阅读说明：本技术 一种5-(2-氟苯基)-1h-吡咯-3-甲醛的制备方法 (Preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde ) 是由 吕志波 毛成龙 王丽 曹燕 王永广 吕玲 于 2021-10-14 设计创作，主要内容包括：本发明涉及一种5-(2-氟苯基)-1H-吡咯-3-甲醛的制备方法,包括以下步骤：将2-(2-氟苯甲酰基)丙二腈溶于溶剂中,加入金属催化剂和冰乙酸,抽真空、氢气置换,升温,进行第一次还原反应；反应完毕后,降温,过滤,反应液中加入雷尼镍以及水,抽真空、氢气置换,保温,进行第二次还原反应；反应完毕,过滤,对滤液进行减压浓缩,降温,加入四氢呋喃水溶液,保温,搅拌打浆,过滤,水洗,干燥,得到5-(2-氟苯基)-1H-吡咯-3-甲醛。本发明以2-(2-氟苯甲酰基)丙二腈为原料通过一锅法合成5-(2-氟苯基)-1H-吡咯-3-甲醛,避免多步中间体的分离过程,减少三废的产生,环境友好,降低成本,有利于工业化规模生产,所得产品收率和纯度高。(The invention relates to a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde, which comprises the following steps: dissolving 2- (2-fluorobenzoyl) malononitrile in a solvent, adding a metal catalyst and glacial acetic acid, vacuumizing, replacing hydrogen, heating, and carrying out a first reduction reaction; after the reaction is finished, cooling, filtering, adding Raney nickel and water into the reaction solution, vacuumizing, replacing with hydrogen, preserving heat, and carrying out a second reduction reaction; and after the reaction is finished, filtering, concentrating the filtrate under reduced pressure, cooling, adding a tetrahydrofuran aqueous solution, preserving heat, stirring and pulping, filtering, washing with water, and drying to obtain the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde. The method takes 2- (2-fluorobenzoyl) malononitrile as a raw material to synthesize the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde by a one-pot method, avoids the separation process of multi-step intermediates, reduces the generation of three wastes, is environment-friendly, reduces the cost, is beneficial to industrial mass production, and has high yield and purity of the obtained product.)

1. A preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is characterized by comprising the following steps:

dissolving 2- (2-fluorobenzoyl) malononitrile in a solvent, adding a metal catalyst and glacial acetic acid, vacuumizing, replacing for 3 times with nitrogen, pressurizing with hydrogen, heating, and performing a first reduction reaction;

after the first reduction reaction is finished, cooling to below 30 ℃, filtering to remove the metal catalyst, transferring the reaction liquid into a clean reaction kettle, adding Raney nickel and water, vacuumizing, replacing for 3 times with nitrogen, pressurizing with hydrogen, preserving heat, and carrying out the second reduction reaction;

and after the second reduction reaction is finished, filtering to remove Raney nickel, washing the Raney nickel by tetrahydrofuran, concentrating the filtrate under reduced pressure until a large amount of solids appear, cooling, adding a tetrahydrofuran aqueous solution, preserving heat, stirring and pulping, filtering, washing with water, and drying to obtain the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.

2. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: the plastid ratio of the 2- (2-fluorobenzoyl) malononitrile to the solvent in the step (1) is 1:5, the solvent is one or more of tetrahydrofuran, acetonitrile, acetone, pyridine and dimethyl sulfoxide, and the metal catalyst is one or more of 10% palladium carbon, platinum carbon, palladium hydroxide and zinc powder.

3. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: the feeding amount of the metal catalyst in the step (1) is 3-5% of that of the 2- (2-fluorobenzoyl) malononitrile.

4. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: the mass ratio of the 2- (2-fluorobenzoyl) malononitrile to the glacial acetic acid in the step (1) is 1: 1.2-1.6.

5. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: the temperature of the first reduction reaction in the step (1) is 45-50 ℃, and the reaction time is 8-9 h.

6. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: and (3) judging the completion of the first reduction reaction in the step (2) comprises sampling for reaction monitoring, wherein the 2- (2-fluorobenzoyl) malononitrile is remained to be less than 0.5%.

7. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: the feeding amount of the Raney nickel in the step (2) is 3-7% of that of the 2- (2-fluorobenzoyl) malononitrile.

8. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: the temperature of the second reduction reaction in the step (2) is 15-25 ℃, and the reaction time is 15-16 h.

9. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: and (3) judging the completion of the second reduction reaction in the step (3) comprises sampling and carrying out reaction monitoring, wherein the generated intermediate state is less than 0.2 percent.

10. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: in the step (3), the volume ratio of tetrahydrofuran to water in the tetrahydrofuran aqueous solution is 1:5, the temperature range of reduced pressure concentration is 40-45 ℃, the temperature of heat preservation is 20-30 ℃, and the pulping time is 3-4 h.

Technical Field

The invention relates to the field of chemical pharmaceutical preparations, and in particular relates to a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.

Background

Vorexant fumarate, chemical name: 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine monofumarate is a potassium ion competitive acid blocker developed by Wuta, Japan (Takeda), a new drug application is filed in 3 months in 2014 in Tokyo province, the drug has a strong and durable gastric acid secretion inhibition effect, and simultaneously has an early termination effect on gastric acid secretion by inhibiting the binding effect of K on H, K-ATP enzyme (proton pump) in the last step of gastric acid secretion of gastric parietal cells, and the drug is used for treating gastric ulcer, duodenal ulcer, reflux esophagitis and the like.

The 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is an important intermediate of Voranolan fumarate, so that a new synthesis process is developed, the cost is reduced, the operation is simplified, the yield is improved, and the method has important significance for realizing industrial production, and has the following structure:

the synthesis methods for preparing the compound I in the prior art mainly comprise the following two methods:

the patent EP2327692 reports a preparation method of the compound I, and the synthesis route is as follows:

route (WO 2010098351) also reports a preparation method of compound I, and the synthetic route is as follows:

the method takes o-fluoro acetophenone as a starting material, and compounds I are obtained through bromination, substitution condensation, palladium-carbon dechlorination, DIBAL reduction and oxidation.

Route ② also takes o-fluoro acetophenone as a starting material, and is different from the method in that cyano is used for replacing an ethyl ester group, and a target product is directly obtained by Raney nickel reduction. The method is still long, although the steps are reduced. The method has the advantages of long steps, generation of a large amount of organic solvent waste liquid, low total yield, high cost and no contribution to industrial mass production.

The two routes are compared to know that the route II reduces the reaction steps, but has more operation steps on the whole, generates a large amount of organic solvent waste liquid, has low total yield and higher cost, and is not beneficial to industrial mass production.

Disclosure of Invention

In order to solve the problems in the background art, the invention provides a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.

The invention provides a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde, which comprises the following steps:

dissolving 2- (2-fluorobenzoyl) malononitrile in a solvent, adding a metal catalyst and glacial acetic acid, vacuumizing, replacing for 3 times with nitrogen, pressurizing with hydrogen, heating, and performing a first reduction reaction;

after the first reduction reaction is finished, cooling to below 30 ℃, filtering to remove the metal catalyst, transferring the reaction liquid into a clean reaction kettle, adding Raney nickel and water, vacuumizing, replacing for 3 times with nitrogen, pressurizing with hydrogen, preserving heat, and carrying out the second reduction reaction;

and after the second reduction reaction is finished, filtering to remove Raney nickel, washing the Raney nickel by tetrahydrofuran, concentrating the filtrate under reduced pressure until a large amount of solids appear, cooling, adding a tetrahydrofuran aqueous solution, preserving heat, stirring and pulping, filtering, washing with water, and drying to obtain the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.

The reaction route of the invention is as follows:

preferably, the plastid ratio of the 2- (2-fluorobenzoyl) malononitrile to the solvent in the step (1) is 1:5, the solvent is one or more of tetrahydrofuran, acetonitrile, acetone, pyridine and dimethyl sulfoxide, and the metal catalyst is one or more of 10% palladium carbon, platinum carbon, palladium hydroxide and zinc powder.

Preferably, the feeding amount of the metal catalyst in the step (1) is 3-5% of the feeding amount of the 2- (2-fluorobenzoyl) malononitrile.

Preferably, the mass ratio of the 2- (2-fluorobenzoyl) malononitrile to the glacial acetic acid in the step (1) is 1: 1.2-1.6.

Preferably, the temperature of the first reduction reaction in the step (1) is 45-50 ℃, and the reaction time is 8-9 h.

Preferably, the judging that the first reduction reaction in the step (2) is completed includes sampling for reaction monitoring, and the 2- (2-fluorobenzoyl) malononitrile is remained to be less than 0.5%.

Preferably, the feeding amount of the raney nickel in the step (2) is 3-7% of that of the 2- (2-fluorobenzoyl) malononitrile.

Preferably, the temperature of the second reduction reaction in the step (2) is 15-25 ℃, and the reaction time is 15-16 h.

Preferably, the determination of the completion of the second reduction reaction in step (3) includes sampling for reaction monitoring, and the generated intermediate state is less than 0.2%.

