CN111548369A - Method for simply and conveniently preparing high-purity olopatadine hydrochloride intermediate - Google Patents
Method for simply and conveniently preparing high-purity olopatadine hydrochloride intermediate Download PDFInfo
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- CN111548369A CN111548369A CN202010486910.0A CN202010486910A CN111548369A CN 111548369 A CN111548369 A CN 111548369A CN 202010486910 A CN202010486910 A CN 202010486910A CN 111548369 A CN111548369 A CN 111548369A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
Abstract
The invention provides a simple and convenient method which is more suitable for industrial mass production and preparation of high-purity [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide. Taking triphenylphosphine and 1, 3-dibromopropane as starting materials, and carrying out reflux reaction in n-heptane to obtain (3-bromopropyl) triphenyl phosphonium bromide; the obtained (3-bromopropyl) triphenyl phosphonium bromide is directly reacted with dimethylamine aqueous solution by a one-pot method without separation, after the reaction is finished, n-heptane is concentrated and water in the system is taken out to obtain a crude product of the [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide, and the crude product is thermally pulped by absolute ethyl alcohol to obtain the high-purity [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a novel preparation method of a key intermediate of olopatadine hydrochloride. The intermediate structure of olopatadine hydrochloride related by the invention is as follows:
background
Olopatadine hydrochloride was developed by japan synergetics fermentation company. First obtained approval by the U.S. Food and Drug Administration (FDA) for marketing 18.12 months before 1996; approved by the Japan pharmaceutical and medical device integration institution (PMDA) to come into the market at 12 months and 22 days in 2000; approved by European drug administration (EMA) to be marketed in 2002, 5/17/month; the approval of import registration is finished at 23.7.7.2002 in China, and the application manufacturer is Aierkang (China) ophthalmic product limited company.
Olopatadine hydrochloride has selective antagonism mainly on histamine H1 receptor, and can inhibit the generation and liberation of chemical transmitters (leukotriene, thromboxane, PAF, etc.), and has inhibitory effect on the liberation of neurotransmitter tachykinin. It has the main functions as follows: firstly, antihistaminic action; secondly, the anti-allergic effect is achieved; thirdly, inhibiting the generation and liberation of transmitters; and fourthly, inhibition effect on tachykinin liberation. Currently approved dosage forms are: eye drops, tablets, nasal sprays, and the like. The indications include: allergic conjunctivitis, urticaria, allergic rhinitis, seasonal allergic rhinitis.
From the present point of view, the market demand for olopatadine hydrochloride and its intermediates is still not small. In particular, the [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide needs to be excessive in the subsequent Wittig reaction to completely convert another intermediate isoxepac, so that the demand of the intermediate [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide is larger and is about 5 times of that of the isoxepac; about 15-18 kg is required to prepare 1kg olopatadine hydrochloride. The synthetic route is as follows:
the existing method for producing the compound mainly takes triphenylphosphine and 1, 3-dibromopropane as starting materials, and the compound 123B1-10 is obtained by heating reaction in toluene, cooling and centrifugal separation; drying, reflux-reacting with dimethylamine water solution in ethanol, concentrating ethanol and residual dimethylamine water solution, adding anhydrous ethanol into the residue, heating for dispersion, centrifuging, and filtering to obtain compound 123B 2-10.
The current preparation method has the following main defects:
firstly, in order to inhibit the disubstituted byproduct 123B1-X2 in the reaction of triphenylphosphine and 1, 3-dibromopropane and to improve the conversion rate of triphenylphosphine as much as possible, in the actual production process, 1, 3-dibromopropane needs to be added in excess. Generally, the feeding molar ratio of triphenylphosphine to 1, 3-dibromopropane is 1.00: 1.10-1.20. Based on 1, 3-dibromopropane as a liquid, the excess can be removed during centrifugation to give 123B1-10 as a solid. However, 1, 3-dibromopropane is a good alkylating agent, belongs to genotoxic compounds, and has certain penetrating power to plastics, and even if protective clothing is worn in the production process, the contact between personnel and residual 1, 3-dibromopropane is inevitable in the processes of gas mist generated in centrifugal separation, centrifugal discharging, material drying, packaging and the like, so that the problems that the operators are allergic to the 1, 3-dibromopropane and the like are caused: symptoms such as eye stinging, lacrimation, skin allergy, hand and foot weakness, etc. appear.
