CN109970712A - A kind of refining methd of Fasudic hydrochloride - Google Patents
A kind of refining methd of Fasudic hydrochloride Download PDFInfo
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- CN109970712A CN109970712A CN201711449582.1A CN201711449582A CN109970712A CN 109970712 A CN109970712 A CN 109970712A CN 201711449582 A CN201711449582 A CN 201711449582A CN 109970712 A CN109970712 A CN 109970712A
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- fasudic hydrochloride
- methylene chloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention discloses a kind of method for synthesizing and refining of Fasudic hydrochloride, 5- isoquinoline sulfonate moiety is raw material, DMF is catalyst, thionyl chloride is chlorinating agent and solvent, methylene chloride is beaten after reflux concentration, obtain 5- isoquinoline sulfonyl chloride hydrochloride, it neutralizes to extract and obtains the dichloromethane solution of 5- isoquinoline sulfonyl chloride, it is added dropwise in the dichloromethane solution of homopiperazine, low-temp reaction obtains 1- (5- isoquinolinesulfonylcompounds) homopiperazine, dilute hydrochloric acid is added dropwise into reaction solution, solid Fasudic hydrochloride crude product one is precipitated after cooling, after the aqueous solution of crude product one neutralizes, methylene chloride extracts, with HCl- ethanol solution tune acid, obtain Fasudic hydrochloride crude product two, ethanol water purification, it is dry, to obtain satisfactory high-purity finished product.The method of the invention can largely remove thionyl chloride, facilitate subsequent operation and amplification production；Fasudic hydrochloride crude product one is directly precipitated by cooling in two-phase solvent, a large amount of pigment impurities can be removed.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of refining methd of Fasudic hydrochloride.
Background technique
Fasudic hydrochloride is a kind of Novel cardiovascular drug, has extensive pharmacological action.The change of Fasudic hydrochloride
Scientific name is known as hexahydro -1- (5- sulfonyl isoquinolin) -1H-1,4- diazepine hydrochloride, its molecular structure belongs to 5- isoquinoline
Quinoline sulfamide derivative.It is light by increasing myosin as a kind of RHO kinase inhibitor, that is, intracellular novel C a2+ antagonist
The activity expansion blood vessel of chain phosphatase (MLCP), reduces the tension of endothelial cell, is effectively improved brain tissue microcirculation, improve spider web
The prognosis of gap bleeding (SAH) patient under film, does not generate and aggravates robber's blood of brain, at the same can antagonism inflammatory factor, protect nerve anti-
Apoptosis promotes nerve regneration.
But it is difficult to have removed thionyl chloride by concentration in synthesis in existing Fasudic hydrochloride finished product, amplification is produced
There is certain difficulty.The pigment of product is not easy to remove in reaction, has a certain impact to the drug effect of Fasudic hydrochloride, therefore go
Except pigment has very important meaning in bulk pharmaceutical chemicals.
Summary of the invention
It is synthesized for existing Fasudic hydrochloride finished product, the present invention is directed to find easy to operate be easy to get to the original of high-purity
Expect the refining methd of medicine.
