CN113045501B - Preparation method of telmisartan intermediate - Google Patents
Preparation method of telmisartan intermediate Download PDFInfo
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- CN113045501B CN113045501B CN202110329537.2A CN202110329537A CN113045501B CN 113045501 B CN113045501 B CN 113045501B CN 202110329537 A CN202110329537 A CN 202110329537A CN 113045501 B CN113045501 B CN 113045501B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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Abstract
The invention relates to a preparation method of an intermediate 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde of telmisartan. The preparation method comprises the following steps: 3-methyl-4-n-butylamido-5-nitrobenzoic acid and SOCl 2 React to acylReacting chlorine with benzenesulfonyl hydrazide to prepare an intermediate (1); intermediate (1) is coated with Zn, CaCl 2 Reducing with ethanol, and performing cyclization in acetic acid to prepare an intermediate (2); the intermediate (2) is prepared into 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde in the presence of alkali. The method has the advantages of few reaction steps and low cost.
Description
Technical Field
The invention belongs to the field of drug synthesis and organic synthesis, and particularly relates to a preparation method of a telmisartan intermediate.
Background
7-methyl-2-n-propyl-3HThe (5) -benzimidazole aldehyde is a key intermediate for preparing the antihypertensive drug telmisartan, and compared with the intermediate 2-n-propyl-4-methyl-6-carboxyl benzimidazole, the aldehyde group of the (5) -benzimidazole is easier to react withNCondensation of-methyl o-phenylenediamine to produce the 2-n-propyl-4-methyl-6 (1' -methylbenzimidazol-2-yl) benzimidazole intermediate. The northeast agriculture university takes o-phenylmethylamine as a starting material, prepares 3-methyl-4-n-butylamido benzyl chloride through acylation and Blanc reaction, prepares 3-methyl-4-n-butylamidobenzaldehyde through the reaction with hexamethylenetetramine, and then obtains 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde through nitration, reduction with iron powder/glacial acetic acid and cyclization. As shown in the following formula:
the method has cheap raw materials, long reaction steps and low yield, can generate a large amount of iron mud to pollute the environment, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a telmisartan intermediate 7-methyl-2-n-propyl-3 which has novel route, low raw material price and small environmental pollutionHIndustrial process for the preparation of (E) -benzimidazole-5-carbaldehyde.
Telmisartan intermediate 7-methyl-2-n-propyl-3HA process for the preparation of (E) -benzimidazole-5-carbaldehyde, characterized in that it comprises the following steps:
step 1:
the 3-methyl-4-n-butylamido-5-nitrobenzoic acid is mixed with 5 times of SOCl 2 Mixing, reflux reacting for 1h, and distilling under reduced pressure to recover excessive SOCl 2 Dissolving the residue in dichloromethane, cooling to 0 deg.C, adding certain amount of triethylamine and benzenesulfonyl hydrazide, reacting at 0 deg.C for 1h, then reacting at room temperature for 3h, and pouringAdding into water, separating layers, extracting with dichloromethane, drying, and concentrating to obtain intermediate (1). The step avoids the introduction of water, and the two-step reaction is completed in one pot. The crude intermediate (1) is directly used for the next reaction.
Step 2:
under the protection of nitrogen, dissolving the intermediate (1) in ethanol/glacial acetic acid, and adding catalytic amount of Fe powder and PdCl 2 Adding hydrogen at room temperature to 0.15-0.2MPa, reacting for 1h, filtering to recover catalyst, distilling under reduced pressure to recover ethanol, heating the rest solution under reflux for 1h, distilling under reduced pressure to recover glacial acetic acid, adding ethyl acetate to dissolve the residue, and adding NaHCO 3 The solution is stirred, separated, extracted by ethyl acetate, and the organic phases are combined, washed by water, dried and concentrated to prepare the intermediate (2). The two-step reaction is completed in one pot.
