CN109734702B - Method for preparing rupatadine fumarate by adopting micro-channel reaction device - Google Patents
Method for preparing rupatadine fumarate by adopting micro-channel reaction device Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 108
- JYBLCDXVHQWMSU-WLHGVMLRSA-N (e)-but-2-enedioic acid;8-chloro-11-[1-[(5-methylpyridin-3-yl)methyl]piperidin-4-ylidene]-5,6-dihydrobenzo[1,2]cyclohepta[2,4-b]pyridine Chemical compound OC(=O)\C=C\C(O)=O.CC1=CN=CC(CN2CCC(CC2)=C2C3=NC=CC=C3CCC3=CC(Cl)=CC=C32)=C1 JYBLCDXVHQWMSU-WLHGVMLRSA-N 0.000 title claims abstract description 22
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Abstract
The invention discloses a method for preparing rupatadine fumarate by using a microchannel reaction device, which optimizes the process on the known path for synthesizing rupatadine fumarate, utilizes the microchannel reaction device, has the advantages of greatly shortened reaction time, high flux, stable product quality, strong continuity, easy operation, high safety and easy separation, is favorable for continuous amplification production, can effectively overcome the defects of the traditional synthesis path, and remarkably improves the yield by 90 percent. The desloratadine prepared in the production process is continuously separated and subjected to liquid separation, and the solution is directly put into the next reaction to obtain the rupatadine, so that the yield is not reduced, and the operation is simplified.
Description
Technical Field
The invention relates to a method for preparing rupatadine fumarate, in particular to a method for preparing rupatadine fumarate by adopting a microchannel reaction device, and belongs to the field of pharmaceutical chemistry.
Background
Rupatadine Fumarate (Rupatadine Fumarate), chemical name 8-chloro-11- [1- [ (5-methyl-3-pyridyl) methyl ] -4-piperidinylidene ] -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridine Fumarate. It was successfully developed by Uriach pharmaceutical, Spain, and first marketed in Spain in 2003. It is a new generation of tricyclic antihistamine medicine, and has dual effects of antihistaminic and antagonistic Platelet Activating Factor (PAF). Is also the only strong and efficient antiallergic drug which has the antihistaminic effect and the PAF antagonistic activity and is on the market at present. The medicine can selectively block H1 receptor, has weak blocking effect on 5-hydroxytryptamine, acetylcholine, prostaglandin F2 and leukotriene D4, can be non-competitively combined with platelet activating factor receptor, and can inhibit sensitized cell degranulation. The compound has the advantages of definite action mechanism, good bioavailability, stable curative effect and the like and good safety treatment window, thereby attracting a plurality of people in the medical field to develop improved research on the synthesis method.
According to the report of domestic and foreign literature on the synthetic route of rupatadine fumarate, the synthesis method is generally carried out according to the following reaction that 2-nitrile-3-methylpyridine is taken as a starting material, the raw material is reacted with sulfuric acid in tert-butyl alcohol to obtain 2-tert-butyroyl-3-methylpyridine, the reaction is carried out with 3-chlorobenzyl chloride in the presence of n-butyllithium to prolong the carbon chain, and POCl is used for prolonging the carbon chain3Removing one molecule of tert-butyl alcohol, and cyclizing in the presence of trifluoromethanesulfonic acid to obtain a tricyclic structure. Then the intermediate is reacted with 3- (4-chloropiperidine methyl) -5-methylpyridine through Grignard reaction to obtain corresponding alcohol, and the alcohol is dehydrated by sulfuric acid to obtain rupatadine which is then salified with fumaric acid. The intermediate 3- (4-chloropiperidine methyl) -5-methylpyridine cannot be directly purchased and needs to be prepared by an additional synthetic route. The method has the problems of relatively more steps, relatively complex operating conditions, certain potential safety hazard and the like.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems in the prior art, the invention provides a method for preparing rupatadine fumarate by adopting a microchannel continuous flow reaction device, so as to solve the problems of complicated steps, overlong reaction time and the like in the reaction process of the traditional synthetic method, improve the reaction efficiency and be suitable for industrial production.