The present invention discloses a kind of refining methd of Fasudic hydrochloride, using 5- isoquinoline sulfonate moiety as starting material, through including
Chlorination obtains high purity product with homopiperazine condensation, soda acid processing step, and synthetic route is as follows:
Wherein:
(1) in 5- isoquinoline sulfonate moiety, DMF is catalyst, and thionyl chloride, stirring, heating reflux reaction 1.5- is added
2.5h, reaction temperature are 75-85 DEG C, and 5- isoquinoline sulfonyl chloride hydrochloride is obtained after concentration；
(2) in dichloromethane solution, 5- isoquinoline sulfonyl chloride hydrochloride is added, is cooled to -5~5 DEG C, it is slow under stirring
Sodium bicarbonate is added, adjusts pH value to 5-6, standing separates methylene chloride phase, and aqueous solution is extracted 2-3 times with methylene chloride again, merges
Methylene chloride phase, dries, filters, and obtains the dichloromethane solution of faint yellow 5- isoquinoline sulfonyl chloride；
(3) into the dichloromethane solution of homopiperazine, lower dropwise addition 5- isoquinoline sulfonyl chloride dichloromethane solution is stirred, control is anti-
Answer liquid temperature at -10~0 DEG C, after being added dropwise, -10~0 DEG C keeps the temperature 1 hour, then heats to 15~25 DEG C, stirs 0.5-
1.5 hour；PH to 4.5~5.5 is adjusted, is cooled to -10~0 DEG C, keeps the temperature half an hour, filtering is washed 1-2 times with saturated brine, obtained
To Fasudic hydrochloride crude product one；
(4) Fasudic hydrochloride crude product one is added under stirring into water, heating makes it dissolve, and methylene chloride, stirring is added
It stands afterwards and separates methylene chloride phase, aqueous solution is extracted 1-2 times with methylene chloride again；Obtained aqueous solution adds methylene chloride,
PH to 10~11 is adjusted, methylene chloride phase is separated, aqueous solution is extracted 2-3 times with methylene chloride again, liquid separation, the methylene chloride that will be obtained
Mutually merge；Neutralizing treatment 2-3 times, then washed 1-2 times with saturated brine, it dries, filters, obtained filtrate tune acid to 4.5~5.5,
It is cooled to -10~0 DEG C, keeps the temperature 20-40min, filtering obtains Fasudic hydrochloride crude product two after washing is dry；
(5) in Fasudic hydrochloride crude product two, ethanol water is added, temperature rising reflux 20-40min relaxes to hydrochloric acid method
Your crude product two of ground it is complete it is molten after, heat filter, filtrate slow cooling keeps the temperature 20-40min to 0~10 DEG C, and filtering obtains salt after washing is dry
Sour Fasudil finished product.
Further, it is beaten 3-4 times after concentration with methylene chloride in step (1) and filters to obtain 5- isoquinoline sulfonyl chloride hydrochloric acid
Salt.By methylene chloride mashing after reaction concentration, thionyl chloride can be largely removed, facilitates and subsequent directly cools down in two-phase solvent
Fasudic hydrochloride crude product one is precipitated, a large amount of pigment impurities can be removed, and the method is easy to operate, is suitble to industrialization big raw
It produces.
Further, it is dilute hydrochloric acid that reagent used in pH is adjusted in step (3), and the concentration of the dilute hydrochloric acid is 3.5-
4.5mol/L。
Further, it is sodium hydrate aqueous solution that reagent used in pH is adjusted in step (4), the sodium hydrate aqueous solution
Concentration is 20-30%.
Further, the sodium hydrate aqueous solution that alkali used in neutralizing treatment 2-3 times is 0.3-0.5% in step (4).
Further, it is HCl- ethanol solution that reagent used in pH is adjusted in step (4).
Further, drying means is that anhydrous magnesium sulfate is dry in step (2) and step (4).
Further, in step (5), the addition volume of ethanol water is 4.5-5.5 times of Fasudic hydrochloride crude product
Two weight.
Further, in step (5), the concentration of ethanol water is 90~91%.
Further, in step (4) and step (5), washing reagent used is 95% ethyl alcohol.
The method of the invention effectively removes thionyl chloride, and can effectively remove the pigment of product in reaction, obtains
Fasudil finished product purity up to 99.99%, be of great significance to the drug effect for improving Fasudic hydrochloride.And the present invention
The method amplification production easy to accomplish.
Detailed description of the invention
Fig. 1 is the purity analysis report that the present invention prepares Fasudic hydrochloride.
Specific embodiment
Unless stated otherwise, the reagent selected in following embodiment is commercially available general reagent, and the method is conventional
Experimental method.
Embodiment 1
Thionyl chloride 8L is first added into dry 20L glass reaction kettle, 5- isoquinoline sulfonate moiety 2kg is added, under stirring
N,N-Dimethylformamide (DMF) 200ml is added, controls reacting liquid temperature at 50 DEG C hereinafter, after addition, is warming up to back
Stream flows back 2 hours.It is concentrated to dryness, obtains off-white powder, methylene chloride 4L is added, is concentrated to dryness, adds methylene chloride 4L and beat
Slurry, filtering, obtains off-white powder, then is beaten twice, and filtering obtains off-white color 5- isoquinoline sulfonyl chloride HCl, solid.
