Name: 114798-26-4|(1-((2'-(1H-Tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methanol|98%
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1
[ 133909-99-6 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

2
[ 1310-58-3 ]
[ 114798-26-4 ]
[ 124750-99-8 ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol; at 38 - 42℃;	Example-3Preparation of potassium salt of 2-butyl-4-chloro-l-[2'- (IH- tetrazoI-5-yl) [1, T- biphenyI]-4-yl] methyl} IH -imidazole-5-methanolTo the product obtained in Example 2 i.e. 2-butyl-4-chloro-l-[2'- (IH- tetrazol-5-yl) [1, l'-biphenyl]-4-yl] methyl} IH -imidazole-5-methanol (38gm) is suspended in propan-2- ol (130 ml) and solution is heated to 40+20C. A solution of potassium hydroxide (6.05gm) dissolved in water (6 ml) and propan-2-ol (50 ml) was added while maintaining the temperature at 40+20C. prorhoan-2-ol (100 ml) was distilled from reaction mass and fresh propan-2-ol (100 ml) and Heptane (30ml) was added. Reaction mass was cooled to 20-250C and n-Heptane (50ml) was added. The slurry was stirred for lhour and obtained solid was filtered, dried. Weight-38.12 gm

Reference： [1]Patent: WO2007/119246,2007,A2 .Location in patent: Page/Page column 14

3
[ 114798-26-4 ]
[ 124750-99-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium hydroxide; In methanol; isopropyl alcohol; at 20℃; for 0.5h;	85 g of losartan was suspended in isopropanol (250 ml), and a solution prepared by dissolving 12.1 g of potassium hydroxide in methanol (85 ml) was slowly added thereto, followed by stirring for 30 minutes at room temperature. The resulting solution was filtered to remove insoluble materials and the filtrate was refluxed while adding cyclohexane (1,000 ml) thereto. Then, the resulting mixture was distilled to remove 340 ml of solvent and the residue containing solids was slowly cooled to room temperature. After stirring for 4 hours, the solid material was filtered, washed with a mixture of isopropanol and cyclohexane, and dried at 45 C, to obtain 87.3 g of the title <n="9"/>compound (yield: 90 %).[68][69] Melting point: 269C to 274C[70] 1H-NMR (DMSO-d6, ppm): 7.65 (IH, m), 7.4 (2H, m), 7.3 (IH, m), 7.15 (2H, d),6.95 (2H, d), 5.45 (IH, br), 5.3 (2H, s), 4.4 (2H, s), 2.54 (2H, m), 1.55 (2H, m), 1.31 (2H, m), 0.9 (3H, t).
33%	With potassium hydroxide; In methanol; for 4h;Heating / reflux;	A mixture of 2-n-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}-1H-imidazole-5-methanol (1 g) in dry methanol (8.75 mL) was warmed to reflux temperature. Then, potassium hydroxide (99 mg) in dry methanol (1.7 ml) was added and the mixture was refluxed for 4 h. The reaction was cooled to room temperature, treated with charcoal and filtered. The filtrate was concentrated to a volume of 1.5-1.75 mL, and after addition of acetonitrile (4.2 mL) again to a volume of 1.5-1.75 mL. Further acetonitrile (4.2 mL) was added and the solution was concentrated to a volume of 3 mL. The suspension was stirred at 0-5C overnight and the solid was filtered, washed with cold acetonitrile (3 x 1.5 mL) and dried at 60C overnight to give 231 mg (33%) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta 0.79 (t, J = 7.4 Hz, 3 H, CH3), 1.24 (m, 2 H, CH3-CH2-CH2-), 1.46 (qn, J = 7.6 Hz, CH2-CH2-CH2-), 2.48 (bs, 2 H, CH2-CH2-C-), 4.29 (s, 2 H, CH2-OH), 5.19 (s, 2 H, CH2-N), 5.30 (bs, 1 H, OH), 6.88 (d, J = 8 Hz, 2 H, H-Ar), 7.07 (d, J = 8 Hz, 2 H, H-Ar), 7.40 (d, J = 7.6 Hz, 1 H, H-Ar), 7.49 (td, J = 7.6 and 1.1 Hz, 1 H, H-Ar), 7.57 (td, J = 7.5 and 1.1 Hz, 1 H, H-Ar), 7.85 (d, J = 7.6 Hz, 1 H, H-Ar) ppm. 13C-NMR (100 MHz, DMSO-d6) delta 14.3 (CH3), 22.3, 26.5 and 29.8 (CH2), 47.2 (CH2-N), 52 (CH2-OH), 125.9, 127.4, 127.9, 130.1, 130.7 and 131.2 (CH-Ar), 125.9, 126.3, 133.3, 135.3, 140.5, 141.8, 148 and 161.4 (C-ipso-Ar) ppm. IR (upsilon): 3734 (OH), 1259 (C-O) cm-1.
	With potassium hydroxide; In methanol; for 1h;pH 9;Reflux;	Example-1 Preparation of <strong>[114798-26-4]Losartan</strong> potassium Form I [85][86] Potassium hydroxide flakes (15.2 g) was added to methanol (200 ml) and stirred for30 min at 25-3O0C. <strong>[114798-26-4]Losartan</strong> (100 g) was added to the above prepared mixture and heated to reflux (65-680C) for an hour. The pH of the reaction mixture was checked. It should be more than 9. (If not then added solution of potassium hydroxide in methanol till pH more than 9 is obtained). Activated charcoal (5 g slurry in 25 ml methanol) was added to the reaction mixture and further refluxed for an hour. The reaction mixture was filtered hot through hyflo bed. The bed was washed twice with hot methanol (550C) (50 ml x 2). Again activated charcoal (5 g slurry in 25ml methanol) was added to the filtrate and refluxed for an hour. The reaction mixture was filtered hot through hyflo bed. The bed was washed twice with hot methanol (550C) (50 ml x X). Methanol was distilled out completely from the filtrate at atmospheric pressure. High vacuum was applied till all the material gets solidified. Acetone (50 ml) was added and distilled out completely at atmospheric pressure. This step is repeated twice. Again acetone (300 ml) was added and refluxed for an hour. (Note: solid does not dissolve). The suspension was cooled to 25-3O0C during period of 1 to 2 hours. The suspension was further cooled to 5-1O0C and maintained for one hour. The product was filtered; the solid cake was washed with chilled acetone (1O0C) (50 ml x 2) and suck dried. The product was dried in oven under vacuum at 60-700C to give <strong>[114798-26-4]Losartan</strong> potassium Form I (90-94 g)

Reference： [1]Patent: WO2007/133040,2007,A1 .Location in patent: Page/Page column 7; 8
[2]Patent: EP1833801,2008,B1 .Location in patent: Page/Page column 15
[3]Patent: WO2010/46804,2010,A2 .Location in patent: Page/Page column 6

4
[ 852357-69-8 ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 Removal of the Protecting Group from a Compound (VI) 10 g (0.02 moles) of (2-butyl-5-chloro-3-{2'-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol are dissolved in 50 ml of 37% aqueous hydrochloric acid under stirring at a temperature of 15-20 C. The mixture is stirred for a further 4h, then washed 3 times with 25 ml of toluene. The aqueous phase is poured into a solution of 55 g of sodium acetate in water, the formed precipitate is filtered, thoroughly washed with water and dried under vacuum at 70 C., thereby obtaining 8 g of losartan. NMR: 1H (DMSO, 300 mHz): delta0.80 (3H, t, J=10, CH3), 1.25 (2H, sest, J=10, CH3CH2), 1.45 (2H, quin, J=10, CH3CH2CH2), 2.45-2.55 (2H, m, CH3CH2CH2CH2), 4.30 (2H, 2H, CH2OH), 5.30 (2H, s, CH2Ar), 7.10 (4H, s, ArH), 7.45-7.70 (4H, m, ArH). EXAMPLE 4 Removal of the Protecting Group from a Compound (VI) 10 g (0.02 moles) of (2-butyl-5-chloro-3-{2'-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol are dissolved in 50 ml of 40% aqueous hydrobromic acid under stirring at a temperature of 15-20 C. The mixture is stirred for a further 4h, then washed 3 times with 25 ml of toluene. The aqueous phase is poured into a solution of 55 g of sodium acetate in water, the formed precipitate is filtered, thoroughly washed with water and dried under vacuum at 70 C., thereby obtaining 7.8 g of losartan. Operating analogously, from the respective intermediates of formula (VI) obtainable according to Example 1, the following compounds: valsartan, irbesartan, candesartan and olmesartan can be obtained.
		EXAMPLE 3 Removal of the Protecting Group from a Compound (VI) 10 g (0.02 moles) of (2-butyl-5-chloro-3-{2'-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol are dissolved in 50 ml of dichloromethane and gaseous HCl is bubbled at a temperature of 0-10 C. After 2h the reaction mixture is poured into a solution of 55 g of sodium acetate in water, the formed precipitate is filtered, thoroughly washed with water and dried under vacuum at 70 C., thereby obtaining 7.8 g of losartan.

Reference： [1]Patent: US2005/119488,2005,A1 .Location in patent: Page/Page column 4
[2]Patent: US2005/119488,2005,A1 .Location in patent: Page/Page column 4

5
[ 114798-26-4 ]
[ 124750-92-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	With pyridine; potassium permanganate; tetrabutyl-ammonium chloride; In water; acetone; at 40 - 50℃; for 1h;Product distribution / selectivity;	To a 2000 ml three necked round bottom flask equipped with condenser, mechanical stirrer, and thermometer was added de-ionized water (250 ml), potassium permanganate (0.25 mol) and stirred for about 15 minutes. Tetrabutylammonium chloride (0.30 ml) was added in four portions in 20 minutes. After stirring vigorously for 30 minutes, pyridine (100 ml) and acetone (650 ml) were added and the reaction mixture stirred for another 30 minutes.The dark purple solution was transferred into a 2000 ml three necked flask equipped with condenser, mechanical stirrer, and thermometer. The solution was warmed up to an internal temperature 40 C. <strong>[114798-26-4]Losartan</strong> (0.1 ml) [QUESTION: What is the total amount by weight of <strong>[114798-26-4]Losartan</strong>?] was added into the reaction mixture in portions with continued stirring. The internal temperature of the reaction mixture was maintained below 50 C. After one hour, the reaction was completed. To the reaction mixture, was added 30% formaldehyde solution (200 ml) slowly with the temperature maintained below 50 C. The reaction mixture was stirred until the purple color disappeared. Brown precipitates were also formed.The contents of the reaction vessel were filtered. The brown solid was washed with 1.0 M NaOH (100 ml×3). The filtrate was almost colorless. The filtrate was concentrated on a rotary evaporator to about of the original volume and stirred with mechanical stirrer and cooled in ice bath. A 6 M HCl solution was added dropwise to reduce the pH of the mixture to about 2. White precipitates were formed during acidification. The precipitate was filtered, washed with de-ionized water, dried in the air and recrystallized in 2-propanol to give white solid of losartan 5-carboxylic acid (EXP-3174). Yield for the reaction was calculated at 78%.The potassium salt of <strong>[114798-26-4]Losartan</strong> was also used for the reaction. The yield was 72%. 1H NMR(DMSO-d6, 400 MHz): 7.64(d, 1H), 6.62(t, 1H), 7.55(t, 1H), 7.59(d, 1H), 7.07(d, 2H), 6.96(d, 2H), 5.62(s, 2H), 2.55(t, 2H), 1.51(q, 2H), 1.21(m, 2H), 0.85(t, 3H)
	With sodium periodate; ruthenium(III) trichloride hydrate; potassium hydroxide; In water; at 0℃;	Step A: Water (100 ml), potassium hydroxide (152.4 mmol) was added to a four-necked flask at 0 C followed by losartan (10.9 mmol) Sodium periodate (25.9 mmol) and ruthenium (III) chloride monohydrate (0.5 mmol) And the reaction mixture is added 0 C Under stirring overnight. The reaction mixture was filtered. Adding isopropyl alcohol to the filtrate in a stirred state, heating the solution to 25 C and stirring for 2.5 hours, adding phosphoric acid thereto, maintaining the temperature below 30 C. The mixture was stirred for 30 minutes and the resulting product was filtered, washed with water and the residue was dried in vacuo to give 2-butyl-4-chloro-1 - ((2 '- (1H-tetrazol- - [1,1'-biphenyl] -4-yl) methyl) -1H-imidazole-5-carboxylic acid.
		Step A: To the four-necked flask was added water (100 ml), potassium hydroxide (152.4 mmol) at 0 C, followed by the addition of chlorine(10.9 mmol), sodium periodate (25.9 mmol) and ruthenium (III) chloride monohydrate (0.5 mmol) were added and the reaction mixture was stirred at 0 & lt; 0 & gt; C overnight.The reaction mixture was filtered.To the filtrate was added isopropanol in a stirred state, the solution was heated to 25 C and stirred for 2.5 hours,To which phosphoric acid is added,Maintaining the temperature below 30 & lt; 0 & gt; C.The mixture was stirred for 30 minutes and the resulting product was filtered, washed with water, and the residue was dried in vacuo to give 2-butyl-4-chloro-1 - ((2 '- (1H-tetrazol- - [1,1'-biphenyl] -4-yl) methyl) -1H-imidazole-5-carboxylic acid.

Reference： [1]Patent: US2008/90885,2008,A1 .Location in patent: Page/Page column 2
[2]Patent: CN104496971,2016,B .Location in patent: Paragraph 0042-0044
[3]Patent: CN104447899,2017,B .Location in patent: Paragraph 0119; 0120; 0121

6
[ 57598-33-1 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

7
[ 114772-53-1 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[3]Journal of Chemical Research,2015,vol. 39,p. 451 - 454
[4]Patent: US5663186,1997,A

8
[ 79047-41-9 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Patent: US5128355,1992,A

9
[ 83857-96-9 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Synthesis,2014,vol. 46,p. 3249 - 3255
[3]Journal of Chemical Research,2015,vol. 39,p. 451 - 454
[4]Patent: WO2007/133040,2007,A1
[5]Patent: CN110467604,2019,A

10
[ 114772-54-2 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Journal of Chemical Research,2015,vol. 39,p. 451 - 454
[3]Patent: US5663186,1997,A
[4]Patent: WO2007/133040,2007,A1
[5]Patent: CN110467604,2019,A

11
[ 74201-13-1 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

12
[ 84392-32-5 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

13
[ 114772-55-3 ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium azide; In 1-methyl-pyrrolidin-2-one;	The second step: N-methylpyrrolidone were added 150ml; input of formula (1) compound 43g, the end of the catalyst, sodium azide 30g, reaction, the reaction product was extracted with aqueous sodium hydroxide, sodium nitrite, ethyl acetate was added dropwise to hydrochloric acid to pH 3-5, filtered and the cake washed with water to give yellow-brown crude wet product losartan. Three-neck flask was added 50g of losartan obtained by the above route, 250ml of tetrahydrofuran was added; stirring was dissolved, was added sodium borohydride 20 1.5g, 3ml methanol was added dropwise, stirred for 20 2 hours, and water was added, THF was evaporated to give a white losartan (yield 99.0%, purity 98.5%). It can be used for subsequent preparation of losartan potassium, without bleaching.
91%	With sodium azide; zinc trifluoromethanesulfonate; In water; at 100℃; for 6h;Green chemistry;	Sodium azide (82 mg, 1.25 mmol) and zinctrifluomethanesulfonate was added to a solution of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2?-cyano) -[1,1?-biphenyl] -4-yl]-methyl}-1H-imidazole (7) (0.190 g, 0.5 mmol) in water at room temperature.The resultant mixture was heated to 100C and maintained at thistemperature for 6 h. The resulting precipitated solid was filtered andwashed with water. The crude product was dissolved in acetone atroom temperature and then heated under reflux for 1 h, and thencooled to room temperature. The resultant reaction mixture wasstirred at room temperature for 2h, during which a crystalline solidwas formed. The crystals were filtered, washed with acetone, anddried under vacuum at 50-60C to afford 0.192 g (91%) of the titlecompound losartan (8)
91%	With sodium azide; triethylamine hydrochloride; In toluene; at 90 - 95℃;	Put 40 g of toluene into a four-necked flask, and add 20 g of compound 4, 10.3 g of sodium azide, and 18 g of triethylamine hydrochloride under slow stirring.After the feeding, the temperature is raised to 90-95 C, and the reaction is held for 35-45 hours. After the reaction is completed, 40g of water is added, the temperature is lowered to 60-70 C, and the mixture is left to stand and separate.40 ml of n-butanol was added to dissolve, washed twice with 20 g of a saturated sodium chloride aqueous solution, 0.4 g of triphenylphosphine and 0.8 g of activated carbon were added, and the temperature was raised to 50-60 C. with stirring for decolorization for 2 hours.Hot filtration, rinse the filter cake with 10ml n-butanol, and combine the filtrates, control the temperature to 50-80 C, and vacuum dry under 0.08MPa above vacuum. Dry the dried material and add 7.7g liquid alkali (mass concentration of about 50% concentrated hydrogen) Sodium oxide solution) and 160g of water,The solution was stirred and dissolved. After adding 10 g of toluene to the aqueous layer for extraction twice, 80 ml of dichloromethane was added to the aqueous layer, and the temperature was lowered to 10-15 C.7.5% hydrochloric acid (volume concentration) was added dropwise, the pH was adjusted to 3-4, and the temperature was maintained at 10-15 C for 1 hour, and then lowered to 0-5 C for 1 hour.Filter, filter cake was rinsed with 20 ml of dichloromethane and 40 g of water, and dried under reduced pressure to obtain 20.2 g of losartan, yield 91%, azide ion content (HPIC detection): not detected (detection limit: 0.081 ppm).