In order to solve the technical problem, the invention discloses a method for preparing rupatadine fumarate by adopting a micro-channel reaction device, which comprises the following steps:
(1) respectively dissolving 3, 5-lutidine and N-bromosuccinimide in an organic solvent, respectively pumping into a first mixer of a microchannel reaction device at the same time, fully mixing, and then entering a first microreactor for reaction;
(2) respectively and simultaneously pumping an ethanol solution of loratadine and an aqueous solution of alkali into a second mixer of the microchannel reaction device, and after fully mixing, feeding the mixture into a second microreactor for reaction; pumping the reaction effluent of the second microreactor and the extraction solvent into a third mixer of the microchannel reaction device respectively and simultaneously, and after fully mixing, feeding the mixture into an oil-water separator for separation to obtain a carbon tetrachloride solution of desloratadine;
(3) pumping the reaction effluent of the first microreactor in the step (1) and the carbon tetrachloride solution of desloratadine obtained by separation in the step (2) into a fourth mixer of the microchannel reaction device respectively, pumping the fully mixed solution and triethylamine into a fifth mixer of the microchannel reaction device respectively and simultaneously for full mixing, and then feeding the mixture into a third microreactor for reaction;
(4) and (4) collecting reaction effluent liquid of the third microreactor in the step (3), washing with water, drying, filtering, and adding an organic solution of fumaric acid for crystallization to obtain rupatadine fumarate.
The reaction principle of the above preparation method is shown in FIG. 1.
Specifically, in the step (1), the organic solvent is carbon tetrachloride; the concentration of the carbon tetrachloride solution of the 3,5 dimethyl pyridine is 0.25-0.65 mol/L, preferably 0.5 mol/L; the concentration of the N-bromosuccinimide in the carbon tetrachloride solution is 0.3-0.75 mol/L, preferably 0.6 mol/L.
The flow rate of the carbon tetrachloride solution of the 3, 5-lutidine is 0.35-0.85 mL/min, preferably 0.5 mL/mol; the flow rate of the N-bromosuccinimide carbon tetrachloride solution is 0.4-0.85 mL/mol, preferably 0.5 mL/mol; the volume of the first micro-reactor is 5-50 mL, the reaction residence time is 5-45 min, preferably 30min, the reaction temperature is 25-100 ℃, and preferably 50 ℃.
In the step (2), the concentration of the ethanol solution of loratadine is 0.45-0.75 mol/L, preferably 0.52 mol/L; the concentration of the alkali aqueous solution is 3.5-5.5 mol/L, and the potassium hydroxide aqueous solution is preferably 4.5 mol/L.
The flow rate of the loratadine ethanol solution is 0.35-0.95 mL/min, preferably 0.5 mL/min; the flow rate of the alkali water solution is 0.65-1.1 mL/mol, preferably 0.8 mL/mol; the volume of the second micro reactor is 5-50 mL, the reaction residence time is 15-45 min, preferably 30min, the reaction temperature is 50-100 ℃, and preferably 80 ℃.
The extraction solvent is any one of carbon tetrachloride, ethyl acetate, chloroform or dichloromethane, preferably carbon tetrachloride, and the flow rate of the extraction solvent is 0.9-1.35 mL/min, preferably 1.0 mL/min.
In the step (3), the flow rate of the reaction effluent of the first microreactor in the step (1) is 0.6 mL/min-1.65 mL/min, and preferably 1.0 mL/min; the flow rate of the carbon tetrachloride solution of the desloratadine obtained by separating in the step (2) is 0.55-1.55 mL/min, and preferably 1.0 mL/min; the flow rate of triethylamine is 0.15-0.85 mL/min, preferably 0.3 mL/min; the volume of the third micro-reactor is 5-100 mL, the reaction residence time is 10-45 min, preferably 20min, the reaction temperature is 10-50 ℃, and preferably 25 ℃.
In the step (4), the crystallization method comprises the steps of adding a fumaric acid solution dissolved in methanol into the filtered product, heating and refluxing, cooling to room temperature, and then storing at low temperature to precipitate crystals.
The microchannel reaction device is made of polytetrafluoroethylene and comprises a first feeding pump, a second feeding pump, a third feeding pump, a fourth feeding pump, a fifth feeding pump, a sixth feeding pump, a first mixer, a second mixer, a third mixer, a fourth mixer, a fifth mixer, a first microreactor, a second microreactor, a third microreactor, an oil-water separator and a receiving device, wherein the first feeding pump and the second feeding pump are connected with the first mixer in a parallel connection mode through connecting pipes, the first mixer and the first microreactor are connected with each other in a series connection mode through connecting pipes, the third feeding pump and the fourth feeding pump are connected with the second mixer in a parallel connection mode through connecting pipes, the second mixer and the second microreactor are connected with each other in a series connection mode through connecting pipes, the second microreactor and the fifth feeding pump are connected with the third mixer in a parallel connection mode through connecting pipes, the third mixer is connected with the oil-water separator in series through a connecting pipe, the oil-water separator and the first microreactor are connected with the fourth mixer in parallel through a connecting pipe, the sixth feeding pump and the fourth mixer are connected with the fifth mixer in parallel through a connecting pipe, and the fifth mixer, the third microreactor and the receiving device are connected with each other in series through a connecting pipe.
