CN109553539A - A kind of preparation method of benzalkonium chloride - Google Patents
A kind of preparation method of benzalkonium chloride Download PDFInfo
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- CN109553539A CN109553539A CN201710892199.7A CN201710892199A CN109553539A CN 109553539 A CN109553539 A CN 109553539A CN 201710892199 A CN201710892199 A CN 201710892199A CN 109553539 A CN109553539 A CN 109553539A
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Abstract
The invention discloses a kind of preparation methods of benzalkonium chloride.The preparation method includes the following steps that fatty alkyl dimethyl tertiary amine and benzyl chloride in organic solvent, at 30~70 DEG C, are carried out salt-forming reaction, obtain fatty alkyl dimethyl benzyl ammonium chloride by (1)；The fatty alkyl is dodecyl, myristyl or cetyl；The organic solvent is one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, acetone and acetonitrile or a variety of；(2) in organic solvent, the mixture for the fatty alkyl dimethyl benzyl ammonium chloride being prepared there are two types of containing or in three kinds of steps (1), is crystallized.Preparation method process of the invention is simple, high income, up to 90% or more；Content in relation to substance is low, purity is high, and up to 99% or more, water content is low, it can be achieved that product appearance form is good, the simple effect of post-processing, meets the requirement of pharmacopoeia of each country, is suitble to industrialized production pharmaceutical grade benzalkonium chloride.
Description
Technical field
The present invention relates to a kind of preparation methods of benzalkonium chloride.
Background technique
Benzalkonium chloride is a kind of quaternary cationic surfactant with bactericidal effect, is eye as pharmaceutic adjuvant
Common bacteriostatic agent in section's preparation.The mixture of chlorodimethyl benzyl hydrocarbon ammonium, USP 38, BP are defined as in foreign pharmacopeia
2013 and EP 8.0 provides that its alkyl composition is mainly dodecyl benzyl dimethyl ammonium chloride, myristyl benzyl dimethyl chlorine
Change ammonium and cetalkonium chloride.Due to different (the domestic and international benzalkonium chloride quality of the sterilization idiocratic of 3 kinds of homologues
The research of difference, bear subgroup etc., Chinese pharmacists [J] the 4th phase of volume 19 in 2016,808~811), foreign pharmacopeia is by controlling it
Relative scale makes inhibitory effect when products application keep relative stability.The U.S. and European Pharmacopoeia also all define benzene and prick chlorine simultaneously
Impurity content in ammonium product limits the content of benzyl alcohol less than 0.5%, and less than 0.1%, benzyl chloride content is less than benzaldehyde content
0.05%.
Document 1 (CN 1267405C), which is disclosed, synthesizes dodecyl dimethyl with benzyl chloride with corresponding tertiary amine mixture
The mixture of benzyl ammonium chloride and myristyl benzyl dimethyl ammonium chloride.It should be pointed out that there are many drawbacks for this method.
Firstly, the higher alkyldimethylbenzylammonium quaternary ammonium salt of purity, this method have selected high-temperature pressure distil(l) in order to obtain
For benzyl chloride as reactant, this undoubtedly increases energy consumption of reaction, the cost of the reaction of raising.Secondly, the violent in toxicity in final product
Matter benzyl chloride content highest is unexpectedly up to 4.82%.The product for the benzalkonium chloride that obvious this method synthesizes is not able to satisfy medicinal requirements.
Document 2 (US 5414124) reports the in the mixed solvent synthesis of alkyl dimethylbenzyl based quaternary ammonium salt in glycol and water
The method of solution.The disadvantages of the method are as follows reaction temperature is excessively high, the concentration of quaternary ammonium salt is lower in final reaction product.
Document 3 (RU 2123491) is reported with the mixed tertiary amine (fatty alkyl two of mainly 12-16 carbon chain lengths
Methyl tertiary amine) and benzyl chloride alkyl diol and water in the mixed solvent, reaction finally obtain concentration be 50-80% fatty alkyl
Dimethyl benzyl quaternary ammonium salt solution.The disadvantages of the method are as follows final product purity is not high, raw material tertiary amine mixture content is relatively high,
It needs to remove them.