Into 50L glass reaction kettle, methylene chloride 12L is added, adds and is previously obtained 5- isoquinoline sulfonyl chloride hydrochloride,
- 5~5 DEG C are cooled to, saturated sodium bicarbonate aqueous solution is added with stirring, adjusts pH to 5~6, controls reacting liquid temperature -5~5
DEG C, methylene chloride phase is separated, aqueous solution extracts 2 times (methylene chloride 4L × 2) with methylene chloride again, merges methylene chloride phase, uses
0.5~1kg of anhydrous magnesium sulfate is dried, filtered, and obtains faint yellow 5- isoquinoline sulfonyl chloride clarified solution, for use.
Into 50L glass reaction kettle, homopiperazine 2.6kg+ methylene chloride 8L is added, is cooled to -10~0 DEG C, stirring is lower to be added
Enter 5- isoquinoline sulfonyl chloride dichloromethane solution obtained above, controls reacting liquid temperature at -10~0 DEG C, after addition, react
Liquid is in yellow green, and -10~0 DEG C or less keeps the temperature 1 hour, then heats to 15~25 DEG C, is stirred 1 hour.The dilute salt of 4mol/L is added dropwise
Acid adjusts pH to 4.5~5.5, controls 15~25 DEG C of reacting liquid temperature, and solid is precipitated in cooling, is cooled to -10~0 DEG C, heat preservation half
Hour, filtering is washed 1 time with 1L saturated brine, obtains off-white powder (Fasudic hydrochloride crude product one).
Into 20L glass reaction kettle, water 8L is added, is added with stirring the crude product one being previously obtained, heats up, make it dissolve,
Methylene chloride 4L is added, methylene chloride phase is separated after stirring, aqueous solution uses 4L methylene chloride to extract 1 time again；Obtained aqueous solution
4L methylene chloride is added, 25% sodium hydrate aqueous solution is added, pH to 10~11 is adjusted, separates methylene chloride phase, aqueous solution is again
2 times (4L × 2) are extracted with methylene chloride, liquid separation mutually merges obtained methylene chloride.With 0.4% sodium hydrate aqueous solution
2 times (4L × 2) are washed, then are washed 1 time (4L) with saturated brine, 0.5~1kg of anhydrous magnesium sulfate is added and dries, filters, obtains
Filtrate goes in 20L glass reaction kettle, with HCl- ethanol solution tune acid to 4.5~5.5, is cooled to -10~0 DEG C, heat preservation half is small
When, filtering, filter cake 1L95% ethanol washing obtains off-white powder, 70 ± 5 DEG C normal pressure forced air drying 4 hours or more, obtain hydrochloric acid
Two 2.1kg of Fasudil crude product, yield 67.01%.
Into 20L glass reaction kettle, two 2kg of Fasudil crude product is added, adds 90~91% ethanol water (volumes
It is 5 times of amount Fasudic hydrochloride crude product weight) 10L, it is warming up to reflux, reflux about half an hour, after crude product is entirely molten, heat filter is filtered
Liquid is gone in another 20L glass reaction kettle, and slow cooling keeps the temperature half an hour to 0~10 DEG C, filtering, with 95% ethyl alcohol of about 1.5L
Washing, obtains off-white color finished product, 100 ± 5 DEG C normal pressure forced air drying 10 hours or more, obtain Fasudil finished product 1.745kg, yield
87.25%, purity 99.99%, as shown in Figure 1.