90%	With pyrrolidine; sodium azide; sulfuric acid; tetrabutylammomium bromide; In toluene; at 95℃; for 42h;Green chemistry;	To a 1000 ml four-necked flask, 27.2 g of tetrahydropyrrole and 160 mL of toluene were added successively to stir. Drop to it 19.0 g of concentrated sulfuric acid was added and stirred at 25 C for 2 h. To the resulting mixture was added 66.0 g of chloronitrile, 26.0 g of sodium azide and the like Tetrabutylammonium bromide (0.8 g), the temperature was raised to 95 C, and the reaction was stirred for 42 h. Cooled to 50 C, 45 mL of sodium hydroxide solution and 220 mL of drinking water were added to the reaction system, Saponification 1h. The upper toluene phase was separated and washed with 15 mL of sodium hydroxide solution and 90 mL of drinking water The toluene phase was combined and the aqueous phase was combined. 15 g of sodium nitrite and 25 mL of water were added and stirred. The temperature was lowered to 25 C and the mixture was added dropwise 6N hydrochloric acid to adjust the pH to 7.0, add 230mL ethyl acetate, and stir. Continue to drop 6N hydrochloric acid to adjust the pH to 4.0, stirring crystallization 3h. The filter cake was rinsed with ethyl acetate. The filter cake was collected and dried at 65 C under reduced pressure to give losartan. The yield was 90% and the purity was 98.4%.
85.4%		Example 2: Preparation of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2?-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-imidazole (Losartan) (Method 1) [100] 2-butyl-4-chloro-5-hydroxymethyl-1-[(2?-cyano-biphenyl-4-yl)-methyl]-imidazole (379.9g) and n-butanol (1.5L) were added into a reactor, and the solid compound (370.7g) obtained in Example 1-1 was added thereto while stirring the mixture. The reaction mixture was stirred for 24 hours while maintaining the internal temperature of the reaction mixture at 100~120. The temperature inside the reactor was cooled to room temperature, and 28% ammonia water (1.0L) and water (1.0L) were added thereto dropwise for phase separation. To the obtained organic layer, water (1.7L) and sodium hydroxide (240.0g) were added, and the mixture was stirred at room temperature for 2 hours, and then phase preparation was conducted again. To the obtained organic layer, water (1.5L), sodium hydroxide (64.0g) and sodium chloride (400g) were added, and phase preparation was conducted again. Finally, water (1.8L) was added to the organic layer, and with stirring the pH of the mixture was adjusted to 3~4 by using sulfuric acid, and then the mixture was stirred for 15~17 hours. The generated solid was filtered, washed with n-butanol (0.9L) and dried under nitrogen to obtain the title compound (361.2g, yield: 85.4%).[101] 1H NMR (delta ppm, DMSO-d6), 0.79 (t, 3H), 1.22 (m, 2H), 1.44 (m, 2H), 2.49 (t, 2H), 4.32 (s, 2H), 5.23 (s, 2H), 7.03 (d, 2H), 7.08 (d, 2H), 7.52 (d, 1H), 7.57 (t, 1H), 7.66 (m, 2H)
82%		Losartan was obtained by a method similar to that used in Example 1 using 100 g of2-n-butyl-4-chloro-5-hydroxymethyl-l-[(2'-cyanobiphenyl-4-yl)methyl]imidazole-5-m ethanol (263 mmol) as a starting material while varying the reaction conditions as <n="8"/>shown in Table 1.[64] Table 1 [Table 1]
78%		Losartan was obtained by a method similar to that used in Example 1 using 100 g of2-n-butyl-4-chloro-5-hydroxymethyl-l-[(2'-cyanobiphenyl-4-yl)methyl]imidazole-5-m ethanol (263 mmol) as a starting material while varying the reaction conditions as <n="8"/>shown in Table 1.[64] Table 1 [Table 1]
76%		Losartan was obtained by a method similar to that used in Example 1 using 100 g of2-n-butyl-4-chloro-5-hydroxymethyl-l-[(2'-cyanobiphenyl-4-yl)methyl]imidazole-5-m ethanol (263 mmol) as a starting material while varying the reaction conditions as <n="8"/>shown in Table 1.[64] Table 1 [Table 1]
> 75%	With sodium azide; triethylamine hydrochloride; In 1-methyl-pyrrolidin-2-one; at 25 - 105℃; for 28 - 30h;Product distribution / selectivity;	To a stirred solution of 2-n-butyl-4-chloro-l-[2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl) imidazole ( 105 gm, 0.276 M ) prepared by the process described in step I in 210 ml of N-methyl pyrrolidinone at room temperature was added Triethyl amine hydrochloride ( 75 gm, 0.545 M ) and sodium azide (35 gm, 0.54 M) at room temperature ( 25 - 30C). The reaction temperature was raised to 103-1050C and maintained for 28-30 hours. TLC showed the absence of starting material. The reaction mixture was cooled to 45 - 50C and charged 300 ml of toluene, 800 ml of water with stirring. The organic layer was separated and 'aqueous layer was washed with 250 ml of toluene. The aqueous layer was treated with 10 grams of activated carbon and filter through celite. Aqueous layer PH was adjusted to 4.3-4.5 with acetic acid (70 - 75 ml) and was stirred for 8 hours at 25 - 300C. The aqueous solution was filtered and washed with water to get the Losartan of the formula (1). (Yield: > 75%). Melting point: 180.5 - 181.2 HPLC Purity: > 98%IR v max (KBR): 3376.27 , 1579.77, 1468.86, 762.88, 556.41H NMR (CDC13) delta , 0.87 (t, 3H), 1.31 (sext, 2H), 1.54 (quint, 2H), 2.57 (t,2H),4.45 (s,2H), 5.30 (s,2H), 7.01 - 7.68 (m, 8H). 13C NMR (CDC13) delta , 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72 MS (m/z) = 423.5 (M+l).; To a stirred solution of 2-n-butyl-4-cMoro-l-[2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl) imidazole ( 105 gm, 0.276 M ) prepared by the process described in step I in 210 mi of N-methyl pyrrolidinone at room temperature was added TEA HCl ( 75 gm, 0.545 M ) and sodium azide (35 gm, 0.54 M) at room temperature ( 25 - 300C).5 The reaction temperature was raised to 103-105C and maintained for 28-30 hours. TLC showed the absence of starting material.The reaction mixture was cooled to 45 - 50C and charge 300 ml of toluene, 800 ml of water with stirring. The organic layer was separated and aqueous layer was washed with 250 ml of toluene. The aqueous layer is treated with 10 grams of activated carbon and0 filter through celite. Aqueous layer PH was adjusted to 4.3-4.5 with acetic acid (70 - 75 ml) and was stirred for 8 hours at 25 - 30C. The aqueous solution was filtered and washed with water to get Losartan of the formula 1. (Yield: > 75% ). Melting point: 180.5 - 181.2 HPLC Purity: > 98%?5 IR. v max (KBR): 3376.27 , 1579.77, 1468.86, 762.88, 556.41H NMR (CDC13) delta , 0.87 (t, 3H), 1.31 (sext, 2H), 1.54 (quint, 2H), 2.57 (t,2H), 4.45 (s,2H), 5.30 (s,2H), 7.01 - 7.68 (m, 8H). EPO <DP n="18"/>13C NMR (CDC13) delta , 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72 MS (m/z) = 423.5 (MH-I).
75%	With sodium azide; triethylamine hydrochloride; In 1-methyl-pyrrolidin-2-one; toluene; at 110℃;	Example-2[124][125] Preparation of Losartan (V); [126] A mixture of2-n-Butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole (IV) (125.0 g), sodium azide (85.6 g), triethyl amine hydrochloride (TEA-HCl) (181.0 g), l-Methyl-2-pyrrolidinone (NMP) (125.0 ml) and toluene (500.0 ml) were heated at 11O0C for 30-35 hours. Caustic solution (19.75g in 300ml water) was added to it and the layers were separated. Acetic acid was added to the aqueous layer and pH was adjusted to 4 to 4.5. The product was filtered and solid washed with water. The solid was triturated with Acetone (500.0 ml) to give pure Losartan (V) (105.0 g).[127] Yield: 75.0%[128] Purity (By HPLC): 99.25%
> 75%	With sodium azide; triethylamine hydrochloride; In 1-methyl-pyrrolidin-2-one; at 25 - 105℃;	Step-II: Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidazole [Losartan] of the formula (1); To a stirred solution of 2-n-butyl-4-chloro-1-[2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl) imidazole (105 gm, 0.276 M) prepared by the process described in step I in 210 ml of N-methylpyrrolidinone at room temperature was added Triethyl amine hydrochloride (75 gm, 0.545 M) and sodium azide (35 gm, 0.54 M) at room temperature (25-30 C.). The reaction temperature was raised to 103-105 C. and maintained for 28-30 hours. TLC showed the absence of starting material.The reaction mixture was cooled to 45-50 C. and charged 300 ml of toluene, 800 ml of water with stirring. The organic layer was separated and aqueous layer was washed with 250 ml of toluene. The aqueous layer was treated with 10 grams of activated carbon and filter through celite. Aqueous layer PH was adjusted to 4.3-4.5 with acetic acid (70-75 ml) and was stirred for 8 hours at 25-30 C. The aqueous solution was filtered and washed with water to get the Losartan of the formula (1). (Yield: >75%).Melting point 180.5-181.2HPLC Purity: >98%IR. v max (KBR): 3376.27, 1579.77, 1468.86, 762.88, 556.41H NMR (CDCl3) delta, 0.87 (t, 3H), 1.31 (sext, 2H), 1.54 (quint, 2H), 2.57 (t, 2H), 4.45 (s, 2H), 5.30 (s, 2H), 7.01-7.68 (m, 8H).13C NMR (CDCl3) delta, 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72MS (m/z)=423.5 (M+1).
75 - 84%		100 g of 2-n-butyl-4-chloro-5-hydroxymethyl- 1 - [(2'-cyanobiphenyl-4-yl)methyl] imidazole (263 mmol) prepared in Reference Example, 72.4 g of triethylamine hydrochloride (526 mmol, 2 mole equivalents) and 34.2 g of sodium azide (526 mmol, 2 mole equivalents) were successively added to N-methyl-2-pyrrolidinone (300 ml), and the resulting mixture was kept at 120C for 12 hours and then cooled to 80C. Purified water (600 ml) and acetone (600 ml) were added to the resulting solution and 6N hydrogen chloride aqueous solution was added thereto to adjust the pH to 4.0. Then, 100 mg of losartan was seeded thereto and stirred for 6 hours while slowly cooling to room temperature to allow the formation of a solid material. 6N hydrogen chloride aqueous solution was added thereto to adjust the pH to 3.5. The resulting suspension was cooled to 5C and stirred for 3 hours. The resulting precipitates were filtered under a reduced pressure, washed with a mixture of 300 ml of purified water and 100 ml of acetone, and dried at 45C, to obtain 82.5 g of the title compound (yield: 76 %) as a tiny yellow solid.[57][58] Melting point: 185C to 187C[59] Purity: 97.0% (HPLC)[60] 1H-NMR (CDCl3, ppm): 7.65 (2H, m), 7.5 (2H, m), 7.0 (4H, m), 5.2 (2H, s), 4.3 (2H, s), 2.4 (2H, m), 1.4 (2H, m), 1.2 (2H, m), 0.8 (3H, t); Losartan was obtained by a method similar to that used in Example 1 using 100 g of2-n-butyl-4-chloro-5-hydroxymethyl-l-[(2'-cyanobiphenyl-4-yl)methyl]imidazole-5-m ethanol (263 mmol) as a starting material while varying the reaction conditions as <n="8"/>shown in Table 1.[64] Table 1 [Table 1]
		1. 9 g (5 mmol) of the, hydroxymethyl-imidazol-1-ylmethyl biphenylcarbonitrile"from the previous step is suspended in 10 ml of dry toluene under argon. To this suspension is added at room temperature under stirring 2.8 ml of a 1.8 molar solution of AlEt3 in toluene. Stirring of the suspension was continued for additional 3 hours. Then A solution of 10 mmol diethyl aluminium azide in toluene, which is prepared in a separate flask, is added via syringe. (This 10 mmol of Et2Al-N3 was prepared by stirring 10 mmol of Et2AICl and 10 mmol of NaN3 in toluene at room temperature over night to give a white suspension of NaCl, but the diethyl aluminium azide is dissolved in toluene). The rection mixture is heated to reflux (~111 C), external temperature ca. 140 C. conversion is controlled by HPLC analysis. After refluxing for 24 hours the reaction mixture was cooled to room temperature and finally quenched on an aqueous solution of 40 mmol of NaNO2 in 40 ml of 2N hydrochloric acid. Then additional 20 ml of 2N HCl is added under stirring to dissolve the precipitated Aluminium hydroxide. Finally the product was isolated from the aqueous phase by extraction with ethyl acetate. The combined organic phases (toluene/EtOAc) are washed 2 times with 25 ml of water and evaporated to dryness in vacuum to give crude Losartan. The crude Losartan can be purified by crystallization from CH3CN or CH3CN/water mixtures, according to literature; (J. O. C. , 59,6391 (1994) ).
	With ammonium chloride; In ethanol; water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile;	Step E Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g, 1.0 eq), sodium azide (3 eq), and ammonium chloride (3 eq) were mixed and stirred in DMF (150 mL) in a round bottom connected to a reflux condenser under N2. An oil bath with a temperature controller was then used to heat the reaction at 100 C. for 2 days, after which the temperature was raised to 120 C., for 6 days. The reation was cooled and 3 more equivalents of ammounium chloride and sodium azide were added. The reaction was again heated for 5 more days at 120 C. The reaction was cooled, the inorganic salts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with ehtyl acetate (2*200 mL), the organic layers were collected, dried (MgSO4) and the solvent removed in vacuo, to yield a dark yellow oil. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow solid. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid; m.p. 183.5-184.5. Upon cooling, the mother liquor yielded an additional 1.03 g of product as a light yellow solid; m.p. 179.0-180.0. NMR (200 MHz, DMSO-d6) delta 7.75-7.48 (m, 4H); 7.07 (d, 2H, J=9 Hz); 7.04 (d, 2H, J=9 Hz); 5.24 (s, 2H); 5.24 (bs, 1H); 4.34 (s, 2H); 2.48 (t, 2H, J=7 Hz); 1.48 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz). Anal. Calcd. for C22 H23 ClN6 O: C, 62.48; H, 5.48; Cl, 8.38. Found for the solids which did not dissolve in 100 mL of acetonitrile: C, 62.73; H, 5.50; Cl, 8.26. Found for the solids obtained from the mother liquor: C, 62.40; H, 5.23; Cl, 8.35.
	With ammonium chloride; In ethanol; water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile;	Step E Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g, 1.0 eq), sodium azide (3 eq), and ammonium chloride (3 eq) were mixed and stirred in DMF (150 mL) in a round bottom connected to a reflux condenser under N2. An oil bath with a temperature controller was then used to heat the reaction at 100 C. for 2 days, after which the temperature was raised to 120 C., for 6 days. The reaction was cooled and 3 more equivalents of ammonium chloride and sodium azide were added. The reaction was again heated for 5 more days at 120 C. The reaction was cooled, the inorganic salts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with ethyl acetate (2*200 mL), the organic layers were collected, dried (MgSO4) and the solvent removed in vacuo, to yield a dark yellow oil. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow solid. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid; m.p. 183.5-184.5. Upon cooling, the mother liquor yielded an additional 1.03 g of product as a light yellow solid; m.p. 179.0-180.0. NMR (200 MHz, DMSO-d6)delta7.75-7.48 (m, 4H); 7.07 (d, 2H, J=9 Hz); 7.04 (d, 2H, J=9 Hz); 5.24 (s, 2H); 5.24 (bs, 1H); 4.34 (s, 2H); 2.48 (t, 2H, J=7 Hz); 1.48 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz). Anal. Calcd. for C22 H23 ClN6 O: C, 62.48; H, 5.48; Cl, 8.38.
	In ethanol; ethyl acetate; acetonitrile;	Part E Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g) was converted to the above product by the procedure described in Example 90, Part C. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow solid. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid; m.p. 183.5-184.5. Upon cooling, the mother liquor yielded an additional 1.03 g of product as a light yellow solid; m.p. 179.0-180.0. NMR (200 MHz, DMSO-d6) delta7.75-7.48 (m, 4H); 7.07 (d, 2H, J=9 Hz); 7.04 (d, 2H, J=9 Hz); 5.24 (s, 2H); 5.24 (bs, 1H); 4.34 (s, 2H); 2.48 (t, 2H, J=7 Hz); 1.48 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz). Anal. Calcd. for C22 H23 ClN6 O: C, 62.48; H, 5.48; Cl, 8.38. Found for the solids which did not dissolve in 100 mL of acetonitrile: C, 62.73; H, 5.50; Cl, 8.26. Found for the solids obtained from the mother liquor: C, 62.40; H, 5.23; Cl, 8.35.
	With sodium azide; triethylamine hydrochloride; In PEG400; chlorobenzene; at 95 - 98℃; for 35h;	ExampIe-2Preparation of 2-butyI-4-chIoro-l- [2'- (IH- tetrazoI-5-yI) [1, l'-biphenyl]- 4 -yl] methyl} IH -imidazoIe-5-methanoI <n="15"/>To a mixture of Triethyl amine hydrochloride (90gm; 0.65moles) in chlorobenzene (350 ml), Sodium azide (42.0gm; 0.64mole) was added. Reaction mass stirred for lhour and compound obtained in Example I (50gm; 0.13 moles) and PEG400 (12.5ml) were charged. Reaction mass was heated to 95-980C and maintained for 34 hours .The progress of reaction was monitored by HPLC and after completion, reaction mass was cooled to 0-5 C and. methanol (250ml) was added. The pH of reaction mass was adjusted to 3.5 by 1:1HC1 solution. Resultant mixture was stirred for 10-15rninute and again the pH of reaction mass was adjusted to 11 by KOH solution. Aqueous layer separated and washed with toluene. Ethyl acetate (450ml) was added to reaction mass and pH was adjusted to 4.5 and stirred overnight and obtained solid was filtered and dried. Weight-48.0gm
	With ammonium chloride; In ethanol; water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile;	Step E Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g, 1.0 eq), sodium azide (3 eq), and ammonium chloride (3 eq) were mixed and stirred in DMF (150 mL) in a round bottom connected to a reflux condenser under N2. An oil bath with a temperature controller was then used to heat the reaction at 100 C. for 2 days, after which the temperature was raised to 120 C., for 6 days. The reation was cooled and 3 more equivalents of ammounium chloride and sodium azide were added. The reaction was again heated for 5 more days at 120 C. The reaction was cooled, the inorganic salts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with ehtyl acetate (2*200 mL), the organic layers were collected, dried. (MgSO4) and the solvent removed in vacuo, to yield a dark yellow oil. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow solid. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid; m.p. 183.5-184.5. Upon cooling, the mother liquor yielded an additional 1.03 g of product as a light yellow solid; m.p. 179.0-180.0. NMR (200 MHz, DMSO-d6) delta 7.75-7.48 (m, 4H); 7.07 (d, 2H, J=9 Hz); 7.04 (d, 2H, J=9 Hz); 5.24 (s, 2H); 5.24 (bs, 1H); 4.34 (s, 2H); 2.48 (t, 2H, J=7 Hz); 1.48 (t of t, 2H, J=7,7Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz). Anal. Calcd. for C22 H23 ClN6 O: C, 62.48; H, 5.48; Cl, 8.38. Found for the solids which did not dissolve in 100 mL of acetonitrile: C, 62.73; H, 5.50; Cl, 8.26. Found for the solids obtained from the mother liquor: C, 62.40; H, 5.23; Cl, 8.35.

