CN110330447A - A kind of preparation method and applications of Nafamostat Mesilate intermediate - Google Patents
A kind of preparation method and applications of Nafamostat Mesilate intermediate Download PDFInfo
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- CN110330447A CN110330447A CN201910640255.7A CN201910640255A CN110330447A CN 110330447 A CN110330447 A CN 110330447A CN 201910640255 A CN201910640255 A CN 201910640255A CN 110330447 A CN110330447 A CN 110330447A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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Abstract
The invention belongs to intermediate preparation fields, and in particular to a kind of preparation method and applications of Nafamostat Mesilate intermediate.The preparation method of the Nafamostat Mesilate intermediate includes: that in a solvent, neighbour/p-aminobenzoic acid reacts under the action of catalyst with cyanamide；Wherein the catalyst is acidic alcohol or hydrochloric acid methanol, preferably acidic alcohol.The present invention also provides the methods that Nafamostat Mesilate contamination levels product are further prepared using this method.Using the preparation method of Nafamostat Mesilate intermediate of the present invention, the reaction time is shortened, reaction yield is improved, reduces production cost and pressure store, there are biggish implementary value and economic results in society.It is carried out qualitative and quantitative analysis simultaneously by contamination levels product to impurity in Nafamostat Mesilate production, the quality standard of product can be improved, important directive significance is provided for safe medication.
Description
Technical field
The invention belongs to intermediate preparation fields, and in particular to a kind of preparation method of Nafamostat Mesilate intermediate and
It is applied.
Background technique
Nafamostat Mesilate is the protease inhibitors of synthesis, can be used for improving acute symptom (the acute pancreas of pancreatitis
Acute pancreatitis, traumatic pancreatitis after adenositis, chronic pancreatitis acute exacerbation, postoperative acute pancreatitis, pancreatic ductography)；Or
For treating disseminated intravascular coagulation (DIC)；Or patient's blood for preventing hemorrhagic lesions or hemorrhagic tendency
The solidification (haemodialysis and plasma exchange) of perfusion blood when external liquid circulation.
Hydrochloric acid 4- guanidinobenzoic acid, Chinese nickname: p -guanidinobenzoic acid hydrochloride, No. CAS: 42823-46-1, molecular formula:
C8H9N3O2HCl, molecular weight: 215.64.Hydrochloric acid 4- guanidinobenzoic acid is important organic centre of Nafamostat Mesilate preparation
Body, the further investigation to the synthesis of hydrochloric acid 4- guanidinobenzoic acid, has advantageously reduced the production cost of Nafamostat Mesilate.
In addition, hydrochloric acid 4- guanidinobenzoic acid can be also used for synthesizing another Pancreatitis drug camostat, people's acrosome
Protease inhibitors 4- guanidinobenzoic acid -4- acetylamino phenyl ester hydrochloride, and as Proteinase inhibitor, be expected to
Develop into contraceptive series of products.
Existing hydrochloric acid 4- guanidinobenzoic acid is as made from p-aminobenzoic acid and cyanamide addition, such as
CN103641749A obtains mixed liquor it discloses p-aminobenzoic acid to be uniformly mixed with concentrated hydrochloric acid, ethyl alcohol, by cyanamide water
Solution is added drop-wise in above-mentioned mixed liquor at a temperature of 10-15 DEG C, and 25-35min drop finishes, and reacts at room temperature 8-12h, is filtered, and washing obtains
P -guanidinobenzoic acid hydrochloride.In this method, the mass percent concentration of the cyanamide aqueous solution is 50%, shelf-life pole
It is short, it is unfavorable for the storage and subsequent production of raw material；And the yield of product p -guanidinobenzoic acid hydrochloride is 40% or so, relatively
It is lower.
In addition, process impurity is one of raw material and the key factor of quality of the pharmaceutical preparations research.In order to preferably to methanesulfonic acid naphthalene
Mo Sita carry out quality research, it is necessary to its impurity is studied, controlled a safety, reasonable limits it
It is interior, to guarantee the quality and safety of Nafamostat Mesilate product, important directive significance is provided for safe medication.
6- amidino groups -2- naphthalene -3- guanidine benzoate mesylate be Nafamostat Mesilate product major impurity at
Point, however, the synthesis in relation to 6- amidino groups -2- naphthalene -3- guanidine benzoate mesylate at present yet there are no research report.