Specifically, the reaction raw materials enter a mixer of a microchannel reaction device through an HPLC pump or an injection pump to be mixed, and then enter a reactor to be reacted; the models of the first mixer, the second mixer, the third mixer, the fourth mixer and the fifth mixer are T-shaped, Y-shaped or inverted Y-shaped, and the Y-shaped is preferred; the first microreactor, the second microreactor and the third microreactor are channel reactors or core-type structure reactors, and preferably channel reactors; the third micro reactor is a pipeline type reactor filled with dimethylaminopyridine powder and needs to be replaced at regular time.
The diameter of the connecting pipe is 0.1-5 mm, wherein the diameter of the connecting pipe between the first micro-reactor and the first mixer, between the second micro-reactor and the third mixer, between the third mixer and the fourth mixer, and between the fourth mixer and the fifth mixer is 0.5-5 mm, preferably 2-5 mm, and the length of the connecting pipe is 0.5-60 m.
Compared with the prior art, the invention has the following advantages:
1. the method optimizes the process on the known path for synthesizing the rupatadine fumarate, utilizes a microchannel reaction device, greatly shortens the reaction time, has high flux, stable product quality, strong continuity, is beneficial to continuous amplification production, has simple operation, high safety and easy separation, can effectively overcome the defects of the traditional synthesis path, and obviously improves the yield by 90 percent.
2. The desloratadine prepared in the production process is continuously separated and subjected to liquid separation, and the solution is directly put into the next reaction to obtain the rupatadine, so that the yield is not reduced, and the operation is simplified.
Drawings
The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 is a reaction scheme of the preparation process of the present invention;
FIG. 2 is a schematic diagram of a microchannel reaction apparatus and synthesis route according to the present invention; wherein, 1 is a first feeding pump, 2 is a second feeding pump, 3 is a third feeding pump, 4 is a fourth feeding pump, 5 is a fifth feeding pump, 6 is a sixth feeding pump, 7 is a first mixer, 8 is a second mixer, 9 is a third mixer, 10 is a fourth mixer, 11 is a fifth mixer, 12 is an oil-water separator, and 13 is a receiver.
FIG. 3 is a schematic view of the oil-water separator.
Detailed Description
The invention will be better understood from the following examples.
The structures, proportions, and dimensions shown in the drawings and described in the specification are for understanding and reading the present disclosure, and are not intended to limit the scope of the present disclosure, which is defined in the claims, and are not essential to the skilled in the art. In addition, the terms "upper", "lower", "front", "rear" and "middle" used in the present specification are for clarity of description, and are not intended to limit the scope of the present invention, and the relative relationship between the terms and the relative positions may be changed or adjusted without substantial technical changes.
The microchannel reactor apparatus according to the following embodiment, as shown in fig. 2, includes a first feed pump 1 (a carbon tetrachloride solution tank connected to 3, 5-lutidine), a second feed pump 2 (a carbon tetrachloride solution tank connected to NBS), a third feed pump 3 (an ethanol solution tank connected to loratadine), a fourth feed pump 4 (an aqueous solution tank connected to KOH), a fifth feed pump 5 (a carbon tetrachloride solution tank connected to), a sixth feed pump 6 (a triethylamine solution tank connected to), a first mixer 7, a second mixer 8, a third mixer 9, a fourth mixer 10, a fifth mixer 11, a first microreactor, a second microreactor, a third microreactor, an oil-water separator 12, and a receiver 13.
The first feed pump 1 and the second feed pump 2 are connected in parallel via a connecting pipe to the first mixer 7, the first mixer 7 and the first microreactor are connected in series via a connecting pipe, the third feed pump 3 and the fourth feed pump 4 are connected in parallel via a connecting pipe to the second mixer 8, the second mixer 8 and the second microreactor are connected in series via a connecting pipe, the second microreactor and the fifth feed pump 5 are connected in parallel via a connecting pipe to the third mixer 9, the third mixer 9 and the oil-water separator 12 are connected in series via a connecting pipe, the oil-water separator 12 and the first microreactor are connected in parallel via a connecting pipe to the fourth mixer 10, the sixth feed pump 6 and the fourth mixer 10 are connected in parallel via a connecting pipe to the fifth mixer 11, the third microreactor and the receiver 13 are connected in series by a connecting tube. The reaction raw materials enter a mixer through an HPLC pump or an injection pump and then enter a micro-reactor for reaction.
