CN106187928B - A kind of preparation method of irsogladine maleate - Google Patents
A kind of preparation method of irsogladine maleate Download PDFInfo
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- CN106187928B CN106187928B CN201610622174.0A CN201610622174A CN106187928B CN 106187928 B CN106187928 B CN 106187928B CN 201610622174 A CN201610622174 A CN 201610622174A CN 106187928 B CN106187928 B CN 106187928B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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Abstract
The present invention provides a kind of preparation methods of irsogladine maleate, belong to drug and chemosynthesis technical field.This method, which is included under basic catalyst, uses 2, in a kind of aprotic intensive polar solvent condensation reaction occurs for 5- dichlorobenzonitrile and dicyandiamide, obtain intermediate II in glycerol formal with maleic acid at salt, recrystallized then at the in the mixed solvent of acetic acid-acetone and irsogladine maleate be made.Operation of the present invention is simple, can effectively shorten reaction time, high yield, high-purity, has good industrial application value.
Description
Technical field
The invention belongs to chemical pharmaceutical technology fields, are related to a kind of novel amino triazine class gastric mucosa protective agent maleic acid
The preparation method of Irsogladine.
Background technique
It is clinical at present that mostly with proton pump inhibitor (PPI) for main treatment peptic ulcer, Acidinhibitor is fast and obvious, but
There are Ulcer cicatrization qualities it is unbalanced, easy to recur the problems such as；In terms of gastric mucosal protection, now based on bismuth agent and ulcerlmin.Horse
Carrying out sour Irsogladine is a kind of novel amino triazine class gastric mucosa protective agent, and stomach lining can be protected by number of mechanisms, clinical
Data shows that Irsogladine is effective in cure in terms for the treatment of gastritis, gastric ulcer and prevention gastric cancer.Irsogladine maleate
By improving the mechanism such as horizontal, the increase Gastric Mucosa Blood Flow of cAMP in human neutrophil, it is finally reached via series reaction glutinous
The effect of film protection and antiulcer, when being used alone biology, in terms of relatively anti-better than other types burst
Ulcer preparation, with H2RA or PPI preparation is likely to be breached more preferably therapeutic effect when sharing.This product is by Nippon Shinyaku Co., Ltd. (JP) Tokyo To, Japan
Research Institute is entreated, is listed in Japan within 1989, the ministry of Health of China approval of import in 1993.The irsogladine maleate side of taking
Just, adverse reaction is few, cheap, does not influence HpAssessment is eradicated, in addition its unique mechanism of action, is increasingly subject in foreign countries
Pay attention to.
The Chinese chemical name of irsogladine maleate is known as the entitled 2,4- diamino -6-(2,5- dichlorophenyl of chemistry) -1,
3,5- triazine maleates, chemical structural formula are as follows:
Preparation method in relation to irsogladine maleate, existing disclosed technical literature, can be mainly divided into following several
Method:
US3966728 is related to 2,5- dichlorobenzonitrile and dicyandiamide for raw material, at potassium hydroxide in methyl cellosolve
Reason, in ethylene glycol with potassium hydroxide treatment, handled to obtain intermediate II (Irsogladine) with metallic sodium in ethyl alcohol or methanol；
Or with 2,5- dichlorobenzoic acid, 2,5- methyl p-dichlorobenzene, 2,5- dichloro-benzenes ethyl benzoate, 2,5- dichlorobenzoic acid fourth
Ester, 2,5- dichlorobenzoyl chloride, 2,5- dichloro-benzamide, 2,5- dichlorobenzoic acid acid anhydride and biguanides are raw material, in methanol or second
Reflux obtains intermediate II (Irsogladine) in alcohol, and technology path is as follows:
WO2015151190 and it is related to using intermediate II and maleic acid in methyl cellosolve with cluster CN104245682
80 DEG C or so at salt.
Chinese Journal of Pharmaceuticals, 1998,29 (9), anti-ulcer agent maleic acid disclosed in P389~391, Li Shaoshun etc.
The synthesis of Irsogladine and Chinese Journal of Modern Applied Pharmacy magazine, 1998,15 (3), P34~35, Malaysia disclosed in full Zhe Shan etc.
