CN110343086A - A kind of preparation method of Olopatadine hydrochloride - Google Patents
A kind of preparation method of Olopatadine hydrochloride Download PDFInfo
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- CN110343086A CN110343086A CN201910724658.XA CN201910724658A CN110343086A CN 110343086 A CN110343086 A CN 110343086A CN 201910724658 A CN201910724658 A CN 201910724658A CN 110343086 A CN110343086 A CN 110343086A
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- olopatadine hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
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Abstract
The present invention discloses a kind of preparation method of Olopatadine hydrochloride, comprising the following steps: prepares Olopatadine hydrochloride crude product；Prepare olopatadine free alkali；Prepare Olopatadine hydrochloride.The present invention has carried out upgrading to committed step, has the advantage that 1, reduces reaction step, reduces loss, improves production efficiency；2, reduce hydrogen generation, guarantee that quality and yield are constant while reducing security risk 3, reduce processing difficulty；4, reaction temperature is optimized, the reaction of low temperature harshness has been picked out, has reduced the dependence to equipment；5, it rejects original individually except isomery step；6, high income and high-quality.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, relate generally to a kind of preparation method of Olopatadine hydrochloride.
Background technique
Olopatadine hydrochloride (Olopatadine hydrochloride) is used as novel H1Receptor antagonist has oral
Long-acting, highly selective excellent antisensitizer without CNS inhibition, acardia toxicity.Its chemical name is: (Z) -11- [3- (diformazan
Base amino) propylidene] -6,11- dihydro-dibenzo [b, e] oxa- Zhuo -2- acetic acid hydrochloride, CAS:140462-76-6.It is tied
Structure formula is as follows:
。
It is mainly at present chemical synthesis to the preparation of Olopatadine hydrochloride, part producing producer uses 3,3- dimethylamino
Base propyl magnesium chloride (CAS:19070-16-7) and intermediate Isoxepac (CAS:55453-87-7) have blocking group
Isoxepac carry out Grignard reaction, by salt be deprotected be made, part producing producer use [3- (dimethylamino)
Propyl] triphenylphosphonium bromide hydrobromate (CAS:27710-82-3) passes through n-BuLi or sodium hydride extracts hydrogen atom
Phosphonium ylide is made, Isoxepac of the phosphonium ylide with intermediate Isoxepac or with blocking group carries out Wittig and reacts,
It is made by being deprotected at salt.That there are reaction routes is excessively complicated for two methods, is related to nitrogen ultra low temperature reaction, to equipment requirement
Height, and product impurity height is prepared, isomers is more, and separating difficulty is big, and yield is low, and product quality is bad.
Therefore, the existing technology needs to be improved and developed.
Summary of the invention
In view of above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide a kind of preparation sides of Olopatadine hydrochloride
Method optimizes upgrading to preparation process, reduces reaction step, optimizes reaction condition, it is intended to solve existing Olopatadine hydrochloride
The excessively complicated problem of reaction route.
Technical scheme is as follows:
A kind of preparation method of Olopatadine hydrochloride, wherein the following steps are included:
(1) in anhydrous tetrahydro furan solvent, 20 ~ 22 DEG C of temperature control, (3- dimethylaminopropyl) triphenylphosphinebromide (CAS:
It 18355-96-9) is reacted with sodium hydride and prepares phosphonium ylide；Isoxepac is added and carries out Wittig reaction；Quenching reaction；It is added
For concentrated hydrochloric acid tune pH value to 6 ± 0.2, vacuum distillation obtains solid to dry；Solid is dissolved in acetone, and concentrated hydrochloric acid is added dropwise, and white is precipitated
Solid；After being added dropwise, 10 ~ 15 DEG C are cooled to, is stirred 8 ~ 15 hours；It filters, obtains white solid, drying to constant weight, obtains hydrochloric acid
Olopatadine crude product；
(2) Olopatadine hydrochloride crude product adds water tune PH to 6 ± 0.2, is warming up to reflux, adds active carbon to be stirred at reflux 0.2 ~ 1.0 small
When；It filters, filtrate is cooled to 10 ~ 15 DEG C while stirring, precipitates crystal, and dries, obtains olopatadine free alkali；
(3) it olopatadine free alkali and concentrated hydrochloric acid to be added in tetrahydrofuran, stirs 2 ~ 4 hours, filters, drying obtains solid；
Active carbon, acetone and purified water is added in solid, is warming up to reflux 0.2 ~ 1.0 hour；Filtering, filtrate are cooled to 10 ~ 15 DEG C, heat preservation
It 18 ~ 30 hours, filters, drying obtains Olopatadine hydrochloride.
