CN114195657B - Synthetic method of bromhexine hydrochloride suitable for industrialization - Google Patents
Synthetic method of bromhexine hydrochloride suitable for industrialization Download PDFInfo
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- CN114195657B CN114195657B CN202210156256.6A CN202210156256A CN114195657B CN 114195657 B CN114195657 B CN 114195657B CN 202210156256 A CN202210156256 A CN 202210156256A CN 114195657 B CN114195657 B CN 114195657B
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- C07—ORGANIC CHEMISTRY
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0006—Controlling or regulating processes
- B01J19/0013—Controlling the temperature of the process
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- B01J4/00—Feed or outlet devices; Feed or outlet control devices
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- C07—ORGANIC CHEMISTRY
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- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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- C07—ORGANIC CHEMISTRY
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- C07C2601/14—The ring being saturated
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Abstract
The invention belongs to the field of industrialized production, and particularly relates to a synthetic method of bromhexine hydrochloride suitable for industrialization, wherein a guide pipe is arranged at the top of a reaction cylinder, the top of the reaction cylinder is fixedly connected with the bottom of the guide pipe, transmission pipes are symmetrically arranged at two ends of the guide pipe, the bottom of the transmission pipes is fixedly connected with the top of the reaction cylinder, a heat preservation cylinder is arranged on the outer surface of the reaction cylinder, the outer surface of the reaction cylinder is fixedly connected with two ends of the heat preservation cylinder, a low-temperature mechanism is arranged in the heat preservation cylinder, the inner wall of the heat preservation cylinder is fixedly connected with two ends of the low-temperature mechanism, a support mechanism is arranged at the bottom of the reaction cylinder, the bottom of the reaction cylinder is fixedly connected with the top of the support mechanism, a flow guide mechanism is arranged in the support mechanism, the inner wall of the support mechanism is contacted with the bottom of the flow guide mechanism, and support plates are uniformly arranged at the bottom of the flow guide mechanism, and the bottom of the flow guide mechanism is contacted with the top of the supporting plate.
Description
Technical Field
The invention belongs to the field of industrial production, and particularly relates to a synthetic method of bromhexine hydrochloride suitable for industrialization.
Background
Bromhexine hydrochloride, namely bromhexine hydrochloride, bisolbane, bisexpectorant and brombenyl cyclohexylamine, has a chemical name of N-methyl-N-cyclohexyl-2-amino-3, 5-dibromophenylmethanamine hydrochloride and a molecular formula of: C14H20Br2N 2. HCL, molecular weight: 412.60 bromhexine hydrochloride is a common expectorant at home and abroad, has strong phlegm dissolving effect, can decompose and break polysaccharide cellulose in phlegm, inhibit the synthesis of acidic mucopolysaccharide protein, reduce phlegm viscosity, and is beneficial to expectoration. Is clinically applicable to patients with phlegm which is difficult to expectorate, such as chronic bronchitis, asthma, bronchiectasis, silicosis, and the like. Bromhexine hydrochloride has good safety and definite curative effect in clinical application, and is recorded in Chinese pharmacopoeia, national basic drug catalogues and national basic medical insurance, industrial injury insurance and fertility insurance drug catalogues. The existing various bromhexine hydrochloride synthesis process technical routes have the problems of poor product quality, environmental pollution and the like, and also have the problem of poor quality stability, and the content of active ingredients is reduced quickly in the preparation process and the long-term storage process, so that the quality of the medicine and the safety and the effectiveness of the medicine are not ensured. The 2010 version of Chinese pharmacopoeia improves the standards of related substances of bromhexine hydrochloride, and specifies that the peak area of a single impurity is not more than 0.2 percent of the main peak area of a control solution, and the sum of the peak areas of the impurities is not more than 1.5 times (0.3 percent) of the main peak area of the control solution. The bromhexine hydrochloride obtained by the original synthesis technology and the refining method usually needs to be refined and crystallized for multiple times to meet the standard requirements of pharmacopeia, so that the waste of resources such as manpower, energy, raw and auxiliary materials and the like is caused, the product cost is increased, and the requirements of industrial continuous production are not met. Therefore, the improvement of the new synthesis process technology of bromhexine hydrochloride and the improvement of the product quality and the quality stability are urgent tasks of research departments and production enterprises. In recent years, many researchers have made continuous efforts to improve the synthesis technology, product quality and product quality stability of bromhexine hydrochloride, and a synthetic method suitable for industrial bromhexine hydrochloride is proposed to solve the above-mentioned problems.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a synthetic method of bromhexine hydrochloride suitable for industrialization, and solves the problems of waste of raw and auxiliary materials and the like.