Reference： [1]Patent: CN106674205,2017,A .Location in patent: Paragraph 0020; 0022; 0028
[2]Journal of Chemical Research,2015,vol. 39,p. 451 - 454
[3]Patent: CN110467604,2019,A .Location in patent: Paragraph 0054-0059
[4]Patent: CN107056756,2017,A .Location in patent: Paragraph 0030-0032; 0034; 0038; 0041; 0044; 0047; 0050-0059
[5]Patent: WO2012/148148,2012,A2 .Location in patent: Page/Page column 10
[6]Patent: WO2007/133040,2007,A1 .Location in patent: Page/Page column 6; 7
[7]Patent: WO2007/133040,2007,A1 .Location in patent: Page/Page column 6; 7
[8]Patent: WO2007/133040,2007,A1 .Location in patent: Page/Page column 6; 7
[9]Patent: WO2007/20654,2007,A1 .Location in patent: Page/Page column 9; 13; 16-17
[10]Patent: WO2010/29457,2010,A2 .Location in patent: Page/Page column 12
[11]Patent: US2010/190996,2010,A1 .Location in patent: Page/Page column 7-8
[12]Patent: WO2007/133040,2007,A1 .Location in patent: Page/Page column 6; 7
[13]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[14]Patent: WO2005/14602,2005,A1 .Location in patent: Page/Page column 51-52
[15]Patent: US5962500,1999,A
[16]Patent: US5608075,1997,A
[17]Patent: US5138069,1992,A
[18]Patent: WO2007/119246,2007,A2 .Location in patent: Page/Page column 13-14
[19]Patent: US5663186,1997,A

14
[ 133909-97-4 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

15
[ 133051-88-4 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

16
[ 133910-00-6 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

17
[ 579-75-9 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

18
[ 21615-34-9 ]
[ 114798-26-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[2]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547

19
[ 104-15-4 ]
[ 114798-26-4 ]
2-n-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol p-toluenesulfonate [ No CAS ]

Reference： [1]Patent: US6350880,2002,B1 .Location in patent: Example 1

20
[ 124750-99-8 ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sulfuric acid; In water; ethyl acetate; at 10 - 25℃; for 1h;pH 3.6 - 3.8;Purification / work up;	42.66 g of potassium salt of losartan were dissolved in 430 ml water, 130 ml ethyl acetate were added, and it was acidified at a temperature of 21 to 25 C to a pH of 3.6-3. 8 with concentrated sulphuric acid, cooled below 10C, and stirred for 1 hour. The formed solid was filtered, redispersed in 145 ml ethyl acetate, filtered once again, and DRIED IN VACUO at 50 C overnight to yield 36.6 g losartan.;Example 15 (Preparation of pharmaceutically usable losartan potassium via crystalline losartan potassium) As already described, to 10.2 g crude losartan of Example 14 (chromatographic purity 98.73%) in 59 ml i-propanol, a solution of 1.4 g potassium hydroxide in 1.5 mi water at a temperature of 38-40 C to a pH of 10 over half an hour was added. Approximately 19 ml of azeotropic mixture i-propanol/water were removed by distillation, 36 mi n-heptane were added, and reaction mixture was stirred at room temperature until a white solid was formed. The resulting mixture was diluted with 14 ml n-heptane, filtered, washed with 26 mi n-heptane, and dried in vacuo at 50 C to yield 8.57 g losartan potassium (yield : 77%, chromatographic purity: 99.67%). The resulting potassium salt of losartan was dissolved in 86 ml water, 26 mi ethyl acetate were added, and it was acidified at a temperature of 21-25 C to a pH of 3.6-3. 8 with concentrated sulphuric acids, cooled below 10 C, and stirred for 1 hour. The formed solid was filtered, redispersed in 29 mi ethyl acetate, filtered once again, and DRIED IN VACUO at 50 C overnight to yield 7.35 g losartan (yield of the phase: 93%, chromatographic purity: 99.82%). The resulting product was dissolved in 20 ml i-propanol, 1.96 g potassium t- butoxide in a temperature range between 10 C and 25 C were added. The reaction mixture clarified. Adense, white solid was formed when 27 ml n-heptane were added. Reaction mixture was stirred at room temperature for 1 hour, filtered and washed with 13 ml n-heptane, DRIED IN VACUO at 50 C overnight to yield 7.66 g losartan potassium (yield of the phase: 96%, chromatographic purity: 99.88%, total yield : 69%).

Reference： [1]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 51; 53
[2]Patent: US6350880,2002,B1 .Location in patent: Example 1
[3]Patent: US6350880,2002,B1 .Location in patent: Example 1
[4]Patent: US6350880,2002,B1 .Location in patent: Example 1

21
2-n-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol p-toluenesulfonate [ No CAS ]
[ 114798-26-4 ]

Reference： [1]Patent: US6350880,2002,B1 .Location in patent: Example 1

22
[ 114798-26-4 ]
[ 124750-99-8 ]

Yield	Reaction Conditions	Operation in experiment
94 - 96%	With potassium tert-butylate; In isopropyl alcohol; at 10 - 25℃;Product distribution / selectivity;	To 40.81 g losartan of Example 1 in 110 ml i-propanol was added 10.86 g of potassium t-butanolate a temperature between 10C and 25C. The reaction mixture clarified. A dense white precipitate was formed when 150 ml of n-heptane was added and stirred at room temperature for 1 hour. It was filtered and washed with 75 mi n-heptane, dried at 50 C C IN VACUO overnight to yield 43.25 g of losartan potassium.; Example 14 (Preparation of pharmaceutically usable losartan potassium via crystalline losartan sodium) To 20.4 g crude losartan (chromatographic purity of 98.73%) in 120 ml i-propanol, a solution of 2.75 g sodium hydroxide in 2.9 mi water was added at a temperature of 38-40C to a pH of 10 during half an hour. Approximately 18 mi of azeotropic MIXTURE I-PROPANOL/WATER WERE REMOVED BY DISTILLATION, 70 MI N-HEPTANE WERE added, and it was stirred at room temperature until a white solid was formed. The resulting solid was diluted with 28 ml n-heptane, filtered, washed with 55 mi n- heptane, and DRIED IN VACUO at 50 C to yield 18.5 g crystalline losartan sodium (yield : 87%, chromatographic purity : 99.42%). The obtained substance was dissolved in 185 ml water, 56 mi ethyl acetate were added, and it was acidified at a temperature of 21-25 C to a pH of 3.6-3. 8 with concentrated sulphuric acid, cooled below 10C, and stirred for 1 hour. The formed solid was filtered, redispersed in 64 ml ethyl acetate, filtered once again, and DRIED IN VACUO at a temperature of 50 C overnight to yield 16. 5 g losartan (yield of the phase: 94%, chromatographic purity: 99.74%). The resulting product was dissolved in 45 ml i-propanol, 4.39 g potassium TERT- butoxide between 10C and 25C were added. The reaction mixture clarified. A dense, white precipitate was formed when 60 mi n-heptane were added, and it was stirred at room temperature for 1 hour. It was filtered and washed with 30 ml n-heptane, DRIED IN VACUO at 50 C overnight to yield 16.9 g losartan potassium (yield of the phase: 94%, chromatographic purity: 99. 91 %, overall yield : 77%).; Example 15 (Preparation of pharmaceutically usable losartan potassium via crystalline losartan potassium) As already described, to 10.2 g crude losartan of Example 14 (chromatographic purity 98.73%) in 59 ml i-propanol, a solution of 1.4 g potassium hydroxide in 1.5 mi water at a temperature of 38-40 C to a pH of 10 over half an hour was added. Approximately 19 ml of azeotropic mixture i-propanol/water were removed by distillation, 36 mi n-heptane were added, and reaction mixture was stirred at room temperature until a white solid was formed. The resulting mixture was diluted with 14 ml n-heptane, filtered, washed with 26 mi n-heptane, and dried in vacuo at 50 C to yield 8.57 g losartan potassium (yield : 77%, chromatographic purity: 99.67%). The resulting potassium salt of losartan was dissolved in 86 ml water, 26 mi ethyl acetate were added, and it was acidified at a temperature of 21-25 C to a pH of 3.6-3. 8 with concentrated sulphuric acids, cooled below 10 C, and stirred for 1 hour. The formed solid was filtered, redispersed in 29 mi ethyl acetate, filtered once again, and DRIED IN VACUO at 50 C overnight to yield 7.35 g losartan (yield of the phase: 93%, chromatographic purity: 99.82%). The resulting product was dissolved in 20 ml i-propanol, 1.96 g potassium t- butoxide in a temperature range between 10 C and 25 C were added. The reaction mixture clarified. Adense, white solid was formed when 27 ml n-heptane were added. Reaction mixture was stirred at room temperature for 1 hour, filtered and washed with 13 ml n-heptane, DRIED IN VACUO at 50 C overnight to yield 7.66 g losartan potassium (yield of the phase: 96%, chromatographic purity: 99.88%, total yield : 69%).
93.7%		Example 5: Preparation of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2?-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-imidazole potassium salt (<strong>[114798-26-4]Losartan</strong> potassium) [110] 2-butyl-4-chloro-5-hydroxymethyl-1-[(2?-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-imidazole (122.6g) prepared according to the method of Example 2 was suspended in isopropanol (580mL). A solution of potassium hydroxide (19.2g) dissolved in isopropanol (580mL) was slowly added thereto dropwise. After the mixture was dissolved completely, the temperature was elevated to simply distill 60~70% of the used isopropanol. After distillation was completed, the temperature was cooled to 40~50 and cyclohexane (580mL) was slowly added thereto dropwise over about 1 hour. After the dropwise addition, the mixture was slowly cooled to room temperature and then stirred for 2 hours, and the generated solid was filtered and washed twice with a mixture liquid of isopropanol and cyclohexane, and dried under nitrogen to obtain the title compound (125.4g, yield: 93.7%).[111] 1H NMR (delta ppm, DMSO-d6), 0.80 (t, 3H), 1.24 (m, 2H), 1.48 (m, 2H), 2.49 (t, 2H), 4.31 (d, 2H), 5.20 (s, 2H), 6.90 (d, 2H), 7.10 (d, 2H), 7.28 (d, 1H), 7.35 (m, 2H), 7.53 (d, 1H)
92%	With potassium hydroxide; In water; acetonitrile; for 0.25 - 0.333333h;Product distribution / selectivity;	Example-9 Preparation of losartan potassium form 1: A suspension of free losartan (25g; 0. 059MOL) in acetonitrile (150M]) is treated with a solution of potassium hydroxide (85%, 3.9g ; 0.059 mol) in water (20ml). The mixture is stirred for 15-20 min. to obtain a clear solution. The solution is diluted with isopropyl ether (150MT). The resulting solution is distilled to remove water as an azeotrope. The distillation is continued till the moisture content of the solution is less than 0. 1%. The crystalline solid thus obtained is filtered and found to be form I as established by extensive analytical methods. Yield: 25g (92%) Example-10 Preparation of losartan potassium form 1: A suspension of free losartan (25g; 0. 059MOL) in ACETONITRILE (500MOI) is treated with a solution of potassium hydroxide (85%, 3.9g ; 0.059 mol) in water (15ml). The mixture is stirred for 15-20 min. to obtain a clear solution. The resulting solution is distilled to remove water as an azeotrope. The distillation is continued with drop wise addition of acetonitrile (500ML), till the moisture content of the solution is less than 0.1%. The crystalline solid thus obtained is filtered and found to be form I as established by extensive analytical methods. Yield: 25g (92%)

