CN113061135A - Method for continuously synthesizing xanthinol nicotinate by micro-channel - Google Patents
Method for continuously synthesizing xanthinol nicotinate by micro-channel Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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Abstract
The invention relates to a method for continuously synthesizing xanthinol nicotinate by a microchannel, which comprises the steps of introducing 2-methylamino ethanol and epichlorohydrin into a first reaction module of a microchannel reactor to perform addition reaction; the addition reaction liquid enters a second reaction module, and simultaneously, an ethanol solution of theophylline sodium salt is added into the second module for condensation reaction; the condensation reaction feed liquid is subjected to solid-liquid separation, the feed liquid is collected, nicotinic acid is added into a salification kettle to react to generate xanthinol nicotinate, and a crude xanthinol nicotinate product is obtained after cooling, crystallization and separation.
Description
Technical Field
The invention relates to the technical field of organic synthesis of chemical raw material medicines, in particular to a method for continuously synthesizing xanthinol nicotinate by a micro-channel.
Background
Xanthinol nicotinate, chemical name: 7- [ 2-hydroxy-3- [ (2-hydroxyethyl) methylamino ] -propyl ] theophylline nicotinate is a vasodilator, and is used for treating ischemic cerebrovascular diseases, cerebral injury diseases such as apoplexy sequelae, cerebral trauma and cerebral operation sequelae, as well as thromboangiitis obliterans, phlebitis and the like.
At present, the main industrial production route of xanthinol nicotinate is that epichlorohydrin reacts with methylamine ethanol to generate chloramine propanol, and the chloramine propanol is condensed with theophylline and then salified with nicotinic acid. The production mode of the production route is intermittent reaction, the problems of multiple equipment, long reaction period, high labor intensity, large control fluctuation of process parameters, low yield and the like exist, the intermediate product chloramine propanol is unstable in property and cannot be placed for a long time, the intermediate product chloramine propanol needs to be prepared at present, inconvenience is caused to production, in addition, the addition reaction is violent in heat release, the temperature is not easy to control, the reaction effect is not influenced, and safety risk exists.
Disclosure of Invention
Aiming at the problems of long reaction period, unstable process parameter control, low product yield and the like at present, the invention provides a method for continuously synthesizing xanthinol nicotinate by a micro-channel, which has the advantages of short reaction time, high efficiency, stable temperature control and high product yield.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a method for continuously synthesizing xanthinol nicotinate by a micro-channel specifically comprises the following steps:
1) introducing 2-methylaminoethanol and epoxy chloropropane into a first reaction module of the microchannel reactor to perform an addition reaction, controlling the temperature of the addition reaction to be 15-50 ℃ and the retention time of a feed liquid to be 5-150 s;
2) introducing the feed liquid of the addition reaction and the ethanol solution of the theophylline sodium salt into a second reaction module for condensation reaction, controlling the temperature of the condensation reaction to be 50-90 ℃ and the retention time of the feed liquid to be 10-80 s;
3) introducing the feed liquid of the condensation reaction into a cooling module for cooling, controlling the discharging temperature of the feed liquid to be 20-50 ℃, and controlling the retention time of the feed liquid to be 15-100 s;
4) carrying out solid-liquid separation on the cooled feed liquid;
5) adding nicotinic acid into the feed liquid after solid-liquid separation for reaction, and cooling and centrifuging to obtain a xanthinol nicotinate crude product;
compared with the prior art, the method for continuously synthesizing xanthinol nicotinate by the micro-channel provided by the invention has the following advantages:
(1) the invention adopts a microchannel reaction technology with a first reaction module and a second reaction module connected in series to replace a kettle type intermittent reaction in the addition and condensation reaction process, and realizes the continuity of the reaction process by controlling the reaction temperature and time of each step, so that the reaction time is shortened from several hours to several minutes, the production efficiency is greatly improved, other side reactions caused by overlong reaction time are avoided, under the continuous reaction of addition and condensation, the addition product is obtained to obtain the 1-chloro-3- [ (2-hydroxyethyl) methylamino ] -2-propanol, the addition product is ready to use, and the risk of decomposition and deterioration caused by long standing time is avoided.
(2) The microchannel reactor used in the invention has extremely large specific surface area, so that the microchannel reactor has good heat exchange performance, a large amount of heat released in the addition reaction process can be rapidly led out, the reaction temperature can be well controlled without solvent, the phenomenon of local overheating is avoided, the process safety is improved, the use of solvent in the process is reduced, the generation of impurities is reduced, the product conversion rate and the product quality are improved, and the method is suitable for the requirements of industrial production.