And step 3:
dissolving the intermediate (2) in ethylene glycol, adding a certain amount of solid, heating to 165 ℃ and adding alkali, reacting for 10-15min, releasing a large amount of gas, cooling, filtering, recovering most of ethylene glycol under reduced pressure, adding water and ethyl acetate to the residue, stirring, layering, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, recrystallizing with ethyl acetate/petroleum ether to obtain 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde. Adjusting the water phase to acidity with concentrated hydrochloric acid at 10-15 deg.C, precipitating crystal, filtering, washing with water, neutralizing with sodium hydroxide to form salt, concentrating, cooling, and drying to obtain sodium benzene sulfinate.
Further, in the step 1 and the second step of reaction, the feeding molar ratio of the 3-methyl-4-n-butylamido-5-nitrobenzoic acid to the benzenesulfonyl hydrazide to the triethylamine is 1: 1.1-1.2: 1.3-1.5.
In step 2, ethanol and iceThe volume ratio of acetic acid is 1: 1 to 1: 2; the feeding molar ratio is the intermediate (1): fe: PdCl 2 = 1：0.20-0.25：0.01-0.02。
In step 3, the alkali is Na 2 CO 3 Powder and K 2 CO 3 And (3) powder. The feeding molar ratio of the intermediate (2) to the alkali is 1: 0.6-0.7. The solid matter is soft glass powder, industrial zeolite, broken porcelain powder and ceramsite, and the particle size of the solid matter is 30-40 meshes; the dosage of the solid is 5 to 10 percent of the dosage of the intermediate (2).
Compared with the prior art, the invention has the following advantages:
the invention discloses an intermediate 7-methyl-2-n-propyl-3 of telmisartanHA novel synthetic route for benzimidazole-5-aldehyde. The raw materials are cheap and easy to obtain, the reaction condition is mild, the yield is high, the environmental pollution is low, and the method is suitable for industrial production.
Detailed Description
The invention is further described with reference to specific examples, but the scope of protection of the invention is not limited thereto.
Example 1
Preparation of intermediate (1)
266g (1mol) of 3-methyl-4-n-butylamido-5-nitrobenzoic acid are reacted with 590g (5mol) of SOCl 2 Mixing, reflux reacting for 1h, and distilling under reduced pressure to recover excessive SOCl 2 The residue was dissolved in 5L of dichloromethane, cooled to 0 deg.C, added with 131.3g (1.3mol) of triethylamine and 189g (1.1mol) of benzenesulfonylhydrazide, reacted at 0 deg.C for 1h, then reacted at room temperature for 3h, poured into 3L of water, separated into layers, extracted 2 times with 3L of dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate (1) which was used directly in the next reaction in 93% yield. 1 H NMR（300MHz，CDCl 3 ) δ 1.04(t, J = 7.2Hz, 3H), 1.72-1.84(m, 2H), 2.40 (s, 3H), 2.42(t, J = 7.2Hz, 2H), 7.21-7.31(m, 1H), 7.54-7.63(m, 2H),7.84-7.93(m, 2H),7.95 (s,1H), 8.00 (s,1H), 8.12 (s,1H), 8.32 (s,1H), 9.01 (s, 1H). Elemental analysis: c 18 H 20 N 4 O 6 S, calculating a value: c, 51.42, H, 4.79, N, 13.33, S, 7.63, found: c, 51.40, H, 4.80, N, 13.31, S, 7.60。
Example 2
Preparation of intermediate (1)
While 152g (1.5mol) of triethylamine and 206g (1.2mol) of benzenesulfonyl hydrazide were used in place of 131.3g (1.3mol) of triethylamine and 189g (1.1mol) of benzenesulfonyl hydrazide in example 1, the other operations were not changed to obtain intermediate (1) in a yield of 93.7%.