The model of the first mixer, the second mixer, the third mixer, the fourth mixer and the fifth mixer is Y-shaped. The first micro reactor, the second micro reactor and the third micro reactor are channel reactors.
FIG. 3 is a schematic diagram showing the structure of the oil-water separator, wherein the first bottleneck 121 is the inlet of the oil-water mixture, the bottleneck 122 is the outlet of the water phase, and the protruding parts 123 and 126 are the inlet and outlet of the backflow condensed water; 124 refers to an inner tank for holding the oil water mixture, an inner tank for the mixture to stratify, an oil phase is discharged from an outlet at 127, and a pipe for oil water mixture injection should extend to a position 125.
Example 1:
dissolving 0.1mol of 3, 5-dimethylpyridine in 200mL of carbon tetrachloride, and loading the dissolved 3, 5-dimethylpyridine in a first raw material storage tank after the dissolved 3, 5-dimethylpyridine is completely dissolved; dissolving 0.12mol of N-bromosuccinimide (NBS) in 200mL of carbon tetrachloride, and loading the solution in a second raw material storage tank after the N-bromosuccinimide (NBS) is completely dissolved; dissolving 0.052mol of loratadine in 100mL of ethanol, and loading the loratadine in a third raw material storage tank after the loratadine is completely dissolved; dissolving 0.893mol of KOH in 200mL of water, and loading the solution in a fourth raw material storage tank after the solution is completely dissolved; loading 200mL of carbon tetrachloride solution in a fifth raw material storage tank; 50mL of triethylamine solution is loaded in a sixth raw material storage tank; loading 0.05mol of dimethylaminopyridine in front of a third microreactor; namely 3,5 dimethyl pyridine, brominating agent (N-bromosuccinimide), loratadine, alkali (potassium hydroxide) and catalyst (dimethyl ammonia)Phenylpyridine) in a molar ratio of 1: 1.2: 0.5: 9: 0.5; simultaneously pumping feed liquid into a microchannel reaction device through a first feeding pump 1 and a second feeding pump 2, mixing the feed liquid by a first mixer 7, and then reacting in a first microreactor with the inner diameter of a coil pipe being 0.5mm, and setting a micro-reaction parameter: the flow rate of the carbon tetrachloride solution of 3, 5-lutidine is 0.5mL/min, the flow rate of the carbon tetrachloride solution of NBS is 0.5mL/min, the flow rate of the continuous flow in the step is 1.0mL/min, the reaction temperature is controlled at 50 ℃, the retention time is 30min, and the reaction mainly generates the carbon tetrachloride solution of 5-bromomethyl-3-methylpyridine; meanwhile, the feed liquid is simultaneously pumped into the microchannel reaction device through the third feed pump 3 and the fourth feed pump 4, mixed by the second mixer 8 and then enters the second microreactor with the inner diameter of the coil pipe being 0.5mm for reaction, and the parameters of the micro-reaction are set as follows: the flow rate of the ethanol solution of the loratadine is 0.5mL/min, the flow rate of the aqueous solution of KOH is 0.8mL/min, the flow rate of the continuous flow of the step is 1.3mL/min, the reaction temperature is controlled at 80 ℃, the retention time is 30min, and the reaction mainly generates the loratadine; when the reaction liquid of the second microreactor flows out, a fifth feeding pump 5 pumps the carbon tetrachloride solution into the microchannel reaction device, the carbon tetrachloride solution is mixed with the reaction liquid obtained in the second microreactor through a third mixer 9 and then enters an oil-water separator 12, the desloratadine is extracted from the reaction liquid by the carbon tetrachloride solution in the mixing process, the aqueous phase is removed from an outlet after entering the oil-water mixer, the obtained desloratadine solution enters the next reaction from the bottom of the oil-water separator, and the parameters of the microreactor are set: the flow rate of the carbon tetrachloride solution is 1.0 mL/min; simultaneously pumping the effluent obtained by the first microreactor and the effluent obtained after the oil-water separator is separated into a fourth mixer 10 for mixing, simultaneously pumping the solution mixed by the fourth mixer 10 and the triethylamine solution in a sixth raw material liquid storage tank into a fifth mixer 11 for mixing, and then enabling the mixed solution to enter a third microreactor with the inner diameter of a coil being 0.5mm and loaded with a catalyst (dimethylaminopyridine) for mixing reaction, and setting microreactor parameters: the flow rate of the carbon tetrachloride solution of 5-bromomethyl-3-methylpyridine is 1.0mL/min, the flow rate of the carbon tetrachloride solution of desloratadine is 1.0mL/min, the flow