91 - 93%	With potassium hydroxide; In tert-butyl methyl ether; water; isopropyl alcohol; at 20 - 55℃; for 3h;Product distribution / selectivity;	A 250 ml flask equipped with a magnetic stirrer bar, a thermometer and a reflux condenser was charged with 20 ml of iso- propyl alcohol, 80 ml of t-butyl methyl ether, 1 ml of water and 20 g (47.3 mmols) of <strong>[114798-26-4]Losartan</strong> free acid at room temperature to give a suspension. In a second flask 3.24 g (49.6 mmols) of KOH were dissolved in 60 ml of isopropyl alcohol by heating. The KOH solution was filtered and added to the above suspension while stirring. After the addition was complete the reaction mixture was stirred for 3 hours at room temperature. White crystals started to precipitate which were collected by filtration and dried to yield 2O g (92 % yield) of <strong>[114798-26-4]Losartan</strong> potassium with a relative purity of 99.9 % (HPLC). Compared to EXAMPLE 1, the addition of small amounts of water increases the yield; A 850 ml flask equipped with a magnetic stirrer bar, a thermometer and a reflux condenser was charged with 10 ml of isopropyl alcohol, 40 ml of t-butyl methyl ether, 0.5 ml of water and 10 g (23.6 mmols) of <strong>[114798-26-4]Losartan</strong> free acid and the resulting suspension was heated to 550C. In a second flask 1.62 g (24.8 mmols) of KOH were dissolved in 30 ml of isopropyl alcohol by heating. The KOH solution was filtered and added to the above suspension while stirring. After the addition was complete, the reaction mixture was stirred for 1 hour at 550C. The reaction mixture was cooled to room temperature over about 1 hour and stirred over night at this temperature. The precipi- <n="11"/>tated white crystals were collected by filtration and dried to yield 10.14 g (93 % yield) of <strong>[114798-26-4]Losartan</strong> potassium with a relative purity of 99 % (HPLC); A 850 ml flask equipped with a magnetic stirrer bar, a thermometer and a reflux condenser was charged with 10 ml of iso- propyl alcohol, 13.3 ml of t-butyl methyl ether, 0.5 ml of water and 10 g (23.6 mmols ) of <strong>[114798-26-4]Losartan</strong> free acid at room temperature and the resulting suspension was heated to 550C. In a second flask 1.62 g (24.8 mmols) of KOH were dissolved in 30 ml of isopropyl alcohol by heating. The KOH solution was filtered and then added to the above suspension while stirring. At this point the solvent is approximately a 75:25 mixture of isopropyl alcohol and t-butyl methyl ether. After the addition was complete the reaction mixture was stirred for 1 hour at 550C. The reaction mixture was cooled to room temperature over about 1 hour and stirred over night at this temperature. The precipitated white crystals were collected by filtration and dried to yield 9.9 g (91 % yield) of <strong>[114798-26-4]Losartan</strong> potassium with a relative purity of 99.9 % (HPOC).
90.0%	With potassium hydroxide; In methanol;	Example-3[131][132] Preparation of <strong>[114798-26-4]Losartan</strong> potassium (I); [133] 85% Potassium hydroxide (15.02 g) solution was added to a mixture of <strong>[114798-26-4]Losartan</strong> (V) (100.0 g) in methanol (300.0 ml). The reaction mixture was heated to get clear solution. Activated charcoal was added to the reaction mixture and stirred well. The mixture was filtered through hyflow bed to remove charcoal. The filtrate was distilled to evaporate the solvent completely. Acetone (300.0 ml) was added to it and stirred. The resulting precipitates were filtered and washed with acetone (100.0 ml) and suck dried. The solid was dried in oven to give <strong>[114798-26-4]Losartan</strong> potassium (I) (98.0 g).[134] Yield: 90.0%[135] Purity (By HPLC):99.85%
87.15%	With potassium hydroxide; In methanol; at 25 - 63℃; for 4 - 5h;Heating / reflux;Product distribution / selectivity;	To a stirred solution of 2-n~buryl-4-cltauloro-5-hydroxymethyl-l-[(2'-(lH-tetrazole-5- yl)biphenyl-4-yl)methyl] imidazole (<strong>[114798-26-4]Losartan</strong> of the formula (I)) obtained in step II (50 gm, 0.118 M) in 250 ml of methanol was added potassium hydroxide powder [ 7.6 gm ( 86%), 0.118 3VTj at room temperature (25 - 30C). The reaction temperature was raised to reflux (60 - 63C) and maintained for 4-5 hours at 60 - 63C. The reaction mixture was cooled to 35 - 40C. This was filtered through celite and the clarified solution was concentrated to remove most of methanol at 45 - 5O0C under reduced pressure. 100 ml of Methyl ethyl ketone was added and distillation continued to distill most of the methanol/methyl ethyl ketone mixture. Residue was diluted with 200 ml of Acetone and contents cooled to 5 - 10C for 30 minutes and product filtered and washed with 50 ml of acetone. Product was dried under reduced pressure to yield 47.5 grams. (87.15% of theory) of <strong>[114798-26-4]Losartan</strong> Potassium of the formula (2). HPLC Purity. 99.81%. IR. v max (KBR): 3201.01 , 1580.73, 1460.18, 764.81, 540.09 ' H NMR (MeOD) delta , 0.87 (t, 3H), 1.33 (sext, 2H), 1.53 (quint, 2H), 2.56 (t,2H), 4.43 (s,2H), 5.24 (s,2H), 6.89 - 7.53 (m, 8H).13C NMR (MeOD) delta , 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72 MS (m/z) = 423.3 (M+l).; To a stirred solution of 2-n-butyl-4-chloro-5-hydroxymethyl-l-[(2'-(lH-tetrazole-5- yl)biphenyl-4-yl)methyl] imidazole (<strong>[114798-26-4]Losartan</strong> T) obtained by the process described in step ? (50 gm, 0.118 M) in 250 ml of methanol was added potassium hydroxide powder [ 7.6 gm ( 86%), 0.118 M] at room temperature (25 - 30C). The reaction temperature is raised to reflux (60 - 63 C) and maintained for 4-5 hours at 60 - 63 C. The reaction mixture was cooled to 35 - 400C. This was filtered through celite and the clarified solution was concentrated to remove most of methanol at 45 - 500C under reduced pressure. 100 ml of Methyl ethyl ketone was added and distillation continued to distill most of the methanol/methyl ethyl ketone mixture. Residue was diluted with 200 ml of Acetone and contents cooled to 5 - 100C for 30 minutes and product filtered and washed with 50 ml of acetone. Product was dried under reduced pressure to yield 47.5 grams. (87.15% of theory) <strong>[114798-26-4]Losartan</strong> Potassium of he formula (2). HPLC Purity: 99.82%. IR v max (KBR): 3201.01 , 1580.73, 1460.18, 764.81, 540.091H NMR (MeOD) delta , 0.87 (t, 3H), 1.33 (sect, 2H), 1.53 (quint, 2H)5 2.56 (t,2H),4.43 (s,2H), 5.24 (s,2H), 6.89 - 7.53 (m, 8H).13C NMR (MeOD) delta , 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72 MS (m/z) = 423.3 (M+l).
87%	With potassium hydroxide; In tert-butyl methyl ether; isopropyl alcohol; at 20℃; for 3h;Product distribution / selectivity;	A 850 ml flask equipped with a magnetic stirrer bar, a thermometer and a reflux condenser was charged with 20 ml of iso- propyl alcohol, 80 ml of t-butyl methyl ether and 20 g (47.3 mmols ) of <strong>[114798-26-4]Losartan</strong> free acid at room temperature to give a suspension. In a second flask 3.24 g (49.6 mmols) of KOH were dissolved in 60 ml isopropyl alcohol by heating. The KOH solution was filtered and added to above suspension while stirring. At this point the solvent is approximately a 50:50 mixture of isopropyl alcohol and t-butyl methyl ether. After the addition was complete the reaction mixture was stirred for 3 hours at room temperature. White crystals started to precipitate which were collected by filtration and dried to yield 19 g (87 % yield) of <strong>[114798-26-4]Losartan</strong> potassium with a relative purity of 99 % (HPLC) .
87.15%	With potassium hydroxide; In 1-methyl-pyrrolidin-2-one; at 25 - 63℃;Product distribution / selectivity;	Step-III: Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidazole: Potassium salt of <strong>[114798-26-4]Losartan</strong> formula (2).; To a stirred solution of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidazole (<strong>[114798-26-4]Losartan</strong> I) obtained by the process described in step II (50 gm, 0.118 M) in 250 ml of methanol was added potassium hydroxide powder [7.6 gm (86%), 0.118 M] at room temperature (25-30 C.). The reaction temperature is raised to reflux (60-63 C.) and maintained for 4-5 hours at 60-63 C. The reaction mixture was cooled to 35-40 C. This was filtered through celite and the clarified solution was concentrated to remove most of methanol at 45-50 C. under reduced pressure. 100 ml of Methyl ethyl ketone was added and distillation continued to distill most of the methanol/methyl ethyl ketone mixture. Residue was diluted with 200 ml of Acetone and contents cooled to 5-10 C. for 30 minutes and product filtered and washed with 50 ml of acetone. Product was dried under reduced pressure to yield 47.5 grams. (87.15% of theory) <strong>[114798-26-4]Losartan</strong> Potassium of the formula (2).HPLC Purity: 99.82%.IR. v max (KBR): 3201.01, 1580.73, 1460.18, 764.81, 540.091H NMR (MeOD) delta, 0.87 (t, 3H), 1.33 (sext, 2H), 1.53 (quint, 2H), 2.56 (t, 2H), 4.43 (s, 2H), 5.24 (s, 2H), 6.89-7.53 (m, 8H).13C NMR (MeOD) delta, 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72MS (m/z)=423.3 (M+1).
87.15%	With potassium hydroxide; In methanol; at 25 - 63℃;	Step-III: Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidazole: <strong>[114798-26-4]Losartan</strong> Potassium Salt 2To a stirred solution of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidazole (<strong>[114798-26-4]Losartan</strong> acid) (50 gm, 0.118 M) obtained by the process described in step (II) in 250 ml of methanol was added potassium hydroxide powder [7.6 gm (86%), 0.118 M] at room temperature (25-30 C.). The reaction temperature was raised to reflux (60-63 C.) and maintained for 4-5 hours at 60-63 C. The reaction mixture was cooled to 35-40 C. This was filtered through celite and the clarified solution was concentrated to remove most of methanol at 45-50 C. under reduced pressure. 100 ml of Methyl ethyl ketone was added and distillation continued to distill most of the methanol/methyl ethyl ketone mixture. Residue was diluted with 200 ml of Acetone and contents cooled to 5-10 C. for 30 minutes and product filtered and washed with 50 ml of acetone. Product was dried under reduced pressure to yield 47.5 grams. (87.15% of theory) <strong>[114798-26-4]Losartan</strong> Potassium.HPLC Purity: 99.79%.IR. nu max (KBR): 3201.01, 1580.73, 1460.18, 764.81, 540.091H NMR (MeOD) delta, 0.87 (t, 3H), 1.33 (sext, 2H), 1.53 (quint, 2H), 2.56 (t, 2H), 4.43 (s, 2H), 5.24 (s, 2H), 6.89-7.53 (m, 8H).13C NMR (MeOD) delta, 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72MS (m/z)=423.3 (M+1).
77 - 86%	With potassium hydroxide; In water; isopropyl alcohol; at 38 - 40℃; for 0.5h;pH 10 - 12;Product distribution / selectivity;	To 40.81 g losartan of Example 1 in 235 ml i-propanol, a solution of 5.5 g potassium hydroxide in 5.7 ml of water was added at a temperature of 38-40 C to a pH 12 during half an hour. Approximately 35 mi of azeotropic mixture i- propanol/water were removed by distillation, 141.5 ml of n-heptane were added, and reaction mixture was stirred at room temperature until a white precipitate was formed. The resulting precipitate was diluted with 54 ml n-heptane, filtered, washed with 108 ml n-heptane, and DRIED IN VACUO at 50C to yield 21.36 g of losartan potassium.; Example 6 (Formation of potassium salt of losartan-method 2) To 10.2 g losartan of Example 1 in 59 ml i-propanol, a solution of 1.4 g of potassium hydroxide in 1.5 mi of water was added at a temperature of 38-40 OC to a pH of 10 during half an hour. Approximately 19 ml of azeotropic mixture i- propanol/water were removed by distillation, 36 mi n-heptane were added, and reaction mixture was stirred at room temperature until a white solid was formed. The resulting solid was diluted with 14 mi n-heptane, filtered, washed with 26 ml n-heptane, and DRIED IN VACUO at 50 C to yield 8.57 g losartan potassium.; Example 15 (Preparation of pharmaceutically usable losartan potassium via crystalline losartan potassium) As already described, to 10.2 g crude losartan of Example 14 (chromatographic purity 98.73%) in 59 ml i-propanol, a solution of 1.4 g potassium hydroxide in 1.5 mi water at a temperature of 38-40 C to a pH of 10 over half an hour was added. Approximately 19 ml of azeotropic mixture i-propanol/water were removed by distillation, 36 mi n-heptane were added, and reaction mixture was stirred at room temperature until a white solid was formed. The resulting mixture was diluted with 14 ml n-heptane, filtered, washed with 26 mi n-heptane, and dried in vacuo at 50 C to yield 8.57 g losartan potassium (yield : 77%, chromatographic purity: 99.67%). The resulting potassium salt of losartan was dissolved in 86 ml water, 26 mi ethyl acetate were added, and it was acidified at a temperature of 21-25 C to a pH of 3.6-3. 8 with concentrated sulphuric acids, cooled below 10 C, and stirred for 1 hour. The formed solid was filtered, redispersed in 29 mi ethyl acetate, filtered once again, and DRIED IN VACUO at 50 C overnight to yield 7.35 g losartan (yield of the phase: 93%, chromatographic purity: 99.82%). The resulting product was dissolved in 20 ml i-propanol, 1.96 g potassium t- butoxide in a temperature range between 10 C and 25 C were added. The reaction mixture clarified. Adense, white solid was formed when 27 ml n-heptane were added. Reaction mixture was stirred at room temperature for 1 hour, filtered and washed with 13 ml n-heptane, DRIED IN VACUO at 50 C overnight to yield 7.66 g losartan potassium (yield of the phase: 96%, chromatographic purity: 99.88%, total yield : 69%).; Comparative Example 16 (Preparation of potassium salt according to known prior art) To 40.81 g losartan (chromatographic purity 98.73%) in 153 ml i-propanol, a mixture of 10 g potassium hydroxide, 5.1 mi water, and 100 ml i-propanol was added at a temperature of 38-40 C to a pH of 10-11 during half an hour. Approximately 140 ml of the solvent (i-propanol/water mixture) were removed by distillation, and 92 ml n-heptane were added. It was stirred at room temperature until a white precipitate was formed. The precipitate was diluted with 54 mi n- heptane, filtered, washed with 70 ml n-heptane, and DRIED IN VACUO at 50 C to yield 38.4 g losartan potassium (yield : 86%, chromatographic purity: 99.67%).
	With potassium hydrogencarbonate; In methanol; at 55℃;Heating / reflux;	10 g of <strong>[114798-26-4]Losartan</strong> free acid are dissolved in 40 ml of methanol. 2. 38 g of potassium bicarbonate are added and the mixture is stirred under reflux until complete dissolution. The resulting solution is kept at 55 C under magnetic stirring until evaporation of 35 ml of the solvent. A precipitate is obtained which is cooled to room temperature, diluted with 25 ml of methyl-tertbutyl ether and filtered. The formed solid is dried in a static dryer at 45-50 C for approx. 3 hours, to give, after cooling to room temperature, 9.9 g of <strong>[114798-26-4]Losartan</strong> potassium crystalline modification III.
	With potassium hydroxide; In water; at 20℃;Product distribution / selectivity;	29.3 g purified losartan were suspended in 293 mi water. At room temperature the pH was adjusted to 9.3 with a 10% aqueous potassium hydroxide solution. The reaction mixture was clarified. The solution was filtered and LYOPHILIZED to yield 31.8 g white, completely amorphous product losartan potassium.
	With potassium hydrogencarbonate; In methanol; for 4h;Heating / reflux;	Example 2 Potassium salt of 2-BUTYL-4-CHLORO-1-[(2 -TETRAZOL-5-YL)-1, 1 -BIPHENYL-4-YL]-5- (HYDROXYMETHYL) -IMIDAZOLE (LOSARTAN, III) A suspension of 10 g (0.015 mol) OF 2-BUTYL-4-CHLORO-1-[(2 -1-TRITYL-LH-TETRAZOL-5-YL)-1, 1- biphenyl-4-yl]-5- (hydroxymethyl)-imidazole (trityl losartan, IV) in 100 ml of anhydrous methanol was refluxed for 7 hr. The solution was then concentrated to ca 1/5 of its volume and the after-cooling-precipitated methyltriphenylmethyl ether (XIII) was sucked off and washed with a small amount of ice-cold methanol. 3.71 g (90 %) of methyltriphenylmethyl ether (XIII) were obtained. The filtrate was evaporated and the evaporation residue was dissolved in 100 ml of methanol. 1.50 g of KHC03 was added and the mixture was refluxed for 4 hr. Methanol was then evaporated and after acetone was added the evaporation residue crystallized. The crystals were sucked off and washed with a small amount of ice-cold acetone. 5.29 g (76.5 %) of the potassium salt OF 2-BUTYL-4-CHLORO-1- [ (2 - triphenylmethyltetrazol-5-yl)-1, 1 -BIPHENYL-4-YL]-5- (HYDROXYMETHYL) imidazole (III) were obtained. Mp (DSC) 229. 7 C (change of cryst. form) and 274. 6 C. H NMR spectra (DMSO): 0.83 t, J=7. 27,3H ; 1.26 m, 2H; 1.48 m, 2H; 2. 51 t, J=7. 53,2H ; 4.34 s, 2H; 5.23 s, 2H; 6.93 d, J=8, 36,2H ; 7.13 D, J=8. 34,2H ; 7.32-7. 39 m, 3H; 7.55 m, 1H.
	With potassium hydroxide; In water;pH 9 - 10;	To 200 g DI water 1.2g of KOH was added to make a basic solution. 10 g of the free acid of losartan was then added into the basic solution, and stirred until dissolved. The pH, was monitored and adjusted as necessary to a pH in the 9-10 range using IN KOH solution.

