A method for catalytic synthesis of famotidine intermediate 1,3-dichloropropanone

Abstract

The application provides a catalytic synthesis method of famotidine intermediate 1,3-dichloropropanone, the catalytic synthesis method is that a molecular sieve loaded phosphotungstic heteropoly acid catalyst is used as a catalyst of a reaction system of 1,3-dichloropropanol and hydrogen peroxide, the phosphotungstic heteropoly acid is a solid catalyst, but the specific surface area is small, by loading the phosphotungstic heteropoly acid on the molecular sieve, the phosphotungstic heteropoly acid can have the acid catalytic activity and the large specific surface area; in addition, the molecular sieve in the application can strengthen the carbonylation reaction activity in the reaction process, shorten the reaction time, the reaction can be carried out at a lower reaction temperature, the catalyst loss is reduced, the reaction process is simple, the operation is convenient, meanwhile, the yield of 1,3-dichloropropanone is high, the highest can reach 80%, and the application has a wide application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of bulk drug, in particular to a catalytic synthesis method of famotidine intermediate 1,3-dichloropropanone. BACKGROUND

[0002] Famotidine is an antacid and gastric mucosa protective drug, and is one of the drugs for treating digestive system diseases.

[0003] It is used for inhibiting gastric acid secretion and can also inhibit the secretion of protease. Famotidine is another H2 receptor antagonist after cimetidine and ranitidine, and its strength is 30-100 times that of cimetidine and 6-10 times that of ranitidine. It has inhibitory effect on the increase of gastric acid and pepsin secretion caused by basic secretion and various stimulations.

[0004] At present, 1,3-dichloropropanone is an important intermediate in the synthesis process of famotidine. The synthesis methods of 1,3-dichloropropanone include hydrogen peroxide oxidation method and sodium dichromate oxidation method. However, in the current hydrogen peroxide oxidation method, the catalyst is the most important and often needs to be used to improve the catalytic oxidation efficiency. In the prior art, CN107954847A discloses a method for catalytically synthesizing 1,3-dichloropropanone by using silica supported phosphotungstic heteropoly acid. Although the modified catalyst can increase the catalytic performance of the heteropoly acid, the specific surface area of the support is limited, and the catalytic performance of the heteropoly acid cannot be fully utilized. CN103752339A discloses an aluminum-doped mesoporous molecular sieve supported phosphotungstic acid catalyst, its preparation and application in the synthesis of benzoic acid. The mesoporous molecular sieve is MCM-48, and the content of phosphotungstic acid heteropoly acid is 5-45% by weight, and the balance is aluminum-doped MCM-48 mesoporous molecular sieve. When the catalyst is applied to the synthesis of benzoic acid, the reaction can be carried out under relatively mild conditions, but there is no record about the catalytic oxidation of 1,3-dichloropropanone.

[0005] According to the above problems, the present application is proposed. SUMMARY

[0006] The present application provides a catalytic synthesis method of famotidine intermediate 1,3-dichloropropanone, which uses a molecular sieve supported phosphotungstic acid catalyst as a catalyst for the reaction system of 1,3-dichloropropanol and hydrogen peroxide.

[0007] In the molecular sieve supported phosphotungstic acid catalyst, the content of the phosphotungstic acid heteropoly acid is 60-80% by weight; and the molecular sieve is Zn-MOR molecular sieve.

[0008] The preparation method of the Zn-MOR molecular sieve is as follows:

[0009] Step 1: Mix zinc salt, sodium aluminate, sodium hydroxide, silicon source and water to obtain a gel;

[0010] Step 2: The prepared gel is placed in a reaction vessel for hydrothermal crystallization;

[0011] Step 3: Remove the block product obtained from the reactor, filter it, air dry it naturally, and then put it into an oven to dry. The solid block obtained after drying is the prepared Zn-MOR molecular sieve.

[0012] In step 1, the zinc salt is either zinc chloride or zinc nitrate.

[0013] The silicon source is any one of silica sol, silica fume, and sodium silicate.