(II) technical scheme
The technical scheme adopted by the invention for solving the technical problems is as follows: the invention relates to a synthetic method of bromhexine hydrochloride suitable for industrialization, which comprises the following steps;
s1: 3, 5-dibromo-2-aminobenzaldehyde is used as a raw material, diisobutylaluminum hydride, aluminum hydride, sodium cyanoborohydride or 9-BNN is used as a reducing agent, and a solvent can be selected from lower aliphatic alcohols such as methanol and ethanol, preferably methanol; reducing 3, 5-dibromo-2-aminobenzaldehyde into 3, 5-dibromo-2-aminobenzol;
s2: 3, 5-dibromo-2-aminobenzene alcohol is reacted at low temperature of 5-10 ℃ by a concentrated hydrochloric acid and zinc chloride system and adding a small amount of phosphorus trichloride (0.01-0.02 eq) to obtain 2, 4-dibromo-6- (chloromethyl) -aniline hydrochloride;
s3: carrying out substitution reaction on 2, 4-dibromo-6- (chloromethyl) -aniline hydrochloride and N-methylcyclohexylamine in a dichloromethane/DMF (dimethyl formamide/dimethyl formamide) mixed system by taking sodium carbonate, potassium carbonate and lithium carbonate as acid-binding agents (preferably sodium carbonate), and finally acidifying by using hydrochloric acid to obtain bromhexine hydrochloride;
in step S2, the reaction cylinder is used to perform the low-temperature reaction on 3, 5-dibromo-2-aminobenzol.
Preferably, the top of the reaction cylinder is provided with a guide pipe, the top of the reaction cylinder is fixedly connected with the bottom of the guide pipe, transmission pipes are symmetrically arranged at two ends of the guide pipe, the bottom of the transmission pipes is fixedly connected with the top of the reaction cylinder, a heat preservation cylinder is arranged on the outer surface of the reaction cylinder, the outer surface of the reaction cylinder is fixedly connected with two ends of the heat preservation cylinder, a low-temperature mechanism is arranged inside the heat preservation cylinder, the inner wall of the heat preservation cylinder is fixedly connected with two ends of the low-temperature mechanism, a supporting mechanism is arranged at the bottom of the reaction cylinder, the bottom of the reaction cylinder is fixedly connected with the top of the supporting mechanism, a flow guide mechanism is arranged inside the supporting mechanism, and the inner wall of the supporting mechanism is contacted with the bottom of the flow guide mechanism.
Preferably, the bottom of water conservancy diversion mechanism evenly is provided with the backup pad, and the bottom of water conservancy diversion mechanism contacts with the top of backup pad, the bottom of backup pad is provided with the bracing piece, and the bottom of backup pad and the right-hand member fixed connection of bracing piece, the inside of water conservancy diversion mechanism is provided with blocking mechanism, and the inner wall of reaction cylinder contacts with blocking mechanism's surface.
Preferably, the water conservancy diversion mechanism includes the guide plate, the bottom of guide plate evenly is provided with the honeycomb duct, and the bottom of guide plate and the right-hand member fixed connection of honeycomb duct, the left end of honeycomb duct is provided with the connector, and the left end of honeycomb duct and the inner wall fixed connection of connector.
Preferably, the supporting mechanism includes solid fixed ring, gu fixed ring's bottom evenly is provided with the backup pad, and gu the fixed ring's bottom and the top fixed connection of backup pad, the bottom of backup pad is provided with the steadying board, and the bottom of backup pad and the inner wall fixed connection who stabilizes the board.