Although the embodiment 8 in document 4 (CN 102807494A) provides a kind of synthesis dodecyl dimethyl benzyl chloride
Change the mixture method of ammonium and myristyl benzyl dimethyl ammonium chloride.But the process of its undisclosed purifying of this method.If
The complete raw material of unreacted does not have purification process, and the purity for causing product final is relatively low, and easy to absorb moisture, and this method produces
Product out is not able to satisfy medicinal demand.And since purity is not high enough, add in post-processing in order to improve the stability of product
Enter a certain amount of water, and the water content of product is caused to increase, net purity decline, and product viscosity is big, need to use slicer
Slice crushing is carried out, it is not easy to handle.
In summary the prior art is analyzed, and the method for synthesizing benzalkonium chloride at present is largely by tertiary amine mixture and chlorination
Benzyl is reacted, but the purity of universal final product is not high, contains a large amount of unreacting material and benzyl alcohol, benzaldehyde
Etc. related substance, need further to refine the standard that can be only achieved pharmaceutical grade.Presently commercially available pharmaceutical grade benzalkonium chloride is mostly
The glue or cake mass of yellow, the weighing in subsequent use are inconvenient.
Therefore with high purity, the related substance for needing to develop a kind of benzalkonium chloride obtained is few, water content is few, product appearance shape
State is good, is easily handled, and can satisfy the preparation method of medical industry demand.
Summary of the invention
The technical problem to be solved by the present invention is to receive to overcome the preparation method of benzalkonium chloride in the prior art to exist
Rate is low, it is high to contain toxic by-products, water content, production operation is complicated, the excessively high disadvantage of cost, and provides a kind of benzalkonium chloride
Preparation method.Benzalkonium chloride method for preparing raw material preparation process of the invention is simple, high income, and product purity is high, water content
It is low, it can be achieved that product appearance form is good, the simple effect of post-processing, the requirement of pharmacopoeia of each country can be met, be suitble to industrialized production
Pharmaceutical grade benzalkonium chloride.
The present invention provides a kind of preparation methods of benzalkonium chloride comprising following steps:
(1) in organic solvent, at 30~70 DEG C, fatty alkyl dimethyl tertiary amine and benzyl chloride are subjected to salt-forming reaction,
Obtain fatty alkyl dimethyl benzyl ammonium chloride；The fatty alkyl is dodecyl, myristyl or cetyl；
The organic solvent is one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, acetone and acetonitrile or a variety of；
(2) in organic solvent, the fatty alkyl dimethylbenzyl being prepared there are two types of containing or in three kinds of steps (1)
The mixture of ammonium chloride, is crystallized.
In step (1), the molar ratio of the fatty alkyl dimethyl tertiary amine and the benzyl chloride can be somebody's turn to do for this field
Conventional molar ratio in class salt-forming reaction, mole of heretofore described fatty alkyl dimethyl tertiary amine and the benzyl chloride
Than being preferably 1:(0.9~1.1), it is more preferably 1:1.
In step (1), the dosage of the organic solvent can be the dosage of such salt-forming reaction of this field routine, the present invention
Described in organic solvent and the mass ratio of the fatty alkyl dimethyl tertiary amine be preferably (2~5): 1, be more preferably (3
~4): 1.
In step (1), the salt-forming reaction preferably carries out in anhydrous conditions, and described is anhydrous with this field routine
, such as do not influence reaction.
In step (1), the temperature of the salt-forming reaction is preferably 40~60 DEG C, is more preferably 50 DEG C.
In step (1), the salt-forming reaction preferably carries out under an inert atmosphere；The inert atmosphere is preferably
For one of nitrogen, argon and helium or a variety of.