The preparation method of the Olopatadine hydrochloride, wherein in step (1), (3- dimethylaminopropyl) triphenyl
The quality of bromide phosphine and Isoxepac is 1 ~ 3:1 than range；(3- dimethylaminopropyl) triphenylphosphinebromide and sodium hydride
Quality is 2 ~ 8:1 than range.
The preparation method of the Olopatadine hydrochloride, wherein in step (2), between Olopatadine hydrochloride crude product and water
Mass ratio be 2 ~ 5:1.
The preparation method of the Olopatadine hydrochloride, wherein in step (3), the proportional region olopatadine of each raw material
The quality of free alkali and concentrated hydrochloric acid is 1 ~ 2:1 than range, and acetone: the range of purified water mass ratio is 2.5 ~ 4.5:1.
The preparation method of the Olopatadine hydrochloride, wherein in step (1), the quenching reaction is to sequentially add nothing
Water methanol, the aqueous tetrahydrofuran solution that mass concentration is 40 ~ 70%, purified water, quenching reaction.
The utility model has the advantages that the preparation method of Olopatadine hydrochloride provided by the present invention, on the basis of existing technology, to pass
Key step has carried out upgrading, has the advantage that 1, reduces reaction step, reduces loss, improves production efficiency；2,
Reduce hydrogen generation, reduces security risk, 3, guarantee that quality and yield are constant while reduce processing difficulty；4, it optimizes
Reaction temperature has picked out the reaction of low temperature harshness, has reduced the dependence to equipment；5, it rejects original individually except isomery step；6, yield
It is high and high-quality.
Detailed description of the invention
Fig. 1 is the process flow chart of the preparation method of Olopatadine hydrochloride of the present invention.
Specific embodiment
The present invention provides a kind of preparation method of Olopatadine hydrochloride, to make the purpose of the present invention, technical solution and effect
Clearer, clear, the present invention is described in more detail below.It should be appreciated that specific embodiment described herein is only
To explain the present invention, it is not intended to limit the present invention.
The present invention provides a kind of preparation method of Olopatadine hydrochloride, as shown in Figure 1, comprising the following steps:
(1) in anhydrous tetrahydro furan solvent, 20 ~ 22 DEG C of temperature control, (3- dimethylaminopropyl) triphenylphosphinebromide (CAS:
It 18355-96-9) is reacted with sodium hydride and prepares phosphonium ylide；Isoxepac is added and carries out Wittig reaction；Sequentially add no water beetle
Alcohol, the aqueous tetrahydrofuran solution that mass concentration is 40 ~ 70%, purified water, quenching reaction；Concentrated hydrochloric acid tune pH value is added to 6 ± 0.2,
Vacuum distillation obtains solid to dry；Solid is dissolved in acetone, and concentrated hydrochloric acid is added dropwise, and white solid is precipitated；After being added dropwise, it is cooled to
It 10 ~ 15 DEG C, stirs 8 ~ 15 hours；It filters, obtains white solid, drying to constant weight, obtains Olopatadine hydrochloride crude product；
Wherein, (3- dimethylaminopropyl) triphenylphosphinebromide (CAS:18355-96-9): the quality of Isoxepac compares model
It encloses for 1 ~ 3:1；(3- dimethylaminopropyl) triphenylphosphinebromide (CAS:18355-96-9): the quality of sodium hydride compares range
For 2 ~ 8:1.
