CN106632032B - Dequalinium Chloride and preparation method thereof - Google Patents
Dequalinium Chloride and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention provides a kind of preparation methods of Dequalinium Chloride and the like, and in particular to a kind of the method for preparing compound of formula I, comprising the following steps: (1) Formula II compound is added to containing Cl‑In the solution of water, reaction；(2) oxidant is added into the product of step (1), reacts；Wherein, R and R1It is each independently selected from H atom and C1~C6 alkyl, n is 4~20.The method of the present invention yield with higher.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the preparation method of Dequalinium Chloride and the like.
Background technique
Dequalinium Chloride (CAS:522-51-0) also known as dequaline chloride are broad spectrum antibiotic, are mainly used for acute laryngopharyngitis, mouth
Chamber bactericidal antiphlogistic etc..Dequalinium Chloride is a kind of cationic surfactant, to gram-positive bacteria, Gram-negative bacteria and white
Color candida albicans, conveyor screw etc. have killing effect.
The bacterium for leading to canker sore can be effectively killed after Dequalinium Chloride oral cavity medicine.Clinical research is using normal
On the basis of rule treatment canker sore, add the Dequalinium Chloride lozenge used and there are antibacterial and anti-inflammation functions, as a result treatment group is total effective
Rate has no the generation of adverse reaction up to 90.7%.Dequalinium Chloride treatment is light, moderate canker sore has significant in efficacy, use
Convenient, patient is easy to the advantages that receiving, few side effects, is worth clinical promotion and application.
The characteristics of Dequalinium Chloride is that bactericidal range is wide, effect is fast, effect is strong, and almost without toxicity and irritation, and it is lived
Property is not influenced by saliva and serum, will not be absorbed by the blood, be excreted after taking with excrement.From the point of view of toxicity test,
The product is the high kind of a safety, to the harmfulness of pregnant woman, breast feeding women also very little.
With the deterioration of environment, oral cavity and Throat diseases have become common disease, frequently-occurring disease.Dequalinium Chloride is clinically
It is widely used always.
Chinese patent CN103387537A discloses a kind of preparation method of compound Dequalinium Chloride, which uses nothing
As reaction dissolvent Dequalinium Chloride is prepared, product yield is about 45% in the isoamyl alcohol of poison.How Dequalinium Chloride is improved
Yield is that technical staff endeavours to solve the problems, such as always.
Summary of the invention
The inventors discovered that preparing Dequalinium Chloride and the like using the method for the present invention, product yield can be improved.
It is an object of the present invention to provide a kind of methods for preparing Dequalinium Chloride and the like, and of the invention is another
A purpose is to provide a kind of method that high yield prepares Dequalinium Chloride and the like.
First aspect present invention provides a kind of the method for preparing compound of formula I, comprising the following steps:
(1) Formula II compound is added to containing Cl-In the solution of water, reaction；
(2) oxidant is added into the product of step (1), reacts；
Wherein, R and R1 is each independently selected from H atom and C1~C6 alkyl, and n is 4~20.
In one embodiment, iodide ion is contained in the product of step (1), the oxidant that step (2) is added can incite somebody to action
Iodide ion is oxidized into elemental iodine.
Surprisingly it has been found that in aqueous solution, the reaction that iodide ion is oxidized to elemental iodine is easier inventor
Occur, and occur more abundant, by converting elemental iodine for iodide ion, so that the yield of compound of formula I (such as Dequalinium Chloride)
It is higher.
Inventor also found, when using water-free solvent (such as methanol) as reaction dissolvent, the oxidation of iodide ion is anti-
It should be less likely to occur, the yield of compound of formula I (such as Dequalinium Chloride) is lower.
In one embodiment, the method for preparing compound of formula I of any one of present invention, it is described to contain Cl-With water
Solution is the solution containing HCl and water, preferably hydrochloric acid.
In one embodiment, the concentration of HCl is 20wt% or more, preferably 20~37wt%, then example in the hydrochloric acid
Such as 20~30wt%.
Use hydrochloric acid as reaction raw materials, other base cations will not be introduced, is conducive to the purification of product.
Use concentrated hydrochloric acid (HCl concentration about 20~37wt%) as reaction raw materials, wherein Cl-The concentration of ion compared with
Height is conducive to reaction balance and carries out to the direction for generating compound of formula I (such as Dequalinium Chloride).
