CN107216311B - (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1, the refining methd of 4- Diazesuberane hydrochloride - Google Patents
(s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1, the refining methd of 4- Diazesuberane hydrochloride Download PDFInfo
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- CN107216311B CN107216311B CN201610162333.3A CN201610162333A CN107216311B CN 107216311 B CN107216311 B CN 107216311B CN 201610162333 A CN201610162333 A CN 201610162333A CN 107216311 B CN107216311 B CN 107216311B
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- C07—ORGANIC CHEMISTRY
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- 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 invention discloses (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1s; the refining methd of 4- Diazesuberane hydrochloride; it comprises the concrete steps that: by (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1; the in the mixed solvent of ethyl alcohol and acetonitrile composition is added in 4- Diazesuberane hydrochloride, crude; it is heated to reflux to being completely dissolved; cooling crystallization is stirred, filtration drying is up to highly finished product.The present invention significantly improves the liquid phase purity and active constituent content of product, and highly finished product purity is made to reach 99.85% or more, single miscellaneous respectively less than 0.1%.The present invention is also convenient for the large-scale production of product, and easy to operate, cost is relatively low.
Description
Technical field
The present invention relates to a kind of refining methds, and in particular to one kind (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -
3- methyl-1, the refining methd of 4- Diazesuberane hydrochloride.Belong to pharmaceutical technology field.
Background technique
The Glanatec eye drops of Japan's listing, effective component are (s) -4- [(4- fluoro isoquinolin -5- base) sulphonyl
Base] -3- methyl-1,4- Diazesuberane hydrochloride hydrate, for treating intraocular hypertension and glaucoma (other glaucoma treatments
Medicine therapeutic effect is undesirable or this product is used in the case where not being available).
Without (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1 of the crystallization water, 4- Diazesuberane
Hydrochloride can be used as the prevention and treatment agent of the cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, brain edema, special
Be not as the cerebral angiospasms disease such as cerebral apoplexy inhibitor be it is useful, the structural formula of compound is as follows:
Preparation (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1 at present, 4- Diazesuberane hydrochloric acid
The key step of salt compound is as follows:
Contain the biggish impurity of some polarity in the hydrochloric acid product salt obtained according to the preparation method, these impurity effects should
The quality of product and the quality for using hydrate obtained by this hydrochloride, it is therefore desirable to (s) -4- [(4- fluoro isoquinolin -
5- yl) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride refined to obtain the product of high-purity.
(s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1 at present, 4- Diazesuberane hydrochloride
There are mainly two types of refining methds:
Method one: obtained HCl, solid is added portionwise patent CN103068818B in the case where ice water is cooling
It in the sodium hydroxide solution of 3.6w.t.%, is extracted with toluene, 20w.t.% sodium chloride solution cleans combined organic phase, distillation
It removes solvent and obtains Yellow amorphous purpose object.The purpose object obtained in this way is the higher base of purity, to
It obtains desired hydrochloride also to need that base is acidified into salt on this basis, the method process is cumbersome, troublesome in poeration.
Method two: the hydrochloride, crude chloroform that patent application WO9920620A will be obtained: methanol=10:1 (volume ratio)
Column chromatography is carried out to refine, the highly finished product purity 98.2% that the method obtains, yield only has 58.6%, and is not suitable for extensive
Metaplasia produces.
Summary of the invention
The purpose of the present invention is to overcome above-mentioned the deficiencies in the prior art, provide one kind (s) -4- [(4- fluoro isoquinolin -
5- yl) sulfonyl] -3- methyl-1, the refining methd of 4- Diazesuberane hydrochloride.
To achieve the above object, the present invention adopts the following technical solutions:
(s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1, the purification of 4- Diazesuberane hydrochloride
Method comprises the concrete steps that: by (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane salt
The in the mixed solvent of ethyl alcohol and acetonitrile composition is added in hydrochlorate crude product, is heated to reflux to being completely dissolved, stirs cooling crystallization, crosses and be filtered dry
Dry highly finished product to obtain the final product；Wherein, the mass volume ratio of crude product and ethyl alcohol, acetonitrile is 1g:5~5.2mL:1~1.1mL, the hydrochloric acid
The structural formula of salt compound is as follows:
Preferably, the stirring and crystallizing time is 2~3 hours.
Preferably, the drying is dried under reduced pressure for 35~40 DEG C.