(3) The condensation reaction is a nucleophilic substitution reaction and can be carried out only by converting theophylline into theophylline sodium salt, and the invention directly uses the theophylline sodium salt for synthesizing the xanthinol nicotinate, thereby greatly reducing the cost of raw materials.
Preferably, the molar flow rate ratio of the feed materials of the 2-methylamino ethanol, the epichlorohydrin and the theophylline sodium salt is 1.0-1.1: 1.05-1.2: 1, more preferably 1.03 to 1.07: 1.07-1.10: 1.
preferably, in the step 1), the temperature of the addition reaction is controlled to be 20-40 ℃, and the retention time of the feed liquid is 20-80 s.
Preferably, in the step 2), the condensation reaction temperature is controlled to be 65-80 ℃, and the retention time of the feed liquid is 15-60 s.
Preferably, in the step 3), the discharging temperature of the material liquid of the cooling module is controlled to be 30-40 ℃, and the retention time of the material liquid is controlled to be 30-80 s.
By accurately controlling the feeding flow rate and the material liquid retention time of the 2-methylamino ethanol, the epichlorohydrin and the theophylline sodium salt, the reaction time is greatly reduced, and the reaction efficiency is effectively improved.
Preferably, in the step 4), the solid-liquid separation is to remove solids by centrifugation with a continuous discharge centrifuge.
The solid-liquid separation adopts the continuous discharging centrifugal machine, so that the continuity of the desalting process is realized, and the operation is fast and efficient.
Preferably, in the step 2), the mass ratio of the theophylline sodium salt to the ethanol is 1: 5-8, and preferably the mass ratio of the theophylline sodium salt to the ethanol is 1: 6 to 7.
Preferably, in the step 2), the pH value of the ethanol solution of theophylline sodium salt is 7.5-11.5, more preferably 8.0-10, and the alkali for adjusting the pH value is at least one of sodium hydroxide, sodium carbonate and sodium bicarbonate.
Preferably, the molar amount of the nicotinic acid in the step 5) is 0.93 to 1.2 times, and more preferably 0.95 to 1.0 times that of the theophylline sodium salt in the step 2).
Preferably, in the step 5), the reaction temperature is 50-80 ℃ and the reaction time is 0.5-5 hours, more preferably, the reaction temperature is 60-75 ℃ and the reaction time is 1-3 hours.
The optimal reaction temperature can meet the heat required by dissolution of nicotinic acid, and when the temperature is too high, the precipitation speed of xanthinol nicotinate is too high, so that unreacted nicotinic acid is easily wrapped, the incomplete reaction is caused, and the product quality is reduced.
Preferably, in the step 5), the temperature is reduced to 5-25 ℃, and more preferably, the temperature is 15-20 ℃.
Preferably, the method for continuously synthesizing the xanthinol nicotinate by the micro-channel further comprises the step of refining the crude xanthinol nicotinate, and the refining method comprises the following steps: and adding ethanol into the xanthinol nicotinate crude product, heating for dissolving, decoloring and refining by using a carbon fiber filter, cooling and crystallizing a decolored solution, and carrying out solid-liquid separation to obtain the xanthinol nicotinate product.
The carbon fiber continuous decoloring technology is adopted to replace the traditional activated carbon decoloring technology, the carbon fibers can be regenerated and reused, the generation of waste carbon is avoided, the operation environment is improved, the regeneration and replacement of the carbon fiber filter element can be carried out on line, the operation is simple and convenient, the labor intensity is reduced, the whole process is in linkage control, and the production efficiency is high.
Preferably, the mass ratio of the xanthinol nicotinate crude product to the ethanol is 1: 7-12, and preferably the mass ratio is 1: 8 to 10.
Preferably, the temperature of the decolorization is 50-80 ℃, and more preferably, the temperature of the decolorization is 65-70 ℃.
Preferably, the reflux ratio of the decolorized circulating liquid to the produced liquid is 2-6, and more preferably 3-4.
Preferably, the ratio of the flow speed of the inlet and outlet materials of the decolorizing liquid to the filtering area of the carbon fiber filter is 20-40: 1L/min m2More preferably 25 to 30: 1L/min m2。
By setting the flow rate and reflux ratio of the decolouring liquid, the detention time of the liquid in the filter is regulated and controlled, the expected decolouring effect is achieved, and the continuous decolouring process is realized.