Secondly, the compound 123B1-10 is a good alkylating agent and also has potential risks of sensitization, genotoxicity and the like.
Thirdly, in the current production process, in order to avoid the excessive byproduct 123B1-X2 in the intermediate 123B2-10 from being finally transferred to the olopatadine hydrochloride finished product, the intermediate 123B1-10 is usually separated by centrifugation, and the byproduct 123B1-X2 is dissolved in toluene to achieve the purpose of removing most 123B1-X2, but the 1, 3-dibromopropane also has a residue, so that the harm to operators is difficult to avoid.
Fourthly, in the process of preparing 123B2-10, a mixed solution of dimethylamine aqueous solution and ethanol is used to react with 123B1-10 at 70-80 ℃ in a violent reflux state, the molar ratio of dimethylamine in the reaction feeding is about 6-8 times that of dimethylamine, and because the boiling point of the dimethylamine aqueous solution is about 50 ℃, in the violent reflux process, dimethylamine is hardly volatilized from the system, so that waste is caused, and the difficulty in treating waste gas is increased. Although the ethanol containing dimethylamine concentrated under normal pressure after the reaction can be used indiscriminately, the aqueous solution containing a large amount of dimethylamine concentrated later can not be recycled and can only enter a sewage treatment link for treatment, thereby increasing the workload of sewage treatment.
Fifthly, the post-treatment of the preparation 123B2-10 has very good water solubility, and the reaction system contains a large amount of water, so that the solvent needs to be completely concentrated and dried, otherwise, the yield is remarkably reduced. The proportion of water in the azeotrope of ethanol and water is relatively small, the water in the azeotrope only accounts for about 5 percent, and a large amount of water still remains in the system after the ethanol is concentrated. Even under the condition of reduced pressure, when the single batch feeding amount is large, the temperature is required to be increased to at least over 90 ℃, so that the finally residual water in the material can be well steamed, and the energy consumption is increased; meanwhile, if the water residual quantity is too small, the residue in the kettle can be formed into hard blocks, so that the stirring of the reaction kettle is very easy to be locked and stop rotating, and the blocked materials can not be dispersed any more even if absolute ethyl alcohol is added and heated to reflux. The concentration degree of the solvent is difficult to control in the process of post-treating the concentrated solvent.
The current process has more problems in terms of Environmental Health and Safety (EHS): is not very friendly to the environment; the material waste is more; the unnecessary injury to the personnel is easily caused; damage to the equipment is easily caused. And is therefore not well suited for industrial scale production.
Disclosure of Invention
The invention provides a method for preparing [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide, which is more suitable for industrial mass production. The method is characterized by comprising the following steps:
firstly, triphenylphosphine and 1, 3-dibromopropane are used as starting materials, and reflux reaction is carried out in n-heptane, so as to obtain a compound 123B 1-10; then reacting with dimethylamine aqueous solution to obtain 123B 2-10;
secondly, the obtained intermediate 123B1-10 directly reacts with dimethylamine aqueous solution by a one-pot method without centrifugal separation, after the reaction is finished, n-heptane is concentrated and water in the system is taken out to obtain 123B2-10 n-heptane dispersion liquid, and then the dispersion liquid is subjected to centrifugal separation, and the obtained solid is refined by hot pulping of ethanol and is dried; thus, a refined product 123B2-10 was obtained.
In conclusion, the intermediate of olopatadine hydrochloride is prepared by the method. The advantages are that:
firstly, the intermediate 123B1-10 does not need to be separated, and the injury of various bromine-containing alkylating reagents and intermediates to personnel in the processes of separation, drying, packaging and the like is avoided.
The residual small amount of 1, 3-dibromopropane reacts with dimethylamine in the subsequent ammonolysis process to generate N1，N1，N3，N3Tetramethyl-1, 3-propanediamine dihydrobromide, thereby reducing the chemical injury of alkylating agents such as 1, 3-dibromopropane and 123B1-10 to personnel.
Thirdly, the impurity 123B1-X2 is easily dissolved in ethanol and removed in the process of separating 123B2-10, so that the aim of removing the impurity can be completely fulfilled without centrifugal separation and purification of 123B 1-10; another by-product N1，N1，N3，N3Tetramethyl-1, 3-propanediamine dihydrobromide can also be removed by dissolving it in ethanol; therefore, support is provided for preparing the 123B2-10 with high purity by adopting a one-pot method.