It is starting material that the synthesis of sour Irsogladine, which uses 2,5- dichloroaniline, carries out diazotising and 2,5- dichloro-benzenes is made in cyaniding
Nitrile, then the condensation in the glycol monoethyl ether (methyl cellosolve) with dicyandiamide, are made intermediate II (Irsogladine), then with Malaysia
Irsogladine maleate is made at salt in dioxanes in acid, and technology path is as follows:
Shandong Technology Univ's journal (natural science edition), 2008,22 (3), P64~67, Dong Sufang etc. disclose Malaysia
The study on the synthesis of sour Yi Suolading, also with 2,5- dichlorobenzonitrile and dicyandiamide for raw material, in glycol monoethyl ether (the molten fibre of methyl
Agent) in handled with potassium isopropoxide, obtain intermediate II (Irsogladine), then with maleic acid in dioxanes at salt be made maleic acid she
Suo Lading.
Chinese journal of Medicinal Chemistry, 2001,12 (3), P155~156, Meng Fanhao etc. disclose anti-ulcer agent maleic acid
The new synthetic method of Irsogladine, using paracide as starting material, through acetylation, bromoform reaction, cyaniding, cyclization, at salt five
Step, which is reacted, is made irsogladine maleate, and technology path is as follows:
Since intermediate II (Irsogladine) is difficult to be dissolved in general organic solvent, if selecting solvent and catalyst improper,
It is low to will lead to reaction yield, the reaction time is long and impurity is more, meanwhile, salt-forming reaction is also that solubility is crucial, therefore this condensation walks
Rapid and salt-forming steps are committed steps, and the applicant gropes through a large amount of practice, are prepared for irsogladine maleate with flying colors.
Summary of the invention
On the basis of the basis of comprehensive previous work and experiment, the present invention provides the one of synthesis irsogladine maleate
Kind new method.
Of the invention is: the shortcomings that overcoming the prior art and insufficient, provide it is a kind of be suitble to large-scale production maleic acid she
The method of Suo Lading.It can in high yield, obtain irsogladine maleate to high-purity, can be used as industrial method and be subject to greatly
Large-scale production.Discharging of waste liquid of the present invention is minimum, and purification number is minimum, can remove impurity and product face by simply refining
Color, it is easy to obtain meeting clinical medicinal irsogladine maleate.
The present invention is to realize above-mentioned purpose with step by the following technical programs:
A kind of preparation method of irsogladine maleate, it is characterized in that by following steps preparation:
(1) 2,5- dichlorobenzonitrile and dicyandiamide contract in a kind of aprotic intensive polar solvent and under basic catalyst
Reaction is closed, intermediate II is obtained；
(2) at salt in glycerol formal, solid is beaten with appropriate solvent for intermediate II and maleic acid, obtain maleic acid she
Suo Lading, i.e. chemical compounds I crude product；
(3) chemical compounds I is recrystallized in the in the mixed solvent of acetic acid and acetone, obtains chemical compounds I highly finished product.
In addition, the present invention also proposes following attached technical scheme:
Aprotic intensive polar solvent described in step (1) is 1,3- dimethyl-2-imidazolinone (DMI) or hempa
Amide (HMPA), the basic catalyst be selected from sodium tungstate or Si-Al molecular sieve, preferably 40~100 DEG C of reaction temperature；Step
(2) molar ratio of intermediate II and maleic acid described in is 1:1~1.1, and preferably 40~60 DEG C of reaction temperature, the solid is beaten
Slurry solvent is the mixed solvent of alcohol-water (85:15)；The volume ratio of step (3) acetic acid and acetone is 1:6~10, dissolution
Temperature is 40~50 DEG C.
The irsogladine maleate prepared using the method for the present invention, due to having used suitable reaction dissolvent and catalyst,
So that preparation intermediate II (Irsogladine) high income, purity is high, the reaction time is few, product non-coloring, and it is straight can not have to purification
It connects to enter and react in next step；When at salt, due to using glycerol formal, so that product non-coloring, by simply refining just
It can obtain colourless irsogladine maleate crystallization.
Specific embodiment
The following examples can be further described the present invention, however, these embodiments should not be used as to this
The limitation of invention scope.