Preferably, the temperature reduction crystallization is carried out to reduce the temperature to-5-25 ℃, and more preferably to reduce the temperature to 5-15 ℃.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1:
a method for continuously synthesizing xanthinol nicotinate by a micro-channel specifically comprises the following steps:
and starting a temperature control system of the microchannel reactor, and controlling the temperature of the first reaction module to be 20 ℃, the temperature of the second reaction module to be 90 ℃ and the temperature of the cooling module to be 40 ℃. Starting a metering pump of the 2-methylamino ethanol and the epichlorohydrin, controlling the flow rate of the 2-methylamino ethanol to be 0.60mol/min, controlling the flow rate of the epichlorohydrin to be 0.64mol/min, carrying out addition reaction on the materials in the first reaction module, and keeping the retention time of the material liquid to be 80 s. And starting an ethanol solution metering pump of theophylline sodium salt when the addition reaction is finished, and introducing an ethanol solution of theophylline sodium salt into the second reaction module for condensation reaction, wherein the mass ratio of the theophylline sodium salt to the ethanol is 1: and 7, adjusting the pH value to 8.0 by using sodium bicarbonate, controlling the feeding flow rate to be 0.60mol/min, and keeping the material in the second reaction module for 80 s. Then the material liquid enters a cooling module for cooling, the discharging temperature of the material liquid is controlled to be 25 ℃, and the material liquid stays in the cooling module for 30 s.
When the feed liquid flows out of the discharge hole of the microchannel reactor, a continuous discharge centrifuge is started to remove inorganic salt by centrifugation, and the centrifugal filtrate is collected to a condensation feed liquid dumping tank for later use.
Adding 30L of desalted condensation feed liquid into a 50L glass reaction kettle, wherein the feeding amount is 4071.4g of theophylline sodium salt, stirring and heating to 70 ℃, adding 2357.3g of nicotinic acid, and carrying out heat preservation reaction for 0.5 hour to generate xanthinol nicotinate.
Cooling to 15 ℃, discharging, centrifuging and drying to obtain 8601.8g of wet weight of the xanthinol nicotinate crude product, drying to obtain 8028.0g of dry weight, and bagging and temporarily storing for later use.
Adding 4000g of dried xanthinol nicotinate crude product and 40L of ethanol into a 50L dissolving kettle A, heating to 65 ℃, starting a dissolving kettle material transferring metering pump, and controlling the flow rate to be 20L/min m2The feeding is carried out to the decoloration circulation jar in, opens carbon fiber filter's material transfer pump and carries out full return circulation decoloration, opens decoloration liquid extraction valve after 30 minutes, adjusts the frequency conversion of decoloration pump, and the control reflux ratio is 3, and decoloration liquid business turn over material velocity of flow is 25 for carbon fiber filter's filter area ratio: 1L/min m2And continuously and stably extracting the decolored liquid, and after the material liquid in the dissolving kettle A is discharged, switching to a dissolving kettle B which is prepared with the material liquid in the same proportion in advance to discharge the material liquid, so as to alternately realize the continuity of the decolored process.
And (4) feeding the decolorized filtrate into a 50L crystallization kettle, cooling the feed liquid to 25 ℃, discharging the material, and centrifuging and spin-drying the material. Drying the filter cake to obtain 3787.2g of xanthinol nicotinate, wherein the refining yield based on the crude product is 94.68%, the comprehensive yield based on theophylline sodium salt is 86.80%, and the content of liquid chromatography is 99.94%.
Example 2:
a method for continuously synthesizing xanthinol nicotinate by a micro-channel specifically comprises the following steps:
and starting a temperature control system of the microchannel reactor, and controlling the temperature of the first reaction module to be 50 ℃, the temperature of the second reaction module to be 50 ℃ and the temperature of the cooling module to be 30 ℃. Starting a metering pump of the 2-methylamino ethanol and the epichlorohydrin, controlling the flow rate of the 2-methylamino ethanol to be 0.62mol/min, controlling the flow rate of the epichlorohydrin to be 0.66mol/min, carrying out addition reaction on the materials in the first reaction module, and keeping the retention time of the feed liquid to be 150 s. And starting an ethanol solution metering pump of theophylline sodium salt when the addition reaction is finished, and introducing an ethanol solution of theophylline sodium salt into the second reaction module for condensation reaction, wherein the mass ratio of the theophylline sodium salt to the ethanol is 1: and 8, adjusting the pH value to 11.5 by using sodium carbonate, controlling the feeding flow rate to be 0.60mol/min, and keeping the material in the second reaction module for 80 s. Then the material liquid enters a cooling module for cooling, the discharging temperature of the material liquid is controlled to be 30 ℃, and the material liquid stays in the cooling module for 15 s.