Preferably, the low temperature mechanism includes the breather pipe, the right-hand member of breather pipe is provided with a reposition of redundant personnel section of thick bamboo, and the right-hand member of breather pipe and the left end fixed connection of a reposition of redundant personnel section of thick bamboo, the right-hand member symmetry of a reposition of redundant personnel section of thick bamboo is provided with the shunt tubes, and the right-hand member of a reposition of redundant personnel section of thick bamboo and the left end fixed connection of shunt tubes, the right-hand member of shunt tubes is provided with leads the warm ring, and the right-hand member of shunt tubes and the external fixed surface of leading the warm ring are connected.
Preferably, the blocking mechanism comprises a pull ring, a force-bearing rod is arranged at the top of the pull ring, the top of the pull ring is fixedly connected with the bottom of the force-bearing rod, a blocking plate is arranged at the top of the force-bearing rod, and the top of the force-bearing rod is fixedly connected with the bottom of the blocking plate.
Preferably, a rubber ring is arranged inside the blocking plate, the inner wall of the blocking plate is fixedly connected with the outer surface of the rubber ring, a rubber plate is arranged at the bottom of the blocking plate, and the top of the rubber plate is fixedly connected with the bottom of the blocking plate.
The invention has the following beneficial effects:
1. according to the device, the flow guide mechanism is arranged, so that the production efficiency can be greatly improved when the bromhexine hydrochloride is manufactured, the collection working time of the device after the manufacturing is greatly saved, the device can be dispersedly collected through the flow guide plate arranged inside the flow guide mechanism when the device is collected, the collection effect of the device is further improved, the leakage condition can not occur during collection through the connectors uniformly arranged outside the flow guide mechanism, and the production efficiency of the bromhexine hydrochloride is further greatly improved.
2. The reaction cylinder and the supporting mechanism are fixed through the fixing ring arranged in the supporting mechanism, and the reaction cylinder is supported through the supporting plate uniformly arranged at the bottom of the fixing ring, so that the blocking mechanism arranged at the bottom of the reaction cylinder is not in direct contact with the flow guide mechanism and the ground, the liquid can be recovered by utilizing the self gravity of the liquid during collection, no external force is needed, and the use stability of the supporting mechanism can be greatly improved through the stabilizing plate arranged at the bottom of the supporting mechanism.
3. The low-temperature mechanism is arranged, so that the stability of the device can be greatly improved, the low-temperature mechanism can ensure that the internal temperature of the reaction cylinder in the device is always kept at low temperature when the 2, 4-dibromo-6- (chloromethyl) -aniline hydrochloride is prepared, the reaction effect is good, the reaction time is greatly shortened, low-temperature air can be uniformly distributed in the temperature guide ring through the flow dividing pipe arranged in the low-temperature mechanism, the internal temperature of the reaction cylinder is always at a lower level, and cold air can be uniformly distributed in the temperature guide ring through the air pipe, so that the working efficiency of the device is improved.
4. The device can greatly improve the use effect of the device by arranging the blocking mechanism, the device can ensure that the reaction cylinder forms a closed space when the device is used for carrying out chemical reaction by arranging the blocking mechanism, the blocking mechanism can be in close contact with the inner wall of the reaction cylinder by the rubber plate arranged at the bottom of the blocking mechanism, the reaction cylinder is further ensured not to be leaked when working, and the blocking plate arranged at the top of the blocking mechanism can be contracted by the rubber ring arranged at the top.
5. The guide plate is arranged, so that the use effect of the guide mechanism can be greatly improved, the liquid in the reaction cylinder can uniformly flow into the guide pipe for recovery through the guide plate, the liquid can be ensured not to splash during recovery through the guide plate, the recovery efficiency is high, and the recovery effect of the device can be ensured through the matched use of the guide plate and the guide pipe.
6. The distribution pipe is arranged, so that the use effect of the low-temperature mechanism can be greatly improved, the cold air transmitted by the low-temperature mechanism can be uniformly distributed in the temperature guide ring by the distribution pipe, the temperature in the temperature guide ring can be quickly reduced and maintained in a range required by reaction, the temperature in the temperature guide ring can be quickly reduced by matching the distribution pipe with the distribution pipe, the temperature in the reaction barrel can be reduced by the temperature guide ring, and the temperature in the reaction barrel can meet the reaction requirement.