Example 3
Preparation of intermediate (2)
420g (1mol) of the intermediate (1) was dissolved in a mixed solvent of 1L of ethanol and 1.5L of glacial acetic acid, and 14g (0.25mol) of Fe powder and 3.56g (0.02mol) of PdCl were added 2 Stirring, vacuumizing, replacing with nitrogen, introducing hydrogen to maintain the pressure at 0.15-0.2MPa, reacting at room temperature for 1h, filtering after the reaction is finished, and distilling under reduced pressure to recover ethanol. Heating and refluxing the rest solution under nitrogen protection for 1h, distilling under reduced pressure to recover glacial acetic acid, dissolving the residue with 1L ethyl acetate, and dissolving with 1L of hydrochloric acid (HCO) 3 The solution was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate (2) in 91% yield. 1 H NMR（300MHz，CDCl 3 ) δ 0.99(t, J = 7.2Hz, 3H), 1.80-1.89(m, 2H), 2.86(t, J = 7.2Hz, 2H), 2.50 (s, 3H), 7.22-7.31(m, 1H), 7.54-7.61(m, 2H), 7.82-7.91 (m, 2H),7.95 (s,1H),7.99(s,1H),8.11(s,1H), 8.30 (s,1H), 12.65 (s, 1H). Elemental analysis: c 18 H 20 N 4 O 3 S, calculating a value: c, 58.05, H, 5.41, N, 15.04, S, 8.61, found: c, 58.00, H, 5.40, N, 15.07, S, 8.59. With 11.2g (0.2mol) Fe powder and 1.78g (0.01mol) PdCl 2 Instead of 14g (0.25mol) of Fe powder and 3.56g (0.02mol) of PdCl 2 The other operations were unchanged, intermediate (2), yield 90%.
Example 4
7-methyl-2-n-propyl-3HPreparation of (E) -benzimidazole-5-carbaldehyde
372g (1mol) of intermediate (2) are dissolved in 8L of ethylene glycol, 18.6g of technical zeolite (40 mesh) are added, the mixture is heated to 160 ℃ and 165 ℃ and 74.2g (0.7mol) of Na are added 2 CO 3 Stirring the powder vigorously, discharging a large amount of gas, reacting for 5min, cooling, filtering, and distilling under reduced pressure to recover most of ethylene glycolAdding 3L water and 3L ethyl acetate into the residue, stirring, layering, extracting with ethyl acetate for 3 times, mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, and recrystallizing with ethyl acetate/petroleum ether to obtain 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde in 79% yield. Adjusting the water phase to acidity with concentrated hydrochloric acid at 10-15 deg.C, precipitating crystal, filtering, washing with water, adding NaOH to neutralize to form salt, concentrating, cooling, and drying to obtain sodium benzenesulfonate with yield of 83%. 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde: 1 H NMR（300MHz，CDCl 3 ) δ 0.99(t, J = 7.2Hz, 3H), 1.80-1.84(m, 2H), 2.51(s, 3H), 2.87 (t, J = 7.2Hz, 2H), 7.71(s, 1H), 7.90(s, 1H),9.98 (s,1H), 12.65 (s, 1H). Elemental analysis: c 12 H 14 N 2 O, calculated value: c, 71.26, H, 6.98, N, 13.85, found: c, 71.22, H, 6.99, N, 13.87. Sodium benzene sulfinate: mp>300℃;IR(KBr)υ3072, 3007, 1475, 1439, 1237,1224, 1199, 1150, 1130, 855, 847, 732 cm -1 Consistent with standard IR data.
Example 5
7-methyl-2-n-propyl-3HPreparation of (E) -benzimidazole-5-carbaldehyde
372g (1mol) of the intermediate (2) are dissolved in 8L of ethylene glycol, 37.2g of soft glass powder (30 meshes) are added, the mixture is heated to 160 ℃ and 165 ℃, and 82.8g (0.6mol) of K is added 2 CO 3 Stirring the powder vigorously, discharging a large amount of gas, reacting for 4min, cooling, filtering, recovering most of ethylene glycol under reduced pressure, adding 3L of water and 3L of ethyl acetate into the residue, stirring, layering, extracting with ethyl acetate for 3 times, mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, recrystallizing with ethyl acetate/petroleum ether to obtain 7-methyl-2-n-propyl-3HBenzimidazole-5-aldehyde in 81% yield. Adjusting the water phase to acidity with concentrated hydrochloric acid at 10-15 deg.C, precipitating crystal, filtering, washing with water, adding NaOH to neutralize to form salt, concentrating, cooling, and drying to obtain sodium benzene sulfinate with yield of 80%.
