CN103333166A - Method for catalyzed synthesis of vinpocetine by using solid acid and alkali - Google Patents

Abstract

The invention discloses a method for synthesizing vinpocetine by solid acid-base catalysis. The method comprises the following steps: Step 1, solid alkali hydrolysis: sending the vincamine ethanol solution into a solid alkali hydrolysis column to carry out hydrolysis reaction; 2. Molecular sieve dehydration: pass the hydrolyzed vincamine ethanol solution through the molecular sieve dehydration column for dehydration reaction; Step 3, solid acid dehydration esterification: the dehydrated feed liquid enters the solid acid dehydration esterification column for solid acid dehydration esterification , you can. The present invention adopts strong alkali instead of sodium hydroxide to catalyze the hydrolysis of vincamine, and solid strong acid replaces concentrated sulfuric acid for dehydration and esterification to obtain vinpocetine. The catalyst used in the method can be conveniently separated from the product, reducing production costs; in the production process of the inventive method It does not produce acid-base wastewater, has good environmental protection, and is more suitable for industrial production; it can be reused, effectively reducing production costs, and the solid acid-base used does not corrode the equipment, does not produce acid-base wastewater, and is green and environmentally friendly.

Description

Utilize the method for solid acid-base catalyzed synthesis of vinpocetine

technical field

The invention belongs to the technical field of chemical industry, and in particular relates to a method for synthesizing vinpocetine by solid acid-base catalysis.

Background technique

Vinpocetine is a cerebral vasodilator that can inhibit phosphodiesterase activity, selectively increase cerebral blood flow, increase cerebral oxygen consumption, and improve cerebral metabolism. It is mainly used clinically to improve sequelae of cerebral infarction, sequelae of cerebral hemorrhage, cerebral Various symptoms induced by arteriosclerosis, etc.

At present, Vinpocetine is mainly produced through a chemical semi-synthesis process using vincamine as a raw material. The production process mostly involves expensive catalysts such as 2-fluoro-1,3,5,trinitrobenzene and Ti(OEt), and the use of acetonitrile as a solvent is highly toxic and poor in environmental protection. It has been found that vincamine can be hydrolyzed by sodium hydroxide to obtain vincamine, and then vincamine is dehydrated and esterified with concentrated sulfuric acid to obtain vinpocetine with a total yield of 90%. However, the above-mentioned liquid acid-base catalyzed production process It needs to consume a lot of acid and alkali, produce a large amount of acid and alkali wastewater, and put a lot of pressure on environmental protection.

Contents of the invention

Aiming at the defects in the prior art, the object of the present invention is to provide a method for utilizing solid acid-base catalysis to synthesize Vinpocetine.

The present invention is achieved through the following technical solutions,

The present invention provides a kind of method utilizing solid acid-base catalysis to synthesize Vinpocetine, and described method comprises the steps:

Step 1, solid alkali hydrolysis: the vincamine ethanol solution is sent into the solid alkali hydrolysis column, and the hydrolysis reaction is carried out;

Step 2, molecular sieve dehydration: the hydrolyzed vincamine ethanol solution is passed through a molecular sieve dehydration column for dehydration reaction;

Step 3, solid acid dehydration esterification: the dehydrated feed liquid enters the solid acid dehydration esterification column for solid acid dehydration esterification.

Preferably, in step 1, the vincamine ethanol solution is sent to a solid alkali hydrolysis column at a flow rate of (0.1-10) times column volume/hour, and the column temperature is 60-180°C.

Preferably, in step 1, the solid base is one of monosodium aluminoxide and disodium aluminoxide or a mixture thereof, and the particle size of the solid base is 0.1-2 mm.

Preferably, in step 2, the vincamine ethanol solution passes through the molecular sieve dehydration column at a flow rate of (0.1-10) column volumes/hour, and the column temperature is 60-180°C.

Preferably, in step 2, the packing of the column is 3A molecular sieve.

Preferably, in step 3, the dehydrated feed liquid enters the solid acid dehydration esterification column at a rate of (0.1-10) times column volume/hour.

Preferably, in step 3, the packing of the column is a mixture of solid strong acid and 3A molecular sieve packing.

Preferably, in step 3, the volume percentage of 3A molecular sieve filler in the mixture is 1-10%, and the column temperature is 60-180°C.

Preferably, in step 3, the solid strong acid used is SO ₄ ^-2 /ZrO ₂ , SO ₄ ^2- /TiO ₂ -CeO ₂ , SO ₄ ^2- /TiO ₂ -Fe ₂ O ₃ ,

A mixture of one or more of SO ₄ ^2- /TiO ₂ -MoO ₃ , SO ₄ ^-2 /TiO ₂ -ZrO ₂ (STZ), MoO ₃ /TiO ₂ .

Preferably, in step 3, the particle size of the solid strong acid is 0.1-2mm.