Drawings
FIG. 1 is a front view of the present invention;
FIG. 2 is a schematic view of the internal structure of the drawing of the present invention;
FIG. 3 is a schematic view of the configuration of the deflector mechanism of the present invention;
FIG. 4 is a schematic structural view of the support mechanism of the present invention;
FIG. 5 is a schematic structural view of the cryogenic mechanism of the present invention;
FIG. 6 is a schematic structural view of the blocking mechanism of the present invention;
in the figure: the device comprises a reaction cylinder 1, a guide pipe 2, a transmission pipe 3, a heat preservation cylinder 4, a flow guide mechanism 5, a support mechanism 6, a low-temperature mechanism 7, a blocking mechanism 8, a support plate 9, a support rod 10, a flow guide plate 51, a flow guide pipe 52, a connector 53, a support plate 61, a stabilizing plate 62, a fixing ring 63, a flow dividing pipe 71, a temperature guide ring 72, a flow dividing cylinder 73, a vent pipe 74, a pull ring 81, a stress rod 82, a rubber plate 83, a rubber ring 84 and a blocking plate 85.
Detailed Description
A method for industrially synthesizing bromhexine hydrochloride according to an embodiment of the present invention will be described below with reference to fig. 1 to 6.
As shown in FIGS. 1-6, the method for synthesizing bromhexine hydrochloride suitable for industrialization comprises the following steps;
s1: 3, 5-dibromo-2-aminobenzaldehyde is used as a raw material, diisobutylaluminum hydride, aluminum hydride, sodium cyanoborohydride or 9-BNN is used as a reducing agent, and a solvent can be selected from lower aliphatic alcohols such as methanol and ethanol, preferably methanol; reducing 3, 5-dibromo-2-aminobenzaldehyde into 3, 5-dibromo-2-aminobenzol;
s2: 3, 5-dibromo-2-aminobenzene alcohol is reacted at low temperature of 7 ℃ by a concentrated hydrochloric acid and zinc chloride system and a small amount of phosphorus trichloride (0.02 eq) to obtain 2, 4-dibromo-6- (chloromethyl) -aniline hydrochloride;
s3: carrying out substitution reaction on 2, 4-dibromo-6- (chloromethyl) -aniline hydrochloride and N-methylcyclohexylamine in a dichloromethane/DMF (dimethyl formamide/dimethyl formamide) mixed system by taking sodium carbonate, potassium carbonate and lithium carbonate as acid-binding agents (preferably sodium carbonate), and finally acidifying by using hydrochloric acid to obtain bromhexine hydrochloride;
in step S2, the reaction of 3, 5-dibromo-2-aminobenzol with the reaction tube 1 needs to be performed at a low temperature.
The top of the reaction cylinder 1 is provided with a guide pipe 2, the top of the reaction cylinder 1 is fixedly connected with the bottom of the guide pipe 2, two ends of the guide pipe 2 are symmetrically provided with transmission pipes 3, the bottom of the transmission pipes 3 is fixedly connected with the top of the reaction cylinder 1, the outer surface of the reaction cylinder 1 is provided with a heat preservation cylinder 4, the outer surface of the reaction cylinder 1 is fixedly connected with two ends of the heat preservation cylinder 4, the inner part of the heat preservation cylinder 4 is provided with a low-temperature mechanism 7, the inner wall of the heat preservation cylinder 4 is fixedly connected with two ends of the low-temperature mechanism 7, the bottom of the reaction cylinder 1 is provided with a support mechanism 6, the bottom of the reaction cylinder 1 is fixedly connected with the top of the support mechanism 6, the inner part of the support mechanism 6 is provided with a flow guide mechanism 5, the inner wall of the support mechanism 6 is contacted with the bottom of the flow guide mechanism 5, the use effect of the low-temperature mechanism 7 can be greatly improved by arranging a shunt pipe 71, the shunt pipe 71 can evenly distribute cold air transmitted by the low-temperature mechanism 7 into a heat guide ring 72, and then make the inside temperature of ring 72 that leads to reduce fast and maintain in the required within range of reaction, and use with reposition of redundant personnel section of thick bamboo 73 cooperation through shunt tubes 71 and can make the inside temperature of ring 72 that leads to reduce fast, and can make the inside temperature of reaction tube 1 reduce through ring 72 that leads to lead to, and then make the inside temperature of reaction tube 1 accord with the reaction demand.