In step (1), in the salt-forming reaction, the process of the reaction can be using the conventional prison in this field
Survey method (such as TLC, HPLC or NMR) is monitored, when generally being disappeared with chlorination benzyl compound or no longer being reacted eventually for reaction
Point；In the present invention, the time of the salt-forming reaction is preferably 3~5h.
In step (1), the salt-forming reaction may also include following post-processing step: it is after reaction, cooling, it is precipitated solid
Body；Preferably after reaction, reaction system is cooled to -10 DEG C~10 DEG C, and crystallization filters.
In step (2), the organic solvent of the crystallization can be organic solvent conventional in such preparation method of this field, this
In invention be preferably methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, acetone, butanone, cyclohexanone, acetonitrile, ethyl acetate,
Butyl acetate, methylene chloride, chloroform, hexamethylene, one of ether and petroleum ether or a variety of are more preferably acetone, fourth
Ketone, one of acetonitrile and ethyl acetate or a variety of.
In step (2), the dosage of the organic solvent of the crystallization can be dosage conventional in the art, heretofore described
Organic solvent and the mass ratio of the mixture be preferably (4~8): 1, be more preferably (5~7): 1.
In step (2), in the mixture, the dodecyl benzyl dimethyl ammonium chloride (abbreviation C12), it is described
Myristyl benzyl dimethyl ammonium chloride (abbreviation C14) and the cetalkonium chloride (abbreviation C16) matter
Ratio is measured, can be reasonably selected as needed；In the present invention preferably: C12:C14=(0.5~5): 1, C12:C16=(0.5~5): 1,
C14:C16=(0.5~5): 1 or C12:C14:C16=(2~8): (2~5): 1；It is more preferably C12:C14=(2~4): 1, C12:C16
=(2~4): 1, C14:C16=(2~4): 1, C12:C14:C16=8:5:1 or 2:2:1.
In step (2), the mixture can be mode conventional in the art, such as be dissolved in the organic solvent
In, form homogeneous solution；It is preferably dissolved at 30 DEG C~60 DEG C in the present invention.
In step (2), the crystallization preferably carries out in anhydrous conditions, and described is anhydrous with this field routine
, such as do not influence reaction.
In step (2), the crystallization preferably carries out under an inert atmosphere；The inert atmosphere is preferably
One of nitrogen, argon and helium are a variety of.
In step (2), the crystallization may also include following post-processing step: after mixing, cooling, solid, which is precipitated, is
It can；- 10 DEG C~10 DEG C are preferably cooled to, crystallization filters.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: benzalkonium chloride preparation method process of the invention is simple, and high income is reachable
90% or more；Purity is high, up to 99% or more, the content in relation to substance is below USP requirement, and each impurity content is basic
On all be bound requirements 1/10th or less；Water content is low, it can be achieved that product appearance form is good, the simple effect of post-processing,
The requirement of pharmacopoeia of each country can be met, be suitble to industrialized production pharmaceutical grade benzalkonium chloride.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
The preparation of 1 dodecyl benzyl dimethyl ammonium chloride of embodiment
The Dodecyl Dimethyl Amine of 100.00kg (469.5mol), 62.40kg are added in 1000L reaction kettle
The benzyl chloride of (493.0mol) and the acetone of 400.00kg stir 5h at 50 DEG C.Then it is cooled to 0 DEG C.After solid precipitation, mistake
Filter, dry 145.88kg white solid, total recovery 91.5%.Dodecyl benzyl dimethyl ammonium chloride purity is
99.5%.
The preparation of 2 myristyl benzyl dimethyl ammonium chloride of embodiment
The dodecyldimethylamine base tertiary amine of 40.00kg (166.0mol), 19.96kg are added in 500L reaction kettle
The benzyl chloride of (157.7mol) and the acetonitrile of 200.00kg stir 4h at 60 DEG C.Then -10 DEG C are cooled to.After solid precipitation,
Filtering, dry 53.50kg white solid, total recovery 92.3%.Myristyl benzyl dimethyl purity of ammonia chloride is
99.6%.
