CN108912046B - A kind of preparation method for treating ocular hypertension pharmaceutical intermediate - Google Patents
A kind of preparation method for treating ocular hypertension pharmaceutical intermediate Download PDFInfo
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention belongs to pharmaceutical technology fields, more particularly to a kind of preparation method for treating ocular hypertension pharmaceutical intermediate, the present invention provides a kind of methods that highly selective sulfonation 4- fluorine isoquinolin prepares 4- fluorine isoquinoline-5-sulfonic acid, using heteropoly acid as additive to 4- fluorine isoquinolin carry out sulfonating reaction when, improve the conversion ratio of 4- fluorine isoquinolin, and the ratio of 8 sulfonation byproducts is reduced, compared with prior art, the selectivity of target product significantly improves.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method for treating ocular hypertension pharmaceutical intermediate.
Background technique
Glaucoma is a kind of painless retinal ganglial cells degenerative disease, and the irreversible damage optic nerve of energy is led
Visual impairment is caused even to blind.Glaucoma seriously affects the health of global more than 6,000 ten thousand people, oneself becomes the current second largest blinding
Disease.The pathogenesis of glaucoma is complicated, but mainly thinks that intraocular pressure raising is the first cause for leading to glaucoma at present.Cause
This, reducing intraocular pressure becomes the main means for the treatment of glaucoma.
Rho/ROCK signal path effectively adjusts oneself research hotspot as glaucoma treatment to intraocular pressure.The suppression of such target spot
Preparation can reduce intraocular pressure by increasing aqueous humor discharge rate, have lesser side effect and preferable tolerance.It is auspicious easyproly
You are a kind of novel ROCK inhibitors, which is researched and developed by Kowa company Ltd, is ratified in September, 2014 by Japanese Ministry of Health, Labour and Welfare
Listing, the treatment for glaucoma and ocular hypertension.
Auspicious your chemical name of easypro ground is the fluoro- 5- of (S) -4- (2- methyl-1,4- diaza heptane -1- sulfonyl)-isoquinolin
Hydrochloride dihydrate, molecular formula C15H23ClFN3O4S, molecular weight 395.88, CAS registration number are 887375-67-9,
Shown in the structural formula of free alkali such as formula (1):
By retrosynthetic analysis it is found that auspicious easypro ground that is keyed by A segment and B segment by sulfonamide, A structure piece
Section is 7 yuan of azacyclo-s, and B structure segment can be 4- fluorine isoquinoline-5-sulfonic acid.Wherein B structure segment passes through sulphur by 4- fluorine isoquinolin
Change reaction to obtain, reaction equation is as shown in Scheme 1:
There are competing for isoquinolin 5 and 8 in sulfonating reaction it can be seen from the reaction equation shown in Scheme 1
Strive relationship；Document Heterocycles, 2011,83 (8): 1771-1781, A Practical Synthesis of Novel
Rho-Kinase Inhibitor, (S) -4-Fluoro-5- (2-methyl-1,4-diazepan-1-ylsulfonyl)
Careful research has been done to step reaction in isoquinoline, FeCl is used in sulfonation process3It can make as additive
Major-minor product reaches 2.4:1, but still has 20% 4- fluorine isoquinolin unreacted complete；Make when using the sulfate of 4- fluorine isoquinolin
Sulfonation is carried out for substrate and sulfur trioxide, then uses SOCl2It carries out one pot reaction and directly prepares 4- fluorine isoquinolin -5- sulphonyl
Although conversion ratio has reached 100% when chlorine, which is only 39%, and reason is still by isoquinolin in sulfonating reaction
5 and 8 there are competitive relations to cause by-product excessive.
Zhang Peng et al. (Shandong chemical industry, 2012, the 5th phase, 25-28, isoquinoline-5-sulfonic acid synthesizes and study on mechanism)
Using isoquinolin as raw material, elder generation and hydrogen chloride generate isoquinoline-5-sulfonic acid at salt, then with oleum orientation reaction, disposable to receive
Rate reaches 84.6%；But fluorine atom is free of in the substrate, different from 4- fluorine isoquinoline structure, resulting in reaction, there are difference.
So developing a kind of highly selective 4- fluorine isoquinolin process for sulfonation, for preparing auspicious easypro ground, you have great importance.