The preparation method of the crude product is: ethyl acetate solution (the following abbreviation under argon gas stream, to 4mol/L hydrogen chloride
For 4N hydrogen chloride/ethyl acetate) in, in the case where ice water is cooling, (s)-tert-butyl 4- [(the 4- fluorine dissolved in ethyl acetate is added dropwise
For isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane -1- carboxylate stirs under ice water cooling condition anti-
It answers, filtration drying after reaction to obtain the final product；Wherein, the ethyl acetate solution of hydrogen chloride and (s)-tert-butyl 4- [(4- fluoro isoquinoline
Quinoline -5- base) sulfonyl] -3- methyl-1, the mass ratio of 4- Diazesuberane -1- carboxylate is 10.4~10.5:1.
Preferably, the time that is stirred to react in crude product preparation process is 2 hours.
Preferably, the drying in crude product preparation process is dried under reduced pressure for 35~40 DEG C.
Hydrochloride, crude is prepared according to the method that patent CN103068818B is recorded in applicant, sends out after liquid phase detects
Existing, product main peak appears in 15 minutes or so, and there are some 0.1% impurity of being greater than to be difficult between 3 minutes or so to 5 minutes
Remove, be difficult purification using the small solvent of methylene chloride isopolarity and remove these impurity, reason may be these impurity polarity compared with
Greatly.Therefore consider to be refined using the biggish solvent of polarity.
In summary consider the mixed solvent using ethyl alcohol and acetonitrile, it is desirable to these impurity are effectively reduced or remove, with
Improve the purity of product.
Applicant carried out a series of experiments to attempt (the results are shown in Table 1):
(1) crude product is stirred at room temperature respectively at ethyl alcohol, acetonitrile, ethyl acetate equal solvent, the impurity in product almost without
It is apparent to reduce.
(2) by crude product in above-mentioned single solvent distinguish heating stirring, even if temperature rise to it is very high cannot all make it dissolve,
It can not achieve ideal recrystallization, but from last refining effect it can be concluded that using methanol or alcohol solvent
Purification can reduce or remove impurity between 3~5 minutes, but the impurity bigger for front polarity is almost without effect, due to
Methanol belongs to the second class solvent, and applicant's selection uses ethyl alcohol；It can reduce or remove 3 minutes and 3 points using acetonitrile solvent purification
Impurity before clock, but for subsequent impurity without impurity-eliminating effect, be easy to control because acetonitrile content ratio is smaller in experiment,
Limit or less is remained in acetonitrile by vapor detection acetonitrile residue；Using ethyl acetate, although ethyl acetate and ethyl alcohol polarity
Be not much different, but the two be to the purification of impurity in the application it is entirely different, ethyl acetate is to impurity almost without essence
Effect processed, it follows that solvent polarity is not the single factor that purification removes impurity, system environment locating for impurity is brought
Many uncertain factors considerably increase the difficulty of refining solvent selection.
(3) single solvent in application method (2) can not achieve heating for dissolving, applicant consider using mixed solvent into
Row is attempted, such as ethylacetate/acetonitrile, ethyl alcohol/ethylacetate/acetonitrile, ethanol/acetonitrile these three situations.It is attempted by test
It was found that: being stirred at room temperature and being heated using ethylacetate/acetonitrile mixed solvent cannot be such that crude product dissolves；Use ethyl alcohol/acetic acid second
Ester/acetonitrile mixed solvent heating can be such that product dissolves, and the obtained product impurity of cooling crystallization decreases, but there are also single miscellaneous
Greater than 0.1% and yield is lower；Product can be made to dissolve well after heating using ethanol/acetonitrile mixed solvent, cooling down
The product of precipitation can effectively remove impurity contained therein, and HPLC detects 99.85% or more purity, and list is miscellaneous to be respectively less than
0.1%, optical purity 99.9%ee, and high income, refining effect are highly desirable.
1. solvent screening process of table
| Refining solvent | Dissolve by heating situation | Highly finished product purity | Highly finished product yield | Refining effect |
| Ethyl alcohol | Slightly soluble | 97.4% | 86.0% | Impurity at 3~5 minutes can be reduced |
| Acetonitrile | Slightly soluble | 96.8% | 87.3% | Impurity before capable of reducing by 3 minutes |
| Ethyl acetate | Slightly soluble | 95.6% | 89.5% | It is almost unchanged |
| Ethylacetate/acetonitrile | Slightly soluble | 97.6% | 82.4% | Impurity before capable of reducing by 3 minutes |
| Ethyl alcohol/ethylacetate/acetonitrile | Quan Rong | 99.7% | 75.6% | It is improved, also list is miscellaneous is greater than 0.1% |
| Ethanol/acetonitrile | Quan Rong | 99.9% | 96.2% | Single miscellaneous respectively less than 0.1% |
Certainly, the specific method that ethanol/acetonitrile mixed solvent is refined in method (3) is not to accomplish in one move, ethyl alcohol
The mixed proportion heating for dissolving situation different with acetonitrile be not identical, and refining effect is not also identical, the volume ratio sieve of ethanol/acetonitrile
Process is selected to be shown in Table 2 and table 3.In addition, being completely dissolved by screening discovery solid in solvent refluxing, refining effect is best.