When the feed liquid flows out of the discharge hole of the microchannel reactor, a continuous discharge centrifuge is started to remove inorganic salt by centrifugation, and the centrifugal filtrate is collected to a condensation feed liquid dumping tank for later use.
Adding 30L of desalted condensation feed liquid into a 50L glass reaction kettle, wherein the feeding amount is 3562.5g of theophylline sodium salt, stirring and heating to 50 ℃, adding 2019.2g of nicotinic acid, and carrying out heat preservation reaction for 3 hours to generate xanthinol nicotinate.
Cooling to 5 ℃, discharging, centrifuging and drying to obtain 7569.6g of wet weight of the xanthinol nicotinate crude product, drying to 7031.4g, bagging and temporarily storing for later use.
Adding 4000g of dried xanthinol nicotinate crude product and 40L of ethanol into a 50L dissolving kettle A, heating to 75 ℃, starting a dissolving kettle material transferring metering pump, and controlling the flow rate to be 25L/min m2Feeding the material into a decoloring circulating tank, starting a material transferring pump of a carbon fiber filter to perform full-reflux circulating decoloring, starting a decoloring liquid extraction valve after 30 minutes, and adjusting the change of a decoloring pumpFrequently, the control reflux ratio is 6, and the filtering area ratio of the decolouring liquid inlet and outlet flow velocity relative to the carbon fiber filter is 30: 1L/min m2And continuously and stably extracting the decolored liquid, and after the material liquid in the dissolving kettle A is discharged, switching to a dissolving kettle B which is prepared with the material liquid in the same proportion in advance to discharge the material liquid, so as to alternately realize the continuity of the decolored process.
And (4) feeding the decolorized filtrate into a 50L crystallization kettle, cooling the feed liquid to 5 ℃, discharging the material, and centrifuging and spin-drying the material. Drying the filter cake to obtain 3749.6g of xanthinol nicotinate, wherein the refining yield based on the crude product is 93.74%, the comprehensive yield based on theophylline sodium salt is 86.03%, and the content of liquid chromatography is 99.95%.
Example 3:
a method for continuously synthesizing xanthinol nicotinate by a micro-channel specifically comprises the following steps:
and starting a temperature control system of the microchannel reactor, and controlling the temperature of the first reaction module to be 15 ℃, the temperature of the second reaction module to be 65 ℃ and the temperature of the cooling module to be 20 ℃. Starting a metering pump of the 2-methylamino ethanol and the epichlorohydrin, controlling the flow rate of the 2-methylamino ethanol to be 0.65mol/min, controlling the flow rate of the epichlorohydrin to be 0.68mol/min, carrying out addition reaction on the materials in the first reaction module, and keeping the retention time of the material liquid to be 20 s. And starting an ethanol solution metering pump of theophylline sodium salt when the addition reaction is finished, and introducing an ethanol solution of theophylline sodium salt into the second reaction module for condensation reaction, wherein the mass ratio of the theophylline sodium salt to the ethanol is 1: and 5, adjusting the pH value to 10 by using sodium bicarbonate, controlling the feeding flow rate to be 0.60mol/min, and keeping the material in the second reaction module for 10 s. Then the material liquid enters a cooling module for cooling, the discharging temperature of the material liquid is controlled to be 35 ℃, and the material liquid stays in the cooling module for 100 s.
When the feed liquid flows out of the discharge hole of the microchannel reactor, a continuous discharge centrifuge is started to remove inorganic salt by centrifugation, and the centrifugal filtrate is collected to a condensation feed liquid dumping tank for later use.
Adding 30L of desalted condensation feed liquid into a 50L glass reaction kettle, wherein the feeding amount is 2850.0g of theophylline sodium salt, stirring and heating to 70 ℃, adding 2084.3g of nicotinic acid, and carrying out heat preservation reaction for 5 hours to obtain xanthinol nicotinate.
Cooling to 20 ℃, discharging, centrifuging and drying to obtain 5999.8g of wet weight of the xanthinol nicotinate crude product, drying 5666.8g, bagging and temporarily storing for later use.