Embodiment one: the preparation of irsogladine maleate
(1), the preparation of intermediate II (Irsogladine)
2,5- dichlorobenzonitrile 447g(2.6mol), 1,3-Dimethyl-2-imidazolidinone (DMI) 894ml, be heated to 65~70
DEG C, dicyandiamide 227g(2.7mol is added) and sodium tungstate 85.8g(0.26mol), maintain 65~70 DEG C to be stirred to react 2h, thin layer mirror
Other reaction end (solvent: n-Butanol acetic acid-water=5:2:0.5), end of reaction is cooled to room temperature, and deionized water is added
894ml stirs 20min, filtering, and solid is washed with deionized, and 70~75 DEG C of vacuum dry 4h obtain white solid intermediate II
(Irsogladine) (635g, 2.48mol), HPLC content 98.9%, yield 95.4%, Mp:264~267 DEG C are directly used in next
Step.
(2), the preparation of irsogladine maleate crude product
Intermediate II (Irsogladine) 630g(2.46mol), glycerol formal 1260ml, be heated to 45~50 DEG C, be added
Maleic acid 285.5g(2.46mol), insulated and stirred 30min is cooled to room temperature, and deionized water 2520ml is added, 20min is stirred,
Filtering, solid alcohol-water (85:15) 1140ml are beaten 1h, filtering, and it is solid to obtain off-white color by 65~70 DEG C of solid vacuum dry 5h
Body powder irsogladine maleate crude product (848g, 2.279mol), yield 92.8%, Mp:182~183 DEG C, HPLC content
99.0%。
(3), the purification of irsogladine maleate
Irsogladine maleate crude product 840g(2.257mol), acetic acid 840ml, be heated to 40~45 DEG C, dissolve lower be added
Acetone 5880ml stirs 20min, is cooled to 0~5 DEG C, heat preservation crystallization 3h, and filtering, solid is washed with proper amount of acetone, and vacuum 50~
55 DEG C of dry 4h, obtain white solid irsogladine maleate highly finished product (813g, 2.185mol), yield 96.8%, and Mp:182.1~
182.8 DEG C, HPLC content 99.9%, unknown impuritie 0.04%, detection method is as follows:
Product of the present invention is taken, ethylene glycol is added to dissolve and dilutes the solution being made in every lml containing about 5mg, it is molten as test sample
Liquid；Precision measures in right amount, and spent glycol quantitatively dilutes the solution for being made and containing 5 μ g in every lml, as contrast solution.According to efficient liquid
Phase chromatography (CP2015 general rule 0512) measurement.It is filler with octadecylsilane chemically bonded silica；With 0.1% methanesulfonic acid solution-
Methanol (80:20) is mobile phase；Detection wavelength is 250nm；Column temperature is 40 DEG C.Take this product 50mg and to through yl benzoic acid methyl esters
10mg is set in same 20ml measuring bottle, is added ethylene glycol to dissolve and is diluted to scale, shakes up, and precision measures 5ml, sets 100ml measuring bottle
In, spent glycol is diluted to scale, shakes up, take l0 μ l inject liquid chromatograph, record chromatogram, Irsogladine peak with to hydroxyl
The separating degree at the cruel peak of benzoic acid first should be greater than 8.Precision measures test solution and each l0 μ l of contrast solution, is injected separately into liquid phase color
Spectrometer, 3 times of record chromatogram to principal component peak retention time.If any impurity peaks, single impurity in test solution chromatogram
Peak area is not greater than contrast solution main peak area (0.1%), and the sum of each impurity peak area is not greater than contrast solution main peak face
3 times long-pending (0.3%).
Embodiment two: the preparation of irsogladine maleate
(1), the preparation of intermediate II (Irsogladine)
2,5- dichlorobenzonitrile 44.7g(0.26mol), hexamethyl phosphoramide (HMPA) 90ml, be heated to 65~70 DEG C, be added
Dicyandiamide 22.7g(0.27mol) and sodium tungstate 8.6g(0.026mol), maintain 65~70 DEG C to be stirred to react 2h, thin layer identifies anti-
Terminal (solvent: n-Butanol acetic acid-water=5:2:0.5) is answered, end of reaction is cooled to room temperature, and deionized water 90ml is added, stirs
20min is mixed, is filtered, solid is washed with deionized, 70~75 DEG C of vacuum dry 4h, and obtaining white solid intermediate II, (Aesop draws
It is fixed) (66g, 0.258mol), HPLC content 98.6%, yield 99.2%, Mp:265~269 DEG C are directly used in next step.