[0014] The effective components of the gel are calculated as zinc salt, SiO2, Al2O3, Na2O and H2O;

[0015] The mass ratio of zinc salt to SiO2 is 1:150-250;

[0016] The mass ratio of SiO2 to sodium aluminate is 6-10:1;

[0017] The mass ratio of sodium aluminate to sodium hydroxide is 1:1.5-3;

[0018] The mass ratio of sodium aluminate to H2O is 1:40-80;

[0019] In step 2, the hydrothermal crystallization temperature is controlled at 180-190℃;

[0020] Furthermore, in step 2, the hydrothermal crystallization time is controlled within 3-5 days;

[0021] Furthermore, the natural air drying time in step 3 is 16–20 h, and the drying temperature in the oven is 70–110 ℃, and the drying time is 7–10 h.

[0022] Furthermore, the preparation method of the molecular sieve-supported phosphotungsten heteropolyacid catalyst is as follows:

[0023] Dissolve phosphotungstic heteropoly acid in water, add the Zn-MOR molecular sieve, stir for 6-16 h, stir at 50-55℃, and then dry at 100-120℃ for 4-8 h to finally obtain the molecular sieve supported phosphotungstic heteropoly acid catalyst.

[0024] Furthermore, the catalytic synthesis method involves reacting a molecular sieve-supported phosphotungsten heteropolyacid catalyst, 1,3-dichloropropanol, and hydrogen peroxide at a constant temperature of 40-48°C for 4-5 hours, yielding 1,3-dichloropropanone as the product after the reaction is complete.

[0025] Furthermore, the mass ratio of 1,3-dichloropropanol, hydrogen peroxide solution, and molecular sieve-supported phosphotungsten heteropolyacid catalyst is 5:4:0.1-0.15; the mass fraction of the hydrogen peroxide solution is 30%.

[0026] Technical effect

[0027] The catalytic synthesis method for 1,3-dichloroacetone of this invention has a high product yield. Phosphotungstic heteropolyacid is a solid catalyst, but its specific surface area is small. By loading phosphotungstic heteropolyacid onto a molecular sieve, it can possess both acid catalytic activity and a large specific surface area. In addition, the Zn-MOR molecular sieve in this invention can enhance the carbonylation reaction activity during the reaction process, shorten the reaction time, and allow the reaction to be carried out at a lower reaction temperature. The reaction yield is high, and the catalyst can be further recycled, reducing catalyst loss. The reaction process is simple and convenient to operate. At the same time, the yield of 1,3-dichloroacetone is high, reaching up to 80%, and it has broad application prospects. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be described in detail below with reference to specific embodiments. The purity and impurity content involved in the embodiments are measured according to the prior art. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0029] Example 1

[0030] Example 1

[0031] Add 10g of sodium hydroxide and 5g of sodium aluminate to 240g of deionized water, stir well, then slowly add 0.2g of zinc chloride, followed by slowly adding 140g of 30wt% silica sol. Stir for 4 hours, then perform hydrothermal crystallization, filter, and dry to obtain Zn-MOR molecular sieve.

[0032] 2g of phosphotungstic heteropoly acid was dissolved in water, and 1g of the Zn-MOR molecular sieve was added. The mixture was stirred for 8 h, stirred at 50℃, and then dried at 105℃ for 6 h to obtain the molecular sieve-supported phosphotungstic heteropoly acid catalyst.

[0033] 50 g of dichloropropanol was added to a four-necked flask, followed by 1 g of molecular sieve-supported phosphotungsten heteropolyacid catalyst. The mixture was stirred, and the reaction temperature was controlled at 45 °C using a constant temperature water bath. Once the temperature was reached, 40 g of 30% hydrogen peroxide was added dropwise with stirring at a uniform rate over 1 hour. After the addition was complete, the mixture was kept at this temperature for 4 hours. After the reaction was finished, the catalyst was recovered by filtration. The yield was calculated based on dichloropropanol, and the yield was 76%.

[0034] Example 2

[0035] Add 10g of sodium hydroxide and 5g of sodium aluminate to 240g of deionized water, stir well, then slowly add 0.22g of zinc chloride, followed by slowly adding 150g of 30wt% silica sol. Stir for 4 hours, then perform hydrothermal crystallization, filter, and dry to obtain Zn-MOR molecular sieve.

