CN102603645A - Method for synthetizing fenflumizole - Google Patents

Abstract

The invention discloses a method for synthesizing fenflumidazole, belonging to the technical field of organic chemical synthesis, comprising: reacting methyl 4-methoxybenzoate and 4-methoxyacetophenone under the action of a catalyst to generate 1,3 -bis(4-methoxybenzene)-1,3 diketone, then react with tert-butyl nitrite to generate 1,2-bis(4-methoxybenzene)-1,2 diketone, and then react with 2, 4-Difluorobenzaldehyde reacts to generate the 2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole. The method of the present invention prepares 1,2-diketone through 1,3-diketone, avoiding the use of KCN.

Description

A kind of method of synthesizing fenflumidazole

technical field

The invention relates to the technical field of organic chemical synthesis, in particular to a method for synthesizing fenflumidazole

Background technique

Fenflumidazole, 2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole, its structural formula is shown in formula (1),

The compound is an important imidazole derivative with anti-inflammatory, analgesic and antipyretic effects (Pharmadynamics and toxicity of fenflumizote, a new non-steroidalanti-inflammatory imidazole derivative. Acta Pharmacol. Toxicol. 53, 288-296 (1983)).

Compared with other NSAIDs, fenflumazole has better activity and lower side effects, especially gastrointestinal inflammation (Antithrombotic and Ulcerogenic Effects of Fenflumizole, a New Anti-Inflammatory Imidazole Derivative, in Rats, Japan . J. Pharmacol. 44, 93-96 (1987)).

In addition, experiments and clinical studies have shown that fenflumizole also has antiplatelet aggregation, can resist platelet adhesion and aggregation, prevent thrombosis, and help prevent atherosclerosis and myocardial infarction (Antiplatelet Effects of Fenflumizole, a New Anti-Inflammatory Drug, in Dogs, Japan. J. Pharmacol. 44, 97-100 (1987)). There are already such products on the market at present.

At present, the synthetic route of fenflumidazole is as follows (Recueil des TravauxChimiques des Pays-Bas et de la Belgique, 48, 1112-23; 1929; Journal of Labeled Compounds and Radiopharmaceuticals, 20 (5), 575-82) as shown in formula (2) ; 1983),

The first step is to condense methoxybenzaldehyde with benzoin to obtain α-hydroxy ketone, the second step is to generate 1,2-diketone under the oxidation of Fehling's reagent, and the last step is to close the ring to form the target product. This route requires the use of highly toxic KCN, which has greater danger.

Contents of the invention

The invention provides a method for synthesizing fenflumidazole, preparing 1,2-diketone through 1,3-diketone and avoiding the use of KCN.

A method for synthesizing 2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole, comprising:

(1) under the action of a catalyst, 4-methoxybenzoic acid methyl ester and 4-methoxyacetophenone react to generate 1,3-bis(4-methoxybenzene)-1,3 diketone, the The molar ratio of 4-methoxyacetophenone and catalyst is 1: 2～4, the mol ratio of 4-methoxyacetophenone and 4-methoxybenzoic acid methyl ester is 1: 0.5～2;

(2) Under the action of a catalyst, the 1,3-bis(4-methoxybenzene)-1,3 diketone reacts with tert-butyl nitrite to generate 1,2-bis(4-methoxybenzene )-1,2 diketone, the molar ratio of described 1,3-bis(4-methoxybenzene)-1,3 diketone and catalyst is 1:0.1～0.5,1,3-bis(4- The mol ratio of methoxybenzene)-1,3 diketone and tert-butyl nitrite is 1: 3～7;

(3) the 1,2-bis(4-methoxybenzene)-1,2 diketone reacts with 2,4-difluorobenzaldehyde and ammonium acetate to generate the 2-(2,4-di Fluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole, the 1,2-bis(4-methoxyphenyl)-1,2 dione and 2,4 - The molar ratio of difluorobenzaldehyde is 1:1.1～2, and the molar ratio of 1,2-bis(4-methoxybenzene)-1,2 diketone and ammonium acetate is 1:2～7.