The preparation of 3 cetalkonium chloride of embodiment
The hexadecyldimethyl benzyl ammonium tertiary amine of 6.00kg (22.3mol), 2.82kg (22.3mol) are added in 50L reaction kettle
Benzyl chloride and 18.00kg ethyl alcohol, stir 6h at 40 DEG C.Then -5 DEG C are cooled to.After solid precipitation, filtering, dry
8.12kg white solid, total recovery 92.1%.Cetalkonium chloride purity is 99.4%.
The preparation of 4 dodecyl benzyl dimethyl ammonium chloride of embodiment
The Dodecyl Dimethyl Amine of 100.00kg (469.5mol), 62.40kg are added in 1000L reaction kettle
The benzyl chloride of (493.0mol) and the acetone of 300.00kg stir 3h at 40 DEG C.Then it is cooled to 0 DEG C.After solid precipitation, mistake
Filter, dry 145.88kg white solid, total recovery 92.5%.Dodecyl benzyl dimethyl ammonium chloride purity is
99.6%.
The preparation of 5 dodecyl benzyl dimethyl ammonium chloride of embodiment
The Dodecyl Dimethyl Amine of 100.00kg (469.5mol), 59.42kg are added in 1000L reaction kettle
The benzyl chloride of (469.5mol) and the isopropanol of 400.00kg stir 5h at 30 DEG C.Then 5 DEG C are cooled to.After solid precipitation,
Filtering, dry 147.30kg white solid, total recovery 92.4%.Dodecyl benzyl dimethyl ammonium chloride purity is
99.7%.
The preparation of 6 myristyl benzyl dimethyl ammonium chloride of embodiment
The dodecyldimethylamine base tertiary amine of 75.00kg (311.2mol), 35.45kg are added in 500L reaction kettle
The benzyl chloride of (280.1mol) and the ethyl alcohol of 250.00kg stir 5h at 40 DEG C.Then -5 DEG C are cooled to.After solid precipitation,
Filtering, dry 94.00kg white solid, total recovery 91.3%.Myristyl benzyl dimethyl purity of ammonia chloride is
99.6%.
The preparation of 7 myristyl benzyl dimethyl ammonium chloride of embodiment
The dodecyldimethylamine base tertiary amine of 75.00kg (311.2mol), 37.40kg are added in 500L reaction kettle
The benzyl chloride of (295.6mol) and the acetonitrile of 200.00kg stir 3h at 50 DEG C.Then it is cooled to 0 DEG C.After solid precipitation, mistake
Filter, dry 98.31kg white solid, total recovery 90.5%.Myristyl benzyl dimethyl purity of ammonia chloride is 99.5%.
The preparation of 8 cetalkonium chloride of embodiment
The hexadecyldimethyl benzyl ammonium tertiary amine of 7.00kg (26.0mol), 3.36kg (26.5mol) are added in 50L reaction kettle
Benzyl chloride and 17.50kg normal propyl alcohol, stir 3h at 50 DEG C.Then -5 DEG C are cooled to.After solid precipitation, filter, it is dry
Obtain 9.47kg white solid, total recovery 92.1%.Cetalkonium chloride purity is 99.5%.
The preparation of 9 cetalkonium chloride of embodiment
The hexadecyldimethyl benzyl ammonium tertiary amine of 7.00kg (26.0mol), 3.22kg (25.5mol) are added in 50L reaction kettle
Benzyl chloride and 25.00kg methanol, stir 4h at 30 DEG C.Then -5 DEG C are cooled to.After solid precipitation, filtering, dry
9.16kg white solid, total recovery 90.9%.Cetalkonium chloride purity is 99.6%.