2. ethyl alcohol of table and acetonitrile volume ratio and solution temperature screening process
| Ethanol/acetonitrile volume ratio | Dissolve by heating situation | Highly finished product purity | Highly finished product yield | Refining effect |
| 1:1 | It is partly dissolved | 98.6% | 96.1% | There is 4 lists are miscellaneous to be greater than 0.1% |
| 2:1 | It is partly dissolved | 98.9% | 95.9% | There is 3 lists are miscellaneous to be greater than 0.1% |
| 3:1 | Most of dissolution | 99.2% | 95.6% | There is 2 lists are miscellaneous to be greater than 0.1% |
| 4:1 | Dissolution | 99.6% | 95.8% | There is 1 list is miscellaneous to be greater than 0.1% |
| 5:1 | Dissolution | 99.8% | 96.2% | Single miscellaneous respectively less than 0.1% |
| 6:1 | Dissolution | 99.7% | 95.3% | There is 1 list is miscellaneous to be greater than 0.1% |
As can be seen from Table 2, when ethanol/acetonitrile volume ratio is 5:1, impurity-eliminating effect is best, and obtained highly finished product list is miscellaneous
Respectively less than 0.1%, and yield is also good.
Influence of 3. mixing time of table to yield
| Mixing time | 0.5 hour | 1 hour | 2 hours | 3 hours | 4 hours |
| Yield | 90.4% | 93.6% | 95.5% | 96.2% | 95.0% |
As can be seen from Table 3,2~3 hours yields of stirring and crystallizing are preferable, and the extension crystallization time makes yield start to drop instead
It is low, main cause be the crystallization time it is too short be easy to cause crystallization insufficient, crystallization overlong time cause part be precipitated crystal
Dissolution causes yield to reduce.
Beneficial effects of the present invention:
The present invention is by dissolving by heating crude product, cooling down crystallization later, thus effectively in ethanol/acetonitrile in the mixed solvent
The impurity in product is removed, to improve the liquid phase purity and active constituent content of product.It is further excellent on the basis of the method
Volume ratio and the stirring and crystallizing time for changing both ethyl alcohol and acetonitrile, to significantly improve the liquid phase purity and effective component of product
Content makes highly finished product purity reach 99.85% or more, single miscellaneous respectively less than 0.1%.The present invention is also convenient for the scale metaplasia of product
It produces, easy to operate, cost is relatively low.
Specific embodiment
Below with reference to embodiment, the present invention will be further elaborated, it should explanation, following the description merely to
It explains the present invention, its content is not defined.
Synthetic method of the present invention is as follows:
(s) of the present invention-tert-butyl 4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- diaza
Cycloheptane -1- carboxylate is prepared referring to the method in Chinese patent CN103068818B embodiment 1.