[0036] 2g of phosphotungstic heteropoly acid was dissolved in water, and 1g of the Zn-MOR molecular sieve was added. The mixture was stirred for 8 h, stirred at 50℃, and then dried at 105℃ for 6 h to obtain the molecular sieve-supported phosphotungstic heteropoly acid catalyst.

[0037] 50 g of dichloropropanol was added to a four-necked flask, followed by 1.5 g of molecular sieve-supported phosphotungsten heteropolyacid catalyst. The mixture was stirred, and the reaction temperature was controlled at 45 °C using a constant temperature water bath. Once the temperature was reached, 40 g of 30% hydrogen peroxide was added dropwise with stirring at a uniform rate over 1 hour. After the addition was complete, the mixture was kept at this temperature for 4 hours. After the reaction was finished, the catalyst was recovered by filtration. The yield was calculated based on dichloropropanol, and the yield was 80%.

[0038] Example 3

[0039] Add 10g of sodium hydroxide and 5g of sodium aluminate to 240g of deionized water, stir well, then slowly add 0.22g of zinc chloride, followed by slowly adding 150g of 30wt% silica sol. Stir for 4 hours, then perform hydrothermal crystallization, filter, and dry to obtain Zn-MOR molecular sieve.

[0040] 2g of phosphotungstic heteropoly acid was dissolved in water, and 1g of the Zn-MOR molecular sieve was added. The mixture was stirred for 8 h, stirred at 50℃, and then dried at 105℃ for 6 h to obtain the molecular sieve-supported phosphotungstic heteropoly acid catalyst.

[0041] 50 g of dichloropropanol was added to a four-necked flask, followed by 2 g of molecular sieve-supported phosphotungsten heteropolyacid catalyst. The mixture was stirred, and the reaction temperature was controlled at 45 °C using a constant temperature water bath. Once the temperature was reached, 40 g of 30% hydrogen peroxide was added dropwise with stirring at a uniform rate over 1 hour. After the addition was complete, the mixture was kept at this temperature for 4 hours. After the reaction was finished, the catalyst was recovered by filtration. The yield was calculated based on dichloropropanol, and the yield was 69%.

[0042] Example 4

[0043] Add 10g of sodium hydroxide and 5g of sodium aluminate to 240g of deionized water, stir well, then slowly add 0.22g of zinc chloride, followed by slowly adding 150g of 30wt% silica sol. Stir for 4 hours, then perform hydrothermal crystallization, filter, and dry to obtain Zn-MOR molecular sieve.

[0044] 2g of phosphotungstic heteropoly acid was dissolved in water, and 1g of the Zn-MOR molecular sieve was added. The mixture was stirred for 8 h, stirred at 50℃, and then dried at 105℃ for 6 h to obtain the molecular sieve-supported phosphotungstic heteropoly acid catalyst.

[0045] 50 g of dichloropropanol was added to a four-necked flask, followed by 0.8 g of molecular sieve-supported phosphotungsten heteropolyacid catalyst. The mixture was stirred, and the reaction temperature was controlled at 45 °C using a constant temperature water bath. Once the temperature was reached, 40 g of 30% hydrogen peroxide was added dropwise with stirring at a uniform rate over 1 hour. After the addition was complete, the mixture was kept at this temperature for 4 hours. After the reaction was finished, the catalyst was recovered by filtration. The yield was calculated based on dichloropropanol, and the yield was 64%.

[0046] Comparative Example 1

[0047] 50g of dichloropropanol was added to a four-necked flask, followed by 1g of silica-supported phosphotungsten heteropolyacid catalyst (CN107954847A) and stirring. The reaction temperature was controlled at 45℃ using a constant-temperature water bath. After reaching the temperature, 40g of 30% hydrogen peroxide was added dropwise with stirring at a uniform rate over 1 hour. After the addition was complete, the mixture was kept at this temperature for 4 hours. The reaction was then completed, and the catalyst was recovered by filtration. The yield was calculated based on dichloropropanol, and the yield was 58%.