Summary of the invention
The object of the present invention is to provide a kind of preparation method for treating ocular hypertension pharmaceutical intermediate, the specific present invention is mentioned
A kind of method that highly selective sulfonation 4- fluorine isoquinolin prepares 4- fluorine isoquinoline-5-sulfonic acid is supplied, present invention discover that heteropoly acid is made
The conversion ratio of substrate 4- fluorine isoquinolin can not only be increased when carrying out sulfonating reaction to 4- fluorine isoquinolin for addO-on therapy, but also
The generation of 8- sulfonation byproducts can be reduced.
The present invention is to be achieved through the following technical solutions above-mentioned purpose, a kind of system for treating ocular hypertension pharmaceutical intermediate
Preparation Method, in the presence of heteropoly acid, 4- fluorine isoquinolin is reacted with sulfonating agent generates 4- fluorine isoquinoline-5-sulfonic acid.
Preferably, the preparation method of the treatment ocular hypertension pharmaceutical intermediate, specifically comprises the following steps:
1) sulfonated reagent is added in reactor and heteropoly acid stirs evenly, then temperature control to -10~10 DEG C of insulated and stirreds；
2) 4- fluorine isoquinolin is added portionwise into reactor, in 4- fluorine isoquinolin adition process temperature of reactor control-
10~10 DEG C；4- fluorine isoquinolin carries out gradient increased temperature reaction after being added between -5~40 DEG C；
3) when 4- fluorine isoquinolin concentration is no longer changed in HPLC detection reaction solution, reaction solution is cooled to 0-5 DEG C；
4) reaction solution is added to quenching reaction in ice water, purified water stirring is then added, sodium hydrate aqueous solution is added dropwise
Regulation system pH to 5-6 stirs 10-20min, and ethyl acetate stirring is added into reactor, using filtering with microporous membrane, collects
Filtrate stratification collects the post-treated white solid for obtaining 4- fluorine isoquinoline-5-sulfonic acid of ethyl acetate layer；
Preferably, the heteropoly acid is phosphotungstic acid or phosphomolybdic acid；
Preferably, the sulfonating agent be the concentrated sulfuric acid, it is chlorosulfonic acid, sulfur trioxide, one or two kinds of in oleum；
Preferably, the additional amount of the heteropoly acid is the 10%-30% of 4- fluorine isoquinolin weight；
Preferably, the additional amount of the sulfonating agent is 4-20 times of 4- fluorine isoquinolin mole；
Preferably, the post-processing, which refers to, is transferred to ethyl acetate layer in crystallization reactor, then heats to 45-55 DEG C of guarantor
Temperature stirring, anti-solvent is added dropwise into crystallization reactor using peristaltic pump, to occur crystal grain in system stops that anti-solvent is added dropwise,
Growing the grain 20-30min is kept the temperature, dropwise addition anti-solvent 4- fluorine isoquinoline-5-sulfonic acid concentration into system is then proceeded to and is no longer changed
When be cooled to room temperature, filtering, dry 4- fluorine isoquinoline-5-sulfonic acid white solid；The anti-solvent be normal heptane, toluene or
Water, further preferably toluene；
The present invention uses heteropoly acid as additive to promote 4- fluorine isoquinolin to prepare 4- fluorine in 5 sulfonating reactions for the first time
Isoquinoline-5-sulfonic acid, compared with prior art, the present invention has the advantage that
1) the method for the present invention is high to the selectivity of 4- fluorine isoquinoline-5-sulfonic acid, major-minor product (4- fluorine isoquinoline in reaction process
Quinoline -5- sulfonic acid/4- fluorine isoquinolin -8- sulfonic acid) it is greater than 8:1；
2) the by-product 4- fluorine that the present invention uses ethyl acetate/toluene that can be effectively removed in reaction as recrystallisation solvent is different
Quinoline -8- sulfonic acid, can make by-product percentage composition be reduced to 0.1% or less；
3) the method for the present invention is easy, can single step reaction prepare 4- fluorine isoquinoline-5-sulfonic acid, without preparing 4- fluorine isoquinoline first
The sulfate of quinoline carries out sulfonation again, and the selectivity of target product is high.