Fourthly, in the process of centrifuging 123B2-10, the safety of the n-heptane is higher than that of the toluene. Compared with toluene and petroleum ether with n-hexane as a main component, n-heptane is less prone to accumulate static electricity, and is more suitable for industrial mass production from the safety perspective.
Fifthly, the consumption of dimethylamine aqueous solution is greatly saved, and the output of three wastes is controlled. Not only reduces the cost, but also lightens the workload of anhydrous treatment.
Sixth, the production operation is simplified, the production efficiency is improved, and the damage to equipment caused by unreasonable operation possibly occurring in the production process is avoided.
Detailed Description
General procedure for preparation of 123B1-10 (solvent screening):
triphenylphosphine (40g, 1.00eq) and 1, 3-dibromopropane (31g, 1.00eq) were added to the respective solvents (120 g each) and heated to reflux to give 123B 1-10. See table one for specific examples and results:
epi-solvent screening
Liquid phase results: peak area of 123B 1-10: peak area of triphenylphosphine: peak area of 123B1-X2
From the results shown in Table one, the double bond impurities 123B1-X2 were significantly larger using protic polar solvents such as ethanol, butanol as reaction solvents, and thus, alcohols were not suitable as solvents. Aprotic polar solvents such as ethyl acetate and butyl acetate are used as reaction solvents, and although the double-connected impurities are better than alcohols as the reaction solvents, the conversion rate of triphenylphosphine is improved along with the rise of the reaction temperature, and the double-connected impurities also have the tendency of becoming larger obviously; in addition, esters have the potential to undergo amine transesterification with dimethylamine, which is an additional consumption of dimethylamine; therefore, esters are not suitable as solvents. The aprotic nonpolar solvent such as toluene and n-heptane is used as a reaction solvent, and the conversion rate of triphenylphosphine and the control of double-connected impurities have obvious advantages compared with the two solvents. The boiling point difference between toluene and n-heptane is not too great, and from the results in table one there is no particularly significant difference, although n-heptane is more advantageous than toluene from a solvent safety standpoint. In view of the above reasons, the present invention selects n-heptane as the reaction solvent.
General procedure for preparation of 123B1-10 (reaction time screening):
triphenylphosphine (1.00eq) and 1, 3-dibromopropane (1.00eq) are added into n-heptane (600g), heated to reflux, and reacted for 24-72 hr to obtain 123B1-10 n-heptane dispersion liquid. See table two for specific examples and results:
TABLE II reaction time screening
Liquid phase results: peak area of 123B 1-10: peak area of triphenylphosphine: peak area of 123B1-X2
Dibromopropane residue: gas phase external standard method contrast detection transverse comparison result (reaction solution is settled, then the upper layer of n-heptane clear solution is taken for detection, the proportion of dibromopropane in the clear solution is obtained)
From the results in the table II, the reaction time is too short, the triphenylphosphine residue is relatively large, and the conversion rate is low; over time, the 123B1-10 produced will continue to react with unreacted triphenylphosphine, resulting in a gradual increase in the double-bonded impurity 123B 1-X2. In addition, the reaction time is prolonged, and the energy consumption is inevitably increased. In consideration of the above reasons, the reaction time is about 55-65 hr.
General procedure for preparation of 123B1-10 (feed mole ratio screen):
triphenylphosphine (1.00eq) and 1, 3-dibromopropane (0.90-1.30 eq) were added to n-heptane (600g), and the mixture was heated to reflux and reacted for about 60hr to obtain an n-heptane dispersion of 123B 1-10. See table three for specific examples and results:
effect of feed molar ratio
Liquid phase results: peak area of 123B 1-10: peak area of triphenylphosphine: peak area of 123B1-X2
Dibromopropane residue: gas phase external standard method contrast detection transverse comparison result (reaction solution is settled, then the upper layer of n-heptane clear solution is taken for detection, the proportion of dibromopropane in the clear solution is obtained)
From the results of Table III, whether the 1, 3-dibromopropane is insufficient (. about.0.91 eq) or excessive (. about.1.30 eq), a portion of the 1, 3-dibromopropane remains and it is difficult to completely convert it to the desired product; and (3) integrating the distribution condition of impurities, wherein the feeding ratio is as follows: 1, 3-dibromopropane (w/w) is suitably present in a molar ratio of 200: 154 (about 1: 1).