The reaction process of the synthetic method of the present invention is shown in formula (3), wherein the catalyzer used in the step (1) is example with sodium hydride, and the catalyzer used in the step (2) is example with iron trichloride:

The catalyst in step (1) is sodium hydride, sodium tert-butoxide, potassium tert-butoxide or lithium tert-butoxide, the reaction is carried out in tetrahydrofuran, the reaction temperature is 50-70°C, and the reaction time is 10-20 hours, generally Under normal circumstances, the reaction is overnight, and it can be done within 10-20 hours.

In the step (2), the catalyst is ferric trichloride, ferric tribromide, ferrous chloride or ferric oxide, and the temperature of reaction is 20-40° C., and the reaction time is 10-20 hours. Generally, it is React overnight, all within 10-20 hours.

The reaction in step (3) is carried out in acetic acid, the reaction temperature is 90-110° C., and the reaction time is 10-20 hours. Generally, the reaction is overnight, and it can be within 10-20 hours.

The specific process of the above steps (1) to (3) is as follows:

(1) Use dry tetrahydrofuran as a solvent, add a catalyst, stir for 10 minutes, add methyl 4-methoxybenzoate, and add 4-methoxyacetophenone dropwise. After the dropwise addition, raise the temperature to 50-70°C and stir for 10-20 hours. After the reaction is complete, add water dropwise, then add dilute HCl to adjust the pH to 2-4, extract with dichloromethane, dry over anhydrous sodium sulfate, and remove the solvent to obtain crude The product was recrystallized from a mixed solvent of petroleum ether and ethyl acetate to obtain the intermediate 1,3-bis(4-methoxybenzene)-1,3-dione;

(2) Add tert-butyl nitrite to the mixture of catalyst and 1,3-bis(4-methoxybenzene)-1,3 diketone, stir at 20-40°C for 10-20 hours, after the reaction is completed , filtered, and the resulting crude product was purified by a silica gel column (petroleum ether: ethyl acetate=10:1) to obtain the intermediate 1,2-bis(4-methoxybenzene)-1,2 diketone, wherein the nitrous acid Tert-butyl ester can be easily prepared industrially from tert-butanol and sodium nitrite;

(3) With acetic acid as solvent, add 1,2-bis(4-methoxybenzene)-1,2 diketone, 2,4-difluorobenzaldehyde and ammonium acetate, reflux at 90-110°C for 10-20 Hour. After the reaction was complete, add saturated _Na2CO3 solution to adjust the pH to 8-10, then extract with ethyl _acetate , wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, remove the solvent and purify the crude product with a silica gel column (petroleum ether : ethyl acetate=5:1), the final product 2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole was obtained.

Beneficial effects of the present invention:

(1) The yield is high, using cheap raw materials and catalysts, and the cost is low;

(2) The use of potassium cyanide is avoided, and the industrial application is safer.

Detailed ways

The productive rate in all following examples is calculated based on the substrate with a small molar amount

Example 1

Step 1,1, the synthesis of 3-bis(4-methoxybenzene)-1,3 diketone

Sodium hydride (60%, 4.0 g, 100 mmol) and dry tetrahydrofuran (50 mL) were added to a 250 mL one-necked flask. After stirring in ice bath for 20 min, methyl 4-methoxybenzoate (7.3 g, 44 mmol) was added, and then 4-methoxyacetophenone (6.0 g, 40 mmol) was added dropwise. After the dropwise addition was completed, the temperature was raised to 60° C. and stirred for 12 hours. After TLC (thin-layer chromatography) showed that the reaction was complete, water was added dropwise to the reaction system to quench the reaction, and dilute hydrochloric acid was added to adjust the pH to about 3, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the obtained crude product was recrystallized from a mixed solvent of petroleum ether and ethyl acetate to obtain 8.0 g of 1,3-bis(4-methoxybenzene)-1,3-dione as a yellow solid. rate of 70%.

¹ H NMR (400MHz, CDCl ₃ , TMS): δ17.12(br, 1H), 7.96(d, 4H, J=8.8Hz), 6.98(d, 4H, J=8.8Hz), 6.74(s, 1H ), 3.88(s, 6H).

Step 2, 1, the synthesis of two (4-methoxybenzene)-1,2 diketones of 2-

Add ferric chloride (0.32g, 2mmol), 1,3-bis(4-methoxybenzene)-1,3 diketone (1.4g, 5mmol) and tert-butyl nitrite (2g, 19.4 mmol), stirred at 30°C for 12 hours. After TLC showed that the reaction was complete, it was filtered through diatomaceous earth, and the solvent was spin-dried, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid 1,2-bis(4-methoxybenzene) -1,2 diketone 960 mg, yield 74%.