In one embodiment, the method for preparing compound of formula I of any one of present invention, wherein step (1), by every 4
The Formula II compound of~6mol is added to 15~20L and contains Cl-In the solution of water, reaction.
The Formula II compound of every 4~6mol is added to 15~20L and contains Cl-It is reacted in the solution of water, is conducive to Formula II
Compound fully disperses and reacts in the solution, avoids Formula II compound because of the very few generation agglomerate of solvent, cannot sufficiently participate in
Reaction.
In one embodiment, the method for preparing compound of formula I of any one of present invention, the oxidant is liquid
Or solid, preferably liquid；
Preferably, the oxidant includes the one or more of following substance: hydrogen peroxide, Oxone and Peracetic acid；
Preferably, the oxidant includes the one or more of following substance: aqueous hydrogen peroxide solution, Oxone aqueous solution
And peroxide acetate aqueous solution.
Preferably, the oxidant is the aqueous hydrogen peroxide solution of 1~5wt% (such as 3wt%)；
Preferably, every 15~20L (such as 18L) contains Cl-In the solution of water, 5~7L (such as 6L) described mistake is added
Aqueous solution of hydrogen is aoxidized, the addition speed of the preferably described aqueous hydrogen peroxide solution is 20~50mL/ minutes, such as 30~40mL/ divides
Clock.
Preferably, the oxidant is the Oxone aqueous solution of 0.3~0.8mol/L (such as 0.5mol/L)；
Preferably, every 15~20L (such as 18L) contains Cl-In the solution of water, it is described that 8~13L (such as 10L) is added
Oxone aqueous solution, the addition speed of the preferably described Oxone aqueous solution are 30~70mL/ minutes, such as 50~60mL/ minutes.
Preferably, the oxidant is the peroxide acetate aqueous solution of 0.3~0.8mol/L (such as 0.5mol/L)；
Preferably, every 15~20L (such as 18L) contains Cl-In the solution of water, it is described that 8~13L (such as 10L) is added
Peroxide acetate aqueous solution, the addition speed of the preferably described peroxide acetate aqueous solution is 30~70mL/ minutes, such as 50~60mL/
Minute.
Inventors have found that if oxidant is added, speed is excessively slow, and the reaction time is too long, and efficiency is too low；If speed is added in oxidant
It spends fastly, reaction may very acutely, and cause, which will lead to, occurs the adverse consequences such as material spray.The addition speed of above-mentioned oxidant has
It is gone on smoothly conducive to reaction.
In one embodiment, the method for preparing compound of formula I of any one of present invention, the oxidant can
Iodide ion is oxidized to elemental iodine, the oxidant cannot aoxidize chloride ion.
Inventors have found that iodide ion selectively can be oxidized to elemental iodine by hydrogen peroxide, Oxone and Peracetic acid,
Without aoxidizing chloride ion.Moreover, the product after hydrogen peroxide, Oxone and Peracetic acid reaction is easy to walk by subsequent processing
Rapid removal, basic noresidue.
In one embodiment, the method for preparing compound of formula I of any one of present invention, have with the next item down or
Multinomial feature:
A) in step (1), reaction carries out at reflux；
B) in step (1), the temperature of reaction is to contain Cl-With the boiling temperature of the solution of water (such as 60~110 DEG C, then
Such as 80~110 DEG C)；
C) in step (1), the time of reaction is 1~2 hour；
D) in step (1), the molar ratio of HCl and Formula II compound is greater than or equal to 1, preferably greater than or equal to 1.5.
In one embodiment, the method for preparing compound of formula I of any one of present invention has with the next item down or more
Item feature:
E) in step (2), the temperature of reaction is 40~70 DEG C (such as 50 DEG C)；
F) in step (2), reaction to free-iodine ion is substantially all be oxidized into elemental iodine until.
In one embodiment, in step (1), reaction is to carry out under normal pressure.
The reaction temperature of step (2) is conducive to redox reaction at 40~70 DEG C (such as 50 DEG C) and goes on smoothly.
In addition, inventors have found that 40~70 DEG C (such as 50 DEG C) at a temperature of, the particle of the elemental iodine of generation is smaller,
Good dispersion, convenient for passing through distillation the step of, remove.If temperature is too low, the reaction time is too long, or is not thorough, or even can
Elemental iodine can be formed, package product occurs at bulky grain.