rate of the continuous flow in the step is 2.0mL/min, the flow rate of the triethylamine solution is 0.3mL/min, and the continuous flow in the step isThe flow rate of (2.3 mL/min) was maintained for 20min, and the reaction produced predominantly rupatadine. And collecting the reaction solution by using a receiver 13, washing with water, drying, filtering, adding a fumaric acid solution dissolved in methanol, heating and refluxing, slowly cooling to room temperature, and standing in a refrigerator for 12 hours to precipitate a white solid compound, namely the rupatadine fumarate, with the yield of 90%. Mass spectrum determination of [ M + H ] of the product]+The peak mass-to-charge ratio is 416.2, the molecular weight of the free radical of the product is 415, and the molecular weight is consistent with the molecular weight of the rupatadine fumarate free radical. [ M-H ] of this product]-The peak mass to charge ratio was 115.1, which is consistent with a molecular weight of 116 for fumaric acid. The test result of TG shows that the product does not contain crystal water, and the elemental analysis result shows that the elemental composition of the product is C26H26ClN3O5·C4H4O4Namely rupatadine fumarate. NMR: (1) δ 2.286(3H, s) and δ 17.91 (primary C): 1 saturated methyl group; δ 3.523(2H, s) and δ 58.79 (sec C): 1 saturated methylene group; δ 7.530(1H, m), 8.292(1H, d), 8.307(1H, d), and δ 137.45 (tertiary C), 147.48 (tertiary C), 148.90 (tertiary C): 3 unsaturated methine groups; δ 132.50 (season C), 132.62 (season C): 2 unsaturated quaternary carbons; the result shows that the product contains a picoline structural fragment in the structure. (2) δ 2.200(4H, m), 2.350(2H, m), 2.662(2H, m), and δ 30.24 (secondary C), 30.36 (secondary C), 54.05 (secondary C), and 54.08 (secondary C): 4 saturated methylene groups; δ 137.44 (season C): unsaturated quaternary carbon; the structure of the product contains a piperidine structural fragment. (3) δ 2.820(2H, m), 3.300(2H, m), and δ 30.67 (secondary C), 31.18 (secondary C): 2 saturated methylene groups; δ 7.064(1H, d), 7.199(1H, m), δ 7.180(1H, dd), δ 7.285(1H, d), 7.563(1H, m), 8.331(1H, dd), and δ 122.40 (tertiary C), 137.25 (tertiary C), 137.45 (tertiary C), 146.44 (tertiary C), 147.48 (tertiary C), 148.90 (tertiary C): 6 unsaturated methine groups; δ 131.63 (season C), 133.34 (season C), 137.44 (season C), 138.03 (season C), 140.22 (season C), 157.20 (season C): 6 unsaturated quaternary C; shows that the structure of the product contains 6, 11-dihydro-5H-benzene [5,6]]Cyclo-heptayl [1,2-b ]]A pyridine structural fragment. (4) δ 6.630(2H, s) and δ 134.21 (tertiary C): symmetrical 2 unsaturated methine groups; δ 166.27 (season C): symmetrical 2 carboxy carbons; this indicated that the product was fumarate. The structure of the compound was further confirmed by mass spectrometry and NMR data.
Example 2:
dissolving 0.1mol of 3, 5-dimethylpyridine in 200mL of carbon tetrachloride, and loading the dissolved 3, 5-dimethylpyridine in a first raw material storage tank after the dissolved 3, 5-dimethylpyridine is completely dissolved; dissolving 0.12mol of N-bromosuccinimide (NBS) in 200mL of carbon tetrachloride, and loading the solution in a second raw material storage tank after the N-bromosuccinimide (NBS) is completely dissolved; dissolving 0.052mol of loratadine in 100mL of ethanol, and loading the loratadine in a third raw material storage tank 3 after the loratadine is completely dissolved; dissolving 0.893mol of KOH in 200mL of water, and loading the solution in a fourth raw material storage tank after the solution is completely dissolved; loading 200mL of carbon tetrachloride solution in a fifth raw material storage tank; 50mL of triethylamine solution is loaded in a sixth raw material storage tank; loading 0.05mol of dimethylaminopyridine in front of a third microreactor; namely, the molar ratio of 3,5 lutidine, brominating agent (N-bromosuccinimide), loratadine, alkali (potassium hydroxide) and catalyst (dimethylaminopyridine) is 1: 1.2: 0.5: 9: 0.5; simultaneously pumping feed liquid into a microchannel reaction device through a first feeding pump 1 and a second feeding pump 2, mixing the feed liquid by a first mixer 7, and then reacting in a first microreactor with the inner diameter of a coil pipe being 0.5mm, and setting a micro-reaction parameter: the flow rate of the carbon tetrachloride solution of 3, 5-lutidine is 0.6mL/min, the flow rate of the carbon tetrachloride solution of NBS is 0.6mL/min, the flow rate of the continuous flow in the step is 1.2mL/min, the reaction temperature is controlled at 50 ℃, the retention time is 30min, and the reaction mainly generates the carbon tetrachloride solution of 5-bromomethyl-3-methylpyridine; meanwhile, the feed liquid is simultaneously