Specific embodiment
In order to make the objectives, technical solutions and advantages of the present invention clearer, With reference to embodiment, to this
Invention is further described.It should be understood that these descriptions are merely illustrative, and it is not intended to limit the scope of the invention.
HPLC condition: chromatographic column Waters Symmetry C18 column (250mmX4.6mm, 5 μm), mobile phase A pH=
7.0 1%V triethylamine aqueous solution (being adjusted using phosphoric acid), Mobile phase B is methanol, VA/B=70/30, elution time 20min；
Detection wavelength is 275nm, 30 DEG C of column temperature；Wherein the HPLC retention time of 4- fluorine isoquinoline-5-sulfonic acid is 5.28min, and 4- fluorine is different
The HPLC retention time of quinoline -8- sulfonic acid is 6.76min.
Phosphotungstic acid, phosphomolybdic acid used in embodiment are examination from Sigma-Aldrich (Shanghai) trade Co., Ltd
Agent rank, concrete specification are respectively phosphotungstic acid hydrate, and No. CAS is 12501-23-4；Phosphorus molybdenum acid hydrate, No. CAS is
51429-74-4；Sulfur trioxide of the oleum containing 62%wt, chemical formula H2SO4·2SO3。
Embodiment 1
The screening of additive, experimental condition refer to Heterocycles, and 2011,83 (8): the introduction in 1771-1781 is complete
At, method particularly includes:
4- fluorine isoquinolin (10mmol, 1.47g), the concentrated sulfuric acid (22mmol, 2.2eq) of 98%wt, three are added in reaction flask
Sulfur oxide (86mmol, 8.6eq), additive (0.3g ,~20%wt) react at 30 DEG C, and HPLC detects 4- fluorine isoquinolin no longer
When conversion, raw material 4- fluorine isoquinolin (A formula compound), target product 4- fluorine isoquinoline-5-sulfonic acid (B formula in reaction solution are counted
Close object) and its area percentage of by-product 4- fluorine isoquinolin -8- sulfonic acid (C formula compound) be shown in Table 1:
Influence of 1 different additive of table to reaction
The above result shows that heteropoly acid can realize the high conversion of substrate and the high selection of target product as additive
Property；Although the complete conversion of substrate may be implemented in phosphotungstic acid compared with phosphomolybdic acid, 8 sulfonation byproducts are more, so this hair
Bright heteropoly acid selects phosphomolybdic acid.
Embodiment 2
When determining phosphomolybdic acid as additive, the present invention to the type of sulfonated reagent and its dosage of phosphomolybdic acid done into
One-step optimization, the method is as follows:
In reaction flask be added 4- fluorine isoquinolin (10mmol, 1.47g), sulfonating agent (11eq), phosphomolybdic acid (74mg-740mg,
5%wt~50%wt) it is reacted at 30 DEG C, when HPLC detection 4- fluorine isoquinolin no longer converts, count raw material 4- fluorine in reaction solution
The area percentage of isoquinolin, target product 4- fluorine isoquinoline-5-sulfonic acid and its by-product 4- fluorine isoquinolin -8- sulfonic acid is shown in Table 2 institutes
Show:
The influence of 2 sulfonating agent type of table and its phosphomolybdic acid dosage to sulfonating reaction
Note: sulfur trioxide is that sulfur trioxide is dissolved in dichloromethane solution；Oleum/chlorosulfonic acid refers to oleum
With the mixture of chlorosulfonic acid, the molar ratio of the two is oleum/chlorosulfonic acid=2/1.
The above result shows that sulfonating agent type is the key influence factor for influencing sulfonating reaction conversion ratio, to target product
Selectivity influence it is little；When wherein with oleum/chlorosulfonic acid mixture (molar ratio 2:1), substrate almost turns
Change, the ratio between major-minor product is 9.4:1；Sulfonating agent is used as in the mixture (molar ratio 2:1) of selected oleum/chlorosulfonic acid
When, with increasing for phosphomolybdic acid dosage, the ratio of major-minor product is gradually risen, but also occurs removing 8 sulfonation by-products on a small quantity
The impurity (< 0.5%) of beyond the region of objective existence, comprehensively considers, and the dosage of phosphomolybdic acid is advisable between the 20-30%wt of 4- fluorine isoquinolin weight.