In one embodiment, the method for preparing compound of formula I of any one of present invention, it is further comprising the steps of
One or more steps:
(3) elemental iodine in the product of step (2) is made to distil,
Preferably, the product of heating stepses (2) makes elemental iodine therein distil,
It is further preferred that heating temperature is about 70~90 DEG C, such as 80~90 DEG C；
Optionally, it also ventilates when heated into the product of step (2), such as blowing air；
Optionally, also by condensing and collecting the elemental iodine to distil out.
In one embodiment, the method for preparing compound of formula I of any one of present invention, further comprising the steps of:
(4) following one or more steps processing is carried out to gained compound of formula I: crystallizes, is filtered, washed, decolourizes and ties again
It is brilliant.
The product of heating stepses (2) makes the method for elemental iodine distillation therein, both can be abundant from product by elemental iodine
Separation, and can be recycled elemental iodine by further condensing, realize making full use of for raw material.
In one embodiment, the method for preparing compound of formula I of any one of present invention, have with the next item down or
Multinomial feature:
G) it is counted using Formula II compound as raw material, the yield of compound of formula I is greater than or equal to 60%, preferably greater than or equal to
70%.
H) purity of compound of formula I is greater than or equal to 95%, preferably greater than or equal to 98%, still more preferably greater than or is equal to
99%.
In one embodiment, the method for preparing compound of formula I of any one of present invention, have with the next item down or
Multinomial feature:
I) R is methyl, ethyl or propyl；
J) R1 is H atom；
K) n=8~12；
In one embodiment, the method for preparing compound of formula I of any one of present invention, compound of formula I are ground quinoline chlorine
Ammonium, Formula II compound are ground quinoline iodine ammonium.
In one embodiment, C1~C6 alkyl refers to the linear chain or branched chain monovalent hydrocarbon of saturation, has 1~6 carbon
Atom, such as 1~5 carbon atom, then such as 1~4 carbon atom, then such as 1~3 carbon atom, including but not limited to first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, n-pentyl, tertiary pentyl, neopentyl, hexyl etc..
In one embodiment, the oxidant does not have Cl-It is oxidized to Cl2Oxidability.
In one embodiment, the oxidant have can be by I-It is oxidized to I2Oxidability.
In one embodiment, Dequalinium Chloride is mainly synthesized by following reaction: with 4- amidoquinaldine (3) and 1,10-
Diiodo- decane is starting material, is reacted in solvent nitrobenzene, and ground quinoline iodine ammonium (2), then land used quinoline iodine ammonium (2) preparation ground are obtained
Quinoline oronain (1), reaction equation is as follows:
Herein, described Dequalinium Chloride and the like refers to the compound with Formulas I structure.
Herein unless otherwise instructed, all equal representation quality scores of percentage.
Advantageous effects of the invention
Some embodiments of the present invention have it is following one or more the utility model has the advantages that
1) method that some embodiments prepare Dequalinium Chloride produces reaction to generation by the iodide ion in removal solution
The direction of object carries out, and improves the yield of Dequalinium Chloride；
2) method that some embodiments prepare Dequalinium Chloride, the mode for removing iodide ion is: ground quinoline iodine ammonium being added to and is contained
Cl-It is reacted in the solution of water, and iodide ion is oxidized to elemental iodine by way of oxidant is added；
The above method had not only improved the yield of Dequalinium Chloride, but also can recycle obtained iodine, and there are also mentioning convenient for product
It is pure；
3) method that some embodiments prepare Dequalinium Chloride makes the elemental iodine in solution distil by way of heating, into
One step recycles elemental iodine by way of condensation, reduces the discharge of waste, improves the utilization of raw material；
4) method that some embodiments prepare Dequalinium Chloride, using hydrogen peroxide, Oxone and Peracetic acid or they
Aqueous solution as oxidant, have it is at low cost, it is easy to operate, after reaction the advantages of noresidue；
5) method that some embodiments prepare Dequalinium Chloride, with product total recovery is high, easy to operate, production cost
Low, stable product quality, product purification are convenient, by-product is easily recycled one or more advantages such as recycling, are suitable for industry
Metaplasia produces.
Specific embodiment
It will refer to specific embodiments of the present invention in detail now.Although describing this in conjunction with these specific embodiments
Invention, it is appreciated that being not intended to limit the invention to these specific embodiments.On the contrary, these embodiments are intended to cover
It may include substitution, change or equivalent embodiments in the spirit and range being defined by the claims.It is retouched in following
In stating, elaborate a large amount of details in order to provide complete understanding of the present invention.The present invention can be not part or all of
It is carried out in the case where these details.In other cases, in order not to obscure the present invention unnecessarily, without detailed
Technological operation known to describing.