Adding 4000g of dried xanthinol nicotinate crude product and 40L of ethanol into a 50L dissolving kettle A, heating to 80 ℃, starting a dissolving kettle material transferring metering pump, and controlling the flow rate to be 40L/min m2The feeding is carried out to the decoloration circulation jar in, opens carbon fiber filter's material transfer pump and carries out full return circulation decoloration, opens decoloration liquid extraction valve after 30 minutes, adjusts the frequency conversion of decoloration pump, and the control reflux ratio is 2, and decoloration liquid business turn over material velocity of flow is 35 for carbon fiber filter's filter area ratio: 1L/min m2And continuously and stably extracting the decolored liquid, and after the material liquid in the dissolving kettle A is discharged, switching to a dissolving kettle B which is prepared with the material liquid in the same proportion in advance to discharge the material liquid, so as to alternately realize the continuity of the decolored process.
The decolorized filtrate enters a 50L crystallization kettle, and the feed liquid is cooled to-5 ℃ and discharged for centrifugal drying. Drying the filter cake to obtain 3724.8g of xanthinol nicotinate, wherein the refining yield based on the crude product is 93.12%, the comprehensive yield based on theophylline sodium salt is 86.09%, and the content of liquid chromatography is 99.96%.
Example 4:
a method for continuously synthesizing xanthinol nicotinate by a micro-channel specifically comprises the following steps:
and starting a temperature control system of the microchannel reactor, and controlling the temperature of the first reaction module to be 40 ℃, the temperature of the second reaction module to be 80 ℃ and the temperature of the cooling module to be 50 ℃. Starting a metering pump of the 2-methylamino ethanol and the epichlorohydrin, controlling the flow rate of the 2-methylamino ethanol to be 0.62mol/min, controlling the flow rate of the epichlorohydrin to be 0.64mol/min, carrying out addition reaction on the materials in the first reaction module, and keeping the retention time of the material liquid to be 5 s. And starting an ethanol solution metering pump of theophylline sodium salt when the addition reaction is finished, and introducing an ethanol solution of theophylline sodium salt into the second reaction module for condensation reaction, wherein the mass ratio of the theophylline sodium salt to the ethanol is 1: and 6, adjusting the pH value to 7.5 by using sodium hydroxide, controlling the feeding flow rate to be 0.60mol/min, and keeping the material in the second reaction module for 15 s. Then the material liquid enters a cooling module for cooling, the discharging temperature of the material liquid is controlled to be 40 ℃, and the material liquid stays in the cooling module for 80 s.
When the feed liquid flows out of the discharge hole of the microchannel reactor, a continuous discharge centrifuge is started to remove inorganic salt by centrifugation, and the centrifugal filtrate is collected to a condensation feed liquid dumping tank for later use.
Adding 30L of desalted condensation feed liquid into a 50L glass reaction kettle, wherein the feeding amount is 4750.0g in terms of theophylline sodium salt, starting stirring, heating to 80 ℃, adding 2894.9g of nicotinic acid, and carrying out heat preservation reaction for 1 hour to obtain xanthinol nicotinate.
Cooling to 25 ℃, discharging, centrifuging and drying to obtain 9980.9g of wet weight of the xanthinol nicotinate crude product, drying to 9323.1g, bagging and temporarily storing for later use.
Adding 4000g of dried xanthinol nicotinate crude product and 40L of ethanol into a 50L dissolving kettle A, heating to 50 ℃, starting a dissolving kettle material transferring metering pump, and controlling the flow rate to be 30L/min m2The feeding is carried out to the decoloration circulation jar in, opens carbon fiber filter's material transfer pump and carries out full return circulation decoloration, opens decoloration liquid extraction valve after 30 minutes, adjusts the frequency conversion of decoloration pump, and the control reflux ratio is 4, and decoloration liquid business turn over material velocity of flow is 30 for carbon fiber filter's filter area ratio: 1L/min m2And continuously and stably extracting the decolored liquid, and after the material liquid in the dissolving kettle A is discharged, switching to a dissolving kettle B which is prepared with the material liquid in the same proportion in advance to discharge the material liquid, so as to alternately realize the continuity of the decolored process.