Compared with the prior art, the present invention has the following beneficial effects:

(1) The present invention adopts strong alkali instead of sodium hydroxide to catalyze the hydrolysis of vincamine, and solid strong acid replaces concentrated sulfuric acid for dehydration and esterification to obtain vinpocetine. Compared with the original method, the catalyst used in this method can be easily separated from the product, which is convenient Recycling reduces production costs; the method of the invention does not produce acid-base wastewater during the production process, which is environmentally friendly and more suitable for industrial production; it can be reused and effectively reduces production costs, and the solid acid-base used does not corrode the equipment and does not produce Acid-alkali wastewater, green and environmental protection.

(2) The present invention uses 3A molecular sieve packing to remove the entrainment in the raw materials and the newly produced water in the reaction, so that the whole reaction is carried out in an anhydrous environment, which promotes the esterification and dehydration reactions, promotes the synthesis of vinpocetine, and improves the reaction efficiency. The conversion rate is as high as 90% or more.

Description of drawings

Other characteristics, objects and advantages of the present invention will become more apparent by reading the detailed description of non-limiting embodiments made with reference to the following drawings:

Fig. 1 is the synthesizing device synoptic diagram of Vinpocetine of the present invention;

Fig. 2 is a schematic diagram of the relationship between time and yield of vinpocetine of the present invention.

Detailed ways

The present invention will be described in detail below in conjunction with specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

Example 1

The present embodiment relates to a kind of method utilizing solid acid-base catalysis to synthesize Vinpocetine, and described method comprises the steps:

Step 1, solid alkali hydrolysis: vincamine and dehydrated alcohol are 1:10 to prepare vincamine ethanol solution by weight ratio, and described vincamine ethanol solution is sent into aluminoxomonosodium (particle size is 0.1mm) hydrolysis column for hydrolysis reaction, the column temperature is 60°C.

Step 2, molecular sieve dehydration: pass the hydrolyzed vincamine ethanol solution through a 3A molecular sieve dehydration column at a flow rate of 30 ml/hour to perform a dehydration reaction, and the column temperature is 60°C.

Step 3, dehydration and esterification of solid acid: the feed liquid after dehydration enters the solid acid SO ₄ ^2- /TiO ₂ -Fe ₂ O with a volume percentage of 1% 3A molecular sieve filler and a particle size of 0.1 mm at a rate of 30 ml/hour ₃ Fill the solid acid dehydration esterification column with solid acid dehydration esterification, and the column temperature is 60°C.

The above-mentioned three packing columns all have a volume of 300 ml and an aspect ratio of 10. Preheating of raw materials and jacket temperature control are adopted to stabilize the column temperature at 60°C in combination. The raw material vincamine ethanol solution is pumped into the packed column reaction system at a rate of 30 ml/hour, and passes through the solid alkali hydrolysis column and molecular sieve dehydration column in turn. and a solid acid dehydration esterification column to carry out hydrolysis, dehydration and re-esterification reactions to form the product Vinpocetine. The product feed liquid was collected at the outlet of the solid acid dehydration esterification column, and the content of vinpocetine was detected by HPLC method. See Figure 1 for a schematic diagram of a vinpocetine synthesis device.

Implementation effect: the reaction yield of vinpocetine is 96%.

Example 2

The present embodiment relates to a kind of method utilizing solid acid-base catalysis to synthesize Vinpocetine, and described method comprises the steps:

Step 1, solid alkali hydrolysis: vincamine and dehydrated alcohol are 1:20 to prepare vincamine ethanol solution by weight ratio, and described vincamine ethanol solution is sent into aluminoxomonosodium (particle diameter is 2mm) hydrolysis column for hydrolysis reaction; column temperature is 180°C;

Step 2, molecular sieve dehydration: the hydrolyzed vincamine ethanol solution is passed through a 3A molecular sieve dehydration column at a flow rate of 3 liters/hour, and the column temperature is 180°C.

Step 3, dehydration and esterification of solid acid: the feed liquid after dehydration enters at a speed of 3 liters/hour and is filled with solid acid with a volume percentage of 10% 3A molecular sieve filler and a particle size of 2 mm solid acid SO ₄ ^-2 /ZrO ₂ The dehydration esterification column is used for dehydration esterification of solid acid, and the column temperature is 180°C.

The above-mentioned three packing columns all have a volume of 300 ml and an aspect ratio of 10. Using raw material preheating and jacket temperature control methods to stabilize the column temperature at 180°C, the raw material vincamine ethanol solution is pumped into the packed column reaction system at a rate of 3 liters/hour, and passes through the solid alkali hydrolysis column and molecular sieve dehydration column in turn. and a solid acid dehydration esterification column to carry out hydrolysis, dehydration and re-esterification reactions to form the product Vinpocetine. The product feed liquid was collected at the outlet of the solid acid dehydration esterification column, and the content of vinpocetine was detected by HPLC method. See Figure 1 for a schematic diagram of a vinpocetine synthesis device.

Implementation effect: the reaction yield of vinpocetine is 91%.

Example 3

The present embodiment relates to a kind of method utilizing solid acid-base catalysis to synthesize Vinpocetine, and described method comprises the steps:

Step 1, solid alkali hydrolysis: vincamine and absolute ethanol are prepared vincamine ethanol solution at a weight ratio of 1:20, and the vincamine ethanol solution is fed into monosodium aluminoxide and dialuminoxine at a flow rate of 2 liters/hour. The mixture of sodium (particle size is 1mm) is hydrolyzed on the column, and the hydrolysis reaction is carried out, and the column temperature is 100°C.