Summary of the invention
In order to improve the yield of hydrochloric acid 4- guanidinobenzoic acid, and avoid the storage of high-concentration cyanamide aqueous solution and subsequent
Production there are the problem of, the present invention provide a kind of new Nafamostat Mesilate intermediate (including hydrochloric acid 4- guanidinobenzoic acid and
3- guanidinobenzoic acid hydrochloride) preparation method.Using preparation method of the present invention, the reaction time is shortened, is improved
Reaction yield reduces production cost and pressure store, has biggish implementary value and economic results in society.
First purpose of the invention is to provide a kind of preparation method of Nafamostat Mesilate intermediate, comprising: in solvent
In, neighbour/p-aminobenzoic acid reacts under the action of catalyst with cyanamide；Wherein, the catalyst is acidic alcohol or hydrochloric acid
Methanol, preferably acidic alcohol.
The Nafamostat Mesilate intermediate structure formula are as follows:
Wherein, work as R1For H, R2For-COOH；Work as R1For-COOH, R2For H.
Synthetic route is as follows:
Wherein, R1For H, R2For-COOH；R1For-COOH, R2For H.
The present invention selects acidic alcohol or hydrochloric acid methanol as catalyst, changes former reaction system state, breaches original
The limit of reaction system polarity and water content, greatly shortens the reaction time, reduces cyanamide quick water in former reaction system
The side reaction of solution increases the yield of intermediate；The use concentration of cyanamide can be used low dense without higher limitation simultaneously
Degree and inexpensive 20%-40% cyanamide, greatly reduce production cost and pressure store.
Preferably, the mass concentration of the acidic alcohol or hydrochloric acid methanol is 25-35%.At this concentration, it is more advantageous to
The abundant progress of reaction improves product yield, shortens the reaction time.
In some embodiments of the invention, the reaction temperature is 50-80 DEG C.With this condition, reaction can be more
Sufficiently, the reaction time is shorter, can be completed within 5-8 hours, while being more favorable to improve product yield.Preferably, the reaction
Temperature is 65-75 DEG C, not only improves the abundant progress of reaction with this condition, and is avoided because excessively high (> 80 DEG C) acceleration of temperature are single
The polymerization reaction of cyanamide, causes polymer to produce, and is unfavorable for the problem of yield improves.
In some embodiments of the invention, the cyanamide is the cyanamide aqueous solution with mass concentration 20%-40%
Form is added drop-wise in system.Preferably, the cyanamide aqueous solution is added dropwise in system under the conditions of 50-60 DEG C,
It is added dropwise under this condition, is more advantageous to cyanamide and is sufficiently reacted with neighbour/p-aminobenzoic acid, improve yield.
In some embodiments of the invention, the molar ratio of the neighbour/p-aminobenzoic acid and cyanamide is 1:1-3, excellent
Select 1:2.
In some embodiments of the invention, the solvent is in methanol, ethyl alcohol, isopropanol, ethyl acetate, glacial acetic acid
One kind；Preferred alcohol.
In some embodiments of the invention, the preparation method further includes post-processing.The post-processing includes: that concentration is anti-
Answer liquid to dry, addition solvent and catalyst, precipitation solid obtains crude product, recrystallizes.Wherein, solvent used in the post-processing
For one of methanol, ethyl alcohol, isopropanol or ethyl acetate.Solvent used in the recrystallization is water, methanol, ethyl alcohol or different
One of propyl alcohol is a variety of, preferred alcohol or low-concentration ethanol aqueous solution.
The preparation method that second purpose of the invention is to provide above-mentioned Nafamostat Mesilate intermediate is preparing methanesulfonic acid
Application in Nafamostat contamination levels product.By contamination levels product to Nafamostat Mesilate production in impurity carry out it is qualitative and
The quality standard of product can be improved in quantitative analysis, and important directive significance is provided for safe medication.