When with " comprising ", " method includes ", " device includes " or the similar language in this specification and the appended claims
When being used in combination, singular " certain ", " some ", "the" include plural reference, unless the context clearly dictates otherwise.Unless
In addition it defines, all technical and scientific terms used herein have general technical staff of the technical field of the invention
Normally understood identical meanings.Finally it should be noted that: the above embodiments are merely illustrative of the technical solutions of the present invention and
It is non-that it is limited；Although the present invention is described in detail with reference to preferred embodiments, those of ordinary skill in the art
It is understood that can still modify to a specific embodiment of the invention or equally be replaced to some technical characteristics
It changes；Without departing from the spirit of the technical scheme of the invention, it should all cover and work as in the claimed technical proposal scope of the present invention
In.
In following specific embodiments, with ground quinoline iodine ammonium (a kind of Formula II compound) and a kind of Dequalinium Chloride (Formulas I chemical combination
Object) for, preparation method of the invention is described.
The structural formula of the substance being related in following specific embodiments, Chinese and No. CAS are as shown in table 1.
Table 1
Quinoline iodine ammonium in ground involved in following specific embodiments is synthesized by following methods:
The synthesis of ground quinoline iodine ammonium
4- amidoquinaldine 4kg (25.3mol), double iodine decane 4.3kg (10.9mol), nitrobenzene 9L are put into reaction
In tank, stirring is heated to 150~160 DEG C, maintains thermotonus 6 hours, is cooled to room temperature, and filters, uses methanol respectively
It foam washing 2 times (each 4L), is filtered dry, with 5% hydrochloric acid solution foam washing 2 times, being washed to pH is 6, is filtered dry, then eluted with proper amount of methanol
Once, it is filtered dry, 60-70 DEG C of drying, obtains lark powder, i.e. decane 1, bis- (the 4- amidoquinaldine iodo) salt of 10- are (referred to as
Quinoline iodine ammonium).Gained ground quinoline iodine ammonium quality 3.64kg, yield about 47%.Through detecting, ground quinoline iodine ammonium fusing point is 300-308 DEG C.
The synthesis (methanol+dry hydrogen chloride gas method) of 1 Dequalinium Chloride of comparative example
Ground quinoline iodine ammonium 3.6kg (5.07mol) and methanol 40L are put into reactor tank, temperature rising reflux 30 minutes, are passed through
Dry hydrogen chloride gas leads to and finishes to being saturated, and keeps the temperature 2 hours.Then it is about 28L that decompression, which steams methanol, is cooled to room temperature, cold
Freezeout crystallization is stood overnight, and is filtered dry, and first twice with 5% hydrochloric acid solution foam washing, then being washed till pH with bubble is 6~7, is discharged, dry
Obtain light gray-white powder, i.e. Dequalinium Chloride crude product 2.69kg.Yield 100.5%.Fusing point is greater than 308 DEG C of decomposition.It is added 30 times
Boiling water and 1% injection-use activated carbon decolourize and recrystallize, obtain the Dequalinium Chloride of the white crystalline of 1.3kg.Yield
50%.Through detecting, Dequalinium Chloride purity is 95.3%
The synthesis (20wt% hydrochloric acid+hydrogen peroxide method) of 1 Dequalinium Chloride of embodiment
Ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration the hydrochloric acid 18L for being 20wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 100~110 DEG C of reflux temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, the hydrogen peroxide of 3wt% is slowly dropped into 30mL/ minutes speed
Aqueous solution 6L (the about 5.29mol containing hydrogen peroxide), abundant quick agitating solution, and 1 hour is kept the temperature at 50 DEG C.Observe solution
It darkens, and there is granular elemental iodine to generate.
Solution in reactor tank is warming up to about 90 DEG C, and is passed through air into solution, elemental iodine is made to distil, and with condensation
Device collects the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution
Temperature drop is to room temperature.
Solution in reactor tank is freezed and stood overnight, Dequalinium Chloride is crystallized.Filtering solution obtains Dequalinium Chloride knot
Crystalline substance is washed twice with methanol, then being washed till pH with bubble is 6~7, discharging, dry lark powder, i.e. Dequalinium Chloride crude product
2.67kg.The yield of Dequalinium Chloride crude product about 100% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 2.08kg, yield 78% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 97.3%.