General procedure for preparation of 123B2-10 (dimethylamine feed ratio selection):
triphenylphosphine (200g) and 1, 3-dibromopropane (154g) were added to n-heptane (600g), and the mixture was heated to reflux and reacted for 60hr to give an n-heptane dispersion of 123B 1-10. After cooling the dispersion to room temperature, 40% dimethylamine aqueous solution (1.00-7.00 eq) was added to the reaction solution, and the mixture was heated to 70-80 ℃ and stirred for reaction for about 8 hours. Concentrating n-heptane and water, if necessary, replenishing part of n-heptane at appropriate time to prevent the system from completely evaporating until water in the system is completely separated out; cooling, crystallizing, filtering, collecting solid, adding anhydrous ethanol, heating to reflux, pulping, filtering, collecting solid, and oven drying; the product 123B2-10 was obtained.
See table four for specific examples and results:
TABLE tetraminolysis reaction and dimethylamine charge ratio screening.
Liquid phase results: peak area of 123B2-10 in the reaction solution: peak area of 123B1-10
And (3) product purity: HPLC (high performance liquid chromatography) detection purity of the finally separated 123B2-10 solid after drying
From the results in table four, the 40% aqueous dimethylamine solution increased to 360g (about 4.19eq), although slightly higher in conversion and yield, but not significantly different from 270g (about 3.14eq) of the feed, but with more water being taken in, requiring more energy and time to remove the water; in the reaction in which 600g (about 6.98eq) of the dimethylamine aqueous solution was charged, the conversion rate was almost 100%, but the yield was rather significantly decreased, probably because a considerable amount of water remained in the system after the n-heptane concentration, which resulted in the loss of the product and the decrease in the yield. For the above reasons, it is preferable to use about 3 equivalents of the aqueous dimethylamine solution.
General procedure for preparation of 123B2-10 (reaction temperature screening):
triphenylphosphine (200g) and 1, 3-dibromopropane (154g) were added to n-heptane (600g), and the mixture was heated to reflux and reacted for 60hr to give an n-heptane dispersion of 123B 1-10. After cooling the dispersion to room temperature, 40% dimethylamine aqueous solution (270g, 3.14eq) was added to the reaction solution, and the mixture was heated to 20 to 80 ℃ and stirred to react for about 8 hours. Concentrating n-heptane and water until the water in the system is completely separated out; cooling, crystallizing, filtering, collecting solid, adding anhydrous ethanol, heating to reflux, pulping, filtering, collecting solid, and oven drying; the product 123B2-10 was obtained. See table five for specific examples and results:
TABLE Penta ammonolysis reaction, reaction temperature screening.
Liquid phase results: peak area of 123B2-10 in the reaction solution: peak area of 123B1-10
And (3) product purity: HPLC (high performance liquid chromatography) detection purity of the finally separated 123B2-10 solid after drying
From the results shown in Table V, the aminolysis reaction was slow at room temperature, and almost complete reaction was achieved within 8hr when the temperature was raised to around the boiling point (49.4 ℃) of 40% aqueous dimethylamine solution, while when the temperature was further raised to over the boiling point of aqueous dimethylamine solution, although no significant vigorous reaction was observed, the conversion rate was slightly decreased, and it was likely that the conversion was decreased due to excessive diffusion of dimethylamine due to excessive temperature. Considering the reasons, the reaction is properly selected at 45-50 ℃.
General procedure for preparation of 123B2-10 (reaction time screening):
triphenylphosphine (200g) and 1, 3-dibromopropane (154g) were added to n-heptane (600g), and the mixture was heated to reflux and reacted for 60hr to give an n-heptane dispersion of 123B 1-10. After cooling the dispersion to room temperature, 40% dimethylamine aqueous solution (270g, 3.14eq) was added to the reaction solution, heated to 45 to 50 ℃, and stirred to react for about 1 to 8 hr. Concentrating n-heptane and water until the water in the system is completely separated out; cooling, crystallizing, filtering, collecting solid, adding anhydrous ethanol, heating to reflux, pulping, filtering, collecting solid, and oven drying; the product 123B2-10 was obtained. See table six for specific examples and results:
TABLE hexaammonolysis reaction, reaction time screening.