The system of embodiment 10 dodecyl benzyl dimethyl ammonium chloride and myristyl benzyl dimethyl ammonium chloride mixt
It is standby
100kg dodecyl benzyl dimethyl ammonium chloride, 25kg myristalkonium are added in 1000L reaction kettle
Ammonium chloride and 500kg acetonitrile.50 DEG C of stirring and dissolvings, -5 DEG C of stirrings precipitate crystal, filtering, and dry 122kg white solid is received
Rate 97.6%.
The system of embodiment 11 dodecyl benzyl dimethyl ammonium chloride and myristyl benzyl dimethyl ammonium chloride mixt
It is standby
100kg dodecyl benzyl dimethyl ammonium chloride, 50kg myristalkonium are added in 1000L reaction kettle
Ammonium chloride and 600kg acetone.30 DEG C of stirring and dissolvings, -10 DEG C of stirrings precipitate crystal, filtering, dry that 145.3kg white is solid
Body, yield 96.8%.
The system of embodiment 12 dodecyl benzyl dimethyl ammonium chloride and cetalkonium chloride mixture
It is standby
90kg dodecyl benzyl dimethyl ammonium chloride, 30kg hexadecyldimethyl benzyl ammonium benzyl are added in 1000L reaction kettle
Ammonium chloride and 720kg ethyl acetate.30 DEG C of stirring and dissolvings, 0 DEG C of stirring precipitate crystal, filtering, dry that 115.7kg white is solid
Body, yield 96.4%.
The system of embodiment 13 myristyl benzyl dimethyl ammonium chloride and cetalkonium chloride mixture
It is standby
56kg myristyl benzyl dimethyl ammonium chloride, 14kg hexadecyldimethyl benzyl ammonium benzyl are added in 1000L reaction kettle
Ammonium chloride and 560kg acetone.40 DEG C of stirring and dissolvings, 10 DEG C of stirrings precipitate crystal, filtering, dry 66.4kg white solid,
Yield 94.9%.
14 dodecyl benzyl dimethyl ammonium chloride of embodiment, myristyl benzyl dimethyl ammonium chloride and cetyl two
The preparation of methylbenzyl ammonium chloride mixt
64kg dodecyl benzyl dimethyl ammonium chloride, 40kg myristalkonium are added in 1000L reaction kettle
Ammonium chloride, 8kg cetalkonium chloride and 560kg butanone.60 DEG C of stirring and dissolvings, -10 DEG C of stirrings are precipitated brilliant
Body, filtering, dry 107.3kg white solid, yield 95.8%.
15 dodecyl benzyl dimethyl ammonium chloride of embodiment, myristyl benzyl dimethyl ammonium chloride and cetyl two
The preparation of methylbenzyl ammonium chloride mixt
30kg dodecyl benzyl dimethyl ammonium chloride, 30kg myristalkonium are added in 1000L reaction kettle
Ammonium chloride, 15kg cetalkonium chloride and 525kg ethyl alcohol.40 DEG C of stirring and dissolvings, -5 DEG C of stirrings are precipitated brilliant
Body, filtering, dry 72.2kg white solid, yield 96.3%.
Comparative example 1
Comparative result is carried out according to 1 disclosure of that of embodiment of 102807494 A of CN.
Comparative example 2
It is carried out according to the method in document " Journal of applied biomedicine 12 (2014) 245-253 "
The preparation of dodecyl benzyl dimethyl ammonium chloride, compares.Specific step is as follows: 21.3g is added in 250mL flask
It is anti-to be heated to 80 DEG C of reflux for (0.1mol) Dodecyl Dimethyl Amine, 12.6g (0.1mol) benzyl chloride and 100mL butanone
Answer 12h.Then 1.8mL water is added, continues back flow reaction 6h.Then -30 DEG C of crystallisation by cooling 12h are cooled to.Crude product was passed through
It is dried under reduced pressure after filter, obtains the dodecyl benzyl dimethyl ammonium chloride containing two molecular crystalline water of 32.5g, yield is
96.0%, purity 95.3%, moisture 9.6%.