The bottom of the flow guide mechanism 5 is uniformly provided with a support plate 9, the bottom of the flow guide mechanism 5 is contacted with the top of the support plate 9, the bottom of the support plate 9 is provided with a support rod 10, the bottom of the support plate 9 is fixedly connected with the right end of the support rod 10, the inner part of the flow guide mechanism 5 is provided with a blocking mechanism 8, and the inner wall of the reaction cylinder 1 is contacted with the outer surface of the blocking mechanism 8, by arranging the flow guide mechanism 5, the production efficiency of the device can be greatly improved when bromhexine hydrochloride is produced, the collection working time of the device after production can be greatly saved by the flow guide mechanism 5, the device can be dispersedly collected by a guide plate 51 arranged in the flow guide mechanism 5 when being collected, the collection effect of the device is improved, and the leakage can not occur during collection by a connector 53 uniformly arranged outside the flow guide mechanism 5, thereby greatly improving the production efficiency of bromhexine hydrochloride.
The supporting mechanism 6 comprises a fixed ring 63, the bottom of the fixed ring 63 is uniformly provided with a supporting plate 61, the bottom of the fixing ring 63 is fixedly connected with the top of the supporting plate 61, the bottom of the supporting plate 61 is provided with a stabilizing plate 62, and the bottom of the supporting plate 61 is fixedly connected with the inner wall of the stabilizing plate 62, by arranging the supporting mechanism 6, the stability of the device can be greatly improved, the reaction cylinder 1 and the supporting mechanism 6 are fixed by the fixing ring 63 arranged in the supporting mechanism 6, the reaction cylinder 1 is supported by the supporting plate 61 uniformly arranged at the bottom of the fixing ring 63, so that the blocking mechanism 8 arranged at the bottom of the reaction cylinder 1 and the flow guide mechanism 5 are not in direct contact with the ground, thereby ensuring that the liquid can be recovered by the self gravity of the liquid during collection without external force, and the use stability of the supporting mechanism 6 can be greatly improved through the stabilizing plate 62 arranged at the bottom of the supporting mechanism 6.
The low temperature mechanism 7 comprises a vent pipe 74, a shunt tube 73 is arranged at the right end of the vent pipe 74, the right end of the vent pipe 74 is fixedly connected with the left end of the shunt tube 73, shunt tubes 71 are symmetrically arranged at the right end of the shunt tube 73, the right end of the shunt tube 73 is fixedly connected with the left end of the shunt tube 71, a temperature guide ring 72 is arranged at the right end of the shunt tube 71, and the right end of the shunt tube 71 is fixedly connected with the outer surface of the temperature guide ring 72, the stability of the device can be greatly improved by arranging the low temperature mechanism 7, the low temperature mechanism 7 can ensure that the internal temperature of the reaction cylinder 1 in the device can be always kept at low temperature when the 2, 4-dibromo-6- (chloromethyl) -aniline hydrochloride is manufactured, so that the reaction effect is good, the reaction time is greatly shortened, and the low temperature air can be uniformly distributed in the temperature guide ring 72 through the shunt tubes 71 arranged in the low temperature mechanism 7, therefore, the temperature inside the reaction cylinder 1 is always at a lower level, and the cold air can be uniformly distributed inside the temperature guide ring 72 through the vent pipe 74, thereby improving the working efficiency of the device.
The blocking mechanism 8 comprises a pull ring 81, the top of the pull ring 81 is provided with a stress rod 82, the top of the pull ring 81 is fixedly connected with the bottom of the stress rod 82, the top of the stress rod 82 is provided with a blocking plate 85, the top of the stress rod 82 is fixedly connected with the bottom of the blocking plate 85, through the blocking mechanism 8, the using effect of the device can be greatly improved, the reaction cylinder 1 can be ensured to form a closed space during chemical reaction by arranging the blocking mechanism 8, and the rubber plate 83 arranged at the bottom of the blocking mechanism 8 can enable the blocking mechanism 8 to be in close contact with the inner wall of the reaction cylinder 1, so that the condition that the reaction cylinder 1 cannot be leaked during working is ensured, and the blocking plate 85 arranged at the top of the blocking mechanism 8 can be contracted through the rubber ring 84 arranged at the top.