Liquid phase results: peak area of 123B2-10 in the reaction solution: peak area of 123B1-10
And (3) product purity: HPLC (high performance liquid chromatography) detection purity of the finally separated 123B2-10 solid after drying
Example 27, example 28, example 29 for the same reaction different reaction time monitoring data. Thus, example 27 and example 28 had no purity and yield data.
Example 30 and example 31 the data obtained were monitored for different reaction times for the same reaction. Thus, example 30 has no purity and yield data.
From the results in table six, the conversion rate reached about 96% after about 2hr of reaction; the reaction is considered to be finished after 4 hours of reaction; the time extension to 8hr is no longer significantly different from the reaction time of 4 hr. In view of the above reasons, the reaction time is preferably 3 to 5 hr.
Comparative example 1 Synthesis of (3-bromopropyl) triphenylphosphonium bromide
600g of toluene is added into a reaction bottle; then adding 200g of triphenylphosphine; 154g of 1, 3-dibromopropane; heating to reflux, and maintaining the temperature for about 60 hr. After the reaction is finished, cooling the reaction liquid to 0-10 ℃; filtration, collection of solids and drying gave 123B1-10, about 306g of product. Yield: 86.5 percent. Liquid phase results: 123B 1-10: triphenylphosphine: 123B1-X2 ═ 99.4: 0.1: 0.5 (excluding other impurities).
Comparative example 2 Synthesis of [3- (dimethylamine) propyl ] triphenylphosphonium bromide hydrobromide
Adding 720g of absolute ethyl alcohol into a reaction bottle, adding about 300g of 123B1-10 obtained in the comparative example 1, adding 450g of 40% dimethylamine aqueous solution, and heating and refluxing for reaction for 4-5 hours; after the reaction is finished, concentrating the dry solvent under reduced pressure, adding 400g of absolute ethyl alcohol into the obtained residue, stirring and heating until reflux is realized, and dispersing the agglomerated solid; cooling and crystallizing; filtration, collection of solids and drying gave 123B2-10, about 273g of product. Single pass yield: 82.9 percent. HPLC: 99.92 percent; wherein: 123B 2-10: triphenylphosphine: 123B1-X2 is 99.97: 0.00: 0.03 (excluding other impurities).
The mother liquor was collected and recovered to yield about 31g of product 123B 2-10. And (3) recovery rate: 9.4 percent. HPLC: 99.63 percent; wherein: 123B 2-10: triphenylphosphine: 123B1-X2 is 99.92: 0.00: 0.08 (excluding other impurities).
The total amount was 123B2-10, which was about 304 g. Total ammonolysis yield: 92.4 percent.
EXAMPLE 32 Synthesis of [3- (dimethylamine) propyl ] triphenylphosphonium bromide hydrobromide
Adding 750kg of n-heptane into a 2000L reaction kettle; then adding 250kg of triphenylphosphine; 192kg of 1, 3-dibromopropane; heating to reflux, and reacting for about 60 hr. After the reaction is finished, cooling the reaction solution to 20-30 ℃; then 335kg of 40% dimethylamine aqueous solution is added; heating to 45-50 ℃, and reacting for about 5hr under heat preservation; the solid in the reaction system gradually and completely dissolved. After the reaction is finished, carrying out reduced pressure concentration, collecting an n-heptane/water azeotrope, adding the separated n-heptane into the reaction system, and continuously concentrating until the water in the reaction system is basically concentrated and dried; cooling the reaction solution, centrifuging, filtering and collecting solid; heating and pulping the collected solid by using absolute ethyl alcohol; cooling, centrifugal filtering, collecting solid, and stoving to obtain 123B2-10 of about 438kg product. Yield: 90.2 percent. HPLC purity: 99.93 percent; wherein: 123B 2-10: triphenylphosphine: 123B1-X2 is 99.96: 0.00: 0.04 (excluding other impurities).