The synthesis (30wt% hydrochloric acid+hydrogen peroxide method) of 2 Dequalinium Chloride of embodiment
Ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration the hydrochloric acid 10L for being 30wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 80~90 DEG C of temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, the hydrogen peroxide of 3wt% is slowly dropped into 30mL/ minutes speed
Aqueous solution 6L (the about 5.29mol containing hydrogen peroxide), abundant quick agitating solution, and 1 hour is kept the temperature at 50 DEG C.Observe solution
It darkens, and there is granular elemental iodine to generate.
Solution in reactor tank is warming up to about 90 DEG C, and is passed through air into solution, elemental iodine is made to distil, and with condensation
Device collects the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution
Temperature drop is to room temperature.
Solution in reactor tank is freezed and stood overnight, Dequalinium Chloride is crystallized.Filtering solution obtains Dequalinium Chloride knot
Crystalline substance is washed twice with methanol, then being washed till pH with bubble is 6~7, discharging, dry lark powder, i.e. Dequalinium Chloride crude product
2.61kg.The yield of Dequalinium Chloride crude product about 97% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 2.24kg, yield 84% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 98.0%.
The synthesis (37wt% hydrochloric acid+hydrogen peroxide method) of 3 Dequalinium Chloride of embodiment
Ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration the hydrochloric acid 10L for being 37wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 60~80 DEG C of temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, the hydrogen peroxide of 3wt% is slowly dropped into 30mL/ minutes speed
Aqueous solution 6L (the about 5.29mol containing hydrogen peroxide), abundant quick agitating solution, and 1 hour is kept the temperature at 50 DEG C.Observe solution
It darkens, and there is granular elemental iodine to generate.
Solution in reactor tank is warming up to about 80 DEG C, and is passed through air into solution, elemental iodine is made to distil, and with condensation
Device collects the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution
Temperature drop is to room temperature.
Solution in reactor tank is freezed and stood overnight, Dequalinium Chloride is crystallized.Filtering solution obtains Dequalinium Chloride knot
Crystalline substance is washed twice with methanol, then being washed till pH with bubble is 6~7, discharging, dry lark powder, i.e. Dequalinium Chloride crude product
2.61kg.The yield of Dequalinium Chloride crude product about 97% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 2.38kg, yield 89% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 98.6%.
The synthesis (20wt% hydrochloric acid+Oxone method) of 4 Dequalinium Chloride of embodiment
Ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration the hydrochloric acid 13L for being 20wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 100~110 DEG C of temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, is slowly added to 0.507mol/L's with 50mL/ minutes speed
The aqueous solution 10L (the about 5.07mol containing Oxone) of Oxone, while sufficiently quick agitating solution.If liquid level is substantially reduced, fit
When supplement hydrochloric acid.After being added dropwise, 50 DEG C keep the temperature 1 hour.It observes that solution colour deepens, and has granular elemental iodine raw
At.
Solution in reactor tank is warming up to 90 DEG C, and is passed through air into solution, so that elemental iodine is distilled, and with condenser
Collect the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution temperature
It is down to room temperature.
It by the solution freezing in reactor tank, and stands overnight, crystallizes Dequalinium Chloride.Filtering solution obtains Dequalinium Chloride
Crystallization, is washed twice with methanol, then being washed till pH with bubble is 6~7, and discharging is dry that lark powder, i.e. Dequalinium Chloride are thick
Product 2.67kg.The yield of Dequalinium Chloride crude product about 100% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 2.08kg, yield 78% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 97.4%.
The synthesis (30wt% hydrochloric acid+Oxone method) of 5 Dequalinium Chloride of embodiment
Ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration the hydrochloric acid 13L for being 30wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 80~90 DEG C of reflux temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, is slowly added to 0.507mol/L's with 50mL/ minutes speed
The aqueous solution 10L (the about 5.07mol containing Oxone) of Oxone, while sufficiently quick agitating solution.If liquid level is substantially reduced, fit
When supplement hydrochloric acid.After being added dropwise, 50 DEG C keep the temperature 1 hour.It observes that solution colour deepens, and has granular elemental iodine raw
At.
Solution in reactor tank is warming up to 90 DEG C, and is passed through air into solution, so that elemental iodine is distilled, and with condenser
Collect the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution temperature
It is down to room temperature.