Comparative example 3
It is carried out according to the method in document " Journal of applied biomedicine 12 (2014) 245-253 "
The preparation of dodecyl benzyl dimethyl ammonium chloride is that water is added without in last handling process with 2 difference of comparative example, is carried out
Comparison.Specific step is as follows: 21.3g (0.1mol) Dodecyl Dimethyl Amine, 12.6g being added in 250mL flask
(0.1mol) benzyl chloride and 100mL butanone are heated to 80 DEG C of back flow reaction 18h.Then -30 DEG C of crystallisation by cooling 12h are cooled to.
Crude product is dried under reduced pressure after filtering, obtains the dodecyl benzyl dimethyl ammonium chloride without containing the crystallization water of 32.7g, is received
Rate is 90.4%, purity 94.1%, moisture 0.8%.
Comparative example 4
According to document, " J.Phys.Chem., 1990,94 (1), the method in 381-387 " carry out dodecyl dimethyl benzyl
The preparation of ammonium chloride, compares.Specific step is as follows: 21.3g (0.1mol) dodecyl two being added in 250mL flask
Methyl tertiary amine, 12.6g (0.1mol) benzyl chloride and 100mL dehydrated alcohol, are heated to 80 DEG C of back flow reaction 36-48h.Reaction knot
Shu Hou, solvent evaporated and unreacted reactant.Crude product is crystallized 3 times with ethyl acetate.It is dried under reduced pressure, obtains 21.80g dodecyl two
Methylbenzyl chloride solid.Yield is 64.3%, purity 99.3%, moisture 0.9%.
Comparative example 5
According to document " Molecules 2007,12,2341-2347 " and " J.Appl.Biomed.2004,2,195-198 "
In method carry out dodecyl benzyl dimethyl ammonium chloride preparation, compare.Specific step is as follows: in 50mL flask
1.0g (0.007mol) dimethyl benzylamine, 2.0g (0.01mol) chlorinated dodecane and 25mL dehydrated alcohol is added, is heated to 80
DEG C back flow reaction 28h.After reaction, solvent evaporated.Crude product carries out column chromatography, and eluent is chloroform/methanol (100/1).
It is finally dried under reduced pressure, obtains 0.84g dodecyl benzyl dimethyl ammonium chloride solid.Yield is 35.3%, and purity is
99.2%, moisture 0.9%.
Effect example 1
The inspection of moisture and purity is carried out to embodiment 1-9, comparative example 1-5, as a result such as table 1.
The Comparative result of 1 embodiment 1-6 of table, comparative example 1-4
| Embodiment | Moisture | Total recovery | Purity |
| Embodiment 1 | 0.9% | 91.5% | 99.5% |
| Embodiment 2 | 0.8% | 92.3% | 99.6% |
| Embodiment 3 | 0.9% | 92.1% | 99.4% |
| Embodiment 4 | 0.7% | 91.5% | 99.6% |
| Embodiment 5 | 0.8% | 92.4% | 99.7% |
| Embodiment 6 | 0.8% | 91.3% | 99.6% |
| Embodiment 7 | 0.7% | 90.5% | 99.5% |
| Embodiment 8 | 0.7% | 92.1% | 99.5% |
| Embodiment 9 | 0.8% | 90.9% | 99.6% |
| Comparative example 1 | 10.7% | 90.3% | 98.8% |
| Comparative example 2 | 9.6% | 96.0% | 95.3% |
| Comparative example 3 | 0.8% | 90.4% | 94.1% |
| Comparative example 4 | 0.9% | 64.3% | 99.3% |
| Comparative example 5 | 0.9% | 35.3% | 99.2% |
In table 1, purity data be with the Mass Calculation of fatty alkyl dimethylbenzyl based quaternary ammonium salt dry product, and it is aqueous
It is unrelated to measure size.It can be seen that from the experimental data in table 1 by fatty alkyl dimethylbenzyl based quaternary ammonium salt produced by the invention
Yield is up to 90% or more, and for water content less than 1.0%, purity may be up to 99% or more.