Claims (10)
1. a kind of refining methd of Fasudic hydrochloride is included chlorination and homopiperazine using 5- isoquinoline sulfonate moiety as starting material
Condensation, soda acid processing step obtain high purity product, and synthetic route is as follows:
It is characterized in that wherein:
(1) in 5- isoquinoline sulfonate moiety, DMF is catalyst, and thionyl chloride is added, and is stirred, heating reflux reaction 1.5-2.5h, instead
Answering temperature is 75-85 DEG C, and 5- isoquinoline sulfonyl chloride hydrochloride is obtained after concentration；
(2) in dichloromethane solution, 5- isoquinoline sulfonyl chloride hydrochloride is added, is cooled to -5~5 DEG C, is slowly added under stirring
Sodium bicarbonate adjusts pH value to 5-6, and standing separates methylene chloride phase, and aqueous solution is extracted 2-3 times with methylene chloride again, merges dichloro
Methane phase, dries, filters, and obtains the dichloromethane solution of faint yellow 5- isoquinoline sulfonyl chloride；
(3) into the dichloromethane solution of homopiperazine, lower dropwise addition 5- isoquinoline sulfonyl chloride dichloromethane solution is stirred, reaction solution is controlled
Temperature is at -10~0 DEG C, and after being added dropwise, -10~0 DEG C keeps the temperature 1 hour, then heats to 15~25 DEG C, stirring 0.5-1.5 is small
When；PH to 4.5~5.5 is adjusted, is cooled to -10~0 DEG C, keeps the temperature half an hour, filtering is washed 1-2 times with saturated brine, obtains hydrochloric acid
Fasudil crude product one；
(4) Fasudic hydrochloride crude product one is added under stirring into water, heating makes it dissolve, and methylene chloride is added, quiet after stirring
It sets and separates methylene chloride phase, aqueous solution is extracted 1-2 times with methylene chloride again；Obtained aqueous solution adds methylene chloride, adjusts pH
To 10~11, methylene chloride phase is separated, aqueous solution is extracted 2-3 times with methylene chloride again, and obtained methylene chloride is harmonious by liquid separation
And；Neutralizing treatment 2-3 times, then washed 1-2 times with saturated brine, it dries, filters, obtained filtrate tune acid to 4.5~5.5, cools down
To -10~0 DEG C, 20-40min is kept the temperature, filtering obtains Fasudic hydrochloride crude product two after washing is dry；
(5) in Fasudic hydrochloride crude product two, ethanol water, temperature rising reflux 20-40min, to Fasudic hydrochloride is added
Crude product two it is complete it is molten after, heat filter, filtrate slow cooling keeps the temperature 20-40min to 0~10 DEG C, and filtering obtains hydrochloric acid method after washing is dry
Relax ground that finished product.
2. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that with two after concentration in step (1)
Chloromethanes is beaten 3-4 times and filters to obtain 5- isoquinoline sulfonyl chloride hydrochloride.
3. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that adjusted used in pH in step (3)
Reagent is dilute hydrochloric acid, and the concentration of the dilute hydrochloric acid is 3.5-4.5mol/L.
4. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that adjusted used in pH in step (4)
Reagent is sodium hydrate aqueous solution, and the concentration of the sodium hydrate aqueous solution is 20-30%.
5. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that neutralizing treatment 2-3 in step (4)
Alkali used in secondary is the sodium hydrate aqueous solution of 0.3-0.5%.
6. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that adjusted used in pH in step (4)
Reagent is HCl- ethanol solution.
7. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that in step (2) and step (4)
Drying means is dry for anhydrous magnesium sulfate.
8. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that in step (5), ethyl alcohol is water-soluble
The weight that volume is 4.5-5.5 times of Fasudic hydrochloride crude product two is added in liquid.
9. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that in step (5), ethyl alcohol is water-soluble
The concentration of liquid is 90~91%.
10. the refining methd of Fasudic hydrochloride according to claim 1, it is characterised in that step (4) and step (5)
In, washing reagent used is 95% ethyl alcohol.
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| CN201711449582.1A CN109970712A (en) | 2017-12-27 | 2017-12-27 | A kind of refining methd of Fasudic hydrochloride |
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| CN201711449582.1A CN109970712A (en) | 2017-12-27 | 2017-12-27 | A kind of refining methd of Fasudic hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111909088A (en) * | 2020-08-04 | 2020-11-10 | 浙江工业大学 | Utilizing BTC/Ph3Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by PO chloro system |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111909088A (en) * | 2020-08-04 | 2020-11-10 | 浙江工业大学 | Utilizing BTC/Ph3Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by PO chloro system |
| CN111909088B (en) * | 2020-08-04 | 2022-03-01 | 浙江工业大学 | Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by using BTC/Ph3PO chloro-system |
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Application publication date: 20190705 |