(2), the preparation of irsogladine maleate crude product
Intermediate II (Irsogladine) 63g(0.246mol), glycerol formal 130ml, be heated to 45~50 DEG C, horse be added
Carry out sour 29g(0.246mol), insulated and stirred 30min is cooled to room temperature, and deionized water 260ml is added, and stirs 20min, it filters,
Solid alcohol-water (85:15) 115ml is beaten 1h, filtering, and 65~70 DEG C of solid vacuum dry 5h obtain white solid powder
Irsogladine maleate crude product (85g, 0.228mol), yield 92.7%, Mp:183~184 DEG C, HPLC content 99.1%.
(3), the purification of irsogladine maleate
Irsogladine maleate crude product 84g(0.23mol), acetic acid 84ml, be heated to 40~45 DEG C, dissolve and lower acetone is added
588ml stirs 20min, is cooled to 0~5 DEG C, heat preservation crystallization 3h, and filtering, solid is washed with proper amount of acetone, and 50~55 DEG C of vacuum
Dry 4h, obtains white solid irsogladine maleate highly finished product (80g, 0.215mol), yield 95.2%, Mp:182.4~183.3
DEG C, HPLC content 99.8%, unknown impuritie 0.03%.
Embodiment three: the preparation of irsogladine maleate
(1), the preparation of intermediate II (Irsogladine)
2,5- dichlorobenzonitrile 44.7g(0.26mol), hexamethyl phosphoramide (HMPA) 90ml, be heated to 65~70 DEG C, be added
Dicyandiamide 22.7g(0.27mol) and Si-Al molecular sieve 13g, it maintains 65~70 DEG C and is stirred to react 2h, thin layer identification terminal
(solvent: n-Butanol acetic acid-water=5:2:0.5), end of reaction is cooled to room temperature, and deionized water is added in filtering, filtrate
90ml stirs 20min, filtering, and solid is washed with deionized, and 70~75 DEG C of vacuum dry 4h obtain white solid intermediate II
(Irsogladine) (62g, 0.242mol), HPLC content 98.1%, yield 93.0%, Mp:264~268 DEG C are directly used in next
Step.
(2), the preparation of irsogladine maleate crude product
Intermediate II (Irsogladine) 60g(0.234mol), glycerol formal 130ml, be heated to 45~50 DEG C, horse be added
Carry out sour 27.2g(0.234mol), insulated and stirred 30min is cooled to room temperature, and deionized water 260ml is added, and stirs 20min, mistake
Filter, solid alcohol-water (85:15) 115ml are beaten 1h, filtering, and 65~70 DEG C of solid vacuum dry 5h obtain off-white powder powder
Last irsogladine maleate crude product (81g, 0.218mol), 93.2 % of yield, Mp:183~184 DEG C, HPLC content 98.9%.
(3), the purification of irsogladine maleate
Irsogladine maleate crude product 81g(0.23mol), acetic acid 81ml, be heated to 40~45 DEG C, dissolve and lower acetone is added
486ml stirs 20min, is cooled to 0~5 DEG C, heat preservation crystallization 3h, and filtering, solid is washed with proper amount of acetone, and 50~55 DEG C of vacuum
Dry 4h, obtains white solid irsogladine maleate highly finished product (77g, 0.207mol), yield 95.0%, Mp:182.2~183.0
DEG C, HPLC content 99.9%, unknown impuritie 0.06%.