Reference： [1]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 49; 52-53
[2]Patent: WO2012/148148,2012,A2 .Location in patent: Page/Page column 11-12
[3]Patent: WO2005/23758,2005,A2 .Location in patent: Page/Page column 13-14
[4]Patent: WO2007/62675,2007,A1 .Location in patent: Page/Page column 9-10
[5]Patent: WO2010/29457,2010,A2 .Location in patent: Page/Page column 12
[6]Patent: WO2007/20654,2007,A1 .Location in patent: Page/Page column 9; 14; 17
[7]Patent: WO2007/62675,2007,A1 .Location in patent: Page/Page column 8
[8]Patent: US2010/190996,2010,A1 .Location in patent: Page/Page column 8
[9]Patent: US2010/222597,2010,A1 .Location in patent: Page/Page column 8
[10]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 48-49; 53-54
[11]Patent: US6350880,2002,B1 .Location in patent: Referential example 1-2
[12]Patent: WO2004/76406,2004,A2 .Location in patent: Page 12
[13]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 54
[14]Patent: WO2005/21535,2005,A2 .Location in patent: Page/Page column 11
[15]Patent: US2006/160871,2006,A1 .Location in patent: Page/Page column 21

23
[ 114798-26-4 ]
losartan hydrochloride [ No CAS ]

Reference： [1]Patent: US6350880,2002,B1 .Location in patent: Example 2

24
[ 114798-26-4 ]
2-n-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol hydrobromide [ No CAS ]

Reference： [1]Patent: US6350880,2002,B1 .Location in patent: Example 3

25
[ 124751-00-4 ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
94.7%		A 6 l 3-necked flask equipped with a reflux condenser was charged with 3 l methanol, 600 g trityl-protected Losartan and 144 g hydroxylammonium chloride. The mixture was heated to 60 C and stirred for 2 hours at this temperature. At the end of the 2 hours, a turbid yellowish solution was obtained. This solution was analyzed by HPLC. The analysis indicated that 99.5 % of the trityl-protected Losartan had been consumed. The solution was aged for another half an hour at 60 C as slightly yellowish crystals started to precipitate. The pH of the mixture was measured as 2.95. The reaction mixture was cooled down to 40 C and 35 ml triethylamine were added to bring the pH to 3.6. The mixture was cooled to 4 C and stirred at 0 to 5 C for 1 hour.The resulting slurry was filtered and the filter cake containing precipitated trityl-methanol was washed with 50 ml cold methanol and sucked to dryness. 210 g wet trityl-methanol were recovered.The methanol was removed from the filtrate under reduced pressure. 900 ml ethyl acetate were added to the obtained residue and the mixture was stirred for 1 hour at 5 to 10 C. A homogeneous precipitate was obtained, filtered and washed with 100 ml cold ethyl acetate.498 g of colorless needles of Losartan were obtained which were dried at 60 C under vacuum to yield 364 g of a white powder (94.7 % yield) .
93.8%		A 1 l 3-necked flask equipped with a thermometer and a reflux condenser was charged with 400 ml isopropanol and 60 g trityl-protected Losartan. The suspension was heated to 60 C at which point 27.1 g hydroxylammonium sulfate were added and the mixture was stirred at 60 to 65 C for 3.5 hours. Towards the end of the reaction period a turbid solution was obtained. A HPLC analysis indicated that 99.2 % of the trityl-protected Losartan had been consumed. The reaction mixture was stirred at 60 to 65 C for an additional half an hour and then cooled to room temperature. The pH of the mixture was measured as 2.4 and 4.5 ml of triethylamine were added to bring the pH to 3.5. Meanwhile, colorless crystals of trityl-methanol started to precipitate. The obtained suspension was cooled to 0 to 5 C and stirred at this temperature for 2 more hours .The obtained suspension was filtered and the precipitated trityl-methanol was washed with 20 ml cold isopropanol. 21.6 g of wet trityl-methanol were recovered.The isopropanol was removed from the filtrate under reduced pressure. 95 ml ethyl acetate were added to the obtained residue and the resulting suspension was stirred for 1 hour at 5 to 10 C. The obtained homogeneous precipitate in ethyl acetate was filtered and washed with 10 ml cold ethyl acetate. 49.2 g of colorless crystals of wet Losartan were obtained which were dried at 60 C under vacuum to yield 36 g of a powder (93.8 % yield).
89%	With TRILITE CMP-12 porous type; In methanol; for 5h;Reflux;Product distribution / selectivity;	One hundred ml of methanol was added to 10 g of (2-butyl-4-chloro-l-((2'-(l- trityl-lH-tetrazol-5-yl) biphenyl-4-yl) methyl)-lH-imidazole-5-yl) methanol, then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE CMP-12 porous type), followed by refluxing for 5 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to Ot and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained solid substance was dissolved into 50 ml of methanol. Then to the methanol solution was added 1.50 g of potassium bicarbonate (KHCO3), refluxed for 4 hours, and vacuum distillated. Then, the solid formed was re-crystallized using a small quantity of cold acetone to obtain 6.02 g (yield rate: 89%) of the standard compound represent by Formula 8: 1H NMR (300 MHz, DMSO-d6), delta7.55 (m, IH), 7.32-7.39 (m, 3H), 7.13 (d, 2H, J=8.34), 6.93 (d, 2H, J=8.34), 5.23 (s, 2H), 4.34 (s, 2H), 2.51 (t, 2H, J=7.53), 1.48 (m, 2H), 1.26 (m, 2H), 0.83 (t, 3H, 3=7.27).

67%	With hydrogenchloride; In 1,4-dioxane; water; at 20℃;	A mixture of 2-n-butyl-4-chloro-1-[{2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-1,1'-biphenyl-4-yl}methyl]-1H-imidazole-5-methanol (368 mg) and 1,4-dioxane (4.4 mL), water (0.88 mL) and 4 N HCl (0.41 mL) was stirred at room temperature overnight. Water (186 mL) was added and the product was extracted with ethyl acetate (186 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (eluant: cyclohexane/ethyl acetate from 9:1 to ethyl acetate, and further to ethyl acetate/MeOH 8:2) to obtain 2-n-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}-1H-imidazole-5-methanol (156 mg, 67%). 1H NMR (400 MHz, CDCl3) delta 0.78 (t, J = 7.4 Hz, 3 H, CH3), 1.24 (m, 2 H, CH3-CH2-CH2-), 1.48 (qn, J = 7.6 Hz, CH2-CH2-CH2-), 2.39 (t, J = 7.8 Hz, CH2-CH2-C-), 4.43 (s, 2 H, CH2-OH), 5.16 (s, 2 H, CH2-N), 6.87 (d, J = 8 Hz, 2 H, H-Ar), 7.04 (d, J = 8 Hz, 2 H, H-Ar), 7.40 (d, J = 7.6 Hz, 1 H, H-Ar), 7.49 (td, J = 7.6 and 1.1 Hz, 1 H, H-Ar), 7.57 (td, J = 7.5 and 1.1 Hz, 1 H, H-Ar), 7.85 (d, J = 7.6 Hz, 1 H, H-Ar) ppm. 13C-NMR (100 MHz, CDCl3) delta 14 (CH3), 22.7, 26.9 and 30.2 (CH2), 47.7 (CH2-N), 52.8 (CH2-OH), 126.5, 128.5, 130, 131, 131.1 and 131.6 (CH-Ar), 123.6, 125.5, 127.3, 136, 139.4, 141.4, 148.9 and 155.9 (C-ipso-Ar) ppm. IR (upsilon): 3360 (broad, OH and NH) cm-1. MS-ES (+): 423 (M++1).
	With hydrogenchloride; In tetrahydrofuran; water; at 20 - 23℃;	A mixture of 29,80 g 5- [2- (4-BROPMOMETHYLBIPHENYL)]-2-TRIPHENYLMETHYL-2H- tetrazol, 43.4 g 2-n-butyl-4-chloro-5-hydroxymethyl-1 H-imidazole and 38.27 g potassium carbonate n 550 ml N, N-dimethylacetamide was stirred at a temperature of 0-5 C for 8 hours and at room temperature overnight, To the mixture 8.02 g NaBH4 and 18 ml water were added. The reaction mixture was cooled to room temperature and intensively stirred for 3 hours. The reaction mixture was under intensive stirring poured into 1.1 I water, filtered, and the precipitate rinsed with 550 ml water. The product was DRIED IN VACUO overnight at room temperature over silica gel. The obtained 2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(tripheniymethyl-2H- tetrazole-5-yl) [1. 1'biphenyl-4-yl] methyl] imidazole was crystallized from CHLOROBUTANE and ethyl acetate with final overall yield of 66.77 g after drying. To a solution of 67.77 g 2-N-BUTYL-4-CHLORO-5-HYDROXYMETHYL-1-[[2'-(TRIPHENIYMETHYL- 2H-tetrazole-5-yl) [1. 1'biphenyl-4-yl] methyl] imidazole in 316 ml of THF were added under intensive stirring of 105.9 g 12% HCI at a temperature of 23 C during one hour. The mixture was intensively stirred at room temperature overnight. 30% NAOH solution was added at a temperature OF 22C during one hour until a pH of 12.5 was reached (approximately 100 ml). THF was evaporated at temperature up to 60C and demineralized water was added till starting volume. The precipitate was filtered, rinsed with 2 x 50 mi demineralized water and disposed. The aqueous phase was extracted with 1 x 50 mi toluene. The organic solvent phase was separated, and 124 ml ethyl acetate were added to the aqueous phase. The reaction mixture was acidified during intensive stirring with a concentrated H2SO4 at a temperature of 21-25 C until a pH of 3.6-3. 8. The mixture was cooled below 10 C and mixed for 1 hour. The precipitate was filtered, digested with 130 mi ethyl acetate, filtered once again and dried overnight in vacuo at a temperature of 50 C. The yield was 40.8 g losartan.
		EXPERIMENT 3 (LOSARTAN)4,7 g of trityl losartan) was dissolved in a mixture of 1 ,8 ml of THF (dichloromethane) and 18 ml of methanol. 0,2 ml of water and 0,06 g of p-toluenesulphonic acid (p-TSA) was added. Reaction mixture was stirred at room temperature for 6 days. A mixture of 12,6 ml dichloromethane and 24,24 ml of water was added, and then ph of reaction mixture was adjusted to pH12 with NaOH 30%. Layers were separated, water layer was washed three times with 12,6 ml of dichloromethane and 15 ml of ethyl acetate was added. pH was adjusted to the value 3,6-3,8 with 1 N HCI and stirring was continued for another two hours at the temperature 50C-IO0C. Product was filtered and washed with 10 ml of ethyl acetate, filtered again and dried at 6O0C. Yield: 2,26 g
	With hydrogenchloride; sodium hydroxide; acetic acid; In methanol; water; ethyl acetate; toluene;	Part C Preparation of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole 1-[(2'-(Triphenylmethyltetrazol-5-yl)-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (920 g), and methanol (2.10 L) were charged to a 12-liter round-bottomed flask, equipped with mechanical stirrer, condenser with N2 inlet and thermometer. The slurry was cooled to ~10 C. and 3.4N hydrochloric acid (700 ml) was added over 10 minutes. After stirring two hours at 10-20 C., the thick slurry was diluted with methanol (500 ml) and warmed to 30 C. After one hour at 30 C., the reaction was neutralized to pH 13 with 10N sodium hydroxide (420 ml). Solvent (largely methanol, 2.3 L) was distilled while 2.3 L D.I. water was added. Heating was discontinued and D.I. water (700 ml) and toluene (1.40 L) was added. After cooling to ~30 C., the organic phase was removed. The aqueous phase was reextracted with toluene (700 ml). Ethyl acetate (1.20 L) was added to the pot containing the aqueous phase. After stirring 10 minutes, acetic acid (130 ml) was added. The mixture was stirred one hour, then let stand overnight. Agitation was restarted and the slurry cooled to ~5 C. The product was isolated by vacuum filtration, reslurried with 1.50 L D.I. water and sucked semi-dry. The wet cake was charged to a 12 L round bottomed flask and reslurried 1/2 hour at ambient temperature with ethyl acetate (4.0 L). The product was isolated by vacuum filtration, washed with 200 ml ethyl acetate and dried in vacuo overnight at 50 C. Yield: 518 g, 88.5%. M.P.: 184-185 C. Purity by HPLC: 98.8%. NMR (200 MHz, DMSO-d6): delta7.61 (m, 4H), 7.05 (m, 4H); 5.24 (s, 2H); 4.32 (s, 2H); 3.35 (br s, 1H); 2.46 (t, 2H, J=7.8 Hz); 1.44 (m, 2H); 1.23 (m, 2H); 0.79 (t, 3H, J=7.2 Hz).
	With hydrogenchloride; sodium hydroxide; acetic acid; In methanol; water; ethyl acetate; toluene;	Part C: Preparation of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole 1-[(2'-(Triphenylmethyltetrazol-5-yl)-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (920 g), and methanol (2.10 L) were charged to a 12-liter round-bottomed flask, equipped with mechanical stirrer, condenser with N2 inlet and thermometer. The slurry was cooled to ~10 C. and 3.4 N hydrochloric acid (700 ml) was added over 10 minutes. After stirring two hours at 10-20C., the thick slurry was diluted with methanol (500 ml) and warmed to 30 C. After one hour at 30 C., the reaction was neutralized to pH 13 with 10 N sodium hydroxide (420 ml). Solvent (largely methanol, 2.3 L) was distilled while 2.3 L D.I. water was added. Heating was discontinued and D.I. water (700 ml) and toluene (1.40 L) was added. After cooling to ~30 C., the organic phase was removed. The aqueous phase was reextracted with toluene (700 ml). Ethyl acetate (1.20 L) was added to the pot containing the aqueous phase. After stirring 10 minutes, acetic acid (130 ml) was added. The mixture was stirred one hour, then let stand overnight. Agitation was restarted and the slurry cooled to ~5 C. The product was isolated by vacuum filtration, reslurried with 1.50 L D.I. water and sucked semi-dry. The wet cake was charged to a 12 L round bottomed flask and reslurried 1/2 hour at ambient temperature with ethyl acetate (4.0 L). The product was isolated by vacuum filtration, washed with 200 ml ethyl acetate and dried in vacuo overnight at 50 C. Yield: 518 g, 88.5%. M.P.: 184185 C. Purity by HPLC: 98.8%. NMR (200 MHz, DMSO-d6): delta 7.61 (m, 4H), 7.05 (m, 4H); 5.24 (s, 2H); 4.32 (s, 2H); 3.35 (br s, 1H); 2.46 (t, 2H, J=7.8 Hz); 1.44 (m, 2H); 1.23 (m, 2H); 0.79 (t, 3H, J=7.2 Hz).

Reference： [1]Patent: WO2006/97121,2006,A1 .Location in patent: Page/Page column 11-12
[2]Patent: WO2006/97121,2006,A1 .Location in patent: Page/Page column 13-14
[3]Patent: WO2006/81807,2006,A2 .Location in patent: Page/Page column 16; 18; 20; 29
[4]Patent: WO2010/67913,2010,A1 .Location in patent: Page/Page column 17-18
[5]Chemical and Pharmaceutical Bulletin,2008,vol. 56,p. 383 - 384
[6]Patent: EP1833801,2008,B1 .Location in patent: Page/Page column 14
[7]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 46-47
[8]Patent: WO2006/50922,2006,A1 .Location in patent: Page/Page column 10
[9]Patent: US5138069,1992,A
[10]Patent: US5128355,1992,A

26
2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole sodium salt [ No CAS ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sulfuric acid; In water; ethyl acetate; at 10 - 25℃; for 1h;pH 3.6 - 3.8;Purification / work up;	35 g sodium salt of losartan were dissolved in 350 mi water, 106 mi of ethyl acetate were added, and it was acidified at a temperature of 21 to 25 C to a pH of 3.6-3. 8 with concentrated sulphuric acid, cooled below 10 C and stirred for 1 hour. The formed solid was filtered, redispersed in 120 mi of ethyl acetate, filtered once again and DRIED IN VACUO at 50C overnight to yield 29.3 g of losartan.; To 20.4 g crude losartan (chromatographic purity of 98.73%) in 120 ml i-propanol, a solution of 2.75 g sodium hydroxide in 2.9 mi water was added at a temperature of 38-40C to a pH of 10 during half an hour. Approximately 18 mi of azeotropic MIXTURE I-PROPANOL/WATER WERE REMOVED BY DISTILLATION, 70 MI N-HEPTANE WERE added, and it was stirred at room temperature until a white solid was formed. The resulting solid was diluted with 28 ml n-heptane, filtered, washed with 55 mi n- heptane, and DRIED IN VACUO at 50 C to yield 18.5 g crystalline losartan sodium (yield : 87%, chromatographic purity : 99.42%). The obtained substance was dissolved in 185 ml water, 56 mi ethyl acetate were added, and it was acidified at a temperature of 21-25 C to a pH of 3.6-3. 8 with concentrated sulphuric acid, cooled below 10C, and stirred for 1 hour. The formed solid was filtered, redispersed in 64 ml ethyl acetate, filtered once again, and DRIED IN VACUO at a temperature of 50 C overnight to yield 16. 5 g losartan (yield of the phase: 94%, chromatographic purity: 99.74%). The resulting product was dissolved in 45 ml i-propanol, 4.39 g potassium TERT- butoxide between 10C and 25C were added. The reaction mixture clarified. A dense, white precipitate was formed when 60 mi n-heptane were added, and it was stirred at room temperature for 1 hour. It was filtered and washed with 30 ml n-heptane, DRIED IN VACUO at 50 C overnight to yield 16.9 g losartan potassium (yield of the phase: 94%, chromatographic purity: 99. 91 %, overall yield : 77%).

Reference： [1]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 50-51; 52

27
2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole magnesium salt [ No CAS ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In water; ethyl acetate; at 10 - 25℃; for 1h;pH 3.6 - 3.8;Purification / work up;	37.9 g magnesium salt of losartan were dissolved in 388 ml demineralized water, 120 ml of ethyl acetate were added, and it was acidified at a temperature of 21 to 25 C to a pH of 3.6-3. 8 with concentrated sulphuric acid, cooled below 10 C and stirred for 1 hour. The formed solid was filtered, redispersed in 130 ML ETHYL acetate, filtered once again, and DRIED IN VACUO at 50 C overnight to yield 32.3 g losartan.

Reference： [1]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 51

28
2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole calcium salt [ No CAS ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In water; ethyl acetate; at 10 - 25℃; for 1h;pH 3.6 - 3.8;Purification / work up;	38.0 g calcium salt of losartan were dissolved in 380 mi water, 115 mi ethyl acetate were added, and it was acidified at a temperature of 21 to 25 C to a pH of 3.6-3. 8 with concentrated sulphuric acid, cooled below 10 C, and stirred for 1 hour. The formed solid was filtered, redispersed in 130 ML ETHYL acetate, filtered once again, and DRIED IN VACUO at 50 C overnight to yield 36.2 g of losartan.