¹ H NMR (400 MHz, CDCl ₃ , TMS): δ 7.94 (d, 4H, J=9.2 Hz), 6.97 (d, 4H, J=9.2 Hz), 3.88 (s, 6H).

Synthesis of step 3, 2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole

To a 25 mL round bottom flask was added 1,2-bis(4-methoxybenzene)-1,2 dione (0.135 g, 0.5 mmol), 2,4-difluorobenzaldehyde (0.142 g, 1 mmol), NH _4OAc (0.182g, 2.4mmol) and acetic acid (3mL) were stirred at 110°C for 12 hours. After TLC showed that the reaction was complete, saturated sodium carbonate solution was added to adjust the pH to about 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain a white solid 2-(2,4-difluorophenyl)-4,5-bis (4-methoxyphenyl)-1H-imidazole 90 mg, yield 46%.

¹ H NMR (400MHz, CDCl ₃ , TMS): δ9.76(br, 1H), 8.30(dd, 1H, J=15.2, 8.8Hz), 7.43(br, 4H), 6.97(t, 1H, J= 7.6Hz), 6.84-6.92 (m, 5H), 3.80 (s, 16H); MS (ESI) Calcd for [(MH) ^- ] 391.3.

Example 2

Step 1,1, the synthesis of 3-bis(4-methoxybenzene)-1,3 diketone

Sodium hydride (60%, 3.2g, 80mmol) and dry tetrahydrofuran (50mL) were added into a 250mL single-necked flask, and after stirring for 20min under ice bath, methyl 4-methoxybenzoate (3.3g, 20mmol) was added, and then Then 4-methoxyacetophenone (6.0 g, 40 mmol) was added dropwise. After the dropwise addition was completed, the temperature was raised to 60° C. and stirred for 12 hours. After TLC showed that the reaction was complete, water was added dropwise to the reaction system to quench the reaction, and the pH was adjusted to about 3 by adding dilute hydrochloric acid, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the obtained crude product was recrystallized from a mixed solvent of petroleum ether and ethyl acetate to obtain 3.9 g of 1,3-bis(4-methoxybenzene)-1,3-dione as a yellow solid. rate of 68%.

Step 2, 1, the synthesis of two (4-methoxybenzene)-1,2 diketones of 2-

Add iron tribromide (148 mg, 0.5 mmol), 1,3-bis(4-methoxybenzene)-1,3 dione (1.4 g, 5 mmol) and tert-butyl nitrite (1.5 g, 15 mmol), stirred at 30°C for 12 hours. After TLC showed that the reaction was complete, it was filtered through diatomaceous earth, and the solvent was spin-dried, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid 1,2-bis(4-methoxybenzene) -1,2 diketone 850 mg, yield 63%.

Synthesis of step 3, 2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole

To a 25 mL round bottom flask was added 1,2-bis(4-methoxybenzene)-1,2 dione (135 mg, 0.5 mmol), 2,4-difluorobenzaldehyde (78 mg, 0.55 mmol), _NH4 OAc (77mg, 1mmol) and acetic acid (3mL) were stirred at 110°C for 12 hours. After TLC showed that the reaction was complete, saturated sodium carbonate solution was added to adjust the pH to about 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain a white solid 2-(2,4-difluorophenyl)-4,5-bis (4-methoxyphenyl)-1H-imidazole 78 mg, yield 40%.

Example 3

Step 1,1, the synthesis of 3-bis(4-methoxybenzene)-1,3 diketone

Sodium hydride (60%, 6.4g, 160mmol) and dry tetrahydrofuran (50mL) were added into a 250mL single-necked flask, and after stirring for 20min under ice bath, methyl 4-methoxybenzoate (8.0g, 48mmol) was added, and then Then 4-methoxyacetophenone (6.0 g, 40 mmol) was added dropwise. After the dropwise addition was completed, the temperature was raised to 60° C. and stirred for 12 hours. After TLC showed that the reaction was complete, water was added dropwise to the reaction system to quench the reaction, and the pH was adjusted to about 3 by adding dilute hydrochloric acid, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the obtained crude product was recrystallized from a mixed solvent of petroleum ether and ethyl acetate to obtain 8.3 g of 1,3-bis(4-methoxybenzene)-1,3-dione as a yellow solid. rate of 72%.