Example IV: the preparation of irsogladine maleate
(1), the preparation of intermediate II (Irsogladine)
2,5- dichlorobenzonitrile 25g(0.145mol), 1,3-Dimethyl-2-imidazolidinone (DMI) 50ml, be heated to 75~80
DEG C, dicyandiamide 12.6g(0.15mol is added) and Si-Al molecular sieve 8g, it maintains 75~80 DEG C and is stirred to react 1h, thin layer identification
Terminal (solvent: n-Butanol acetic acid-water=5:2:0.5), end of reaction is cooled to room temperature, and deionized water is added in filtering, filtrate
50ml stirs 20min, filtering, and solid is washed with deionized, and 70~75 DEG C of vacuum dry 4h obtain white solid intermediate II
(Irsogladine) (33.5g, 0.13mol), HPLC content 98.7%, yield 90.3%, Mp:260~265 DEG C are directly used in next
Step.
(2), the preparation of irsogladine maleate crude product
Intermediate II (Irsogladine) 33g(0.129mol), glycerol formal 70ml, be heated to 45~50 DEG C, horse be added
Carry out sour 15g(0.129mol), insulated and stirred 30min is cooled to room temperature, and deionized water 140ml is added, and stirs 20min, it filters,
Solid alcohol-water (85:15) 70ml is beaten 1h, filtering, and 65~70 DEG C of solid vacuum dry 5h obtain white solid powder horse
Come sour Irsogladine crude product (45g, 0.121mol), 93.2 % of yield, Mp:182~184 DEG C, HPLC content 99.0%.
(3), the purification of irsogladine maleate
Irsogladine maleate crude product 45g(0.121mol), acetic acid 45ml, be heated to 40~45 DEG C, dissolve and lower be added third
Ketone 315ml stirs 20min, is cooled to 0~5 DEG C, heat preservation crystallization 2h, filtering, solid is washed with proper amount of acetone, vacuum 50~55
DEG C dry 4h, obtains white solid irsogladine maleate highly finished product (41g, 0.11mol), yield 91.1%, and Mp:182.7~
183.6 DEG C, HPLC content 99.9%, unknown impuritie 0.02%.
Claims (4)
1. a kind of preparation method of irsogladine maleate shown in formula I, it is characterised in that:
(1) 2,5- dichlorobenzonitrile and dicyandiamide are in 1,3- dimethyl-2-imidazolinone or hexamethyl phosphoramide solvent and wolframic acid
Sodium or silicoaluminophosphate molecular sieve catalyst issue raw condensation reaction, obtain midbody compound shown in formula II；
(2) at salt in glycerol formal, solid is beaten with appropriate solvent, is obtained midbody compound and maleic acid shown in formula II
To irsogladine maleate crude product shown in formula I；
(3) irsogladine maleate crude product shown in formula I is carried out using the mixed solvent of acetic acid and acetone and through re-crystallization step
Purification.
2. the preparation method of irsogladine maleate shown in formula I described in claim 1, it is characterised in that (1) step
Reaction temperature is 40~100 DEG C.
3. the preparation method of irsogladine maleate shown in formula I described in claim 1, it is characterised in that (2) step institute
The molar ratio of midbody compound shown in the formula II stated and maleic acid is 1:1~1.1, and reaction temperature is 40~60 DEG C.
4. the preparation method of irsogladine maleate shown in formula I described in claim 1, it is characterised in that (3) step institute
The volume ratio for stating acetic acid and acetone is 1:6~10, and solution temperature is 40~50 DEG C.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1290754C (en) * | 1986-06-10 | 1991-10-15 | Toru Tsumura | Method of manufacturing benzoguanamine derivatives |
| JPH0770090A (en) * | 1993-09-01 | 1995-03-14 | Taiyo Yakuhin Kogyo Kk | Production of irsogladine and its acid addition salt |
| CN104245682A (en) * | 2014-03-31 | 2014-12-24 | 日本新药株式会社 | Manufacturing method of irsogladine maleate |
-
2016
- 2016-08-02 CN CN201610622174.0A patent/CN106187928B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1290754C (en) * | 1986-06-10 | 1991-10-15 | Toru Tsumura | Method of manufacturing benzoguanamine derivatives |
| JPH0770090A (en) * | 1993-09-01 | 1995-03-14 | Taiyo Yakuhin Kogyo Kk | Production of irsogladine and its acid addition salt |
| CN104245682A (en) * | 2014-03-31 | 2014-12-24 | 日本新药株式会社 | Manufacturing method of irsogladine maleate |
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