Reference： [1]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 51-52

29
[ 114798-26-4 ]
2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydroxide; In water; isopropyl alcohol; at 38 - 40℃; for 0.5h;pH 10 - 12;Product distribution / selectivity;	To 40.81 g losartan of Example 1 in 235 ml i-propanol, a solution of 5.5 g sodium hydroxide in 5.7 mi of water was added at a temperature of 38-40 C to a pH 12 over half an hour. Approximately 35 mi of azeotropic mixture i-propanol/water were removed by distillation. 140 ml n-heptane were added, and reaction mixture was stirred at room temperature until a white solid has been formed. The resulting susoension was diluted with 55 ml of n-heptane, filtered, washed with 110 ml n-heptane, and dried in vacuo at 50 C to yield 35.0 g sodium salt of losartan. Melting point: 191-196 C Water according to Karl-Fisher : 4.2%. Assay of sodium: 4.4% (5.0% calculated to anhydrous substance) Example 3 (Formation of sodium salt of losartan-method 2) To 40.81 g losartan of Example 1 in 235 ml i-propanol, a solution of 5.5 g sodium hydroxide in 5.7 mi of water was added at a temperature of 38-40 C to a pH 10-12 over half an hour. Approximately 35 mi of azeotropic mixture i-propanol/ water were removed by distillation, 140 ml of n-heptane were added, and reaction mixture was stirred at room temperature until a white solid was formed. The resulting dispersion was diluted with 55 mi n-heptane, filtered, washed with 110 ml n-heptane, and DRIED IN VACUO at 50 C to yield 37.0 g sodium salt of losartan. Melting point: 190-198 C Water according to Karl-Fisher : 0.3%.; To 20.4 g crude losartan (chromatographic purity of 98.73%) in 120 ml i-propanol, a solution of 2.75 g sodium hydroxide in 2.9 mi water was added at a temperature of 38-40C to a pH of 10 during half an hour. Approximately 18 mi of azeotropic MIXTURE I-PROPANOL/WATER WERE REMOVED BY DISTILLATION, 70 MI N-HEPTANE WERE added, and it was stirred at room temperature until a white solid was formed. The resulting solid was diluted with 28 ml n-heptane, filtered, washed with 55 mi n- heptane, and DRIED IN VACUO at 50 C to yield 18.5 g crystalline losartan sodium (yield : 87%, chromatographic purity : 99.42%). The obtained substance was dissolved in 185 ml water, 56 mi ethyl acetate were added, and it was acidified at a temperature of 21-25 C to a pH of 3.6-3. 8 with concentrated sulphuric acid, cooled below 10C, and stirred for 1 hour. The formed solid was filtered, redispersed in 64 ml ethyl acetate, filtered once again, and DRIED IN VACUO at a temperature of 50 C overnight to yield 16. 5 g losartan (yield of the phase: 94%, chromatographic purity: 99.74%). The resulting product was dissolved in 45 ml i-propanol, 4.39 g potassium TERT- butoxide between 10C and 25C were added. The reaction mixture clarified. A dense, white precipitate was formed when 60 mi n-heptane were added, and it was stirred at room temperature for 1 hour. It was filtered and washed with 30 ml n-heptane, DRIED IN VACUO at 50 C overnight to yield 16.9 g losartan potassium (yield of the phase: 94%, chromatographic purity: 99. 91 %, overall yield : 77%).
	With sodium t-butanolate; In isopropyl alcohol;Product distribution / selectivity;	To 40.81 g losartan of Example 1 in 120 ml i-propanol, 9.28 g sodium t-butoxid were added. The reaction mixture was clarified, 145 ml n-heptane were added, and it was stirred at room temperature until a white solid was formed. The resulting solid was filtered and washed with 165 ml n-heptane, dried at 40 C in vacuo to yield 37.0 g of sodium salt of losartan. Melting point: 191-196 C Assay of sodium: 4.7% (5.2% calculated to the anhydrous substance).
	With sodium hydroxide; In water; at 20℃;pH 9.62;Product distribution / selectivity;	5.0 g purified losartan were suspended in 50 mi water. At room temperature the pH was adjusted to 9.62 with a 10% aqueous sodium hydroxide solution. The reaction mixture clarified. The solution was filtered and LYOPHILISED to yield 5.2 g amorphous sodium salt of losartan.

Reference： [1]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 47-48; 52
[2]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 48
[3]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 55

30
[ 114798-26-4 ]
2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole magnesium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium ethoxide; In isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To 40.81 g of losartan of Example 1 in 235 mi of i-propanol, 6.07 g magnesium ethoxide were added, and stirred at reflux temperature overnight. Reaction mixture was hot filtered, 650 ml n-heptane were added, and cooled to room temperature for the product to precipitate. It was filtered and washed with 110 mi n-heptane, and DRIED IN VACUO at 50 C to yield 37.9 g losartan magnesium. Melting point: above 300 C Assay of magnesium 2.9% (3.2% calculated to the anhydrous substance).

Reference： [1]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 50

31
[ 114798-26-4 ]
2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole calcium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With calcium hydroxide; In isopropyl alcohol; for 1h;Heating / reflux;	To 40.81 g losartan of Example 1 in 235 ML I-PROPANOL, 3.92 g calcium hydroxide were added, and it was stirred at reflux temperature for 1 hour, and hot filtered. 410 mi n-heptane were added to the filtrate and cooled to room temperature. The solvent was decanted from a resinous residue, and 820 ml n-heptane were added. It was stirred until a white solid crystallized. It was filtered, washed with 110 ml n- heptane, and DRIED IN VACUO at 50 C to yield 39.2 g losartan calcium. Melting point: above 300 C Assay of calcium 4.0% (4.7% calculated to the anhydrous substance).

Reference： [1]Patent: WO2004/66997,2004,A2 .Location in patent: Page/Page column 50

32
[ 67-56-1 ]
[ 124751-00-4 ]
[ 596-31-6 ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
90%; 98%	for 7h;Heating / reflux;	Example 1 2-BUTYL-4-CHLORO-1-[[(2 -TETRAZOL-5-YL)-1, 1 -BIPHENYL-4-YL] METHYL]-5-HYDROXYMETHYL- imidazole A suspension of 10 g (0.015 mol) OF 2-BUTYL-4-CHLORO-1-[[(2 -1-TRITYL-LH-TETRAZOL-5-YL)-1, 1- BIPHENYL-4-YL] METHYL] -5-HYDROXYMETHYL-IMIDAZOLE (TRITYL LOSARTAN, IV) IN 50 ML OF ANHYDROUS methanol was refluxed for 7 hours. The solution was then cooled to-10 C and stirred at this temperature overnight, the precipitated crystals were sucked off and washed with a small amount of ice-cold methanol. 3.7 g (90 %) of methyltriphenylmethyl ether (XIII) were obtained. The combined mother liquors were evaporated and boiled with 50 ml of hexane, the mixture was cooled and the insoluble part was sucked off, stirred at room temperature with 50 ml of cyclohexane for 10 hr, the insoluble part was sucked off. 6.2 g of the product (98 %) were obtained with mp of 186-188 C. H NMR spectra (DMSO): 0. 81 T, J= 7. 24,3H ; 1.27 m, 2H; 1.47 m, 2H; 2. 47 T, J= 7. 57, 2H; 4. 35 s, 2H; 5.26 s, 2H; 7.03-7. 12 m, 4H; 7.49-7. 73 m, 4H.

Reference： [1]Patent: WO2005/21535,2005,A2 .Location in patent: Page/Page column 10

33
trityl losartan [ No CAS ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With methanol; for 4 - 5h;Heating / reflux;	Example-7 PREPNNRTTINN OFFREE LOSARTNN : Trityl losartan (50g; 0. 075mol) is suspended in methanol (250MOI). The resulting mixture is refluxed for 4-5 hours to obtain a clear solution. Methanol is distilled off under reduced pressure. The resulting mass is suspended in toluene (250M1) AND stirred at 45-50C for about 15 min. The free losartan, which is insoluble, is filtered and washed with toluene. Yield : 28g (88%)

Reference： [1]Patent: WO2005/23758,2005,A2 .Location in patent: Page/Page column 13

34
[ 874446-96-5 ]
[ 114798-26-4 ]
[ 838876-28-1 ]

Yield	Reaction Conditions	Operation in experiment
47%	With dmap;scandium tris(trifluoromethanesulfonate); In dichloromethane; at -5 - 20℃; for 16h;	Example 6; Synthesis of 2-butyl-4-chloro-l- [ [ 2 ' - ( lH-tetrazol-5- yl) [ 1 , 1 ' -biphenyl ] -4-yl ] methyl ] -5- [ ( 4- (nitrooxymethyl) phenylcarbonyloxymethyl-lH-imidazole; <strong>[114798-26-4]Losartan</strong> 4- (nitrooxy¬ methyl) benzoic acid ester; To a solution of 2-butyl-4-chloro-l- [ [2 ' - (lH-tetrazol-5- yl) [ 1 , 1 ' -biphenyl] -4-yl] methyl] -IH-imidazole-5-methanol (<strong>[114798-26-4]Losartan</strong>) (3.1 g, 7.27 mmol) Sc (OTf) 3 (0.3 g, 0.61 mmol) and DMAP (1.5 g, 12.12 mmol) in CH2Cl2 (25 ml) kept at - 5 C, under stirring and under nitrogen atmosphere, a solution of 4- (nitrooxymethyl) benzoicacidpentafluorophenyl ester (Example 2 ) (2.2 g, 6.06 mmol) in CH2Cl2 (5 ml) was added. The resulting solution was kept under stirring for further 16 hrs at room temperature . The reaction mixture was poured into a pH 3 buffer solution (50 ml) , acidified with HCl 1 N to pH 3-4 and extracted with CH2Cl2 (2 x 50 ml) . The organic phase was dried on sodium sulfate and evaporated.After purification with Flash chromatography of the residue (CH2Cl2/Me0H 98 : 2 ) the title compound was obtained as a white solid (1.70 g, 47%) . m. p . 155 C EPO <DP n="194"/>1H NMR (DMSO) delta : 7.73-7.56 (7H, m) , 7.24 (lH, d) , 7.00 (4H, m) , 5.60 (2H, s ) , 5.39 (2H, s ) , 5.28 (2H, s ) , 2.61 (2H, t) , 1.53 (2H, m) , 1.28 (2H, m) , 0.82 (3H, t)

Reference： [1]Patent: WO2006/79610,2006,A1 .Location in patent: Page/Page column 192-193

35
[ 838878-70-9 ]
[ 114798-26-4 ]
[ 838876-22-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	With dmap; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;	Example 4; Synthesis of 2-butyl-4-chloro-l- [ [ 2 ' - ( lH-tetrazol-5-yl) [ 1 , 1 ' -biphenyl ] -4-yl ] methyl ] -5- [ ( 3-nitrooxypropyl) carbonyl- oxy] methyl-lH-imidazole; To a solution 2-Butyl-4-chloro-l- [ [2 ' - (lH-tetrazol-5- yl) [ 1 , 1 ' -biphenyl] -4-yl] methyl] -IH-imidazole-5-methanol (<strong>[114798-26-4]Losartan</strong>) (2.13 g, 5.04 mmol) TEA (0.51 g, 5.04 mmol) and DMAP (0.62 g, 5.04 mmol) in DMF (25 ml) kept at O 0C, under stirring and under nitrogen atmosphere, a solution of 4- nitrooxybutanoic acid pentafluorophenyl ester (1.59 g, 5.04 mmol) (Example 1 ) in DMF (5 ml) was added. The resulting solution was kept under stirring for further 4 hrs at room temperature . The reaction mixture was poured into a pH 3 buffer solution (50 ml) , acidified with HCl IN to pH 3-4 and extracted with CH2CI2 (2 x 50 ml) . The organic phase was washed with brine (100 ml) , dried on sodium sulfate and evaporated.After purification with Flash chromatography of the residue (CH2Cl2/Me0H 98 : 2 ) the title compound was obtained as a white solid (1.48 g, 53%) . m. p . 66-680C1H NMR (CDCl3) delta : 7.85 (lH, d) , 7.58 (2H, m) , 7.42 (lH, d) , 7.11 (2H, d) , 6.79 (2H, d) , 5.15 (2H, s ) , 4.94 (2H, s ) , 4.42 (2H, t) , 2.53 (2H, t) ; 2.21 (2H, t) , 1.93 (2H, m) , 1.56 (2H, m) , 1.29 (2H, m) , 0.85 (3H, t) .

Reference： [1]Patent: WO2006/79610,2006,A1 .Location in patent: Page/Page column 191

Yield	Reaction Conditions	Operation in experiment
91%	With montmorillonite K10 Clay; In methanol; dichloromethane; at 38 - 42℃;	General procedure: (1) 409.2 mL of dichloromethane was sequentially added to a 1 L reaction flask.Trityl candesartan cilexetil (42.6 g, 0.050 mol),136.4 mL of anhydrous methanol and 13.6 g of montmorillonite,The temperature is raised to 38 ~ 42 C reflux reaction for 4 ~ 24h,The HPLC content <3.0% of trityl candesartan cilexetil was detected by HPLC until the end of the reaction.The reaction solution is filtered,The filter cake was washed with 68.2 mL of dichloromethane.The filtrates were combined and cooled to 20-25 C.Add 409.2mL of water,The pH was adjusted to 4.5 to 5.5 with 1% dilute hydrochloric acid and stirred for 10 min.After standing for 30 min, the separated organic layer was washed twice with 409.2 mL.(2) The organic layer was evaporated to dryness under reduced pressure.Add methyl tert-butyl ether (MTBE, 341.0 mL) preheated to 35-40 C,Add a little seed crystal, cool to 15 ~ 25 C for 10 h, filter.The obtained wet product was beaten with methyl tert-butyl ether (272.8 mL) at 15 to 25 C for 3 h.Filter and filter cake was washed with methyl tert-butyl ether (68.2 mL).The wet product is vacuum dried at 50-55 C.Candesartan cilexetil 46.4 g, yield 95%.The HPLC purity was 99.4%.(3) Recovery of methyl triphenyl methyl ether:The methyl t-butyl ether solution which was filtered out and washed in the previous step was evaporated to dryness under reduced pressure.Then 200 mL of methanol was added. Cooling to -10 C to precipitate crystals,Filter, wash with methanol and dry.Add 80 mL of heptane to 16 g of dry material.Then, thionyl chloride (6.4 ml) was added dropwise at room temperature.After stirring for 10 min, it was boiled for 20 hours.Half of the solvent was distilled off and the residue was stirred at room temperature for 6 hr then at 0 C overnight. The trityl chloride is filtered off and washed with heptane and used as it is.80% recovery of trityl derivatives from undeprotected starting materials
30%		EXAMPLE 6 An analogous procedure to that described in Example 1 was used, but with 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole in place of compound A and stirring the reaction mixture for 18 hours. The solvent was then removed by evaporation and the residue dissolved in water (5 ml). The aqueous solution was washed with ether (210 ml), acidified with 2M hydrochloric acid to pH4 and extracted with dichloromethane (415 ml). The combined extracts were washed with saturated sodium chloride solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was then triturated with a mixture of ether and hexane to give 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole as a tan solid, in 30% yield; m.p. 102-105 C.; NMR (CDCl3 +d6 -DMSO): 0.86(t,3H), 1.34(m,2H), 1.62(m,2H), 2.60(t,2H), 4.47(s,2H), 5.27(s,2H), 7.4-7.75(m,4H), 7.01(d,2H), 7.14(d,2H); mass spectrum (-ve FAB, DMSO/glycerol) 421 (M--H)-.
		wherein the angiotensin II receptor is selected from the group consisting of 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole; 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole; 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(methoxy-carbonyl)aminomethyl]imidazole; 2-Butyl-4-chloro-1-[(2-carboxybiphenyl-4-yl)methyl]-5-[(propoxycarbonyl)aminomethyl]imidazole; 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde; 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxy-aldehyde 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole; 2-(1E-Butenyl)-4-chloro-1-[(2'-carboiybiphenyl-4-yl)methyl]-imidazole-6-carboxaldehyde; 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole; ...