pumped into the microchannel reaction device through the third feed pump 3 and the fourth feed pump 4, mixed by the second mixer 8 and then enters the second microreactor with the inner diameter of the coil pipe being 0.5mm for reaction, and the parameters of the micro-reaction are set as follows: the flow rate of the ethanol solution of the loratadine is 0.6mL/min, the flow rate of the aqueous solution of KOH is 0.9mL/min, the flow rate of the continuous flow of the step is 1.5mL/min, the reaction temperature is controlled at 80 ℃, the retention time is 30min, and the reaction mainly generates the loratadine; when the reaction liquid of the second microreactor flows out, a fifth feeding pump 5 pumps the carbon tetrachloride solution into the microchannel reaction device, the carbon tetrachloride solution is mixed with the reaction liquid obtained in the second microreactor through a third mixer 9 and then enters an oil-water separator 12, the desloratadine is extracted from the reaction liquid by the carbon tetrachloride solution in the mixing process, the aqueous phase is removed from an outlet after entering the oil-water mixer, the obtained desloratadine solution enters the next reaction from the bottom of the oil-water separator, and the parameters of the microreactor are set: the flow rate of the carbon tetrachloride solution is 1.2 mL/min; simultaneously pumping the effluent obtained by the first microreactor and the effluent obtained after the oil-water separator is separated into a fourth mixer 10 for mixing, simultaneously pumping the solution mixed by the fourth mixer 10 and the triethylamine solution in a sixth raw material liquid storage tank into a fifth mixer 11 for mixing, and then enabling the mixed solution to enter a third microreactor with the inner diameter of a coil being 0.5mm and loaded with a catalyst (dimethylaminopyridine) for mixing reaction, and setting microreactor parameters: the flow rate of the carbon tetrachloride solution of 5-bromomethyl-3-methylpyridine is 1.2mL/min, the flow rate of the carbon tetrachloride solution of desloratadine is 1.2mL/min, the flow rate of the continuous flow in the step is 2.4mL/min, the flow rate of the triethylamine solution is 0.4mL/min, the flow rate of the continuous flow in the step is 2.8mL/min, the reaction stays for 20min, and the rupatadine is mainly generated in the reaction. The reaction solution was collected by a receiver 13, washed with water, dried, filtered, and added with a fumaric acid solution dissolved in methanol, heated under reflux, slowly cooled to room temperature, and left in a refrigerator for 12 hours to precipitate a white solid compound, i.e., rupatadine fumarate, in 83% yield.
Example 3:
dissolving 0.1mol of 3, 5-dimethylpyridine in 200mL of carbon tetrachloride, and loading the dissolved 3, 5-dimethylpyridine in a first raw material storage tank after the dissolved 3, 5-dimethylpyridine is completely dissolved; dissolving 0.12mol of N-bromosuccinimide (NBS) in 200mL of carbon tetrachloride, and loading the solution in a second raw material storage tank after the N-bromosuccinimide (NBS) is completely dissolved; dissolving 0.052mol of loratadine in 100mL of ethanol, and loading the loratadine in a third raw material storage tank after the loratadine is completely dissolved; dissolving 0.893mol of KOH in 200mL of water, and loading the solution in a fourth raw material storage tank after the solution is completely dissolved; loading 200mL of carbon tetrachloride solution in a fifth raw material storage tank; 50mL of triethylamine solution is loaded in a sixth raw material storage tank; loading 0.05mol of dimethylaminopyridine in front of a third microreactor; namely, the molar ratio of 3,5 lutidine, brominating agent (N-bromosuccinimide), loratadine, alkali (potassium hydroxide) and catalyst (dimethylaminopyridine) is 1: 1.2: 0.5: 9: 0.5; simultaneously pumping feed liquid into a microchannel reaction device through a first feeding pump 1 and a second feeding pump 2, mixing the feed liquid by a first mixer 7, and then reacting in a first microreactor with the inner diameter of a coil pipe being 0.5mm, and setting a micro-reaction parameter: the flow rate of the carbon tetrachloride solution of 3, 5-lutidine is 0.4mL/min, the flow rate of the carbon tetrachloride solution of NBS is 0.4mL/min, the flow rate of the continuous flow in the step is 0.8mL/min, the reaction temperature is controlled at 50 ℃, the retention time is 30min, and the reaction mainly generates the carbon tetrachloride solution of 5-bromomethyl-3-methylpyridine; meanwhile, the feed liquid is simultaneously pumped into the microchannel reaction device through the third feed pump 3 and the fourth feed pump 4, mixed by the second mixer 8 and then enters the second microreactor with