Third purpose of the present invention is to provide a kind of Nafamostat Mesilate impurity (6- amidino groups -2- naphthalene -3- guanidine radicals benzene first
Five mesylate of acid esters dimethanesulfonate or 6- amidino groups -2- naphthalene -3- guanidine benzoate) preparation method, comprising:
(1) 3- guanidinobenzoic acid hydrochloride is obtained using the preparation method of above-mentioned Nafamostat Mesilate intermediate；
(2) in a solvent, 3- guanidinobenzoic acid hydrochloride and 6- amidino groups-beta naphthal mesylate are in dehydrating agent N, N '-two
Carbodicyclo hexylimide, the lower reaction of catalyst 4-dimethylaminopyridine effect, generate 6- amidino groups -2- naphthalene -3- guanidinobenzoic acid
Ester；Then with methanesulfonic acid in proportion at salt to get 6- amidino groups -2- naphthalene -3- guanidine benzoate dimethanesulfonate or 6- amidino groups -
Five mesylate of 2- naphthalene -3- guanidine benzoate.
Its synthetic route are as follows:
(1)
(2)
In above-mentioned synthetic reaction, products therefrom include 6- amidino groups -2- naphthalene -3- guanidine benzoate dimethanesulfonate and
Five mesylate of 6- amidino groups -2- naphthalene -3- guanidine benzoate, is stable sterling impurity, can be applicable to raising product
Quality standard in, as liquid phase detection reference substance.
In above-mentioned steps (2), the solvent is selected from methylene chloride, acetonitrile or pyridine；It is preferred that pyridine.
In above-mentioned steps (2), the molar ratio of the 6- amidino groups-beta naphthal mesylate and 3- guanidinobenzoic acid hydrochloride
For 1:1-1.5, preferably 1:1.2.
In above-mentioned steps (2), the 3- guanidinobenzoic acid hydrochloride and dehydrating agent N, N '-dicyclohexylcarbodiimide
(DCC) molar ratio is 1:1-1.5, preferably 1:1.
In above-mentioned steps (2), the 3- guanidinobenzoic acid hydrochloride and catalyst 4-dimethylaminopyridine (DMAP)
Molar ratio is 90-120:1, preferably 100:1.
In above-mentioned steps (2), the reaction temperature is 20 DEG C -50 DEG C, and the reaction time is -48h for 24 hours.
In above-mentioned steps (2), further includes: products therefrom is dissolved in water, removes insoluble matter, filtrate is added in alkaline solution
It is 7-9 (preferably pH is 8) with, adjusting pH, solid is precipitated, it is dry to get 6- amidino groups -2- naphthalene -3- guanidine benzoate.It is described
Alkaline solution is sodium bicarbonate, sodium carbonate, potassium carbonate, saleratus, disodium hydrogen phosphate, sodium phosphate, vulcanized sodium, ammonium sulfide or carbon
Sour hydrogen ammonium, preferably sodium bicarbonate, saleratus；The concentration of the alkaline solution is 0.05-0.15mol/L.
In above-mentioned steps (2) salification process, the methanesulfonic acid of molar ratio 2.0-2.3 is added dropwise to get impurity 6- amidino groups -2- naphthalene
Base -3- guanidine benzoate dimethanesulfonate；The methanesulfonic acid of molar ratio 5.0-6.0 is added dropwise to get impurity 6- amidino groups -2- naphthalene -
Five mesylate of 3- guanidine benzoate.
In above-mentioned steps (2) salification process, reaction is to carry out in a solvent, and the solvent is water, methanol, ethyl alcohol, different
Propyl alcohol；It is preferred that water.
The preparation method of the Nafamostat Mesilate impurity further includes purifying: it is dissolved in water into crude product, adsorption-edulcoration
Afterwards, solvent is added, solid is precipitated to get sterling.Active carbon, diatomite, resin can be used in the absorption, wherein it is preferred that needle
The active carbon of agent 767.The solvent is ethyl alcohol, acetone.
Beneficial effects of the present invention are as follows:
The preparation method of Nafamostat Mesilate intermediate of the present invention have the reaction time is short, reaction yield is high,
Production cost and the low advantage of pressure store, have biggish implementary value and economic results in society.Meanwhile the present invention should also
Method is applied in the preparation of Nafamostat Mesilate contamination levels product, is produced by contamination levels product to Nafamostat Mesilate
Middle impurity carries out qualitative and quantitative analysis, and the quality standard of product can be improved, and important directive significance is provided for safe medication.
Detailed description of the invention
Fig. 1 is the map of 6- amidino groups -2- naphthalene -3- guanidine benzoate dimethanesulfonate.