		wherein the angiotensin II receptor is selected from the group consisting of 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole; 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole; 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(methoxy-. carbonyl)aminomethyl]imidazole; 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[-(propoxycarbonyl)aminomethyl]imidazole; 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-y)methyl]imidazole-5-carboxaldehyde; 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxy-aldehyde; 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole; 2-(1E-Butenyl)-4-chloro-1-[(2'-carboiybiphenyl-4-yl)methyl]-imidazole-6-carboxaldehyde; 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl (hydroxymethyl)imidazole; ...
		III. Salt Formation To 4.0 g (9.46 mmoles) of the free acid is added 10.9 ml of 0.842N KOH solution all in one portion. The slurry is aged at room temperature for 30 minutes, during which time most of the solid dissolves. The cloudy solution is filtered and the solids collected on a sintered glass funnel. The pH of the filtrate is measured at 9.05. The aqueous solution is added slowly to a refluxing azeotropic mixture of cyclohexane/isopropanol (69 C.) whereupon the ternary azeotrope cyclohexane/isopropanol/water (64 C.) begins to distill. When the solution is dry the temperature of the overhead rises to 69 and the potassium salt crystallizes. When the water content of the pot is <0.05% the distillation is halted and the white slurry is cooled to room temperature. The white crystalline solid is collected on a sintered glass funnel and washed with 10-15 ml of cyclohexane/isopropanol 67/33 and dried in a vacuum oven (wt 3.8 g yield 95%).
		Part D Preparation of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole; potassium salt The product of Part C (11.00 g) and isopropanol (30 ml) were charged to a 100 ml round-bottomed flask equipped with magnetic stirrer, thermometer and Dean Stark Trap under nitrogen. The slurry was heated to 40 C. A solution of 87% potassium hydroxide (2.00 g)/isopropanol (20 ml/water (1.0 ml) was added to pH 11 (18.5 ml). Most of the water was removed by azeotropic distillation of isopropanol (20 ml distilled). Heptane (25 ml) was added and the slurry cooled to room temperature. Additional heptane (15 ml) was added and the mixture stirred for 1/2 hr. The product was isolated by vacuum filtration, washed 1*20 ml heptane and dried overnight at 60 C. in vacuo. Yield: 10.33 g, 86%. M.P.: >250 C.
		Part E Preparation of 2-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole and its potassium salt The product of Part C is converted to the title compound and its potassium salt by the procedures of Example 316, Parts C and D.
		Most preferred in the method of the invention are compounds of formula II selected from the following, and pharmaceutically acceptable salts thereof. 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole. 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole. 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4 -yl)-methyl]-5-[(methoxycarbonyl)aminomethyl] imidazole. 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl) -methyl]-5-[(propoxycarbonyl)aminomethyl] imidazole. 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl) methyl]imidazole-5-carboxaldehyde. 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde. 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl -4-yl)methyl]-5-(hydroxymethyl)imidazole. 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl -4-yl)methyl]imidazole-5-carboxaldehyde. 2-Propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl) imidazole. ...
		(1) Preparation of Losartan Prior-Release Layer The losartan prior-release layer was prepared in the same manner as in preparation of losartan-containing prior-release granules in Example 16.
		(1) Preparation of Losartan Granules Losartan granules were prepared in the same manner as in preparation of losartan-containing granules in Process (1) of Example 23.
		(1) Preparation of Losartan Granules Losartan granules were prepared in the same manner as in preparation of losartan-containing granules in Process (1) of Example 23.
		Part E: Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4yl)-methyl]-4-(hydroxymethyl)imidazole (11.93 g) was converted to the above product by the procedure described in Example 90, Part C. The products was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow solid. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid: m.p. 183.5-184.5. Upon cooling, the mother liquor yielded on additional 1.03 g of product as a light yellow solid; m.p. 179.0-180.0. NMR (200 MHz, DSMO-d6) delta 7.75-7.48 (m, 4H); 7.07 (d, 2H, J=7Hz); 7.04 (d, 2H, J=9Hz); 5.24 (s, 2 H); 5.24 (bs, 1H); 4.34 (s, 2H); 2.48 (t, 2H, J=7Hz); 1.48 (t of t, 2H, J=7,7Hz); 1.27 (t of q, 2H, J=7,7Hz); 0.81 (t, 3H, J=7Hz). Anal. Calcd. for C22 H23 ClN6 O: C, 62.48; H, 5.48; Cl. 8.38. Found for the solids which did not dissolve in 100 mL of acetonitrile: C, 62.73; H, 5.50; Cl, 8.26. Found for the solids obtained from the mother liquor: C, 62.40; H, 5.23; Cl, 8.35.
		Part D: Preparation of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole; potassium salt The product of Pact C (11.00 g) and isopropanol (30 ml) were charged to a 100 ml round-bottomed flask equipped with magnetic stirrer, thermometer and Dean Stark Trap under nitrogen. The slurry was heated to 40 C. A solution of 87% potassium hydroxide (2.00 g)/isopropanol (20 ml/water (1.0 ml) was added to pH 11 (18.5 ml). Most of the water was removed by azeotropic distillation of isopropanol (20 ml distilled). Heptane (25 ml) was added and the slurry cooled to room temperature. Additional heptane (15 ml) was added and the mixture stirred for 1/2 hr. The product was isolated by vacuum filtration, washed 1 *20 ml heptane and dried overnight at 60 C. in vacuo. Yield: 10.33 g, 86%. M.P.: >250 C.

37
[ 124751-00-4 ]
[ 596-31-6 ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
95%		Preparation of Losartan from Trityl-Protected Losartan by using Hydroxylammonium ChlorideA 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 380 g of methanol, 120 g of trityl- losartan, 95 g of acetone, 12 g of water, and 28.8 g of hydroxylammonium chloride at room temperature. The mixture was stirred for 2 hours at this temperature. HPLC analysis showed that 99.5 of trityl protected losartan had been consumed. The resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g of methanol and sucked to dryness. Wet methoxytriphenylmethane (70 g) were obtained. The pH of the mixture was adjusted to 3.8-4.2 by adding 50% NaOH solution with external cooling to keep the temperature between 20-250C.To remove the salt and precipitate losartan, 80 g of water was added and the mixture was stirred for 1 hour at room temperature and crude losartan was isolated by filtration. For further purification crude losartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying losartan (72 g) was obtained as a white powder (95 % yield).1H-NMR (DMSO) delta 7.55 (d, IH), 7.36 (m, 2H), 7.31 (d, IH), 7.15 (d, 2H), 6.95 (d, 2H), 5.72 (m, OH), 5.26 (m, 2H), 4.38 (s, 2H), 2.53 (m, 2H), 1.52 (m, 2H), 1.29 (m, 2H), 0.84 (t, 3H). 13C-NMR (DMSO) delta 161, 147, 14I5 140, 135, 132, 131, 130 (2C), 129, 128, 127, 126 (2C), 125, 51, 47, 29, 26, 22, 14.Proton and Carbon NMR of Methoxytriphenylmethane1H-NMR (DMSO) delta 7.67 ( m, 6H), 7.58 (m, 6H), 7.54 (m, 3), 2.95 (s, 3H). 13C-NMR (DMSO) delta 144.1 (3C), 128.7 (6C), 128.3 (6C), 127.4 (3C), 86.9, 52.2 Proton and Carbon NMR of Acetyl LosartanIf last purification step in ethyl acetate is carried out over 4O0C acetyl losartan is formed as a side product. 1H-NMR (DMSO) delta 7.62. (d, 2H), 7.56 (m, IH), 7.50 (d, IH), 7.06 (d,2H), EPO <DP n="12"/>6.94 (d, 2H), 5.21 (m, 2H), 4.95 (s, 2H), 2.53 (m, 2H)3 1.72 (s, 3H), 1.47 (m, 2H), 1.24 (m, 2H)5 0.79 (t, 3H). 13C-NMR (DMSO) delta 170.6, 149.0, 141.6, 139.3, 136.5, 131.5, 131.3, 131.2, 129.8 (2C), 128.7, 128.4, 126.5, 124.7 (2C), 121.4, 51, 47, 29, 26, 22, 20.9, 14.
93%		Preparation of Losartan from Trityl-Protected Losartan by using HydrochloricAcidA 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 380 g of methanol, 12O g of trityl- losartan, 95 g of acetone, and 38.4 g of hydrochloric acid (31 %) at room temperature. The mixture was stirred for 2 hours at this temperature.The mixture was analyzed by HPLC. The analysis showed that 99.2 of trityl protected losartan had been consumed. The resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g of methanol and sucked to dryness. Wet methoxytriphenylmethane (73 g) were obtained. The pH of the mixture was adjusted to 3.8-4.2 by adding 50% NaOH solution with external cooling to keep the temperature between 20-250C. The mixture was concentrated under reduced pressure.To remove the salt and precipitate losartan 80 g of water was added, the mixture was stirred for 1 hour at room temperature and crude losartan was isolated by filtration. Crude losartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying losartan (70.5 g ) was obtained as a white powder (93 % yield).
91.3%		Preparation of Losartan from Trityl-Protected Losartan by using Sulfuric AcidA 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 380 g of methanol, 120 g of trityl- losartan, 95 g of acetone, 12 g of water, and 19.68 g of sulfuric acid (96.5%) at room temperature. The mixture was stirred for 2 hours at this temperature. The mixture was analyzed by HPLC. The analysis showed that 99.1 of trityl EPO <DP n="13"/>protected losartan had been consumed. The resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g methanol and sucked to dryness. Wet methoxytriphenylmethane (71 g) were obtained. The pH of the mixture was adjusted to 3.8-4.2 by adding 50% NaOH solution with external cooling to keep the temperature between 20-250C. The mixture was concentrated under reduced pressure.To remove the salt and precipitate losartan 80 g of water was added, the mixture was stirred for 1 hour at room temperature and crude losartan was isolated by filtration. Crude losartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying losartan (69.2 g) was obtained as a white powder (91.3 % yield).

Reference： [1]Patent: WO2006/98705,2006,A1 .Location in patent: Page/Page column 10-11
[2]Patent: WO2006/98705,2006,A1 .Location in patent: Page/Page column 11
[3]Patent: WO2006/98705,2006,A1 .Location in patent: Page/Page column 11-12

38
[ 141-78-6 ]
C₂₄H₂₅ClN₆O₂ [ No CAS ]
[ 596-31-6 ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
95%		Preparation of Losartan from Trityl-Protected Losartan by using Hydroxylammonium ChlorideA 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 380 g of methanol, 120 g of trityl- losartan, 95 g of acetone, 12 g of water, and 28.8 g of hydroxylammonium chloride at room temperature. The mixture was stirred for 2 hours at this temperature. HPLC analysis showed that 99.5 of trityl protected losartan had been consumed. The resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g of methanol and sucked to dryness. Wet methoxytriphenylmethane (70 g) were obtained. The pH of the mixture was adjusted to 3.8-4.2 by adding 50% NaOH solution with external cooling to keep the temperature between 20-250C.To remove the salt and precipitate losartan, 80 g of water was added and the mixture was stirred for 1 hour at room temperature and crude losartan was isolated by filtration. For further purification crude losartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying losartan (72 g) was obtained as a white powder (95 % yield).1H-NMR (DMSO) delta 7.55 (d, IH), 7.36 (m, 2H), 7.31 (d, IH), 7.15 (d, 2H), 6.95 (d, 2H), 5.72 (m, OH), 5.26 (m, 2H), 4.38 (s, 2H), 2.53 (m, 2H), 1.52 (m, 2H), 1.29 (m, 2H), 0.84 (t, 3H). 13C-NMR (DMSO) delta 161, 147, 14I5 140, 135, 132, 131, 130 (2C), 129, 128, 127, 126 (2C), 125, 51, 47, 29, 26, 22, 14.Proton and Carbon NMR of Methoxytriphenylmethane1H-NMR (DMSO) delta 7.67 ( m, 6H), 7.58 (m, 6H), 7.54 (m, 3), 2.95 (s, 3H). 13C-NMR (DMSO) delta 144.1 (3C), 128.7 (6C), 128.3 (6C), 127.4 (3C), 86.9, 52.2 Proton and Carbon NMR of Acetyl LosartanIf last purification step in ethyl acetate is carried out over 4O0C acetyl losartan is formed as a side product. 1H-NMR (DMSO) delta 7.62. (d, 2H), 7.56 (m, IH), 7.50 (d, IH), 7.06 (d,2H), EPO <DP n="12"/>6.94 (d, 2H), 5.21 (m, 2H), 4.95 (s, 2H), 2.53 (m, 2H)3 1.72 (s, 3H), 1.47 (m, 2H), 1.24 (m, 2H)5 0.79 (t, 3H). 13C-NMR (DMSO) delta 170.6, 149.0, 141.6, 139.3, 136.5, 131.5, 131.3, 131.2, 129.8 (2C), 128.7, 128.4, 126.5, 124.7 (2C), 121.4, 51, 47, 29, 26, 22, 20.9, 14.

Reference： [1]Patent: WO2006/98705,2006,A1 .Location in patent: Page/Page column 10-11

39
[ 874446-96-5 ]
[ 114798-26-4 ]
2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5-[[(4-(nitrooxy)methyl)phenyl]carbonyloxy]methyl-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With dmap; scandium tris(trifluoromethanesulfonate); In dichloromethane; at -5 - 20℃; for 16h;	To a solution of 2-butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl)[1,lr-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol (<strong>[114798-26-4]Losartan</strong>) (3.1 g, 7.27 mmol) Sc(OTf)3 (0.3 g, 0.61 mmol) and DMAP (1.5 g, 12.12 mmol) in CH2C12 (25 ml) kept at -5C, under stirring and under nitrogen atmosphere, a solution of [4-(nitrooxy)methyl]benzoic acid pentafluoro phenyl ester (2.2 g, 6.06 mmol) in CH2CI2 (5 ml) was added. The resulting solution was kept under stirring for further 16 hrs at room temperature. The reaction mixture was poured into a pH 3 buffer solution (about 50 ml), acidified with HC1 1 N to pH 3-4 and extracted with CH2C12 (2 x 50 ml) . The organic phase was dried on sodium sulfate and evaporated.After purification with Flash chromatography of the residue (CH2Cl2/MeOH 98:2) the title compound was obtained as a white solid (1.70 g, 47%). m.p. 155^NMR (DMSO) 5: 7.73-7.56 (5H,m); 7.47 (2H,d);7.24 (lH,d); 7.00(4H,m); 5.60(2H,s); 5.36(2H,s); 5.27(2H,s); 2.56(2H,t); 1.53(2H,m); 1.28(2H,m); 0.82 (3H,t).

Reference： [1]Patent: WO2006/8196,2006,A1 .Location in patent: Page/Page column 24-25

40
[ 838878-70-9 ]
[ 114798-26-4 ]
2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5-[(3-(nitrooxy)propyl)carbonyloxy]methyl-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With dmap; triethylamine; In N,N-dimethyl-formamide;Product distribution / selectivity;	Using the same procedure described in Example 1 but starting from 2-butyl-4-chloro-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol(<strong>[114798-26-4]Losartan</strong>)(2.13 g, 5.04 mmol) and 4-(nitrooxy)butanoic acid pentafluorophenyl ester (1.59 g, 5.04 mmol) TEA (0.7 ml, 5.04 mmol), DMAP (0.615 g, 5.04 mmol) and using DMF as solvent. Then the mixture was diluited with buffer solution(pH=3); the pH was adjusted to 2-3 and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2S04 and evaporated. The residue was purified with Flash chromatography of the residue(CH2Cl2/MeOH 98:2) and the title compound was obtained as a white solid (1.48 g, 53%). m.p. 66-68C^?H NMR (CDC13) 5: 7.85(lH,d), 7.58 (2H,m), 7.42 (lH,d), 7.11(2H,d), 6.79(2H,d), 5.15(2H,s), 4.94(2H,s), 4.42 (2H,t), 2.53(2H,t); 2.21(2H,t), 1.93(2H,m), 1.56(2H,m), 1.29(2H, m) , 0.85(3H,t) .

Reference： [1]Patent: WO2006/8196,2006,A1 .Location in patent: Page/Page column 19-20

41
[ 114798-26-4 ]
[ 63700-19-6 ]
losartan-O-glucuronide [ No CAS ]

Reference： [1]Bioorganic Chemistry,2008,vol. 36,p. 148 - 155

42
[ 114798-26-4 ]
[ 63700-19-6 ]
losartan-N₁-glucuronide [ No CAS ]

Reference： [1]Bioorganic Chemistry,2008,vol. 36,p. 148 - 155

43
[ 114798-26-4 ]
[ 63700-19-6 ]
losartan N<SUB>2</SUB>-D-glucuronide [ No CAS ]

Reference： [1]Bioorganic Chemistry,2008,vol. 36,p. 148 - 155

44
[ 92953-12-3 ]
[ 114798-26-4 ]
[ 538-75-0 ]
[ 1070175-00-6 ]
[ 2387-23-7 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In tetrahydrofuran; at 20℃; for 5h;	Step 2 A solution of dicyclohexylcarbodiimide (DCC) (463mg; 1.2 eq.) in anhydrous tetrahydrofurane (THF) was added dropwise to a solution of losartan (800 mg; 1.67 mmol), 3-methanesulfonylsulfanyl-propionic acid (1.87 mmol) prepared as above described and dimethylaminopyridine (DMAP, 13 mg) in 19 ml of anhydrous THF. The reaction was performed at room temperature, stirring under nitrogen for 5 hours. At the end of the reaction, the dicyclohexylurea (DCU) was removed by filtration. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column, eluding with a mixture of CH2Cl2-methanol (98:2) to give the desired compound.

Reference： [1]Patent: EP1980559,2008,A1 .Location in patent: Page/Page column 10

45
[ 114798-26-4 ]
[ 538-75-0 ]
[ 127588-56-1 ]
[ 1070174-97-8 ]
[ 2387-23-7 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In tetrahydrofuran; at 20℃; for 5h;	Step 2:; A solution of dicyclohexylcarbodiimide (DCC) (463mg; 1.2 eq.) in anhydrous tetrahydrofurane (THF) was added dropwise to a solution of losartan (800 mg; 1.67 mmol), 4-(3-thioxo-3H-1,2-dithiol-4-yl)benzoic acid (475.6 mg; 1.87 mmol) prepared as above described and dimethylaminopyridine (DMAP, 13 mg) in 19 ml of anhydrous THF. The reaction was performed at room temperature, stirring under nitrogen for 5 hours. At the end of the reaction, the dicyclohexylurea (DCU) was removed by filtration. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column, eluting with a mixture of CH2Cl2-methanol (98:2) to give a compound with m.p. 218-222 C.