The rubber ring 84 is provided inside the blocking plate 85, the inner wall of the blocking plate 85 is fixedly connected to the outer surface of the rubber ring 84, the rubber plate 83 is provided at the bottom of the blocking plate 85, the top of the rubber plate 83 is fixedly connected to the bottom of the blocking plate 85, and the rubber ring 84 is provided to contract the blocking plate 85.
The specific working process is as follows:
during operation, the device carries out the packing of raw materials through pipe 2 and the transmission pipe 3 that the top set up, and carry out chemical reaction through inside reaction cylinder 1, keep warm through the heat preservation section of thick bamboo 4 that reaction cylinder 1 outside set up, and let in air conditioning to its inside through the breather pipe 74 that low temperature mechanism 7 both ends set up, and shunt tubes 71 through the inside even setting of low temperature mechanism 7 can be full of air conditioning with leading the inside of warm ring 72 rapidly, and then make leading the temperature reduction of warm ring 72 inner wall, and then make the inside temperature reduction of reaction cylinder 1, and then carry out chemical reaction, and can support reaction cylinder 1 through supporting mechanism 6 that the bottom set up, and can form airtight space with reaction cylinder 1 inside through the inside blocking mechanism 8 that sets up of supporting mechanism 6, and then make reaction cylinder 1 can not appear the condition of revealing when carrying out chemical reaction.
While the present invention has been described with reference to the embodiments shown in the drawings, the present invention is not limited to the embodiments, which are illustrative and not restrictive, and it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (3)
1. A synthetic method of bromhexine hydrochloride suitable for industrialization is characterized by comprising the following steps;
s1: 3, 5-dibromo-2-aminobenzaldehyde is used as a raw material, diisobutylaluminum hydride, aluminum hydride, sodium cyanoborohydride or 9-BNN is used as a reducing agent, and a solvent is methanol; reducing 3, 5-dibromo-2-aminobenzaldehyde to 3, 5-dibromo-2-aminobenzyl alcohol;
s2: 3, 5-dibromo-2-aminobenzene alcohol is reacted at low temperature of 5-10 ℃ by a concentrated hydrochloric acid and zinc chloride system and adding 0.01-0.02eq of phosphorus trichloride to obtain 2, 4-dibromo-6- (chloromethyl) -aniline hydrochloride;
s3: carrying out substitution reaction on 2, 4-dibromo-6- (chloromethyl) -aniline hydrochloride and N-methyl cyclohexylamine by taking sodium carbonate, potassium carbonate and lithium carbonate as acid-binding agents in a dichloromethane/DMF (dimethyl formamide) mixed system, and finally acidifying by using hydrochloric acid to obtain bromhexine hydrochloride;
wherein, in the step S2, the reaction cylinder (1) is used for carrying out low-temperature reaction on the 3, 5-dibromo-2-aminobenzol;
the top of the reaction cylinder (1) is provided with a guide pipe (2), the top of the reaction cylinder (1) is fixedly connected with the bottom of the guide pipe (2), two ends of the guide pipe (2) are symmetrically provided with transmission pipes (3), the bottom of the transmission pipes (3) is fixedly connected with the top of the reaction cylinder (1), the outer surface of the reaction cylinder (1) is provided with a heat preservation cylinder (4), the outer surface of the reaction cylinder (1) is fixedly connected with two ends of the heat preservation cylinder (4), the inner part of the heat preservation cylinder (4) is provided with a low temperature mechanism (7), the inner wall of the heat preservation cylinder (4) is fixedly connected with two ends of the low temperature mechanism (7), the bottom of the reaction cylinder (1) is provided with a support mechanism (6), the bottom of the reaction cylinder (1) is fixedly connected with the top of the support mechanism (6), and the inner part of the support mechanism (6) is provided with a flow guide mechanism (5), the inner wall of the supporting mechanism (6) is contacted with the bottom of the flow guide mechanism (5);