Embodiment 3
Oleum (8.0mol, 8.0eq), chlorosulfonic acid (4.0mol, 4.0eq), phosphorus molybdenum are added in double-layer glass reaction kettle
Sour (36.8g, 25.0%wt) is stirred evenly, then temperature control to -10~10 DEG C of insulated and stirreds；
4- fluorine isoquinolin (147.1g, 1.0mol) is added portionwise into double-layer glass reaction kettle, 4- fluorine isoquinolin was added
Temperature of reactor control is at -10~10 DEG C in journey；4- fluorine isoquinolin carries out gradient increased temperature after being added between -5~40 DEG C
Reaction；The gradient increased temperature refers to heat up stage by stage, and the present invention is warming up to 10 DEG C in 30min by -5, and then 10 DEG C of heat preservations are anti-
0.5h is answered, is warming up to 20 DEG C of insulation reaction 0.5h in 30min by 10 DEG C, is warming up to 30 DEG C of insulation reactions in 30min by 20 DEG C
0.5h is warming up to 40 DEG C of insulation reactions in 30min by 30 DEG C；
HPLC detects 4- fluorine isoquinolin concentration in reaction solution and is no longer changed that (area percentage: raw material A is after 4h
0.12%, it is 99.51%, B/C=9.3 that major-minor, which produces (B+C)), reaction solution is cooled to 0-5 DEG C；
Reaction solution is added to quenching reaction in 3.0kg ice water, the stirring of 1.0kg purified water is then added, 5mol/L is added dropwise
Sodium hydrate aqueous solution regulation system pH to 5-6, stir 10-20min, into reaction kettle be added 3.0L ethyl acetate stirring,
Using filtering with microporous membrane, filtrate stratification is collected, water layer uses 3.0L ethyl acetate to extract again, merges ethyl acetate twice
Ethyl acetate layer weighing is divided into 4 equal portions respectively, is respectively designated as W-1, W-2, W-3, W-4 by layer；
1) directly to ethyl acetate concentration W-1
The ethyl acetate solution of W-1 is carried out to be concentrated to dryness to obtain light yellow particulate matter 54.5g at 45-50 DEG C, is received
Rate be 96.0%, HPLC use area normalization method detection particulate matter in raw material 4- fluorine isoquinolin for 0.14%, target product 4-
Fluorine isoquinoline-5-sulfonic acid 89.82%, by-product 4- fluorine isoquinolin -8- sulfonic acid 9.68%, surplus is unknown impuritie.
2) water is added as anti-solvent crystallization to W-2
W-2 is transferred in crystallization reactor, then heats to 45-55 DEG C of insulated and stirred, using peristaltic pump to crystallization reactor
Middle dropwise addition water to occur crystal grain in system stops that (about addition 2.2L) is added dropwise, keeps the temperature growing the grain 20-30min, then proceed to drip
It adds water to and is cooled to room temperature when 4- fluorine isoquinoline-5-sulfonic acid concentration is no longer changed in system, filtering, dry 4- fluorine isoquinoline
The white solid 52.6g of quinoline -5- sulfonic acid, yield 92.6%；HPLC is using raw material 4- fluorine in area normalization method detection solid
Isoquinolin be 0.06%, target product 4- fluorine isoquinoline-5-sulfonic acid 91.39%, by-product 4- fluorine isoquinolin -8- sulfonic acid 8.42%,
Surplus is unknown impuritie.
3) normal heptane is added as anti-solvent crystallization to W-3
W-2 is transferred in crystallization reactor, then heats to 45-55 DEG C of insulated and stirred, using peristaltic pump to crystallization reactor
Middle dropwise addition normal heptane to occur crystal grain in system stops that (about addition 2.8L) is added dropwise, keeps the temperature growing the grain 20-30min, then after
The continuous normal heptane that is added dropwise is cooled to room temperature when 4- fluorine isoquinoline-5-sulfonic acid concentration is no longer changed into system, filtering, dry
The white solid 48.2g of 4- fluorine isoquinoline-5-sulfonic acid, yield 84.8%；HPLC is using in area normalization method detection solid
Raw material 4- fluorine isoquinolin is 0.04%, target product 4- fluorine isoquinoline-5-sulfonic acid 98.62%, by-product 4- fluorine isoquinolin -8- sulfonic acid
1.31%, surplus is unknown impuritie.