In the present invention, it is put forward for the first time use (3- dimethylaminopropyl) triphenylphosphinebromide (CAS:18355-96-9)
Combination with sodium hydride is used to prepare phosphonium ylide；Reaction condition can be optimized using sodium hydride, reaction condition is wanted in reduction
It asks；It, not only can be with using the combination of (3- dimethylaminopropyl) triphenylphosphinebromide (CAS:18355-96-9) and sodium hydride
The dosage of sodium hydride is reduced, but also can reduce and generate hydrogen and sodium bromide.This way it is possible to avoid because a large amount of hydrogen causes
Security risk, too many sodium bromide will lead to steam shipwreck degree increase, can also reduce crystal amount of precipitation and impurity is caused to be precipitated, lead
It causes yield to reduce impurity to get higher.In the present invention, anhydrous methanol, aqueous tetrahydrofuran solution, the sequence of purified water combine quenching reaction,
Anhydrous methanol is first used, sodium methoxide can be generated with not having reacted sodium hydride in reaction system, then with aqueous tetrahydrofuran solution
In water and generation sodium methoxide generate sodium hydroxide, finally with purified water by whole system in bottle wall a small amount of material handle
At sodium hydroxide, dilution is extracted below with facilitating.During being quenched, if first directly reacted with sodium hydride with water, generation
Hydrogen largely gathers, and cannot quickly drain, and can be easy to cause great safety accident when hydrogen largely generates；Likewise, such as
In fruit subsequent step with water rather than 50% aqueous tetrahydrofuran solution reacted with the sodium methoxide that previous step generates also result in it is same
As a result.Adjusting the solid after being evaporated after pH again is olopatadine and mixtures of impurities, dissolves in acetone and water, and olopatadine and chlorine
The Olopatadine hydrochloride for changing hydrogen molecule formation can largely be dissolved in water and be practically insoluble in acetone.Therefore, toward with object after adjustment pH value
Add hydrochloric acid in the acetone soln of material to form Olopatadine hydrochloride, then make hydrochloric acid Ao Luota because Olopatadine hydrochloride does not dissolve in acetone
It is precipitated, while being cooled to 10 ~ 15 DEG C to further decrease solubility of the Olopatadine hydrochloride in acetone system, makes more voluminous calmly
Product are precipitated, and improve yield.Isomers is the impurity that salification process is formed, and step (1) impurity is to contain E- olopatadine structure
Hydrochloride, i.e. E- Olopatadine hydrochloride hydrochloride (CAS:949141-22-4) removed big by step of the present invention (1)
Measure isomers.The product that this step is precipitated contains the isomers less than 1%.
(2) Olopatadine hydrochloride crude product adds water tune PH to 6 ± 0.2, is warming up to reflux, add active carbon be stirred at reflux 0.2 ~
1.0 hour；It filters, filtrate is cooled to 10 ~ 15 DEG C while stirring, precipitates crystal, and dries, obtains olopatadine free alkali；
Wherein, the mass ratio between Olopatadine hydrochloride crude product and water can be 2 ~ 5:1.
Step (2) primarily to reduce isomers, improve product purity, make isomers close to qualification (be herein salt
Hydrochlorate free alkali process, therefore impurity E before-olopatadine hydrochloride is free forms E- olopatadine, CAS:113806-
06-7).Active carbon decoloring can remove color impurities, improve product purity.The crystallization that cools down again after dissolved clarification can guarantee yield
Under the premise of remove impurity.
(3) it olopatadine free alkali and concentrated hydrochloric acid to be added in tetrahydrofuran, stirs 2 ~ 4 hours, filters, drying is consolidated
Body；Active carbon, acetone and purified water is added in solid, is warming up to reflux 0.2 ~ 1.0 hour；Filtering, filtrate are cooled to 10 ~ 15 DEG C,
Heat preservation 18 ~ 30 hours filters, and drying obtains Olopatadine hydrochloride.
Wherein, the quality of olopatadine free alkali and concentrated hydrochloric acid is 1 ~ 2:1, acetone: the model of purified water mass ratio than range
It encloses for 2.5 ~ 4.5:1.