Step 2, molecular sieve dehydration: the hydrolyzed vincamine ethanol solution is passed through a 3A molecular sieve dehydration column at a flow rate of 2 liters/hour, and the column temperature is 100°C.

Step 3, dehydration and esterification of solid acid: the dehydrated feed liquid enters at a speed of 2 liters/hour and is filled with 20% 3A molecular sieve packing and a particle size of 1 mm solid acid SO4 ^-2 /ZrO ₂ packing for solid acid dehydration The esterification column is used for dehydration and esterification of solid acid, and the column temperature is 100°C.

The above-mentioned three packing columns all have a volume of 300 ml and an aspect ratio of 10. Pre-heating of raw materials and jacket temperature control are used to stabilize the column temperature at 100°C. The raw material vincamine ethanol solution is pumped into the packed column reaction system at a rate of 2 liters/hour, and then passes through the solid alkali hydrolysis column and molecular sieve dehydration column in turn. and a solid acid dehydration esterification column to carry out hydrolysis, dehydration and re-esterification reactions to form the product Vinpocetine. The product feed liquid was collected at the outlet of the solid acid dehydration esterification column, and the content of vinpocetine was detected by HPLC method. See Figure 1 for a schematic diagram of a vinpocetine synthesis device.

Implementation effect: the reaction yield of vinpocetine is 90%.

Example 4

Construct reaction system according to the same parameter of example 1, take samples at different times of operation, calculate the reaction yield of vinpocetine, investigate the deactivation situation of solid superacid-base catalyst. It was found that according to the production process, the yield of Vinpocetine began to decline slightly after 15 days of continuous production, and dropped to about 80% after 40 days. Therefore, the filler used in the reaction needs to be activated and regenerated in a cycle of 20 days to maintain a reaction yield of more than 90%. See Figure 2.

Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art may make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims (10)

1. a method utilizing solid acid-base catalysis to synthesize Vinpocetine, is characterized in that, described method comprises the steps: Step 1, solid alkali hydrolysis: the vincamine ethanol solution is sent into the solid alkali hydrolysis column, and the hydrolysis reaction is carried out; Step 2, molecular sieve dehydration: the hydrolyzed vincamine ethanol solution is passed through a molecular sieve dehydration column for dehydration reaction; Step 3, solid acid dehydration esterification: the dehydrated feed liquid enters the solid acid dehydration esterification column for solid acid dehydration esterification. 2. The method for synthesizing vinpocetine by solid acid-base catalysis as claimed in claim 1, characterized in that, in step 1, the ethanol solution of vincamine is fed into at a flow rate of (0.1 to 10) times column volume/hour Solid base hydrolysis column, the column temperature is 60-180°C. 3. the method utilizing solid acid-base catalysis to synthesize Vinpocetine as claimed in claim 1, is characterized in that, in step 1, described solid base is a kind of in monosodium aluminoxide, disodium aluminoxide or its mixture , the particle size of the solid base is 0.1-2 mm. 4. The method for synthesizing vinpocetine by solid acid-base catalysis as claimed in claim 1, characterized in that, in step 2, the ethanol solution of vincamine passes through molecular sieves at a flow rate of (0.1 to 10) times column volume/hour Dehydration column, the column temperature is 60-180°C. 5. the method utilizing solid acid-base catalyzed synthesis of vinpocetine as claimed in claim 1, is characterized in that, in step 2, the filler of described column is 3A molecular sieve. 6. The method for synthesizing vinpocetine by solid acid-base catalysis as claimed in claim 1, characterized in that in step 3, the dehydrated feed liquid enters at a rate of (0.1-10) times column volume/hour Solid acid dehydration esterification column. 7. the method utilizing solid acid-base catalysis to synthesize Vinpocetine as claimed in claim 1, is characterized in that, in step 3, the filler of described column is the mixture of solid strong acid and 3A molecular sieve filler. 8. the method utilizing solid acid-base catalysis to synthesize Vinpocetine as claimed in claim 7, it is characterized in that, in step 3, the volume percent of 3A molecular sieve filler is 1～10% in the described mixture, and described column temperature is 60～180℃. 9. The method for synthesizing vinpocetine by solid acid-base catalysis as claimed in claim 7, characterized in that, in step 3, the solid strong acid used is SO ₄ ^-2 /ZrO ₂ , SO ₄ ^2- /TiO ₂ One or more of -CeO ₂ , SO ₄ ^2- /TiO ₂ -Fe ₂ O ₃ , SO ₄ ^2- /TiO ₂ -MoO ₃ , SO ₄ ^-2 /TiO ₂ -ZrO ₂ , MoO ₃ /TiO ₂ mixture of species. 10. The method for synthesizing vinpocetine by solid acid-base catalysis as claimed in claim 9, characterized in that, in step 3, the particle diameter of the solid strong acid is 0.1-2mm.

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