the inner diameter of the coil pipe being 0.5mm for reaction, and the parameters of the micro-reaction are set as follows: the flow rate of the ethanol solution of the loratadine is 0.4mL/min, the flow rate of the aqueous solution of KOH is 0.7mL/min, the flow rate of the continuous flow of the step is 1.1mL/min, the reaction temperature is controlled at 80 ℃, the retention time is 30min, and the reaction mainly generates the loratadine; when the reaction liquid of the second microreactor flows out, a fifth feeding pump 5 pumps the carbon tetrachloride solution into the microchannel reaction device, the carbon tetrachloride solution is mixed with the reaction liquid obtained in the second microreactor through a third mixer 9 and then enters an oil-water separator 12, the desloratadine is extracted from the reaction liquid by the carbon tetrachloride solution in the mixing process, the aqueous phase is removed from an outlet after entering the oil-water mixer, the obtained desloratadine solution enters the next reaction from the bottom of the oil-water separator, and the parameters of the microreactor are set: the flow rate of the carbon tetrachloride solution is 0.9 mL/min; simultaneously pumping the effluent obtained by the first microreactor and the effluent obtained after the oil-water separator is separated into a fourth mixer 10 for mixing, simultaneously pumping the solution mixed by the fourth mixer 10 and the triethylamine solution in a sixth raw material liquid storage tank into a fifth mixer 11 for mixing, and then enabling the mixed solution to enter a third microreactor with the inner diameter of a coil being 0.5mm and loaded with a catalyst (dimethylaminopyridine) for mixing reaction, and setting microreactor parameters: the flow rate of the carbon tetrachloride solution of 5-bromomethyl-3-methylpyridine is 0.8mL/min, the flow rate of the carbon tetrachloride solution of desloratadine is 0.9mL/min, the flow rate of the continuous flow in the step is 1.7mL/min, the flow rate of the triethylamine solution is 0.25mL/min, the flow rate of the continuous flow in the step is 1.95mL/min, the reaction stays for 20min, and the rupatadine is mainly generated in the reaction. The reaction solution is collected by a receiver 13, washed by water, dried and filtered, a fumaric acid solution dissolved in methanol is added into the reaction solution, the heating reflux is carried out, the reaction solution is slowly cooled to the room temperature, the reaction solution is placed in a refrigerator for 12 hours, and a white solid compound, namely the rupatadine fumarate, is separated out, and the yield is 80%.
The invention provides a method and a thought for preparing rupatadine fumarate by using a microchannel reaction device, and a method and a way for realizing the technical scheme are many, the above description is only a preferred embodiment of the invention, and it should be noted that for a person skilled in the art, a plurality of improvements and decorations can be made without departing from the principle of the invention, and the improvements and decorations should also be regarded as the protection scope of the invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (3)
1. A method for preparing rupatadine fumarate by adopting a microchannel reaction device is characterized by comprising the following steps:
(1) respectively dissolving 3, 5-lutidine and N-bromosuccinimide in organic solvent carbon tetrachloride, respectively pumping into a first mixer of a microchannel reaction device at the same time, fully mixing, and entering a first microreactor for reaction; wherein the concentration of the carbon tetrachloride solution of the 3, 5-lutidine is 0.25-0.65 mol/L; the concentration of the carbon tetrachloride solution of the N-bromosuccinimide is 0.3-0.75 mol/L; the flow rate of a carbon tetrachloride solution of 3,5 dimethyl pyridine is 0.35-0.85 mL/min, the flow rate of a carbon tetrachloride solution of N-bromosuccinimide is 0.4-0.85 mL/min, the volume of a first micro-reactor is 5-50 mL, the reaction residence time is 5-45 min, and the reaction temperature is 25-100 ℃;
(2) respectively and simultaneously pumping an ethanol solution of loratadine and an aqueous solution of alkali into a second mixer of the microchannel reaction device, and after fully mixing, feeding the mixture into a second microreactor for reaction; pumping the reaction effluent of the second microreactor and the extraction solvent into a third mixer of the microchannel reaction device respectively and simultaneously, and after fully mixing, feeding the mixture into an oil-water separator for separation to obtain a carbon tetrachloride solution of desloratadine; wherein the concentration of the ethanol solution of the loratadine is 0.45-0.75 mol/L, and the concentration of the aqueous solution of the alkali is 3.5-5.5 mol/L; the flow rate of the ethanol solution of the loratadine is 0.35-0.95 mL/min, and the flow rate of the aqueous solution of the alkali is 0.65-1.1 mL/min; the volume of the second micro-reactor is 5-50 mL, the reaction residence time is 15-45 min, and the reaction temperature is 50-100 ℃; the extraction solvent is carbon tetrachloride, and the flow rate of the extraction solvent is 0.9 mL/min-1.35 mL/min;
