, mixed evenly and then separated. The organic layer was washed with 150mL 5% aqueous sodium bicarbonate solution and 150mL saturated brine in turn, and adjusted with acetic acid The pH of the organic layer is 23, and the organic layer is evaporated under reduced pressure until it becomes viscous. The residue is controlled at -50. 795mL of anhydrous ether is added dropwise. At this temperature, stir and crystallize for 23 hours, filter, and use appropriate amount of filter cake. Wash with water and ether, dry under reduced pressure at 40°C,Get 57.88gMontelukast acid.The yield was 98.91%; HPLC: 99.90%.Under the protection of nitrogen flow, add 517mL methanol and 57.88g montelukast acid successively into the 1000mL reaction flask, stir and control the temperature at 10-20, slowly add 3.96g sodium hydroxide,After the addition is complete, stir and react for 60-65min, then add 5.8g activated carbon,8g anhydrous sodium sulfate,Keep at 1030, stir and decolorize for 3040 minutes, filter to remove activated carbon,Anhydrous sodium sulfate, control the temperature not to exceed 35 and concentrate methanol under reduced pressure to a viscous formThe remainder is controlled at -50,413.9mL of n-hexane was added dropwise, at this temperature, stirred and crystallized for 2 to 3 hours, filtered,The filter cake is washed with an appropriate amount of n-hexane and dried under reduced pressure at 40°C,57.17 g montelukast sodium was obtained.Yield 95.20%; HPLC: 99.92%.

Reference： [1]Current Patent Assignee: LUNAN PHARMACEUTICAL GROUP CO LTD - CN111892535, 2020, A Location in patent: Paragraph 0020; 0050-0067

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	151767-02-1	MDL No. :	MFCD00931431
Formula :	C₃₅H₃₅ClNNaO₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LBFBRXGCXUHRJY-HKHDRNBDSA-M
M.W :	608.17	Pubchem ID :	23663996
Synonyms :	MK0476;Montelukast (sodium salt);MK-476	Chemical Name :	Sodium (R,E)-2-(1-(((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)thio)methyl)cyclopropyl)acetate

Num. heavy atoms :	42
Num. arom. heavy atoms :	22
Fraction Csp3 :	0.31
Num. rotatable bonds :	12
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	170.7
TPSA :	98.55 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.53 cm/s

Log Po/w (iLOGP) :	-8.2
Log Po/w (XLOGP3) :	7.72
Log Po/w (WLOGP) :	6.9
Log Po/w (MLOGP) :	5.7
Log Po/w (SILICOS-IT) :	9.38
Consensus Log Po/w :	4.3

[ CAS No. 151767-02-1 ] {[proInfo.proName]}

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Physicochemical Properties

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Safety of [ 151767-02-1 ]

Application In Synthesis of [ 151767-02-1 ]

[ 151767-02-1 ] Synthesis Path-Downstream 1~29

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Inquiry

Lipinski :	2.0
Ghose :	None
Veber :	1.0
Egan :	1.0
Muegge :	2.0
Bioavailability Score :	0.17

Log S (ESOL) :	-8.07
Solubility :	0.00000518 mg/ml ; 0.0000000085 mol/l
Class :	Poorly soluble
Log S (Ali) :	-9.63
Solubility :	0.000000142 mg/ml ; 0.0000000002 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-11.38
Solubility :	0.0000000026 mg/ml ; 0.0 mol/l
Class :	Insoluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	4.75

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H320-H335	Packing Group:	N/A
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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling