CN106316950A - Gliquidone preparation method - Google Patents
Gliquidone preparation method Download PDFInfo
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- CN106316950A CN106316950A CN201510371480.7A CN201510371480A CN106316950A CN 106316950 A CN106316950 A CN 106316950A CN 201510371480 A CN201510371480 A CN 201510371480A CN 106316950 A CN106316950 A CN 106316950A
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- CN
- China
- Prior art keywords
- solvent
- gliquidone
- alkali
- thing
- isoquinolin
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D217/24—Oxygen atoms
Abstract
The invention discloses a gliquidone preparation method. According to the preparation method, isoquinoline and cyclohexyl isocyanate carry out condensation reactions in a solvent in the presence of an alkali to generate gliquidone. 2,5-dimethyl tetrahydrofuran is taken as the solvent, isoquinoline can be well dissolved in 2,5-dimethyl tetrahydrofuran, while gliquidone is difficult to dissolve in 2,5-dimethyl tetrahydrofuran; thus, only a little amount of water is needed in the post treatment, the generated wastewater is largely reduced; the used alkali is common inorganic alkalis such as anhydrous potassium carbonate, and the like, is nontoxic, and is easy to process. The boiling point of 2,5-dimethyl tetrahydrofuran is low, 2,5-dimethyl tetrahydrofuran is easy to recover, moreover, the system is not afraid of water, the solvent can be circularly used, the production cost is reduced, the refluxing temperature is adopted, the operation is easy, the reactions last for 6 hours, and the method is rapid and efficient.
Description
Technical field
The present invention relates to prepare the method for gliquidone, belong to pharmaceutical synthesis field.
Background technology
The gliquidone system second filial generation is administered orally sulfonylureas drugs for diabetes, for high activity parent's beta Cell of islet agent, with beta Cell of islet film
On specific receptor combine, can induce generation appropriate insulin, to reduce blood sugar concentration.This product 2 is administered orally～after 2.5 hours
Reach the highest blood drug level, be the most i.e. completely absorbed.Plasma half-life is 1.5 hours, and metabolism is complete, and its metabolite is not
Having hypoglycemic activity, the metabolite overwhelming majority is drained through biliary tract digestive system.
Synthesis to gliquidone in prior art, uses isoquinolin thing as raw material with DMF, benzene,
Ethyl acetate is as solvent, and with sodium hydrogen, sodium hydroxide, potassium hydroxide is as alkali, at the reaction temperatures with cyclohexyl Carbimide.
Ester effect produces gliquidone, and reaction equation is as follows:
But the method for existing synthesis gliquidone leaves following shortcoming: use DMF, benzene etc. is as molten
Agent, is unfavorable for reclaiming, and toxicity is big；Sodium hydrogen, as inflammable explosive article, easily causes fire, sodium hydroxide, and potassium hydroxide is made
Easily make system become sticky and produce substantial amounts of waste water for alkali；Reaction temperature controls at 0 DEG C, severe reaction conditions；Response time
Long, more than 24 hours, efficiency is low；Cost of material is high, is unfavorable for reclaiming, and there is easily ignitable potential safety hazard.
Summary of the invention
The technical problem to be solved in the present invention is to overcome existing defect, it is provided that a kind of new method preparing gliquidone.
Described method low cost, being easily recycled, reaction condition is gentle, potential safety hazard is little.
In order to solve above-mentioned technical problem, the invention provides following technical scheme:
A kind of method preparing gliquidone, using isoquinolin thing as raw material, it is characterised in that: isoquinolin thing is different with cyclohexyl
In a solvent, there is condensation reaction, generate gliquidone in cyanate under the effect of alkali, reaction equation is as follows:
Wherein, described alkali is selected from Anhydrous potassium carbonate, natrium carbonicum calcinatum, sodium bicarbonate, Lithium hydrate, in tert-butyl alcohol magnesium
Plant or several；
Described solvent is selected from dichloromethane, 2,5-dimethyl-tetrahydrofurans, pyridine, diisopropyl ether, ether, in chloroform
Plant or several；
In such scheme preferably, described isoquinolin thing: cyclohexyl isocyanate: alkali: the weight ratio of solvent is (1～10)
G:(0.25～2.5) g:(0.5～5) g:(5～15) ml.
It is excessive slightly for adding cyclohexyl isocyanate amount, adds alkali and is to ensure that between PH=8-9, so ensure that former
Material isoquinolin thing can react complete completely, and the amount of solvent then wants guarantee system to can be good at disperseing wherein.Too little solvent
The gliquidone generated separates out affects mixing effect too much, and solvent can reduce cause at the post processing product separated out that adds water too much
The loss of yield.
In any of the above-described scheme preferably, reaction temperature is 60-100 DEG C, and the response time is 3-6 hour.The present invention's is anti-
Answering mild condition, the response time is short, and efficiency is high.
In any of the above-described scheme preferably, described alkali is selected from Anhydrous potassium carbonate, sodium bicarbonate, one in Lithium hydrate or
Several.
Alkali selected by the present invention can improve the speed of reaction, and can well be dispersed in the system of water post processing when
The inside.And the alkali used in prior art, such as NaH can use the longest response time on the response time,
In any of the above-described scheme preferably, described alkali is Anhydrous potassium carbonate.It is more conducive to improve productivity and the purity of product.
In any of the above-described scheme preferably, described solvent is selected from dichloromethane, and 2,5-dimethyl-tetrahydrofurans, in pyridine
One or more.
In any of the above-described scheme preferably, described solvent is 2,5-dimethyl-tetrahydrofuran.It is more conducive to improve the product of product
Rate and purity.
The solvent that the present invention uses has good dissolubility to isoquinolin thing, but is poor solvent to product gliquidone,
Have only to a small amount of water when of post processing, greatly reduce the waste water that reaction produces.
In any of the above-described scheme preferably, described isoquinolin thing: cyclohexyl isocyanate: alkali: the mass volume ratio of solvent
For 30g:11.2g:21g:300ml.Productivity and the purity of the product now obtained are the highest.
Preferably, reaction temperature is 80-100 DEG C to any of the above-described scheme.The temperature that the present invention uses is beneficial to improve reaction and produces
The yield of thing, and be easily controlled.
Preferably, reaction temperature is 90 DEG C to any of the above-described scheme.It is more conducive to improve productivity and the purity of product.
Preferably, the response time is 4 hours to any of the above-described scheme.The present invention is to set according to the temperature reacted in the response time
It is that put in order to reactant reacts completely.
Beneficial effects of the present invention:
1, existing synthetic method solvent uses DMF, due to N when of post processing, N-dimethyl formyl
Amine is stronger to the dissolubility of gliquidone, needs to add substantial amounts of poor solvent water, forms the waste water being not easy to process in a large number.
The present invention uses 2, and 5-dimethyl-tetrahydrofuran etc. is as solvent, and but this solvent has good dissolubility the most right to isoquinolin thing
Product gliquidone is poor solvent, has only to a small amount of water post processing when, greatly reduces what reaction produced
Waste water；
2, the sodium hydrogen that prior art uses is the most inflammable and explosive a kind of raw material, is either using or in post processing etc.
All there is the biggest danger in aspect, and the conventional inorganic bases such as the Anhydrous potassium carbonate of the present invention, safety non-toxic, it is beneficial to process.
3, the sodium Hydrogen Energy owing to using is enough and water reacts, and the solvent DMF causing reaction cannot recycled
(reclaim DMF owing to containing water, causing technique unstable；The 2 of the present invention, 5 dimethyl-tetrahydrofurans
Equal solvent boiling point is low, it is easy to reclaiming, and system itself is the most water funk, solvent can recycled, reduce production cost；
4, prior art needs to control reaction temperature 0 DEG C, reacts 24 hours, needs add raw material and prolong according to response situation
In the long response time, consume huge human cost and brine ice cooling.The present invention uses reflux temperature, it is easy to operation reaction
6 hours, rapidly and efficiently.
Accompanying drawing explanation
Fig. 1 is that the product HPLC of the embodiment of the present invention 1 measures the sectional drawing of result after purity.
Detailed description of the invention
Hereinafter the preferred embodiments of the present invention are illustrated, it will be appreciated that preferred embodiment described herein is only used for
Bright and explain the present invention, be not intended to limit the present invention.
Embodiment 1: a kind of method preparing gliquidone
Isoquinolin thing (30g, 74.6mmol), solvent 2,5-dimethyl tetrahydro it is sequentially added in the reaction bulb of 500mL
Furan (300mL) and Anhydrous potassium carbonate (21g, 151.9mmol).Open stirring and heating, be incubated 40 DEG C of stirrings
30 minutes, add cyclohexyl isocyanate (11.2g, 89.5mmol) the most slowly, control to drip at about 30 minutes
Add complete, after dropping, rise high-temperature, 90 DEG C of heating reflux reactions 4 hours.Decompression and solvent recovery 2,5-dimethyl four
Hydrogen furan, obtains white solid.In reaction bulb, add 200mL water, be slowly added dropwise hydrochloric acid regulation PH=3, be cooled to 0-5 DEG C
Stir 1 hour, be filtrated to get gliquidone crude product, productivity 98%.
The gliquidone crude product obtained is put in the there-necked flask of 5L, in bottle, add 3L methanol, be heated to 40 DEG C, to
Adding ammonia/methanol in system, regulation pH is 3, makes gliquidone crude product be completely dissolved, then continuously adds 3g neutral oxygen
Change aluminum and 3g silica gel (200-300 mesh), utilize aluminium oxide to coordinate the impurity in silica gel absorption system completely.At 40 DEG C
Insulated and stirred 2 hours, filters, the hydrochloric acid regulation PH=3 of filtrate 3M, reduces temperature, stirring and crystallizing 4 hours at 0-5 DEG C.
Filtering, filter cake is respectively with water, absolute ethanol washing.It is vacuum dried 12 hours at 40 DEG C, obtains white granular solid,
I.e. gliquidone.Purity is 99.75%, productivity 80%.
Product nuclear magnetic data1HNMR(300MHz,DMSO-d6) δ: 10.27 (s, 1H), 7.74 (d, 2H, J=9Hz),
7.50 (d, 1H, J=6.0Hz), 7.41 (d, 1H, J=6.0Hz), 7.41 (d, 1H, J=6.0Hz), 7.28
(M, 2H), 7.25 (d, 1H, J=6.0Hz), 6.28 (d, 1H, J=6.0Hz), 4.14 (M, 2H), 3.82 (s,
3H), 3.25 (M, 1H), 2.94 (t, 2H, J=9Hz), 1.55 (M, 4H), 1.30 (s, 6H), 1.10 (M, 6H).
Embodiment 2: a kind of method preparing gliquidone
Isoquinolin thing (30g, 74.6mmol), methylene chloride (150mL) it is sequentially added in the reaction bulb of 500mL
And sodium bicarbonate (15g, 178.6mmol).Open stirring and heating, be incubated 40 DEG C and stir 30 minutes, then delay
Slow addition cyclohexyl isocyanate (7.5g, 59.9mmol), controls to drip complete at about 30 minutes, drips complete
Rear liter of high-temperature, 90 DEG C of heating reflux reactions 4 hours.Decompression and solvent recovery dichloromethane, obtains white solid.To reaction
Add 200mL water in Ping, be slowly added dropwise hydrochloric acid regulation PH=3, be cooled to 0-5 DEG C and stir 1 hour, be filtrated to get lattice row
Quinoline ketone crude product, productivity 97.0%.
The gliquidone crude product obtained is put in the there-necked flask of 5L, in bottle, add 3L methanol, be heated to 40 DEG C, to
Adding ammonia/methanol in system, regulation pH is 3, makes gliquidone crude product be completely dissolved, then continuously adds 3g neutral oxygen
Change aluminum and 3g silica gel (300 mesh), utilize aluminium oxide to coordinate the impurity in silica gel absorption system completely.It is incubated at 40 DEG C
Stir 2 hours, filter, the hydrochloric acid regulation PH=3 of filtrate 3M, reduces temperature, crystallize 4 hours at 0-5 DEG C.Filter,
Filter cake is respectively with water, absolute ethanol washing.At 40 DEG C, forced air drying 12 hours, obtain white granular solid, i.e. lattice row
Quinoline ketone.Purity is 99.10%, productivity 79.0%.
Embodiment 3: a kind of method preparing gliquidone
In the reaction bulb of 500mL, be sequentially added into isoquinolin thing (30g, 74.6mmol), solvent pyridine (450mL) with
And Lithium hydrate (15g, 626.6mmol).Open stirring and heating, be incubated 40 DEG C of stirrings 30 minutes, the most slowly
Addition cyclohexyl isocyanate (7.5g, 59.9mmol), control to drip complete at about 30 minutes, after dropping
Rise high-temperature, 80 DEG C of heating reflux reactions 6 hours.Decompression and solvent recovery pyridine, obtains white solid.Add in reaction bulb
Enter 200mL water, be slowly added dropwise hydrochloric acid regulation PH=3, be cooled to 0-5 DEG C and stir 1 hour, be filtrated to get gliquidone thick
Product, productivity 97.1%.
The gliquidone crude product obtained is put in the there-necked flask of 5L, in bottle, add 3L methanol, be heated to 40 DEG C, to
Adding ammonia/methanol in system, regulation pH is 3, makes gliquidone crude product be completely dissolved, then continuously adds 3g neutral oxygen
Change aluminum and 3g silica gel (300 mesh), utilize aluminium oxide to coordinate the impurity in silica gel absorption system completely.It is incubated at 40 DEG C
Stir 2 hours, filter, the hydrochloric acid regulation PH=3 of filtrate 3M, reduces temperature, crystallize 4 hours at 0-5 DEG C.Filter,
Filter cake is respectively with water, absolute ethanol washing.At 40 DEG C, forced air drying 12 hours, obtain white granular solid, i.e. lattice row
Quinoline ketone.Purity is 99.68%, productivity 79.6%.
Embodiment 4: a kind of method preparing gliquidone
Isoquinolin thing (30g, 74.6mmol), solvent diisopropyl ether (150mL) it is sequentially added in the reaction bulb of 500mL
And tert-butyl alcohol magnesium (150g, 880mmol).Open stirring and heating, be incubated 40 DEG C of stirrings 30 minutes, the most slowly
Addition cyclohexyl isocyanate (7.5g, 59.9mmol), control to drip complete at about 30 minutes, after dropping rise
High-temperature, 60 DEG C of heating reflux reactions 3 hours.Decompression and solvent recovery dichloromethane, obtains white solid.In reaction bulb
Add 200mL water, be slowly added dropwise hydrochloric acid regulation PH=3, be cooled to 0-5 DEG C and stir 1 hour, be filtrated to get gliquidone
Crude product, productivity 97.2%.
The gliquidone crude product obtained is put in the there-necked flask of 5L, in bottle, add 3L methanol, be heated to 40 DEG C, to
Adding ammonia/methanol in system, regulation pH is 3, makes gliquidone crude product be completely dissolved, then continuously adds 3g neutral oxygen
Change aluminum and 3g silica gel (300 mesh), utilize aluminium oxide to coordinate the impurity in silica gel absorption system completely.It is incubated at 40 DEG C
Stir 2 hours, filter, the hydrochloric acid regulation PH=3 of filtrate 3M, reduces temperature, crystallize 4 hours at 0-5 DEG C.Filter,
Filter cake is respectively with water, absolute ethanol washing.At 40 DEG C, forced air drying 12 hours, obtain white granular solid, i.e. lattice row
Quinoline ketone.Purity is 99.56%, productivity 79.3%.
Embodiment 5: a kind of method preparing gliquidone
In the reaction bulb of 500mL, be sequentially added into isoquinolin thing (30g, 74.6mmol), solvent ether (45mL) with
And natrium carbonicum calcinatum (15g, 141.5mmol).Open stirring and heating, be incubated 40 DEG C and stir 30 minutes, then delay
Slow addition cyclohexyl isocyanate (7.5g, 59.9mmol), controls to drip complete at about 30 minutes, drips complete
Rear liter of high-temperature, 100 DEG C of heating reflux reactions 6 hours.Decompression and solvent recovery pyridine, obtains white solid.To reaction bulb
Middle addition 200mL water, is slowly added dropwise hydrochloric acid regulation PH=3, is cooled to 0-5 DEG C and stirs 1 hour, be filtrated to get lattice row quinoline
Ketone crude product, productivity 96.5%.
The gliquidone crude product obtained is put in the there-necked flask of 5L, in bottle, add 3L methanol, be heated to 40 DEG C, to
Adding ammonia/methanol in system, regulation pH is 3, makes gliquidone crude product be completely dissolved, then continuously adds 3g neutral oxygen
Change aluminum and 3g silica gel (300 mesh), utilize aluminium oxide to coordinate the impurity in silica gel absorption system completely.It is incubated at 40 DEG C
Stir 2 hours, filter, the hydrochloric acid regulation PH=3 of filtrate 3M, reduces temperature, crystallize 4 hours at 0-5 DEG C.Filter,
Filter cake is respectively with water, absolute ethanol washing.At 40 DEG C, forced air drying 12 hours, obtain white granular solid, i.e. lattice row
Quinoline ketone.Purity is 99.0%, productivity 74.7%.
Comparative example 1:
Weigh in the DMF that 6g isoquinolin thing adds 80ml, after stirring makes it be completely dissolved, add the NaOH that 1.38g grinds,
It is stirring evenly and then adding into 4.38g cyclohexyl isocyanate, is heated at 60 DEG C stirring 20h, after reaction completely, system is inclined
Enter in the frozen water of 300ml, separate out solid, filter, filter cake absolute ethanol washing, obtain gliquidone, productivity 54%.
Finally it is noted that the foregoing is only the preferred embodiments of the present invention, it is not limited to the present invention, to the greatest extent
The present invention has been described in detail by pipe with reference to previous embodiment, and for a person skilled in the art, it is the most permissible
Technical scheme described in foregoing embodiments is modified, or wherein portion of techniques feature is carried out equivalent.All
Within the spirit and principles in the present invention, any modification, equivalent substitution and improvement etc. made, should be included in the present invention's
Within protection domain.
Claims (10)
1. the method preparing gliquidone, using isoquinolin thing as raw material, it is characterised in that: isoquinolin thing and hexamethylene
In a solvent, there is condensation reaction, generate gliquidone in based isocyanate under the effect of alkali, reaction equation is as follows:
Wherein, described alkali is selected from Anhydrous potassium carbonate, natrium carbonicum calcinatum, sodium bicarbonate, Lithium hydrate, in tert-butyl alcohol magnesium
Plant or several；
Described solvent is selected from dichloromethane, 2,5-dimethyl-tetrahydrofurans, pyridine, diisopropyl ether, ether, in chloroform
Plant or several.
Method the most according to claim 1, it is characterised in that: described isoquinolin thing: cyclohexyl isocyanate: alkali:
The mass volume ratio of solvent is (1～10) g:(0.25～2.5) g:(0.5～5) g:(5～15) ml.
Method the most according to claim 1 and 2, it is characterised in that: reaction temperature is 60-100 DEG C, the response time
For 3-6 hour.
Method the most according to claim 3, it is characterised in that: described alkali be selected from Anhydrous potassium carbonate, sodium bicarbonate,
One or more in Lithium hydrate, preferably Anhydrous potassium carbonate.
Method the most according to claim 3, it is characterised in that: described solvent is selected from dichloromethane, 2,5-dimethyl
Oxolane, pyridine, diisopropyl ether, one or more in ether.
Method the most according to claim 3, it is characterised in that: described solvent is 2,5-dimethyl-tetrahydrofuran.
7. according to the method described in claim 4 or 6, it is characterised in that: described isoquinolin thing: cyclohexyl isocyanate:
Alkali: the mass volume ratio of solvent is 30g:11.2g:21g:300ml.
Method the most according to claim 3, it is characterised in that: reaction temperature is 80-100 DEG C.
Method the most according to claim 8, it is characterised in that: reaction temperature is 90 DEG C.
Method the most according to claim 3, it is characterised in that: the response time is 4 hours.
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| CN201510371480.7A CN106316950A (en) | 2015-06-29 | 2015-06-29 | Gliquidone preparation method |
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| CN201510371480.7A CN106316950A (en) | 2015-06-29 | 2015-06-29 | Gliquidone preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191759A (en) * | 2017-12-29 | 2018-06-22 | 天津药物研究院药业有限责任公司 | A kind of gliquidone crystal, preparation method and the drug containing this crystal |
| CN115466213A (en) * | 2022-10-10 | 2022-12-13 | 山东药品食品职业学院 | Medicinal crystal form of gliquidone and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127423A (en) * | 2014-07-30 | 2014-11-05 | 沈阳药科大学 | Gliquidone derivative, preparation method and application thereof |
-
2015
- 2015-06-29 CN CN201510371480.7A patent/CN106316950A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127423A (en) * | 2014-07-30 | 2014-11-05 | 沈阳药科大学 | Gliquidone derivative, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王晓林 等: "格列喹酮合成工艺研究", 《吉林化工学院学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191759A (en) * | 2017-12-29 | 2018-06-22 | 天津药物研究院药业有限责任公司 | A kind of gliquidone crystal, preparation method and the drug containing this crystal |
| CN115466213A (en) * | 2022-10-10 | 2022-12-13 | 山东药品食品职业学院 | Medicinal crystal form of gliquidone and preparation method thereof |
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Application publication date: 20170111 |