Preferably, the volume ratio of tetrahydrofuran to water in the tetrahydrofuran aqueous solution in the step (3) is 1:5, the temperature range of reduced pressure concentration is 40-45 ℃, the temperature of heat preservation is 20-30 ℃, and the pulping time is 3-4 h.

In summary, the invention has the following beneficial technical effects:

the invention uses the intermediate 2- (2-fluorobenzoyl) malononitrile as a raw material to carry out the process for synthesizing the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde by the one-pot method, avoids the separation process of multi-step intermediates, greatly reduces the generation of three wastes, is environment-friendly, improves the yield, reduces the cost, simplifies the steps, is beneficial to industrial mass production, and has high yield and purity of the obtained product.

Drawings

FIG. 1 is a high performance liquid chromatogram of example 1 of the present invention;

FIG. 2 is a high performance liquid chromatogram of example 2 of the present invention;

FIG. 3 is a high performance liquid chromatogram of example 3 of the present invention;

FIG. 4 is a hydrogen spectrum of example 1 of the present invention;

FIG. 5 is a primary mass spectrum of example 1 of the present invention;

FIG. 6 is a secondary mass spectrum of example 1 of the present invention.

Detailed Description

The present invention will be described in further detail with reference to examples.

Example 1

Adding 20g of 2- (2-fluorobenzoyl) malononitrile (compound II), 100mL of tetrahydrofuran, 25g of glacial acetic acid and 1g of 10% palladium-carbon into a 250mL reaction kettle, vacuumizing and replacing for 3 times, hydrogenating by using a double-layer balloon under the pressure of 0.01Mpa, heating to 47 ℃, and preserving heat for reacting for 9 hours; sampling for reaction monitoring, wherein the compound II is 0.12% remained, cooling to below 30 ℃, filtering to remove palladium carbon, transferring the reaction solution into a clean reaction kettle, adding 1g of Raney nickel and 20ml of purified water, vacuumizing and replacing for 3 times, pressurizing to 0.01Mpa, keeping the temperature at 20 ℃, and reacting for 16 hours; sampling and detecting, wherein 0.09% of intermediate transition state is remained, the purity of the reaction liquid is 96.23%, filtering to remove Raney nickel, washing with 10ml of tetrahydrofuran, decompressing and concentrating the filtrate at 40 ℃, evaporating until no liquid flows out basically, cooling to 30 ℃, dropwise adding tetrahydrofuran aqueous solution of 20ml of tetrahydrofuran and 100ml of purified water, keeping the temperature at 20 ℃, stirring for 4H, filtering, washing the filter cake with 20ml of water to obtain 25.32g of brown yellow solid wet product, and drying by electric heating and blowing at 50 ℃ to obtain 17.58g of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde (compound I), the molar yield is 87.42%, the purity is detected by high performance liquid chromatography, the chromatogram is shown in figure 1, the detected purity is 99.49%, the primary mass spectrum is shown in figure 5, the secondary mass spectrum is shown in figure 6, and the hydrogen spectrum is shown in figure 4.

1H-NMR(600MHz,DMSO)，δ(ppm)：6.9(dd,J＝1.8Hz,J＝2.4Hz,1H),7.27-7.35(m,3H),7.77(td,J＝7.8Hz,J＝1.8Hz,1H)7.82(d,J＝1.8Hz,1H)9.76(s,1H)12.14(brs,1H)。

Example 2

Adding 200g of a compound II, 1000mL of acetonitrile and 320g of glacial acetic acid into a 2L high-pressure autoclave, adding 10g of platinum and carbon, vacuumizing, replacing 3 times with nitrogen, then, after vacuumizing, pressurizing hydrogen to 0.10Mpa, heating to 45 ℃, preserving heat, reacting for 8 hours, and pressurizing to 0.1Mpa when the pressure is reduced to 0.01 Mpa; sampling for reaction monitoring, wherein 0.09% of compound II remains, the temperature of the reaction liquid is reduced to below 30 ℃, filtering to remove platinum and carbon, transferring the reaction liquid into a clean reaction kettle, adding 14g of Raney nickel and 200ml of purified water, vacuumizing, replacing for 3 times with nitrogen, vacuumizing again, pressurizing hydrogen to 0.10Mpa, preserving the temperature at 25 ℃, reacting for 15h, and pressurizing to 0.10Mpa when the pressure of the hydrogen is reduced to 0.02 Mpa; sampling and detecting, wherein 0.08% of intermediate transition state is remained, the purity of the reaction solution is 96.63%, Raney nickel is removed by filtering, after 100ml of tetrahydrofuran is used for washing, the filtrate is subjected to reduced pressure concentration at 45 ℃, is evaporated until no liquid flows out basically, is cooled to 30 ℃, is dropwise added with tetrahydrofuran aqueous solution of 200ml of tetrahydrofuran and 1000ml of purified water, is kept at 30 ℃, is stirred for 4 hours, is filtered, the filter cake is washed by 200ml of water to obtain 257.78g of brown yellow solid wet product, is dried by electric heating forced air at 50 ℃ to obtain 177.45g of compound I, has the molar yield of 88.24%, and has the purity detected by high performance liquid chromatography, the chromatogram is shown in figure 2, and the detected purity is 99.41%.