the low-temperature mechanism (7) comprises a vent pipe (74), a flow dividing barrel (73) is arranged at the right end of the vent pipe (74), the right end of the vent pipe (74) is fixedly connected with the left end of the flow dividing barrel (73), flow dividing pipes (71) are symmetrically arranged at the right end of the flow dividing barrel (73), the right end of the flow dividing barrel (73) is fixedly connected with the left end of the flow dividing pipe (71), a temperature guide ring (72) is arranged at the right end of the flow dividing pipe (71), and the right end of the flow dividing pipe (71) is fixedly connected with the outer surface of the temperature guide ring (72);
the bottom of the flow guide mechanism (5) is uniformly provided with supporting plates (9), the bottom of the flow guide mechanism (5) is contacted with the top of the supporting plates (9), the bottom of the supporting plates (9) is provided with supporting rods (10), the bottom of the supporting plates (9) is fixedly connected with the right ends of the supporting rods (10), a blocking mechanism (8) is arranged inside the flow guide mechanism (5), and the inner wall of the reaction cylinder (1) is contacted with the outer surface of the blocking mechanism (8);
the flow guide mechanism (5) comprises a flow guide plate (51), wherein flow guide pipes (52) are uniformly arranged at the bottom of the flow guide plate (51), the bottom of the flow guide plate (51) is fixedly connected with the right end of the flow guide pipe (52), a connector (53) is arranged at the left end of the flow guide pipe (52), and the left end of the flow guide pipe (52) is fixedly connected with the inner wall of the connector (53);
supporting mechanism (6) are including solid fixed ring (63), the bottom of solid fixed ring (63) evenly is provided with backup pad (61), and the bottom of solid fixed ring (63) and the top fixed connection of backup pad (61), the bottom of backup pad (61) is provided with steadying board (62), and the bottom of backup pad (61) and the inner wall fixed connection of steadying board (62).
2. The method for synthesizing bromhexine hydrochloride suitable for industrialization according to claim 1, is characterized in that: the blocking mechanism (8) comprises a pull ring (81), a stress rod (82) is arranged at the top of the pull ring (81), the top of the pull ring (81) is fixedly connected with the bottom of the stress rod (82), a blocking plate (85) is arranged at the top of the stress rod (82), and the top of the stress rod (82) is fixedly connected with the bottom of the blocking plate (85).
3. The method for synthesizing bromhexine hydrochloride suitable for industrialization according to claim 2, is characterized in that: the inner part of the blocking plate (85) is provided with a rubber ring (84), the inner wall of the blocking plate (85) is fixedly connected with the outer surface of the rubber ring (84), the bottom of the blocking plate (85) is provided with a rubber plate (83), and the top of the rubber plate (83) is fixedly connected with the bottom of the blocking plate (85).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210156256.6A CN114195657B (en) | 2022-02-21 | 2022-02-21 | Synthetic method of bromhexine hydrochloride suitable for industrialization |
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| CN202210156256.6A CN114195657B (en) | 2022-02-21 | 2022-02-21 | Synthetic method of bromhexine hydrochloride suitable for industrialization |
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| CN114195657A CN114195657A (en) | 2022-03-18 |
| CN114195657B true CN114195657B (en) | 2022-05-06 |
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| CN112142604A (en) * | 2020-10-28 | 2020-12-29 | 河北国龙制药有限公司 | Preparation method of bromhexine hydrochloride and intermediate thereof |
| CN112266329A (en) * | 2020-09-25 | 2021-01-26 | 江西亿友药业有限公司 | Efficient production method of bromhexine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ES525701A0 (en) * | 1983-09-17 | 1985-02-01 | Espanola De Especialidades Far | PROCEDURE FOR OBTAINING A CYCLOHEXYLAMINE-DERIVED COMPOUND |
| ES526526A0 (en) * | 1983-10-17 | 1985-04-16 | Espanola Especialidades Farmac | PROCEDURE FOR OBTAINING A BENCILAMINE-DERIVED COMPOUND |
| CN102617359A (en) * | 2012-02-24 | 2012-08-01 | 石家庄东方药业有限公司 | Method for preparing bromhexine hydrochloride |
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| CN112266329A (en) * | 2020-09-25 | 2021-01-26 | 江西亿友药业有限公司 | Efficient production method of bromhexine hydrochloride |
| CN112142604A (en) * | 2020-10-28 | 2020-12-29 | 河北国龙制药有限公司 | Preparation method of bromhexine hydrochloride and intermediate thereof |
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