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CAS No. : | 114772-55-3 | MDL No. : | MFCD16619233 |
Formula : | C22H22ClN3O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 379.88 | Pubchem ID : | - |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330 | UN#: | |
Hazard Statements: | H302-H315-H319 | Packing Group: | |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: 2-n-butyl-4-chloro-5-hydroxymethylimidazole With sodium methylate In N,N-dimethyl-formamide at 25℃; for 0.5h; Stage #2: 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile In N,N-dimethyl-formamide at 20℃; for 24h; | |
With sodium methylate 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: tetrahydrofuran / 2 h / 20 °C 2: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 3: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 4: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.0% | Example-1 [117] [118] Preparation of 2-n-Butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl) methyl] -5-(hydroxymethyl)-imidazole (IV); [119] A mixture of 4'-Bromomethyl-2-cyanobiphenyl(II) (125.0 g), l-Methyl-2-pyrrolidinone (NMP) (375.0 ml), anhydrous potassium carbonate (76.0 g) and 2-Butyl-4-chloro-5-formylimidazole (III) (90.0 g) was heated at 7O0C to 750C for about 4-5 hrs. Sodium borohydride (18.0 g) was charged to the reaction mixture at 3O0C. Water (1875.0 ml) was added to it and isopropanol (562.5 ml) was added to the wet cake and heated at 75-8O0C for 1.5 hours. The reaction mixture was cooled at room temperature and filtered. The solid was suck dried and dried in oven to give the title compound (153.0g).[120] Yield: 88.0%[121] Purity (By HPLC): 99.1% | |
With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 20℃; | First Step: successively added toluene 200ml, Bromobiphenyl compound 45g, 2-Butyl-4-chloro-5-formylimidazole 30g, 0.5g of tetrabutylammonium bromide; aqueous sodium hydroxide solution was added at room temperature to the reaction starting material the reaction was complete, The layers were separated and washed. The organic layer was added a reducing agent, water crystallization, filtration and drying, to obtain the compound of formula 1 |
Tags: 114772-55-3 synthesis path| 114772-55-3 SDS| 114772-55-3 COA| 114772-55-3 purity| 114772-55-3 application| 114772-55-3 NMR| 114772-55-3 COA| 114772-55-3 structure
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