Disclosed in 102807494 A of CN in method, do not disclose specific purification step.According to finally obtaining
The product of 174.4kg and the water 18.6kg of addition are calculated, and the water content of product is 10.7%.
Comparative example 2, although yield 96% is higher than the present invention, its purity 95.3% is well below the present invention；It is right
Than embodiment 3, water not being added on the basis of comparative example 2 and is crystallized, total recovery is 90.4% close with the present invention,
Purity 94.1% is far below the present invention.But the concrete operation step of comparative example 3, compared with the present invention, the reaction time is more
Long, reaction temperature is higher.Speculate that reaction temperature is excessively high or the reaction time is too long, will lead to the raw material decomposes of part, so right
Purity than 3 final product of embodiment is much smaller than the present invention.Most importantly, crystallization temperature needs in comparative example 2 and 3
At -30 DEG C, need to be cooled down with liquefied ammonia in the industrial production, and the cooling of -10 DEG C~10 DEG C of the present invention only needs to make
Use brine ice.The two is compared, the former cost is 5~10 times of the latter.
Comparative example 4 and 5, due to the change of method for crystallising and solvent either starting material, yield is below this
Invention.
Comparative example 6
The preparation of 12/myristyl benzyl dimethyl ammonium chloride is carried out according to the embodiment 8 in CN 102807494A,
Then refining methd according to the invention is post-processed, and is compared.Specific step is as follows: being added into the reaction kettle of 500L
12/dodecyldimethylamine base tertiary amine mixture of 200kg n-hexane and 109.5kg (feed intake, i.e. 73kg according to the ratio of 2:1
Dodecyl Dimethyl Amine, 36.5kg dodecyldimethylamine base tertiary amine), it is added with stirring the benzyl chloride of 62kg (490mol),
It is heated to 80 DEG C and carries out reflux band water reaction 8h.After reaction, first normal pressure recycles n-hexane, then removes under reduced pressure remaining unrecovered
N-hexane, until do not have n-hexane, obtain the anhydrous mixture of 12/myristyl benzyl dimethyl ammonium chloride.It is cooled to
50 DEG C, 16.8kg water being added, adds this mixture in 700kg acetone, 30 DEG C of stirring and dissolvings, -10 DEG C of stirrings precipitate crystal,
Filtering, dry benzalkonium chloride product.
Effect example 2
The inspection of moisture, alkyl chain composition and impurity content is carried out to embodiment 10~15 and comparative example 6, as a result
Such as table 2.
The Comparative result of table 2 embodiment 10~15 and comparative example 6
Moisture data is measured with moisture titration in table 2, and tertiary amine content is measured by constant-current titration method, benzyl chloride, benzene
Methanol and benzaldehyde content are measured by HPLC.From Table 2, it can be seen that the process benzalkonium chloride moisture of the invention prepared,
Tertiary amine, benzyl chloride, the content of benzyl alcohol and benzaldehyde are below USP requirement, and each impurity content is substantially all as bound requirements
1/10th or less.And comparative example 6, for moisture 9.5% close to 10% limit, tertiary amine content is 20 times of limit,
Benzyl chloride content is 7 times of limit, and benzaldehyde content is 1.5 times of limit.
Claims (10)
1. a kind of preparation method of benzalkonium chloride, which comprises the steps of:
(1) in organic solvent, at 30~70 DEG C, fatty alkyl dimethyl tertiary amine and benzyl chloride is subjected to salt-forming reaction, obtained
Fatty alkyl dimethyl benzyl ammonium chloride；The fatty alkyl is dodecyl, myristyl or cetyl；It is described
Organic solvent be one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, acetone and acetonitrile or a variety of；
(2) in organic solvent, the fatty alkyl dimethyl benzyl chlorine being prepared there are two types of containing or in three kinds of steps (1)
The mixture for changing ammonium, is crystallized.