Fig. 2 is the map of five mesylate of 6- amidino groups -2- naphthalene -3- guanidine benzoate.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
The preparation of 1 hydrochloric acid 4- guanidinobenzoic acid (Nafamostat Mesilate intermediate) of embodiment
Synthetic route is as follows:
Specific step is as follows:
20g p-aminobenzoic acid is added in 100ml ethyl alcohol, 30% acidic alcohol of 20ml is slowly added to, is warming up to 50
DEG C, 30% cyanamide 40g is added dropwise, drop finishes, and 75 DEG C ± 3 DEG C are reacted 5-7 hours.
Reaction is finished, and is concentrated to dryness in 50 DEG C, and 50ml ethyl alcohol and 30% acidic alcohol of 10ml is added, and agitation and filtration is done
It is dry.It is recrystallized with 20% ethanol water of 5-10 times of volume to get sterling.The yield of gained hydrochloric acid 4- guanidinobenzoic acid is
85%.
The system of 2 6- amidino groups -2- naphthalene -3- guanidine benzoate mesylate (Nafamostat Mesilate impurity) of embodiment
It is standby
(1) preparation of 3- guanidinobenzoic acid hydrochloride
Synthetic route is as follows:
Specific step is as follows:
20g gavaculine is added in 100ml ethyl alcohol, 30% acidic alcohol of 20ml is slowly added to, is warming up to 50
DEG C, 30% cyanamide 40g is added dropwise, drop finishes, and 75 DEG C ± 3 DEG C are reacted 5-7 hours.
Reaction is finished, and is concentrated to dryness in 50 DEG C, and 50ml ethyl alcohol and 30% acidic alcohol of 10ml is added, and agitation and filtration is done
It is dry.With the ethyl alcohol recrystallization of 5-10 times of volume to get sterling.The yield of gained 3- guanidinobenzoic acid hydrochloride is 72%.
(2) preparation of 6- amidino groups -2- naphthalene -3- guanidine benzoate mesylate (Nafamostat Mesilate impurity)
Synthetic route is as follows:
Specific step is as follows:
By 3.4g (0.0158mol) 3- guanidinobenzoic acid hydrochloride, 3.8g (0.0135mol) 6- amidino groups-beta naphthal methylsulphur
Hydrochlorate, 3.4gN, N '-dicyclohexylcarbodiimide (dehydrating agent), 0.02g4- dimethylamino naphthyridine (catalyst) and 50ml pyridine
It adds in reaction flask and reaction 24 hours is stirred at room temperature, filter cake is added in 100ml water and stirred, filters out insoluble matter, filtrate by filtering
It is 8 that 0.1mol/L sodium bicarbonate solution tune pH, which is added dropwise, and solid is precipitated, and is filtered, dry, obtains 6- amidino groups -2- naphthalene -3- guanidine radicals benzene
Formic acid esters.
Obtained solid 3.2g (0.0092mol) is added in 10ml water, dropwise addition 2.0g (0.021mol) methanesulfonic acid, Quan Rong,
30ml acetone is added, 767 active carbon agitation and filtration of 3.0g injection is added, 100ml acetone is added in filtrate again, and solid, mistake is precipitated
It is filtered dry dry to get 6- amidino groups -2- naphthalene -3- guanidine benzoate dimethanesulfonate sterling.
It is detailed in Fig. 1.1H-NMR (DMSO-d6,600MHz): 2.40 (s, 6H), 7.63-7.71 (m, 7H), 7.88 (dd J=
8.0Hz, 1.8Hz, 1H), 8.00 (brs, 1H), 8.02 (d J=1.8Hz, 1H), 8.08 (d J=9.0Hz, 1H), 8.19 (d J
=9.0Hz, 1H), 8.24 (d J=9.0Hz, 1H), 8.58 (s, 1H), 9.19-9.47 (s, 4H), 10.01 (s, 1H).
Alternatively, obtained solid 3.2g (0.0092mol) is added in 10ml water, 5.3g (0.055mol) methanesulfonic acid is added dropwise,
30ml acetone is added in Quan Rong, and 767 active carbon agitation and filtration of 3.0g injection is added, and 100ml acetone is added in filtrate again, is precipitated solid
Body, filtration drying is to get five mesylate sterling of 6- amidino groups -2- naphthalene -3- guanidine benzoate.