(3) pumping the reaction effluent of the first microreactor in the step (1) and the carbon tetrachloride solution of desloratadine obtained by separation in the step (2) into a fourth mixer of the microchannel reaction device respectively, pumping the fully mixed solution and triethylamine into a fifth mixer of the microchannel reaction device respectively and simultaneously for full mixing, and then feeding the mixture into a third microreactor for reaction; the flow rate of the reaction effluent of the first microreactor in the step (1) is 0.6 mL/min-1.65 mL/min; the flow rate of the carbon tetrachloride solution of desloratadine obtained by separating in the step (2) is 0.55-1.55 mL/min; the flow rate of triethylamine is 0.15-0.85 mL/min; the volume of the third micro-reactor is 5-100 mL, the reaction residence time is 10-45 min, and the reaction temperature is 10-50 ℃; the microchannel of the third microreactor is filled with dimethylaminopyridine powder;
(4) and (4) collecting reaction effluent liquid of the third microreactor in the step (3), washing with water, drying, filtering, and adding an organic solution of fumaric acid for crystallization to obtain rupatadine fumarate.
2. The method for preparing rupatadine fumarate by using a microchannel reaction device as claimed in claim 1, wherein in the step (4), the crystallization is carried out by adding a solution of fumaric acid dissolved in methanol to the filtered product, heating under reflux, cooling to room temperature, and then precipitating crystals at a low temperature.
3. The method of claim 1, wherein the microchannel reactor device is made of polytetrafluoroethylene, and comprises a first feeding pump, a second feeding pump, a third feeding pump, a fourth feeding pump, a fifth feeding pump, a sixth feeding pump, a first mixer, a second mixer, a third mixer, a fourth mixer, a fifth mixer, a first microreactor, a second microreactor, a third microreactor, an oil-water separator and a receiving device, wherein the first feeding pump and the second feeding pump are connected with the first mixer through a connecting pipe in parallel, the first mixer and the first microreactor are connected with the connecting pipe in series, the third feeding pump and the fourth feeding pump are connected with the second mixer through a connecting pipe in parallel, the second mixer and the second microreactor are connected with the connecting pipe in series, the second microreactor and the fifth feeding pump are connected with a third mixer through a connecting pipe in a parallel mode, the third mixer is connected with an oil-water separator through a connecting pipe in a series mode, the oil-water separator and the first microreactor are connected with a fourth mixer through a connecting pipe in a parallel mode, the sixth feeding pump and the fourth mixer are connected with the fifth mixer through a connecting pipe in a parallel mode, and the fifth mixer, the third microreactor and the receiving device are connected with each other through connecting pipes in a series mode;
the models of the first mixer, the second mixer, the third mixer, the fourth mixer and the fifth mixer are T-shaped, Y-shaped or inverted Y-shaped; the first micro-reactor, the second micro-reactor and the third micro-reactor are channel reactors or core-type structure reactors.
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| US5407941A (en) * | 1992-05-22 | 1995-04-18 | J. Uriach & Cia. S.A. | 8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,]pyridine |
| ES2087818A1 (en) * | 1993-11-24 | 1996-07-16 | Uriach & Cia Sa J | 8-chloro-11-[1-[(5-methyl-3-pyridyl)-methyl]-4- piperidylidene]-6,11-dihydro-5H-benzo-[5,6]-cycloheptal-[1,2- b]-pyridine fumarate |
| CN108610293A (en) * | 2018-06-15 | 2018-10-02 | 南京工业大学 | Method for preparing dorvitinib intermediate by adopting microchannel reaction device |
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| US5407941A (en) * | 1992-05-22 | 1995-04-18 | J. Uriach & Cia. S.A. | 8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,]pyridine |
| ES2087818A1 (en) * | 1993-11-24 | 1996-07-16 | Uriach & Cia Sa J | 8-chloro-11-[1-[(5-methyl-3-pyridyl)-methyl]-4- piperidylidene]-6,11-dihydro-5H-benzo-[5,6]-cycloheptal-[1,2- b]-pyridine fumarate |
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