And (4) feeding the decolorized filtrate into a 50L crystallization kettle, cooling the feed liquid to 15 ℃, discharging the material, and centrifuging and spin-drying the material. The filter cake is dried to obtain 3758.8g of xanthinol nicotinate, the refining yield based on the crude product is 93.97%, the comprehensive yield based on the theophylline sodium salt is 85.76%, and the content of liquid chromatography is 99.94%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A method for continuously synthesizing xanthinol nicotinate by a micro-channel is characterized by comprising the following steps:
1) introducing 2-methylaminoethanol and epoxy chloropropane into a first reaction module of the microchannel reactor to perform an addition reaction, controlling the temperature of the addition reaction to be 15-50 ℃ and the retention time of a feed liquid to be 5-150 s;
2) introducing the feed liquid of the addition reaction and the ethanol solution of the theophylline sodium salt into a second reaction module for condensation reaction, controlling the temperature of the condensation reaction to be 50-90 ℃ and the retention time of the feed liquid to be 10-80 s;
3) introducing the feed liquid of the condensation reaction into a cooling module for cooling, controlling the discharging temperature of the feed liquid to be 20-50 ℃, and controlling the retention time of the feed liquid to be 15-100 s;
4) carrying out solid-liquid separation on the cooled feed liquid;
5) and adding nicotinic acid into the feed liquid after solid-liquid separation for reaction, and cooling and centrifuging to obtain a xanthinol nicotinate crude product.
2. The microchannel continuous synthesis method of xanthinol nicotinate according to claim 1, wherein the feed of 2-methylaminoethanol, epichlorohydrin and theophylline sodium salt has a molar flow ratio of 1.0 to 1.1: 1.05-1.2: 1.
3. the method for continuously synthesizing xanthinol nicotinate by the micro-channel according to claim 1, wherein in the step 1), the temperature of the addition reaction is controlled to be 20-40 ℃, and the retention time of the feed liquid is 20-80 s; and/or
In the step 2), the condensation reaction temperature is controlled to be 65-80 ℃, and the retention time of the feed liquid is 15-60 s;
and/or
In the step 3), the discharging temperature of the material liquid of the cooling module is controlled to be 30-40 ℃, and the retention time of the material liquid is controlled to be 30-80 s; and/or
In the step 4), the solid-liquid separation is to remove solids by adopting a continuous discharge centrifuge.
4. The method for continuously synthesizing xanthinol nicotinate by the micro-channel as claimed in claim 1, wherein in the step 2), the mass ratio of theophylline sodium salt to ethanol is 1: 5-8; and/or
The pH value of the theophylline sodium salt ethanol solution is 7.5-11.5, and the alkali for adjusting the pH value is at least one of sodium hydroxide, sodium carbonate and sodium bicarbonate.
5. The method for continuously synthesizing xanthinol nicotinate by the micro-channel according to claim 1, wherein the molar amount of the nicotinic acid in the step 5) is 0.93-1.2 times that of the theophylline sodium salt in the step 2); and/or
In the step 5), the reaction temperature is 50-80 ℃ and the reaction time is 0.5-5 hours.
6. The method for continuously synthesizing xanthinol nicotinate by the micro-channel according to claim 1, wherein in the step 5), the temperature is reduced to 5-25 ℃.
7. The method for continuously synthesizing xanthinol nicotinate by the micro-channel according to any one of claims 1 to 6, wherein the method for continuously synthesizing xanthinol nicotinate by the micro-channel further comprises the step of refining the crude xanthinol nicotinate, and the refining method comprises the following steps: and adding ethanol into the xanthinol nicotinate crude product, heating for dissolving, decoloring and refining by using a carbon fiber filter, cooling and crystallizing a decolored solution, and carrying out solid-liquid separation to obtain the xanthinol nicotinate product.
8. The method for continuously synthesizing xanthinol nicotinate by the micro-channel according to claim 7, wherein the mass ratio of the crude xanthinol nicotinate to ethanol is 1: 7-12; and/or
The temperature of the decolorization is 50-80 ℃.
9. The method for continuously synthesizing xanthinol nicotinate by the micro-channel according to claim 7, wherein the reflux ratio of the decolorized circulating fluid to the produced fluid is 2-6; and/or
The ratio of the flow speed of the feeding and discharging of the decolored liquid to the filtering area of the carbon fiber filter is 20-40: 1L/min m2。
10. The method for continuously synthesizing xanthinol nicotinate by the micro-channel according to claim 7, wherein the temperature-reducing crystallization is carried out at a temperature of-5 to 25 ℃.
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| DD122093A1 (en) * | 1975-04-23 | 1976-09-12 | ||
| CN102134241A (en) * | 2011-01-20 | 2011-07-27 | 山东科源制药有限公司 | Synthesis method of xanthinol nicotinate |
| CN108484579A (en) * | 2018-03-28 | 2018-09-04 | 黑龙江鑫创生物科技开发有限公司 | A kind of micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand |
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