2. preparation method as described in claim 1, which is characterized in that in step (1), the fatty alkyl dimethyl tertiary amine
Molar ratio with the benzyl chloride is 1:(0.9~1.1)；
And/or in step (1), the mass ratio of the organic solvent and the fatty alkyl dimethyl tertiary amine is (2~5):
1。
3. preparation method as claimed in claim 2, which is characterized in that in step (1), the fatty alkyl dimethyl tertiary amine
Molar ratio with the benzyl chloride is 1:1；
And/or in step (1), the mass ratio of the organic solvent and the fatty alkyl dimethyl tertiary amine is (3~4):
1。
4. preparation method as described in claim 1, which is characterized in that in step (1), the salt-forming reaction is in anhydrous conditions
It carries out；
And/or in step (1), the temperature of the salt-forming reaction is 40~60 DEG C；
And/or in step (1), the salt-forming reaction carries out under an inert atmosphere；
And/or in step (1), the time of the salt-forming reaction is 3~5h.
5. preparation method as claimed in claim 4, which is characterized in that in step (1), the temperature of the reaction is 50 DEG C；
And/or in step (1), the inert atmosphere is one of nitrogen, argon and helium or a variety of.
6. preparation method as described in claim 1, which is characterized in that in step (1), the salt-forming reaction may also include with
Lower post-processing step: it is after reaction, cooling, solid is precipitated.
7. preparation method as claimed in claim 6, which is characterized in that in step (1), after reaction, reaction system is cooling
To -10 DEG C~10 DEG C, crystallization is filtered.
8. preparation method as described in any one of claims 1 to 7, which is characterized in that in step (2), the crystallization it is organic
Solvent is methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, acetone, butanone, cyclohexanone, acetonitrile, ethyl acetate, butyl acetate,
Methylene chloride, chloroform, hexamethylene, one of ether and petroleum ether or a variety of；
And/or in step (2), the mass ratio of the organic solvent and the mixture is (4~8): 1；
And/or in step (2), in the mixture, the dodecyl benzyl dimethyl ammonium chloride, the tetradecane
The mass ratio of base dimethyl benzyl ammonium chloride and the cetalkonium chloride are as follows: C12:C14=(0.5~
5):1、C12:C16=(0.5~5): 1, C14:C16=(0.5~5): 1 or C12:C14:C16=(2~8): (2~5): 1；
And/or in step (2), the mixture is to be dissolved in the organic solvent, forms homogeneous solution；
And/or in step (2), the crystallization is to carry out in anhydrous conditions；
And/or in step (2), the crystallization is to carry out under an inert atmosphere.
9. preparation method as claimed in claim 8, which is characterized in that in step (2), the organic solvent of the crystallization is third
Ketone, butanone, one of acetonitrile and ethyl acetate or a variety of；
And/or in step (2), the mass ratio of the organic solvent and the mixture is (5~7): 1；
And/or in step (2), in the mixture, the dodecyl benzyl dimethyl ammonium chloride, the tetradecane
The mass ratio of base dimethyl benzyl ammonium chloride and the cetalkonium chloride are as follows: C12:C14=(2~4):
1、C12:C16=(2~4): 1, C14:C16=(2~4): 1, C12:C14:C16=8:5:1 or 2:2:1；
And/or in step (2), the mixture is to dissolve at 30 DEG C~60 DEG C；
And/or in step (2), the inert atmosphere is one of nitrogen, argon and helium or a variety of.
10. preparation method as described in claim 1, which is characterized in that in step (2), after the crystallization further includes following
Processing step: it is after mixing, cooling, solid is precipitated；- 10 DEG C~10 DEG C are preferably cooled to, crystallization filters.
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| CN113861037A (en) * | 2021-09-24 | 2021-12-31 | 泰柯棕化(张家港)有限公司 | Production process of low-residue medicinal benzalkonium chloride |
| CN113861037B (en) * | 2021-09-24 | 2024-07-02 | 泰柯棕化(张家港)有限公司 | Production process of low-residue medicinal benzalkonium chloride |
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