Embodiment 1:
Under protection of argon gas, it is added dropwise into 517g 4N hydrogen chloride/ethyl acetate in the case where ice water is cooling in 89.0g acetic acid second
49.5g (s)-tert-butyl 4- [(4- fluoro isoquinolin -5- base) the sulfonyl] -3- methyl-1 dissolved in ester, 4- diaza cycloheptyl
Alkane -1- carboxylate stir 2 hours in the case where ice water is cooling, filtering, and 35 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro is different
Quinoline -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride 42.0g；
By 42.0g (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloric acid
Salt crude product is added in 210mL ethyl alcohol and 42mL acetonitrile, is heated to return stirring dissolution, after stirring is cooled to room temperature, stirring and crystallizing 2
Hour, filtering, 35 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4-
Diazesuberane hydrochloride highly finished product 40.3g, yield: 96%, purity: 99.93%, single miscellaneous respectively less than 0.1%, > 99.9%
ee(HPLC)。
Embodiment 2:
Under protection of argon gas, it is added dropwise into 672g 4N hydrogen chloride/ethyl acetate in the case where ice water is cooling in 115.7g acetic acid second
64.4g (s)-tert-butyl 4- [(4- fluoro isoquinolin -5- base) the sulfonyl] -3- methyl-1 dissolved in ester, 4- diaza cycloheptyl
Alkane -1- carboxylate stir 2 hours in the case where ice water is cooling, filtering, and 40 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro is different
Quinoline -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride 54.6g；
By 54.6g (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloric acid
Salt crude product is added in 284mL ethyl alcohol and 60mL acetonitrile, is heated to return stirring dissolution, after stirring is cooled to room temperature, stirring and crystallizing 3
Hour, filtering, 40 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4-
Diazesuberane hydrochloride highly finished product 51.87g, yield: 95%, purity: 99.86%, single miscellaneous respectively less than 0.1%, > 99.9%
ee(HPLC)。
Embodiment 3:
Under protection of argon gas, it is added dropwise into 6.76kg 4N hydrogen chloride/ethyl acetate in the case where ice water is cooling in 1.16kg acetic acid
0.65kg (s)-tert-butyl 4- [(4- fluoro isoquinolin -5- base) the sulfonyl] -3- methyl-1 dissolved in ethyl ester, 4- diazacyclo
Heptane -1- carboxylate stir 2 hours in the case where ice water is cooling, filtering, and 38 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro
Isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride 0.56kg；
By 0.56kg (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloric acid
Salt crude product is added in 2.8L ethyl alcohol and 0.62L acetonitrile, is heated to return stirring dissolution, after stirring is cooled to room temperature, stirring and crystallizing 3
Hour, filtering, 38 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4-
Diazesuberane hydrochloride highly finished product 0.54kg, yield: 95.8%, purity: 99.90%, single miscellaneous respectively less than 0.1%, >
99.9%ee (HPLC).
Embodiment 4:
Under protection of argon gas, it is added dropwise into 33.8kg 4N hydrogen chloride/ethyl acetate in the case where ice water is cooling in 5.8kg acetic acid
3.25kg (s)-tert-butyl 4- [(4- fluoro isoquinolin -5- base) the sulfonyl] -3- methyl-1 dissolved in ethyl ester, 4- diazacyclo
Heptane -1- carboxylate stir 2 hours in the case where ice water is cooling, filtering, and 35 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro
Isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride 2.81kg；
By 2.81kg (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloric acid
Salt crude product is added in 14.1L ethyl alcohol and 3.1L acetonitrile, is heated to return stirring dissolution, after stirring is cooled to room temperature, stirring and crystallizing 3
Hour, filtering, 38 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4-
Diazesuberane hydrochloride highly finished product 2.70kg, yield: 96.1%, purity: 99.91%, single miscellaneous respectively less than 0.1%, >
99.9%ee (HPLC).
Embodiment 5:
Under protection of argon gas, it is added dropwise into 517g 4N hydrogen chloride/ethyl acetate in the case where ice water is cooling in 89.0g acetic acid second
49.5g (s)-tert-butyl 4- [(4- fluoro isoquinolin -5- base) the sulfonyl] -3- methyl-1 dissolved in ester, 4- diaza cycloheptyl
Alkane -1- carboxylate stir 2 hours in the case where ice water is cooling, filtering, and 37 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro is different
Quinoline -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride 42.6g；
By 42.6g (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloric acid
Salt crude product is added in 222mL ethyl alcohol and 43mL acetonitrile, is heated to return stirring dissolution, after stirring is cooled to room temperature, stirring and crystallizing 2
Hour, filtering, 37 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4-
Diazesuberane hydrochloride highly finished product 40.73g, yield: 95.6%, purity: 99.89%, single miscellaneous respectively less than 0.1%, >
99.9%ee (HPLC).
Embodiment 6:
Under protection of argon gas, it is added dropwise into 672g 4N hydrogen chloride/ethyl acetate in the case where ice water is cooling in 115.7g acetic acid second
64.4g (s)-tert-butyl 4- [(4- fluoro isoquinolin -5- base) the sulfonyl] -3- methyl-1 dissolved in ester, 4- diaza cycloheptyl
Alkane -1- carboxylate stir 2 hours in the case where ice water is cooling, filtering, and 35 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro is different
Quinoline -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride 55.2g；
By 55.2g (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloric acid
Salt crude product is added in 278mL ethyl alcohol and 61mL acetonitrile, is heated to return stirring dissolution, after stirring is cooled to room temperature, stirring and crystallizing 3
Hour, filtering, 37 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4-
Diazesuberane hydrochloride highly finished product 53.1g, yield: 96.2%, purity: 99.90%, single miscellaneous respectively less than 0.1%, >
99.9%ee (HPLC).