It is detailed in Fig. 2.1H-NMR (DMSO-d6,400MHz): 10.09 (brs, 1H), 9.49 (s, 2H), 9.25 (brs, 2H),
8.60 (s, 1H), 8.26 (d J=9Hz, 1H), 8.17 (d J=8.7Hz, 1H), 8.09 (d J=7.6Hz, 1Hz), 8.03 (d
J=2.2Hz, 1H), 7.99 (s, 1H), 7.89 (d J=8.7Hz, 1H), 7.69 (m, 7H), 2.37 (m, 18H).
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a kind of preparation method of Nafamostat Mesilate intermediate characterized by comprising in a solvent, neighbour/p-aminophenyl
Formic acid reacts under the action of catalyst with cyanamide；Wherein, the catalyst is acidic alcohol or hydrochloric acid methanol, preferably hydrochloric acid second
Alcohol.
2. preparation method according to claim 1, which is characterized in that the mass concentration of the acidic alcohol or hydrochloric acid methanol
For 25-35%.
3. preparation method according to claim 1 or 2, which is characterized in that the reaction temperature is 50-80 DEG C；Preferably,
The reaction temperature is 65-75 DEG C.
4. preparation method according to claim 1 to 3, which is characterized in that the cyanamide is with mass concentration
The cyanamide aqueous solution form of 20%-40% is added drop-wise in system；Preferably, the cyanamide aqueous solution is at 50-60 DEG C
Under the conditions of be added dropwise in system.
5. preparation method according to claim 1 to 4, which is characterized in that the solvent is selected from methanol, ethyl alcohol, isopropyl
One of alcohol, ethyl acetate, glacial acetic acid；Preferred alcohol.
6. -5 any preparation method according to claim 1, which is characterized in that the preparation method further includes post-processing:
Concentration of reaction solution to dry, addition solvent and catalyst, precipitation solid obtains crude product, recrystallizes.
7. the preparation method of any Nafamostat Mesilate intermediate of claim 1-6 is preparing answering in contamination levels product
With.
8. a kind of preparation method of Nafamostat Mesilate impurity characterized by comprising
(1) preparation method for using any Nafamostat Mesilate intermediate of claim 1-6, obtains 3- guanidinobenzoic acid
Hydrochloride；
(2) in a solvent, 3- guanidinobenzoic acid hydrochloride and 6- amidino groups-beta naphthal mesylate are in dehydrating agent N ,-two hexamethylene of N '
Base carbodiimide, the lower reaction of catalyst 4-dimethylaminopyridine effect, generate 6- amidino groups -2- naphthalene -3- guanidine benzoate；With
Methanesulfonic acid is in proportion at salt to get 6- amidino groups -2- naphthalene -3- guanidine benzoate dimethanesulfonate or 6- amidino groups -2- naphthalene -3-
Five mesylate of guanidine benzoate.
9. preparation method according to claim 8, which is characterized in that in step (2), the solvent be selected from methylene chloride,
Acetonitrile or pyridine；It is preferred that pyridine；
And/or in step (2), the reaction temperature is 20 DEG C -50 DEG C；
And/or in step (2), the methanesulfonic acid of molar ratio 2.0-2.3 is added dropwise to get impurity 6- amidino groups -2- naphthalene -3- guanidine radicals benzene
Formic acid esters dimethanesulfonate；Or, the methanesulfonic acid of molar ratio 5.0-6.0 is added dropwise to get impurity 6- amidino groups -2- naphthalene -3- guanidine radicals benzene
Five mesylate of formic acid esters.
10. preparation method according to claim 7, which is characterized in that further include purifying: being dissolved in water into crude product, inhale
After attached removal of impurities, solvent is added, solid is precipitated to get sterling.
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| KR20220145941A (en) * | 2021-04-20 | 2022-10-31 | (주) 성운파마코피아 | Method for manufacturing of guanidino-benzoate sulfonic acid compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220145941A (en) * | 2021-04-20 | 2022-10-31 | (주) 성운파마코피아 | Method for manufacturing of guanidino-benzoate sulfonic acid compound |
| KR102548504B1 (en) | 2021-04-20 | 2023-06-29 | (주)성운파마코피아 | Method for manufacturing of guanidino-benzoate sulfonic acid compound |
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