Claims (4)
1. A preparation method of an intermediate 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde of telmisartan is characterized by comprising the following steps:
step 1:
the 3-methyl-4-n-butylamido-5-nitrobenzoic acid is mixed with 5 times of SOCl 2 Mixing, reflux reacting for 1h, vacuum distilling, recovering excessive SOCl 2 Dissolving the remainder in dichloromethane, cooling to 0 ℃, adding a certain amount of triethylamine and benzenesulfonyl hydrazide, reacting at 0 ℃ for 1h, then reacting at room temperature for 3h, pouring into water, layering, extracting with dichloromethane, drying, and concentrating to obtain an intermediate (1); the step avoids the introduction of water, and the two-step reaction is finished in one pot; the crude product of the intermediate (1) is directly used for the next reaction;
step 2:
under the protection of nitrogen, dissolving the intermediate (1) in ethanol/glacial acetic acid, and adding catalytic amount of Fe powder and PdCl 2 Adding hydrogen at room temperature to 0.15-0.2MPa, reacting for 1h, filtering to recover catalyst, distilling under reduced pressure to recover ethanol, heating the rest solution under reflux for 1h, distilling under reduced pressure to recover glacial acetic acid, adding ethyl acetate to dissolve the residue, and adding NaHCO 3 Stirring the solution, demixing, extracting with ethyl acetate, combining organic phases, washing with water, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain an intermediate (2); the two-step reaction is completed in one pot;
and step 3:
dissolving the intermediate (2) in ethylene glycol, adding a certain amount of solid, heating to 160-165 ℃, adding alkali, violently stirring, discharging a large amount of gas, reacting for 10-15min, cooling, filtering, recovering most of ethylene glycol under reduced pressure, adding water and ethyl acetate into the remainder, stirring, layering, extracting ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, recrystallizing ethyl acetate/petroleum ether to obtain 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde, adjusting the water phase to acidity with concentrated hydrochloric acid at 10-15 ℃, separating out crystals, filtering, washing, neutralizing with sodium hydroxide to form salts, concentrating, cooling, and drying to obtain a byproduct sodium benzene sulfinate; the solid is soft glass powder, industrial zeolite, broken porcelain powder and ceramsite, and the particle size of the solid is 30-40 meshes.
2. The preparation method of telmisartan intermediate 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde according to claim 1, wherein in the step 1, the second step of reaction is carried out, wherein the feeding molar ratio of 3-methyl-4-n-butylamido-5-nitrobenzoic acid to benzenesulfonylhydrazide to triethylamine is 1: 1.1-1.2: 1.3-1.5.
3. The preparation method of telmisartan intermediate 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde according to claim 1, wherein in step 2, the volume ratio of ethanol to glacial acetic acid is 1: 1-1: 2; the feeding molar ratio is the intermediate (1): fe: PdCl 2 ＝1：0.20-0.25：0.01-0.02。
4. The preparation method of 7-methyl-2-n-propyl-3H-benzimidazole-5-aldehyde, an intermediate of telmisartan, according to claim 1, wherein in step 3, the base is Na 2 CO 3 Powder and K 2 CO 3 Powder; the feeding molar ratio of the intermediate (2) to the alkali is 1: 0.6-0.7; the dosage of the solid is 5 to 10 percent of the dosage of the intermediate (2).
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| WO2009123483A1 (en) * | 2008-03-31 | 2009-10-08 | Zaklady Farmaceutyczne Polpharma Sa | Process for preparation of telmisartan |
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