Embodiment 7:
Under protection of argon gas, it is added dropwise into 13.5kg 4N hydrogen chloride/ethyl acetate in the case where ice water is cooling in 2.31kg acetic acid
1.29kg (s)-tert-butyl 4- [(4- fluoro isoquinolin -5- base) the sulfonyl] -3- methyl-1 dissolved in ethyl ester, 4- diazacyclo
Heptane -1- carboxylate stir 2 hours in the case where ice water is cooling, filtering, and 38 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro
Isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride 1.1kg；
By 1.1kg (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloric acid
Salt crude product is added in 5.5L ethyl alcohol and 1.1L acetonitrile, is heated to return stirring dissolution, after stirring is cooled to room temperature, stirring and crystallizing 3
Hour, filtering, 40 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4-
Diazesuberane hydrochloride highly finished product 1.05kg, yield: 95.6%, purity: 99.89%, single miscellaneous respectively less than 0.1%, >
99.9%ee (HPLC).
Comparative example 1:
Under ice water is cooling, by 50g according to [(the 4- fluoro isoquinolin -5- base) sulphonyl of (s) -4- made from 2 method of embodiment
Base] -3- methyl-1,4- Diazesuberane hydrochloride, crude be added 50g 3.6w.t.% sodium hydroxide solution in, stir it is molten
Solution.It is extracted 2 times with 40kg toluene.The organic layer merged is cleaned with 50g 20w.t.% sodium-chloride water solution, solvent is distilled off
Obtain Yellow amorphous object.By obtained base ((s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- bis-
Azepan) 500g 4N hydrogen chloride/ethyl acetate stirring is added, there is solid precipitation, stirring and crystallizing 3 hours, filters, 37 DEG C
It is dried under reduced pressure to constant weight and obtains (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane salt
Hydrochlorate highly finished product 44.2g, yield: 88.3%, purity: 99.8%, single miscellaneous respectively less than 0.1%.
As comparative example 1 as can be seen that the hydrochloride, crude by made from is first made into base and refines, though then it is acidified again
Right purity improves, but process is cumbersome, and experienced two-step reaction, reduces yield.
Comparative example 2:
By 50g according to (s) -4- made from 2 method of embodiment [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,
4- Diazesuberane hydrochloride, crude is added in 150mL ethyl acetate and 100mL acetonitrile, and being heated to return stirring solid cannot
It is completely dissolved, continues to be heated to 100 DEG C or cannot all dissolve.After stirring is cooled to room temperature, stirring and crystallizing 3 hours, filtering,
40 DEG C are dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- diaza cycloheptyl
Heptane hydrochloride salt refining product 41.2g, yield: 82.4%, purity: 97.66%, it is greater than 0.1% there are three singly miscellaneous.
Comparative example 2, which has been used, substitutes ethyl alcohol with ethyl acetate similar in ethyl alcohol polarity, it is made to form mixed solvent with acetonitrile,
It is found through experiments that, being heated to very high temperature cannot still be such that solid is completely dissolved, and cause the product purity being precipitated not high, impurity contains
For amount also without being substantially reduced, yield is relatively low.
Comparative example 3:
By 50g according to (s) -4- made from 2 method of embodiment [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,
4- Diazesuberane hydrochloride, crude is added in 250mL ethyl acetate and 50mL acetonitrile, and being heated to return stirring solid cannot
It is completely dissolved, continues heating or cannot all dissolve.After stirring is cooled to room temperature, stirring and crystallizing 3 hours, filtering, 38 DEG C subtracted
It press dry and dry obtains (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloric acid to constant weight
Salt refining product 40.2g, yield: 80.4%, purity: 97.82%, it is greater than 0.1% there are three singly miscellaneous.
Crude product and ethyl acetate and acetonitrile solvent mass volume ratio are 1g:5mL:1mL in comparative example 3, are found through experiments that,
Cannot still solid be made to be completely dissolved, the product purity of precipitation is not still high, and still there are three biggish impurity, yield is relatively low.