[0048] Comparative Example 2

[0049] 50g of dichloropropanol was added to a four-necked flask, followed by 1g of phosphotungsten heteropolyacid catalyst, and the mixture was stirred. The reaction temperature was controlled at 45℃ using a constant temperature water bath. After reaching the temperature, 40g of 30% hydrogen peroxide was added dropwise with stirring at a uniform rate over 1 hour. The mixture was then kept at this temperature for 4 hours. After the reaction was completed, the catalyst was recovered by filtration. The yield was calculated based on dichloropropanol, and the yield was 54%.

[0050] As can be seen from the examples and comparative examples, the molecular sieve-supported phosphotungsten heteropolyacid catalyst has a better catalytic effect on the reaction of dichloropropanol and hydrogen peroxide than the existing silica-supported phosphotungsten heteropolyacid catalyst and ordinary heteropolyacid catalyst. Moreover, the reaction system with the addition of the molecular sieve-supported phosphotungsten heteropolyacid catalyst has a high yield, and the catalyst can be reused, so it can be applied on a large scale in industrial production.

Claims

1. A catalytic synthesis method for famotidine intermediate 1,3-dichloroacetone, characterized in that, The catalytic synthesis method involves using a molecular sieve-supported phosphotungsten heteropolyacid catalyst as a catalyst in the reaction system of 1,3-dichloropropanol and hydrogen peroxide. In the molecular sieve-supported phosphotungsten heteropolyacid catalyst, the content of phosphotungsten heteropolyacid is 60-80% by weight. The molecular sieve is a Zn-MOR molecular sieve. The preparation method of the Zn-MOR molecular sieve is as follows: Step 1: Mix zinc salt, sodium aluminate, sodium hydroxide, silicon source, and water to obtain a gel; the effective components of the gel are calculated as zinc salt, SiO2, Al2O3, Na2O, and H2O; the mass ratio of zinc salt to SiO2 is 1:150-250; the mass ratio of SiO2 to sodium aluminate is 6-10:1; the mass ratio of sodium aluminate to sodium hydroxide is 1:1.5-3; and the mass ratio of sodium aluminate to H2O is 1:40-80. Step 2: The prepared gel is placed in a reaction vessel for hydrothermal crystallization; Step 3: Remove the block product obtained from the reactor, filter it, air dry it naturally, and then put it into an oven to dry it. The solid block obtained after drying is the prepared Zn-MOR molecular sieve. The catalytic synthesis method involves reacting a molecular sieve-supported phosphotungsten heteropolyacid catalyst, 1,3-dichloropropanol, and 30% hydrogen peroxide at a mass ratio of 0.1-0.15:5:4 at a constant temperature of 40-48℃ for 4-5 hours. After the reaction is complete, 1,3-dichloropropanone is obtained.

2. A catalytic synthesis method for famotidine intermediate 1,3-dichloroacetone as described in claim 1, characterized in that, The preparation method of the molecular sieve-supported phosphotungsten heteropolyacid catalyst is as follows: The phosphotungstic heteropoly acid was dissolved in water, added to the Zn-MOR molecular sieve, stirred for 6-16 hours, stirred at 50-55℃, and then dried at 100-120℃ for 4-8 hours to finally obtain the molecular sieve-supported phosphotungstic heteropoly acid catalyst.

3. A catalytic synthesis method for famotidine intermediate 1,3-dichloroacetone as described in claim 2, characterized in that, In step 1, the zinc salt is either zinc chloride or zinc nitrate. The silicon source is any one of silica sol, silica fume, or sodium silicate.

4. A catalytic synthesis method for famotidine intermediate 1,3-dichloroacetone as described in claim 1, characterized in that, In step 2, the hydrothermal crystallization temperature is controlled at 180-190℃; The hydrothermal crystallization time should be controlled within 3-5 days.

5. A catalytic synthesis method for famotidine intermediate 1,3-dichloroacetone as described in claim 1, characterized in that, In step 3, the natural air drying time is 16–20 h, and the drying temperature in the oven is 70–110 ℃ for 7–10 h.