Step (3) can continue to reduce isomers, so that it (is herein free alkali again at salt mistake that product, which reaches quality requirement,
Journey, therefore impurity before obtains E- olopatadine hydrochloride impurities at salt again).Olopatadine free alkali is added in tetrahydrofuran
Reaction, which is carried out, with hydrochloric acid generates Olopatadine hydrochloride.Active carbon decoloring can remove color impurities, further increase product purity.It rises
Temperature reflux cools down again is precipitated a decontamination process, and cooling, which is precipitated, can guarantee that yield is not affected substantially.
The preparation method of Olopatadine hydrochloride provided by the present invention, on the basis of existing technology, to committed step into
It has gone upgrading, has had the advantage that 1, rejects upper protection and deprotection reaction, from raw material to Olopatadine hydrochloride finished product
Three steps are undergone altogether, reduce reaction step, are reduced loss, are improved production efficiency；2, hydrogen row is reduced by replacement main material
It puts, reduces security risk；3, it reduces post-processing difficulty and guarantees quality and yield 4 simultaneously, by replacement auxiliary material, optimize
Reaction temperature proposes the reaction of low temperature harshness, reduces the dependence to equipment；5, it is not set in reaction process and is separately separated step, from
It is dynamic to realize isomer separation, it rejects original individually except isomery step；6, free and salt-forming steps are only carried out after main reaction, are no longer set
Set other steps, purification while guarantees yield, guarantees yield and quality.
Below by way of specific embodiment, the invention will be further described.
Embodiment 1
(1) 200g (3- dimethylaminopropyl) triphenylphosphinebromide is added in there-necked flask, adds the anhydrous tetrahydro furan of 400g
It mutters, opens stirring, 20 ~ 22 DEG C of temperature control, 40g NaH is added, reflux is warming up to after adding, reacts 1h.Then 100g Aesop is added
Gram acid, return stirring 2 hours, then it is cooled to 0 ~ 15 DEG C, it is slowly added to 30g anhydrous methanol, adding 400g mass concentration is
50% aqueous tetrahydrofuran solution is eventually adding 1600g water quenching reaction.Then reaction solution is subtracted with concentrated hydrochloric acid tune PH=6 ± 0.2
Pressure distillation is evaporated to obtain solid to doing, and solid is dissolved in 1400g acetone, opens stirring, and 40g concentrated hydrochloric acid is added, and white is precipitated admittedly
Body.10 ~ 15 DEG C are cooled to after dripping to be stirred for 10 hours.It filters, obtains white solid, be placed in baking oven and dry to constant weight.It must produce
Product olopatadine hydrochloride, crude, purity 98.67%(Z/E=98.67:0.82), yield 62.4g, this step yield 60.6%.
(2) in there-necked flask, take olopatadine hydrochloride, crude 62.4g that purified water 170g is added, then molten with 20% sodium hydroxide
Liquid tune PH to 6 ± 0.2 is warming up to reflux, and active carbon 2g is added to be stirred at reflux 0.5 hour.It filtering, filtrate is stirred for being cooled to 10 ~
15 DEG C obtain product olopatadine free alkali wet product 78g for crystallization 8 hours.Baking oven drying is placed it in, olopatadine free alkali is obtained
Dry product, purity 99.36%(Z/E=99.36:0.37), yield 51.8g, this step yield 92.0%.
(3) 1000g tetrahydrofuran is added in 2000ml there-necked flask, adds 51.8g Z- olopatadine intermediate, then salt
Sour 36.3g.Stirring 2 hours, filters, and filter cake dries to obtain solid 45g.All solids are added in 250ml there-necked flask, and active carbon is added
1g adds 90 acetone and 30g purified water, is warming up to reflux half an hour.Filtering, filtrate are packed into there-necked flask, are cooled to 10 ~ 15
DEG C, 24 hours are kept the temperature, is filtered.Filter cake is placed in baking oven drying, obtains Olopatadine hydrochloride, purity 99.90%(Z/E=99.90:
0.02), product 44.3g, yield 77.1%.