Reference： [1]Patent: EP1980559,2008,A1 .Location in patent: Page/Page column 9

46
[ 114798-26-4 ]
[ 138584-34-6 ]
[ 138613-25-9 ]
[ 138584-35-7 ]

Reference： [1]Biochemical Pharmacology,2008,vol. 76,p. 763 - 772

47
[ 114798-26-4 ]
[ 138584-34-6 ]
[ 138584-35-7 ]

Reference： [1]Biochemical Pharmacology,2008,vol. 76,p. 763 - 772

48
[ 114798-26-4 ]
[ 727718-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;	A) REPLACEMENT OF LOSARTAN HYDROXYL GROUP BY AZIDE To a stirred suspension of <strong>[114798-26-4]Losartan</strong> (MSD, 0.423 g, 1.00 MMOL) and diphenylphosphoryl azide (Aldrich, 0.259 ML, 1.20 MMOL) in tetrahydrofuran (8 ml) was added DBU (0.329 ml, 2.20 MMOL). After stirring overnight water/acetonitrile (1: 1, 4.8 ml) was added and the mixture was filtered. After addition of neat TFA (to pH 2) the mixture was purified by preparative HPLC (column Phenomenex Luna C18 (2) 5 , UM 21.2 x 250 mm, solvents: A = water/0. 1% TFA and B = ACETONITRILE/0. 1% TFA; gradient 35-45% B over 60 min; flow 10.0 ml/min, UV detection at 214 nm) in several runs to give 99 mg (22%) of the product as white crystals after lyophilisation. Analysis by LC-MS (column Phenomenex Luna C18 (2) 3, UM 50 x 4.60 mm, solvents : A = WATER/0. 1% TFA and B = ACETONITRILE/0. 1% TFA; gradient 20-80% B over 10 min; flow 1 ml/min, UV detection at 214 nm, ESI-MS) gave a peak at 7.3 minutes with M/Z 448.1 (MH+) corresponding to the structure

Reference： [1]Patent: WO2005/30266,2005,A2 .Location in patent: Example 6

49
[ 1185769-64-5 ]
[ 114798-26-4 ]
[ 1185768-47-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap;scandium tris(trifluoromethanesulfonate); In dichloromethane; at 80℃; for 0.666667h;Microwave irradiation;	EXAMPLE 1 2-(((l-((2'- (lH-tetrazol-5-yl)biphenyl-4-yl)methyl) -2- butyl-4-chloro-lH-imidazol-5-yl) methoxy) carbonylamino) ethyl 4- (nitrooxy) butanoate (corresponding to compound (110); <n="171"/>A mixture of <strong>[114798-26-4]Losartan</strong> (2.20 g; 5.20 mmol) , N, N- dimethylaminopyridine (DMAP) (1.16 g; 9.46 mmol) and scandium trifluoromethanesulfonate (0.466 g; 0.946 mmol) and 2- ( (4-nitrophenoxy) carbonylamino) ethyl 4-(nitrooxy)butanoate (Intermediate 2) (1.69 g; 4.73 mol) in CH2CI2 (40 ml) was heated in a microwave apparatus (8O0C, 40 min) . Then the mixture was diluted with CH2CI2 and washed with NaH2PO4 (5%, 2 X 40 ml) . The organic layer was dried over sodium sulfate and concentrated under reduced pressure . The residue was purified by flash chromatography(CH2Cl2/Me0H: 98/2) yielding the title compound.

Reference： [1]Patent: WO2009/106471,2009,A2 .Location in patent: Page/Page column 169-170

50
[ 15761-38-3 ]
[ 114798-26-4 ]
[ 1174760-85-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 24.5h;	(S)-(1-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methyl 2-(tert-butoxycarbonyl)aminopropanoate. (1-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methanol (422 mg, 1.0 mmol) was dissolved in DMF (8.0 mL) at RT and then cool to 0 C. To this solution were added N-(tert-butoxycarbonyl)-L-alanine (378 mg, 2.0 mmol), EDCCl (383 mg, 2.0 mmol), HOBT (270 mg, 2.0 mmol) and N-methylmorpholine (202 mg, 2.0 mmol). The reaction was stirred at 0 C. for 30 min and at RT for 24 h. The reaction was diluted with water (150 ml) and extracted with Ethyl acetate (200 ml). The organic extract was washed by a solution of citric acid in water (10%), water and Sat'd NaCl solution, dried over MgSO4 anhydrous and concentrated with reduced pressure to give glassy solid material. Silica gel liquid chromatography(EtAc/Hexane/AcOH v/v/v=80/100/3) of the material provided the compound, (S)-(1-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methyl 2-(tert-butoxycarbonyl)aminopropanoate (470 mg, 79%) as a colorless solid. The compound is C30H36ClN7O4, LC-MS (ESI, m/z): 592.4[M-H]-.

Reference： [1]Patent: US2010/184814,2010,A1 .Location in patent: Page/Page column 13

51
[ 114798-36-6 ]
[ 114798-26-4 ]

Yield	Reaction Conditions	Operation in experiment
29.2%	With sodium tetrahydroborate; water; sodium hydroxide; In acetonitrile; at 5 - 25℃; for 4.41667h;	Step 2 A mixture of 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazole-5-carbaldehyde (compound 8-2a) (or 2-butyl-4-chloro-1-[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazole-5-carbaldehyde) (101 mg, 0.240 mmol), 1 mol/L aqueous sodium hydroxide solution (0.24 mL) and water (0.24 mL) was cooled to 5 C., and NaBH4 (18.4 mg, 0.486 mmol) was added thereto. The reaction mixture was stirred at 5 C. for 25 min, and then at room temperature for 3 hr. NaBH4 (8.6 mg, 0.23 mmol) was added thereto, and the mixture was stirred for 1 hr. The reaction was monitored by TLC (eluent: chloroform/methanol (10:1)) and HPLC. To the reaction mixture was added water (0.5 mL), and the mixture was washed with diisopropyl ether (0.5 mL). The aqueous layer was acidified to pH 2 with 1% HCl, and extracted three times with ethyl acetate (5 mL). The obtained organic layer was washed with 10% brine (5 ml), dried over magnesium sulfate (0.35 g), and concentrated to dryness to give a white solid (66.1 mg, 65.2% of the theoretical yield). The obtained concentrate was dissolved in water/acetonitrile (4:3, 1.4 mL), and the solution was suspended with water (0.49 mL). Seed crystals were appropriately added thereto, and the suspension was cooled to 5 C. The precipitated solid was filtered, washed with cold water/acetonitrile (4:1, a few mL), and dried under reduced pressure at 40-55 C. to give losartan (compound 9, 29.6 mg, yield 29.2%). melting point: 161-164 C. IR(KBr): 3374(OH), 1604, 1579, 1469 cm-1 1H-NMR (DMSO-d6): delta=7.68 (t, J=7.4 Hz, 1H, biphenyl), 7.66 (d, J=7.4 Hz, 1H, biphenyl), 7.58 (t, J=7.4 Hz, 1H, biphenyl), 7.55 (d, J=7.4 Hz, 1H, biphenyl), 7.08 (d, J=8.2 Hz, 2H, biphenyl), 7.02 (d, J=8.2 Hz, 2H, biphenyl), 5.23 (s, 1H, CH2N), 4.32 (s, 1H, CH2O), 2.45 (t, J=7.5 Hz, 2H, 1-CH2 of Bu), 1.44 (quint, J=7.5 Hz, 2H, 2-CH2 of Bu), 1.23 (sext, J=7.5 Hz, 2H, CH2Me), 0.80 (t, J=7.7 Hz, 3H, CH3 of Bu). MS:m/z=423 (MH+)
		Step-II: Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidazole {Losartan} of the Formula 1 To a stirred solution of 1-(2'-Cyano biphenyl-4-methyl)-2-butyl-4-chloro-5-formyl imidazole (Cyano aldehyde) (100 gm, 0.264 M) prepared by the process described in step (I) in 210 ml of O-Xylene (800 ml) at room temperature was added Tri-n-butyl tin chloride (172 gm, 0.528 M) and sodium azide (34 gm, 0.523 M) at room temperature (25-30 C.). The reaction temperature was raised to 140-143 C. and maintained for 28-32 hours. TLC showed the absence of Cyano aldehyde. The reaction mixture was cooled to 25-30 C. and charged 1N aqueous KOH solution (2.0 Lts), and stirred for 1 hour at room temperature. The organic layer is separated and aqueous layer is washed with toluene (2×600 ml). Aqueous layer was proceeded further without isolation of aldehyde tetrazole. To the stirred solution of the aqueous layer (approximately -2.2 Lts) was added sodium borohydride (9.0 gm, 0.238) at room temperature (25-30 C.). The reaction temperature is raised to 40-45 C. and maintained at this temperature for a period of 1 hour. TLC Showed the absence of aldehyde tetrazole. The reaction mass was cooled to 15-20 C. and the PH is adjusted to 4.0 with dilute HCl, stirred for 5-6 hours at 15-20 C. The cooled solution is filtered and washed with water to give Losartan of the formula 1.Yield 75%Melting point: 179-180.2HPLC Purity: >97%IR. nu max (KBR): 3376.27, 1579.77, 1468.86, 762.88, 556.41H NMR (CDCl3) delta, 0.87 (t, 3H), 1.31 (sext, 2H), 1.54 (quint, 2H), 2.57 (t, 2H), 4.45 (s, 2H), 5.30 (s, 2H), 7.01-7.68 (m, 8H).13C NMR (CDCl3) delta, 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72 MS (m/z)=423.5 (M+1).

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 10198 - 10206
[2]Patent: US2012/232283,2012,A1 .Location in patent: Page/Page column 20.2
[3]Patent: US2010/222597,2010,A1 .Location in patent: Page/Page column 8

52
[ 76-83-5 ]
[ 114798-26-4 ]
[ 124751-00-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 20℃;	Compound 3 was prepared from commercially available losartanpotassium as previously described.2 Briefly, to a solution oflosartan in DMF was added trityl chloride and Et3N. The solutionwas stirred at room temperature overnight after which it wasdiluted with EtOAc, washed with water and brine, dried over Na2-SO4 and solvent removed. The residue was purified by flash columnchromatography on silica gel to obtain a white powder. HPLC[35:65 MeCN/AF (0.1 M), 2 mL/min]: 3.6 min. 1H NMR (400 MHz,DMSO-d6) dH 7.79 (d, J = 6.0 Hz, 1H); 7.61 (t, J = 6.0 Hz, 1H); 7.54(t, J = 6.0 Hz, 1H); 7.31-7.44 (m, 10H); 7.05 (d, J = 6.4 Hz, 2H);6.90 (d, J = 6.4 Hz, 2H); 6.86 (d, J = 6.0 Hz, 6H); 5.24 (t, J = 4.0 Hz,1H); 5.19 (s, 2H); 4.21 (d, J = 4.0 Hz, 2H); 2.37 (t, J = 6.0 Hz, 2H);1.41 (q, J = 6.0 Hz, 2H); 1.15 (sx, J = 6.0 Hz, 2H); 0.73 (t, J = 6.0 Hz,3H). HRMS: calcd for C41H37ClN6O [M+Na], 687.2615, found687.2638.

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2011,vol. 54,p. 754 - 757
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 3931 - 3937

53
[ 114798-26-4 ]
[ 114798-94-6 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2011,vol. 54,p. 754 - 757

54
[ 18039-42-4 ]
[ 114798-26-4 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 10198 - 10206
[2]Patent: US2012/232283,2012,A1
[3]Patent: US2012/232283,2012,A1
[4]Patent: US2012/232283,2012,A1
[5]Patent: US2012/232283,2012,A1

55
[ 1307853-51-5 ]
[ 114798-26-4 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 10198 - 10206

56
[ 512182-38-6 ]
[ 114798-26-4 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 10198 - 10206
[2]Patent: US2012/232283,2012,A1
[3]Patent: US2012/232283,2012,A1

57
[ 1301606-98-3 ]
[ 114798-26-4 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 10198 - 10206
[2]Patent: US2012/232283,2012,A1
[3]Patent: US2012/232283,2012,A1

58
[ 1307853-38-8 ]
[ 114798-26-4 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 10198 - 10206
[2]Patent: US2012/232283,2012,A1
[3]Patent: US2012/232283,2012,A1

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	114798-26-4	MDL No. :	MFCD00865831
Formula :	C₂₂H₂₃ClN₆O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PSIFNNKUMBGKDQ-UHFFFAOYSA-N
M.W :	422.91 g/mol	Pubchem ID :	3961
Synonyms :	1. Losartan

Num. heavy atoms :	30
Num. arom. heavy atoms :	22
Fraction Csp3 :	0.27
Num. rotatable bonds :	8
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	117.11
TPSA :	92.51 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.78 cm/s

[ CAS No. 114798-26-4 ]

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[ 114798-26-4 ] Synthesis Path-Upstream 1~1

[ 114798-26-4 ] Synthesis Path-Downstream 1~58

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[ 114798-26-4 ]

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Log Po/w (iLOGP) :	3.0
Log Po/w (XLOGP3) :	4.36
Log Po/w (WLOGP) :	4.11
Log Po/w (MLOGP) :	3.36
Log Po/w (SILICOS-IT) :	4.94
Consensus Log Po/w :	3.95

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Log S (ESOL) :	-5.22
Solubility :	0.00253 mg/ml ; 0.00000598 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.02
Solubility :	0.000405 mg/ml ; 0.000000959 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-8.41
Solubility :	0.00000165 mg/ml ; 0.0000000039 mol/l
Class :	Poorly soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	3.45

Signal Word:	Danger	Class:	4.1
Precautionary Statements:	P210-P501-P261-P272-P202-P201-P280-P302+P352-P308+P313-P362+P364-P333+P313-P405	UN#:	1325
Hazard Statements:	H317-H361-H228	Packing Group:	Ⅲ
GHS Pictogram:

Yield	Reaction Conditions	Operation in experiment
90%	With potassium hydroxide In methanol; isopropyl alcohol at 20℃; for 0.5 h;	85 g of losartan was suspended in isopropanol (250 ml), and a solution prepared by dissolving 12.1 g of potassium hydroxide in methanol (85 ml) was slowly added thereto, followed by stirring for 30 minutes at room temperature. The resulting solution was filtered to remove insoluble materials and the filtrate was refluxed while adding cyclohexane (1,000 ml) thereto. Then, the resulting mixture was distilled to remove 340 ml of solvent and the residue containing solids was slowly cooled to room temperature. After stirring for 4 hours, the solid material was filtered, washed with a mixture of isopropanol and cyclohexane, and dried at 45 °C, to obtain 87.3 g of the title <n="9"/>compound (yield: 90 percent).[68][69] Melting point: 269°C to 274°C[70] ¹H-NMR (DMSO-d₆, ppm): 7.65 (IH, m), 7.4 (2H, m), 7.3 (IH, m), 7.15 (2H, d),6.95 (2H, d), 5.45 (IH, br), 5.3 (2H, s), 4.4 (2H, s), 2.54 (2H, m), 1.55 (2H, m), 1.31 (2H, m), 0.9 (3H, t).
33%	With potassium hydroxide In methanol for 4 h; Heating / reflux	A mixture of 2-n-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}-1H-imidazole-5-methanol (1 g) in dry methanol (8.75 mL) was warmed to reflux temperature. Then, potassium hydroxide (99 mg) in dry methanol (1.7 ml) was added and the mixture was refluxed for 4 h. The reaction was cooled to room temperature, treated with charcoal and filtered. The filtrate was concentrated to a volume of 1.5-1.75 mL, and after addition of acetonitrile (4.2 mL) again to a volume of 1.5-1.75 mL. Further acetonitrile (4.2 mL) was added and the solution was concentrated to a volume of 3 mL. The suspension was stirred at 0-5°C overnight and the solid was filtered, washed with cold acetonitrile (3 x 1.5 mL) and dried at 60°C overnight to give 231 mg (33percent) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 0.79 (t, J = 7.4 Hz, 3 H, CH₃), 1.24 (m, 2 H, CH₃-CH₂-CH₂-), 1.46 (qn, J = 7.6 Hz, CH₂-CH₂-CH₂-), 2.48 (bs, 2 H, CH₂-CH₂-C-), 4.29 (s, 2 H, CH₂-OH), 5.19 (s, 2 H, CH₂-N), 5.30 (bs, 1 H, OH), 6.88 (d, J = 8 Hz, 2 H, H-Ar), 7.07 (d, J = 8 Hz, 2 H, H-Ar), 7.40 (d, J = 7.6 Hz, 1 H, H-Ar), 7.49 (td, J = 7.6 and 1.1 Hz, 1 H, H-Ar), 7.57 (td, J = 7.5 and 1.1 Hz, 1 H, H-Ar), 7.85 (d, J = 7.6 Hz, 1 H, H-Ar) ppm. ¹³C-NMR (100 MHz, DMSO-d₆) δ 14.3 (CH₃), 22.3, 26.5 and 29.8 (CH₂), 47.2 (CH₂-N), 52 (CH₂-OH), 125.9, 127.4, 127.9, 130.1, 130.7 and 131.2 (CH-Ar), 125.9, 126.3, 133.3, 135.3, 140.5, 141.8, 148 and 161.4 (C-ipso-Ar) ppm. IR (υ): 3734 (OH), 1259 (C-O) cm^-1.

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P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
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P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
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

[ CAS No. 114798-26-4 ]

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Physicochemical Properties

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

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[ 114798-26-4 ] Synthesis Path-Upstream 1~1

[ 114798-26-4 ] Synthesis Path-Downstream 1~58

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