It by the solution freezing in reactor tank, and stands overnight, crystallizes Dequalinium Chloride.Filtering solution obtains Dequalinium Chloride
Crystallization, is washed twice with methanol, then being washed till pH with bubble is 6~7, and discharging is dry that lark powder, i.e. Dequalinium Chloride are thick
Product 2.67kg.The yield of Dequalinium Chloride crude product about 100% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 2.27kg, yield 85% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 97.8%.
The synthesis (37wt% hydrochloric acid+Oxone method) of 6 Dequalinium Chloride of embodiment
Ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration the hydrochloric acid 13L for being 37wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 60~80 DEG C of temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, is slowly added to 0.507mol/L's with 50mL/ minutes speed
The aqueous solution 10L (the about 5.07mol containing Oxone) of Oxone, while sufficiently quick agitating solution.If liquid level is substantially reduced, fit
When supplement hydrochloric acid.After being added dropwise, 50 DEG C keep the temperature 1 hour.It observes that solution colour deepens, and has granular elemental iodine raw
At.
Solution in reactor tank is warming up to 80 DEG C, and is passed through air into solution, so that elemental iodine is distilled, and with condenser
Collect the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution temperature
It is down to room temperature.
It by the solution freezing in reactor tank, and stands overnight, crystallizes Dequalinium Chloride.Filtering solution obtains Dequalinium Chloride
Crystallization, is washed twice with methanol, then being washed till pH with bubble is 6~7, and discharging is dry that lark powder, i.e. Dequalinium Chloride are thick
Product 2.63kg.The yield of Dequalinium Chloride crude product about 98% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 2.32kg, yield 87% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 99.1%.
The synthesis (20wt% hydrochloric acid+Peracetic acid method) of 7 Dequalinium Chloride of embodiment
The hydrochloric acid 13L of ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration about 20wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 100~110 DEG C of reflux temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, is slowly dropped into 50mL/ minutes speed into solution
The aqueous solution 10L (containing about 5.07mol Peracetic acid) of the Peracetic acid of 0.507mol/L, while sufficiently quick agitating solution.
If liquid level is substantially reduced, hydrochloric acid is suitably supplemented.It observes that solution colour deepens, and there is granular elemental iodine to generate.
Solution in reactor tank is warming up to 90 DEG C, and is passed through air into solution, so that elemental iodine is distilled, and with condenser
Collect the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution temperature
It is down to room temperature.
It by the solution freezing in reactor tank, and stands overnight, crystallizes Dequalinium Chloride.Filtering solution obtains Dequalinium Chloride
Crystallization, is washed twice with methanol, then being washed till pH with bubble is 6~7, and discharging is dry that lark powder, i.e. Dequalinium Chloride are thick
Product 2.67kg.The yield of Dequalinium Chloride crude product about 100% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 2.03kg, yield 76% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 97.1%.
The synthesis (30% hydrochloric acid+Peracetic acid method) of 8 Dequalinium Chloride of embodiment
The hydrochloric acid 13L of ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration about 30wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 80~90 DEG C of temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, is slowly dropped into 50mL/ minutes speed into solution
The aqueous solution 10L (containing about 5.07mol Peracetic acid) of the Peracetic acid of 0.507mol/L, while sufficiently quick agitating solution.
If liquid level is substantially reduced, hydrochloric acid is suitably supplemented.It observes that solution colour deepens, and there is granular elemental iodine to generate.
Solution in reactor tank is warming up to 90 DEG C, and is passed through air into solution, so that elemental iodine is distilled, and with condenser
Collect the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution temperature
It is down to room temperature.
It by the solution freezing in reactor tank, and stands overnight, crystallizes Dequalinium Chloride.Filtering solution obtains Dequalinium Chloride
Crystallization, is washed twice with methanol, then being washed till pH with bubble is 6~7, and discharging is dry that lark powder, i.e. Dequalinium Chloride are thick
Product 2.67kg.The yield of Dequalinium Chloride crude product about 100% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 2.22kg, yield 83% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 98.6%.
The synthesis (37% hydrochloric acid+Peracetic acid method) of 9 Dequalinium Chloride of embodiment
The hydrochloric acid 13L of ground quinoline iodine ammonium 3.6kg (5.07mol) and concentration about 37wt% are put into reactor tank, stirring is simultaneously
Temperature rising reflux (about 60~80 DEG C of temperature) reacts 1 hour.
Solution in reactor tank is waited cooling to 50 DEG C, is slowly dropped into 50mL/ minutes speed into solution
The aqueous solution 10L (containing about 5.07mol Peracetic acid) of the Peracetic acid of 0.507mol/L, while sufficiently quick agitating solution.