It can be seen from above-described embodiment that the Olopatadine hydrochloride purity being prepared using the method for the present invention is up to
99.90%, wherein content of isomer only accounts for 0.02%, the content of the isomers being less than far below United States pharmacopoeia specifications in finished product
0.1%。
It should be understood that the application of the present invention is not limited to the above for those of ordinary skills can
With improvement or transformation based on the above description, all these modifications and variations all should belong to the guarantor of appended claims of the present invention
Protect range.
Claims (5)
1. a kind of preparation method of Olopatadine hydrochloride, which comprises the following steps:
(1) in anhydrous tetrahydro furan solvent, 20 ~ 22 DEG C of temperature control, (3- dimethylaminopropyl) triphenylphosphinebromide and hydrogenation
Sodium reaction prepares phosphonium ylide；Isoxepac is added and carries out Wittig reaction；Quenching reaction；Be added concentrated hydrochloric acid tune pH value to 6 ±
0.2, vacuum distillation obtains solid to dry；Solid is dissolved in acetone, and concentrated hydrochloric acid is added dropwise, and white solid is precipitated；After being added dropwise, drop
Temperature stirs 8 ~ 15 hours to 10 ~ 15 DEG C；It filters, obtains white solid, drying to constant weight, obtains Olopatadine hydrochloride crude product；
(2) Olopatadine hydrochloride crude product adds water tune PH to 6 ± 0.2, is warming up to reflux, adds active carbon to be stirred at reflux 0.2 ~ 1.0 small
When；It filters, filtrate is cooled to 10 ~ 15 DEG C while stirring, precipitates crystal, and dries, obtains olopatadine free alkali；
(3) it olopatadine free alkali and concentrated hydrochloric acid to be added in tetrahydrofuran, stirs 2 ~ 4 hours, filters, drying obtains solid；
Active carbon, acetone and purified water is added in solid, is warming up to reflux 0.2 ~ 1.0 hour；Filtering, filtrate are cooled to 10 ~ 15 DEG C, heat preservation
It 18 ~ 30 hours, filters, drying obtains Olopatadine hydrochloride.
2. the preparation method of Olopatadine hydrochloride according to claim 1, which is characterized in that in step (1), (3- diformazan
Base aminopropyl) quality of triphenylphosphinebromide and Isoxepac than range is 1 ~ 3:1；(3- dimethylaminopropyl) triphenyl
The quality of bromide phosphine and sodium hydride is 2 ~ 8:1 than range.
3. the preparation method of Olopatadine hydrochloride according to claim 1, which is characterized in that in step (2), hydrochloric acid is difficult to understand
Mass ratio between Luo Tading crude product and water is 2 ~ 5:1.
4. the preparation method of Olopatadine hydrochloride according to claim 1, which is characterized in that in step (3), each raw material
Proportional region olopatadine free alkali and the quality of concentrated hydrochloric acid than range be 1 ~ 2:1, acetone: the range of purified water mass ratio is
2.5 ~ 4.5:1.
5. the preparation method of Olopatadine hydrochloride according to claim 1, which is characterized in that described to quench in step (1)
Reaction of going out is the aqueous tetrahydrofuran solution sequentially added anhydrous methanol, mass concentration for 40 ~ 70%, purified water, quenching reaction.
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Cited By (4)
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| CN112375060A (en) * | 2020-12-07 | 2021-02-19 | 广州健康元呼吸药物工程技术有限公司 | Post-treatment purification method of olopatadine hydrochloride |
| CN113620920A (en) * | 2021-08-26 | 2021-11-09 | 四川子仁制药有限公司 | Preparation method of olopatadine hydrochloride |
| CN113651792A (en) * | 2021-08-26 | 2021-11-16 | 上海应用技术大学 | Improved synthesis method of doxepin hydrochloride |
| CN114276384A (en) * | 2022-01-07 | 2022-04-05 | 重庆西南制药二厂有限责任公司 | Synthesis method of demethyl olopatadine and intermediate thereof |
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Application publication date: 20191018 |