Example 3

Adding 1kg of compound II into a 10L high-pressure kettle, adding 5L of acetone and 1.3kg of glacial acetic acid, adding 30g of palladium hydroxide, vacuumizing, replacing 3 times with nitrogen, vacuumizing again, increasing the pressure of hydrogen to 0.25Mpa, heating to 50 ℃, carrying out heat preservation reaction for 8 hours, and increasing the pressure to 0.25Mpa when the pressure of the hydrogen is reduced to 0.02 Mpa; sampling for reaction monitoring, wherein the compound II is 0.08 percent remained, cooling to below 30 ℃, filtering to remove palladium hydroxide, transferring the reaction solution into a clean high-pressure kettle again, adding 30g of Raney nickel and 1kg of purified water, vacuumizing, replacing for 3 times by nitrogen, vacuumizing again, pressurizing hydrogen to 0.25Mpa, preserving the temperature at 15 ℃, reacting for 16h, and pressurizing to 0.25Mpa when the hydrogen pressure is reduced to 0.02 Mpa; sampling and detecting, wherein 0.06% of intermediate transition state is remained, the purity of the reaction solution is 95.33%, filtering to remove Raney nickel, washing with 500ml of tetrahydrofuran, concentrating the filtrate at 40 ℃ under reduced pressure, evaporating until no liquid flows out basically, cooling to 25 ℃, dropwise adding 1L of tetrahydrofuran and 5L of tetrahydrofuran aqueous solution of purified water, keeping the temperature at 25 ℃, stirring for 3h, filtering, washing the filter cake with 500ml of water to obtain 1021.21g of brown yellow solid wet product, drying by electric heating and blowing at 50 ℃ to obtain 889.56g of compound I, the molar yield is 88.47%, detecting the purity by high performance liquid chromatography, and the chromatogram is shown in figure 3, and the detected purity is 99.19%.

Example 4

Adding 500L of tetrahydrofuran into a 1000L reaction kettle, adding 100kg of a compound II under stirring, adding 3kg of 10% palladium carbon and 135kg of glacial acetic acid, vacuumizing, replacing for 3 times by nitrogen, vacuumizing again, pressurizing to 0.20Mpa by hydrogen, heating to 45 ℃, preserving heat, stirring, reacting, pressurizing to 0.20Mpa when the pressure is reduced to 0.02Mpa, and preserving heat for 9 hours; sampling for reaction monitoring, wherein the compound II is 0.10% remained, cooling to below 30 ℃, filtering to remove palladium carbon, transferring the reaction solution into a clean reaction kettle, adding 3kg of Raney nickel and 100kg of purified water, vacuumizing, replacing for 3 times with nitrogen, vacuumizing again, pressurizing to 0.20Mpa with hydrogen, keeping the temperature at 25 ℃, keeping the temperature, stirring and reacting for 15 hours, and pressurizing to 0.2Mpa when the hydrogen pressure is reduced to 0.02 Mpa; sampling and detecting, wherein 0.06% of intermediate transition state is remained, the purity of the reaction solution is 96.13%, filtering to remove Raney nickel, washing with 40kg of tetrahydrofuran, concentrating the filtrate at 45 ℃ under reduced pressure, evaporating until no liquid flows out basically, cooling to 30 ℃, dropwise adding a tetrahydrofuran aqueous solution of 87kg of tetrahydrofuran and 500kg of purified water, keeping the temperature at 30 ℃ for about 2 hours, stirring for 4 hours, filtering, washing a filter cake with 200kg of water to obtain 93kg of brown yellow solid wet product, drying by electric heating and air blowing at 50 ℃ to obtain 87.5kg of a compound I, wherein the molar yield is 87.02%, and the purity is 99.26% through detection.

From examples 1 to 4, it can be seen that the method for preparing 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde by the one-pot method provided by the invention is simple and convenient in process operation, less in three wastes generated in the preparation process, less in environmental pollution, lower in cost, easy for large-scale production of products, higher in product yield and purity, more than 85% in product yield, and more than 99% in purity.

The present embodiment is only for explaining the present invention, and it is not limited to the present invention, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present invention.