If liquid level is substantially reduced, hydrochloric acid is suitably supplemented.It observes that solution colour deepens, and there is granular elemental iodine to generate.
Solution in reactor tank is warming up to 80 DEG C, and is passed through air into solution, so that elemental iodine is distilled, and with condenser
Collect the iodine for distilling out.When the color of solution from it is dark brown become shallow palm fibre when, stop heating and blowing air, stirring, to solution temperature
It is down to room temperature.
It by the solution freezing in reactor tank, and stands overnight, crystallizes Dequalinium Chloride.Filtering solution obtains Dequalinium Chloride
Crystallization, is washed twice with methanol, then being washed till pH with bubble is 6~7, and discharging is dry that lark powder, i.e. Dequalinium Chloride are thick
Product 2.63kg.The yield of Dequalinium Chloride crude product about 98% (quinoline iodine ammonium is counted from ground), fusing point are greater than 310 DEG C, decompose simultaneously.
The boiling water of 30 times of quality and 1% injection-use activated carbon decoloration are added into Dequalinium Chloride crude product, and recrystallizes,
Obtain the Dequalinium Chloride of the white crystalline of 1.98kg, yield 86% (from ground, quinoline iodine ammonium is counted).Through detecting, the Dequalinium Chloride
Purity is 98.4%.
Examples 1 to 9 prepares the method for Dequalinium Chloride compared with comparative example 1, can greatly improve the receipts of Dequalinium Chloride
Rate obtains the medicine Dequalinium Chloride of high-purity.The method of Examples 1 to 9 is simple to operation, and the life of Dequalinium Chloride can be greatly reduced
Cost is produced, and reaction condition is mild, is suitable for industrialized production.
In above-mentioned specific embodiment, Dequalinium Chloride method for detecting purity is as follows:
Dequalinium Chloride sample about 0.3g is taken, accurately weighed, acetic acid 40ml on the rocks after low-grade fever and the dissolution that flows back, multiplies heat plus vinegar
Sour mercury test solution 5ml, it is cooling, add crystal violet indicator solution 1 to drip, is titrated to solution with perchloric acid titration liquid (0.1mol/L) and shows ethereal blue
Color, and titration results are corrected with blank test.The perchloric acid titration liquid (0.1mol/L) of every 1ml is equivalent to the ground of 26.38mg
Quinoline oronain C30H40Cl2N4。
Finally it should be noted that: the above embodiments are merely illustrative of the technical scheme of the present invention and are not intended to be limiting thereof；To the greatest extent
The present invention is described in detail with reference to preferred embodiments for pipe, it should be understood by those ordinary skilled in the art that: still
It can modify to a specific embodiment of the invention or some technical features can be equivalently replaced；Without departing from this
The spirit of inventive technique scheme should all cover within the scope of the technical scheme claimed by the invention.
Claims (17)
1. a kind of the method for preparing compound of formula I, comprising the following steps:
(1) Formula II compound is added to containing Cl- In the solution of water, reaction；
(2) oxidant is added into the product of step (1), reacts, the temperature of reaction is 40~70 DEG C；
(3) product of heating stepses (2) makes elemental iodine therein distil, and ventilates when heated into the product of step (2), makes iodine
Simple substance distillation, by condensing and collecting the elemental iodine to distil out；
Wherein, R and R1 is each independently selected from H atom and C1~C6 alkyl, and n is 4~20；
Wherein, step (2) has any one of following feature:
The oxidant is the aqueous hydrogen peroxide solution of 1~5wt%, and every 15~20L contains Cl-In the solution of water, addition 5~
Aqueous hydrogen peroxide solution described in 7L, the addition speed of aqueous hydrogen peroxide solution are 20~50mL/ minutes；
The oxidant is the Oxone aqueous solution of 0.3~0.8mol/L, and every 15~20L contains Cl-In the solution of water, it is added 8
Oxone aqueous solution described in~13L, the addition speed of the Oxone aqueous solution are 30~70mL/ minutes；
The oxidant is the peroxide acetate aqueous solution of 0.3~0.8mol/L, and every 15~20L contains Cl-In the solution of water, add
Enter peroxide acetate aqueous solution described in 8~13L, the addition speed of the peroxide acetate aqueous solution is 30~70mL/ minutes.