4) toluene is added as anti-solvent crystallization to W-4
W-2 is transferred in crystallization reactor, then heats to 45-55 DEG C of insulated and stirred, using peristaltic pump to crystallization reactor
Middle dropwise addition toluene to occur crystal grain in system stops that (about addition 3.3L) is added dropwise, keeps the temperature growing the grain 20-30min, then proceed to
Toluene is added dropwise and is cooled to room temperature when 4- fluorine isoquinoline-5-sulfonic acid concentration is no longer changed into system, filtering, dry 4- fluorine
The white solid 46.8g of isoquinoline-5-sulfonic acid, yield 82.4%；HPLC is using raw material in area normalization method detection solid
4- fluorine isoquinolin is 0.02%, target product 4- fluorine isoquinoline-5-sulfonic acid 99.88% and its by-product 4- fluorine isoquinolin -8- sulfonic acid
0.05%, surplus is unknown impuritie.
Although embodiments of the present invention are described in detail, it should be understood that, without departing from of the invention
In the case where spirit and scope, embodiments of the present invention can be made with various changes, replacement and change.
Claims (6)
1. a kind of preparation method for treating ocular hypertension pharmaceutical intermediate, it is characterised in that: in the presence of heteropoly acid, 4- fluorine is different
Quinoline is reacted with sulfonating agent generates 4- fluorine isoquinoline-5-sulfonic acid；
Include the following steps,
1) sulfonated reagent is added in reactor and heteropoly acid stirs evenly, then temperature control to -10 ~ 10 DEG C of insulated and stirreds；
2) 4- fluorine isoquinolin is added portionwise into reactor, temperature of reactor control is -10 ~ 10 in 4- fluorine isoquinolin adition process
℃；4- fluorine isoquinolin carries out gradient increased temperature reaction after being added between -5 ~ 40 DEG C；
3) when 4- fluorine isoquinolin concentration is no longer changed in HPLC detection reaction solution, reaction solution is cooled to 0-5 DEG C；
4) reaction solution is added to quenching reaction in ice water, purified water stirring is then added, sodium hydrate aqueous solution is added dropwise and adjusts
System pH to 5-6 stirs 10-20min, and ethyl acetate stirring is added into reactor, using filtering with microporous membrane, collects filtrate
Stratification collects the post-treated white solid for obtaining 4- fluorine isoquinoline-5-sulfonic acid of ethyl acetate layer；
The heteropoly acid is phosphotungstic acid or phosphomolybdic acid.
2. preparation method according to claim 1, it is characterised in that: the sulfonating agent is the concentrated sulfuric acid, chlorosulfonic acid, three oxidations
It is one or two kinds of in sulphur, oleum.
3. preparation method according to claim 1, it is characterised in that: the additional amount of the heteropoly acid is 4- fluorine isoquinolin weight
The 10%-30% of amount.
4. preparation method according to claim 1, it is characterised in that: the additional amount of the sulfonating agent is that 4- fluorine isoquinolin rubs
4-20 times of that amount.
5. preparation method according to claim 1, it is characterised in that: the post-processing, which refers to, is transferred to knot for ethyl acetate layer
In brilliant reaction kettle, 45-55 DEG C of insulated and stirred is then heated to, anti-solvent is added dropwise into crystallization reactor using peristaltic pump, to body
Occur crystal grain in system to stop that anti-solvent is added dropwise, keep the temperature growing the grain 20-30min, then proceedes to that anti-solvent 4- into system is added dropwise
Fluorine isoquinoline-5-sulfonic acid concentration is cooled to room temperature when being no longer changed, filtering, dry 4- fluorine isoquinoline-5-sulfonic acid it is white
Color solid.
6. preparation method according to claim 5, it is characterised in that: the anti-solvent is normal heptane, toluene or water.
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| A Practical Synthesis of Novel Rho-Kinase Inhibitor，（S）-4-Fluoro-5-(2-methyl-1 ,4-diazepan-1-ylsulfonyl）isoquinoline;Gomi, N，等;《Heterocycles》;20110524;第83卷(第8期);第1771-1781页 * |
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