Comparative example 4:
By 50g according to (s) -4- made from 2 method of embodiment [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,
4- Diazesuberane hydrochloride, crude is added in 150mL ethyl alcohol, 50mL ethyl acetate and 50mL acetonitrile, is heated to return stirring
Dissolution, after stirring is cooled to room temperature, stirring and crystallizing 3 hours, filtering, 40 DEG C were dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluoro
Isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride highly finished product 37.8g, yield: 75.6%, it is pure
Degree: 99.72%, list is miscellaneous to be greater than 0.1%.
Comparative example 4 can be such that crude product dissolves using ethyl alcohol/ethylacetate/acetonitrile mixed solvent heating, obtained by cooling crystallization
Product in there are also it is single it is miscellaneous be greater than 0.1%, and yield is significant lower.
Comparative example 5:
By 50g according to (s) -4- made from 2 method of embodiment [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,
4- Diazesuberane hydrochloride, crude is added in 150mL ethyl alcohol, 100mL ethyl acetate and 50mL acetonitrile, is heated to reflux and stirs
Mix dissolution, after stirring is cooled to room temperature, stirring and crystallizing 3 hours, filtering, 38 DEG C were dried under reduced pressure to constant weight and obtain (s) -4- [(4- fluorine
For isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane hydrochloride highly finished product 38.1g, yield: 76.2%, it is pure
Degree: 99.78%, list is miscellaneous to be greater than 0.1%.
Comparative example 5 can be such that crude product dissolves using ethyl alcohol/ethylacetate/acetonitrile mixed solvent heating, but cooling crystallization institute
There are also the impurity for being greater than 0.1% in obtained product, yield is still lower.
The hydrochloride highly finished product purity and yield being refining to obtain using method of the invention are all very high, and are suitble to amplification life
It produces.
Above-mentioned, although specific embodiments of the present invention have been described, not to the limit of the scope of the present invention
System, based on the technical solutions of the present invention, those skilled in the art do not need to make the creative labor can make it is each
Kind modification or deformation are still within protection scope of the present invention.
Claims (5)
- (1. s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1, the purification side of 4- Diazesuberane hydrochloride Method, which is characterized in that comprise the concrete steps that: by (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- phenodiazine The in the mixed solvent of ethyl alcohol and acetonitrile composition is added in trioxepane hydrochloride, crude, is heated to reflux to being completely dissolved, stirring cools down Crystallization, filtration drying is up to highly finished product；Wherein, crude product and ethyl alcohol, acetonitrile mass volume ratio be 1g:5~5.2mL:1~ The structural formula of 1.1mL, the hydrochloride compound are as follows:The stirring and crystallizing time is 2~3 hours.
- 2. refining methd according to claim 1, which is characterized in that the drying is 35~40 DEG C and is dried under reduced pressure.
- 3. refining methd according to claim 1, which is characterized in that the preparation method of the crude product is: under argon gas stream, Into the ethyl acetate solution of 4mol/L hydrogen chloride, in the case where ice water is cooling, (the s)-tert-butyl dissolved in ethyl acetate is added dropwise 4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1,4- Diazesuberane -1- carboxylate, under ice water cooling condition It is stirred to react, filtration drying after reaction to obtain the final product；Wherein, the ethyl acetate solution of hydrogen chloride and (s)-tert-butyl 4- [(4- fluorine For isoquinolin -5- base) sulfonyl] -3- methyl-1, the volume mass ratio of 4- Diazesuberane -1- carboxylate is 10.4~ 10.5:1.
- 4. refining methd according to claim 3, which is characterized in that the time that is stirred to react in crude product preparation process is 2 Hour.
- 5. refining methd according to claim 3, which is characterized in that the drying in crude product preparation process is 35~40 DEG C and subtracts It press dry dry.
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| CN101068806A (en) * | 2004-11-29 | 2007-11-07 | 兴和株式会社 | (s)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate |
| CN101973981A (en) * | 2010-10-09 | 2011-02-16 | 南京新港医药有限公司 | Refining method of 1-(5-isoquinoline sulfonyl) homopiperazine hydrochloride |
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| AU9646198A (en) * | 1997-10-22 | 1999-05-10 | Nippon Shinyaku Co. Ltd. | Isoquinoline derivative and drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101068806A (en) * | 2004-11-29 | 2007-11-07 | 兴和株式会社 | (s)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate |
| CN101973981A (en) * | 2010-10-09 | 2011-02-16 | 南京新港医药有限公司 | Refining method of 1-(5-isoquinoline sulfonyl) homopiperazine hydrochloride |
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