As can be seen from comparative examples 1 to 2 and example 32, the simple method for preparing [3- (dimethylamine) propyl ] triphenylphosphonium bromide hydrobromide according to the present invention substantially eliminates the contact of the operator with highly allergenic substances, and ensures the effective protection of the operator; the dosage of dimethylamine is reduced; the product with the quality not lower than the original process level is obtained. The total yield of the [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrogen Australite prepared by the method is 90.2 percent; the total yield (not counting recovery) of the original process step method is 86.5 percent multiplied by 82.9 percent to 71.7 percent, and the total yield is 86.5 percent multiplied by 90.2 percent to 78.0 percent with recovery; the yield was also significantly improved, probably because some of it was lost with the n-heptane mother liquor during the separation of 123B 1-10; after the process is improved, the intermediate 123B1-10 can be more fully utilized, so that the total yield is improved, and the cost is reduced. In the prior art, due to the worry about the residue and conduction problems of double-connected impurities 123B1-X2 in the first step, a one-pot method is not adopted to prepare [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide, but a step method is adopted to separate relatively pure 123B1-10 and then prepare 123B2-10 so as to ensure the purity of an intermediate; after experimental verification, the invention can effectively control the double-connection impurities 123B1-X2 by adopting a one-pot method to prepare 123B2-10 and control the double-connection impurities to a degree basically equivalent to that of a step method. In addition, the invention uses n-heptane to replace toluene as a reaction solvent for reaction, thereby avoiding the risk of flash explosion caused by the accumulation of static electricity when the toluene is centrifugally filtered, and greatly improving the safety of production.
Claims (3)
1. A method for producing a compound [3- (dimethylamine) propyl ] triphenylphosphonium bromide hydrobromide, characterized by: triphenylphosphine and 1, 3-dibromopropane are taken as starting materials, and a compound (3-bromopropyl) triphenyl phosphonium bromide is obtained through reflux reaction in n-heptane; the obtained intermediate (3-bromopropyl) triphenyl phosphonium bromide is directly reacted with dimethylamine aqueous solution by a one-pot method without separation, after the reaction is finished, n-heptane is concentrated and water in the system is taken out to obtain [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide n-heptane dispersion liquid, the dispersion liquid is centrifugally separated, and the obtained solid is thermally pulped and refined by ethanol and is dried; to obtain a refined product of [3- (dimethylamine) propyl ] triphenyl phosphonium bromide hydrobromide.
2. A method for producing a compound [3- (dimethylamine) propyl ] triphenylphosphonium bromide hydrobromide, characterized by: taking n-heptane as a reaction solvent, triphenylphosphine: the feeding molar ratio of the 1, 3-dibromopropane is preferably 1.0: 0.95-1.05; the heating reflux reaction time is preferably 55-65 hr; directly carrying out ammonolysis reaction on an intermediate (3-bromopropyl) triphenyl phosphonium bromide without separating the intermediate and a dimethylamine aqueous solution by adopting a one-pot method, wherein the heating reaction temperature is preferably 45-55 ℃; triphenylphosphine: the feeding molar ratio of the 40% dimethylamine aqueous solution is preferably 1: 2.5-3.5.
3. Purified compound [3- (dimethylamine) propyl group]A process for the production of triphenylphosphonium bromide hydrobromide, characterised in that: [3- (dimethylamine) propyl group obtained by the production method according to claim 1 or 2]Heating the crude product of triphenyl phosphonium bromide hydrobromide with absolute ethyl alcohol to reflux, pulping and purifying to remove the by-product N in the reaction system1，N1，N3，N3-tetramethyl-1, 3-propanediamine dihydrobromide salt.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5116863A (en) * | 1986-03-03 | 1992-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Dibenz[b,e]oxepin derivative and pharmaceutical compositions thereof |
| CN106046053A (en) * | 2016-06-08 | 2016-10-26 | 湖州恒远生物化学技术有限公司 | Preparation method of [3-(dimethylamino)propyl]triphenylphosphonium bromide hydrobromide |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5116863A (en) * | 1986-03-03 | 1992-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Dibenz[b,e]oxepin derivative and pharmaceutical compositions thereof |
| CN106046053A (en) * | 2016-06-08 | 2016-10-26 | 湖州恒远生物化学技术有限公司 | Preparation method of [3-(dimethylamino)propyl]triphenylphosphonium bromide hydrobromide |
Non-Patent Citations (1)
| Title |
|---|
| 袁晓环等: "环苯扎林的合成研究", 《牡丹江医学院学报》 * |
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