2. resulting the method for preparing compound of formula I according to claim 1, it is characterised in that any one of following:
The addition speed of the aqueous hydrogen peroxide solution is 30~40mL/ minutes；
The addition speed of the Oxone aqueous solution is 50~60mL/ minutes；
The addition speed of the peroxide acetate aqueous solution is 50~60mL/ minutes.
3. the method for preparing compound of formula I according to claim 1, described to contain Cl- Solution with water is to contain HCl
With the solution of water.
4. the method for preparing compound of formula I according to claim 1, described to contain Cl- Solution with water is hydrochloric acid.
5. the method for preparing compound of formula I according to claim 4, the concentration of HCl is 20wt% or more in the hydrochloric acid.
6. the method for preparing compound of formula I according to claim 4, the concentration of HCl is 20~37wt% in the hydrochloric acid.
7. the method for preparing compound of formula I according to claim 4, the concentration of HCl is 20~30wt% in the hydrochloric acid.
8. the method for preparing compound of formula I according to claim 1, has the feature that
A) in step (1), reaction carries out at reflux.
9. the method for preparing compound of formula I according to claim 1, has the feature that
B) in step (1), the temperature of reaction is to contain Cl- With the boiling temperature of the solution of water.
10. the method for preparing compound of formula I according to claim 1 has any one of following feature:
C) in step (1), the time of reaction is 1~2 hour；
D) in step (1), Cl- It is greater than 1 with the molar ratio of Formula II compound.
11. the method for preparing compound of formula I according to claim 1 has any one of following feature:
In step (1), the temperature of reaction is 60~110 DEG C；
In step (1), Cl-It is greater than or equal to 1.5 with the molar ratio of Formula II compound.
12. the method for preparing compound of formula I according to claim 1, in step (1), the temperature of reaction is 80~110
℃。
13. the method for preparing compound of formula I according to claim 1 has any one of following feature:
E) in step (2), the temperature of reaction is 40~50 DEG C；
F) it in step (2), reacts until whole iodide ions is all oxidized into elemental iodine by oxidant.
14. the method for preparing compound of formula I according to claim 1 leads to sky into the product of step (2) when heated
Gas.
15. the method for preparing compound of formula I according to claim 1, further comprising the steps of:
(4) following one or more steps processing is carried out to gained compound of formula I: crystallizes, is filtered, washed, decolourizes and recrystallizes.
16. described in any item the method for preparing compound of formula I according to claim 1~15, with any one of following feature:
G) R is methyl, ethyl or propyl；
H) R1 is H atom；
I) n=8~12.
17. described in any item the method for preparing compound of formula I according to claim 1~15, compound of formula I is Dequalinium Chloride,
Formula II compound is ground quinoline iodine ammonium.
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|---|---|---|---|---|
| CN101759709A (en) * | 2008-12-26 | 2010-06-30 | 上海新先锋药业有限公司 | Refining process of 7-ACP.HCL |
| CN102391288A (en) * | 2011-12-03 | 2012-03-28 | 齐鲁安替制药有限公司 | Preparation methods of cefpirome intermediate and cefpirome |
| CN102391289A (en) * | 2011-12-03 | 2012-03-28 | 齐鲁安替制药有限公司 | Synthetic methods of ceftazidime intermediate and ceftazidime |
| CN103387537A (en) * | 2013-07-24 | 2013-11-13 | 珠海经济特区生物化学制药厂 | Preparation method of compound requalinium chloride |
| CN105859615A (en) * | 2016-05-11 | 2016-08-17 | 安徽省逸欣铭医药科技有限公司 | Novel preparation method and novel intermediate of dequalinium chloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101759709A (en) * | 2008-12-26 | 2010-06-30 | 上海新先锋药业有限公司 | Refining process of 7-ACP.HCL |
| CN102391288A (en) * | 2011-12-03 | 2012-03-28 | 齐鲁安替制药有限公司 | Preparation methods of cefpirome intermediate and cefpirome |
| CN102391289A (en) * | 2011-12-03 | 2012-03-28 | 齐鲁安替制药有限公司 | Synthetic methods of ceftazidime intermediate and ceftazidime |
| CN103387537A (en) * | 2013-07-24 | 2013-11-13 | 珠海经济特区生物化学制药厂 | Preparation method of compound requalinium chloride |
| CN105859615A (en) * | 2016-05-11 | 2016-08-17 | 安徽省逸欣铭医药科技有限公司 | Novel preparation method and novel intermediate of dequalinium chloride |
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