Step 2, 1, the synthesis of two (4-methoxybenzene)-1,2 diketones of 2-

Add ferric oxide (399 mg, 2.5 mmol), 1,3-bis(4-methoxybenzene)-1,3 dione (1.4 g, 5 mmol) and tert-butyl nitrite (2 g, 35 mmol) into the test tube ), stirred at 30°C for 12 hours. After TLC showed that the reaction was complete, it was filtered through diatomaceous earth, and the solvent was spin-dried, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid 1,2-bis(4-methoxybenzene) -1,2 diketone 835mg, yield 64%.

Synthesis of step 3, 2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole

To a 25 mL round bottom flask was added 1,2-bis(4-methoxybenzene)-1,2 dione (135 mg, 0.5 mmol), 2,4-difluorobenzaldehyde (142 mg, 1.0 mmol), _NH4 OAc (269mg, 3.5mmol) and acetic acid (3mL) were stirred at 110°C for 12 hours. After TLC showed that the reaction was complete, saturated sodium carbonate solution was added to adjust the pH to about 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain a white solid 2-(2,4-difluorophenyl)-4,5-bis (4-methoxyphenyl)-1H-imidazole 93 mg, yield 47%.

The products in each reaction step in Example 2 and Example 3 were compared by TLC and determined to be consistent with the product obtained in each reaction step corresponding to Example 1.

Claims (9)

1. Synthetic 2-(2,4 difluorobenzene base)-4, the method for two (4-the p-methoxy-phenyl)-1H-imidazoles of 5-is characterized in that, comprising:

(1) under catalyst action; 4-methoxyl methyl benzoate and the reaction of 4-methoxyacetophenone generate 1; Two (the 4-anisoles)-1 of 3-; 3 diketone, the mol ratio of described 4-methoxyacetophenone and catalyzer is 1: 2～4, the mol ratio of 4-methoxyacetophenone and 4-methoxy benzoic acid methyl esters is 1: 0.5～2;

(2) under catalyst action, described 1, two (the 4-anisoles)-1 of 3-; 3 diketone and nitrite tert-butyl reaction generate 1, two (4-anisole)-1,2 diketone of 2-; Described 1, the mol ratio of two (4-anisole)-1,3 diketone of 3-and catalyzer is 1: 0.1～0.5; 1, the mol ratio of two (4-anisole)-1,3 diketone of 3-and nitrite tert-butyl is 1: 3～7;

(3) described 1, two (4-anisole)-1,2 diketone of 2-and 2,4 difluorobenzene formaldehyde and the described 2-(2 of ammonium acetate reaction generation; The 4-difluorophenyl)-4, two (4-the p-methoxy-phenyl)-1H-imidazoles of 5-, described 1; The mol ratio of two (4-anisole)-1,2 diketone of 2-and 2,4 difluorobenzene formaldehyde is 1: 1.1～2; 1, the mol ratio of two (4-anisole)-1,2 diketone of 2-and ammonium acetate is 1: 2～7.

2. method according to claim 1 is characterized in that, the catalyzer described in the step (1) is sodium hydride, sodium tert-butoxide, potassium tert.-butoxide or trimethyl carbinol lithium.

3. method according to claim 1 is characterized in that, the catalyzer described in the step (2) is iron trichloride, ferric bromide, iron protochloride or red oxide of iron.

4. method according to claim 1 is characterized in that, the temperature of reaction is 50～70 ℃ described in the step (1).

5. method according to claim 1 is characterized in that, the temperature of reaction is 20-40 ℃ described in the step (2).

6. method according to claim 1 is characterized in that, the temperature of reaction is 90-110 ℃ described in the step (3).

7. method according to claim 1 is characterized in that, the time of reaction is 10-20 hour described in the step (1).

8. method according to claim 1 is characterized in that, the time of reaction is 10-20 hour described in the step (2).

9. method according to claim 1 is characterized in that, the time of reaction is 10-20 hour described in the step (3).