CN106543042A - A kind of preparation method of Glipizide impurity I - Google Patents
A kind of preparation method of Glipizide impurity I Download PDFInfo
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- CN106543042A CN106543042A CN201610973571.2A CN201610973571A CN106543042A CN 106543042 A CN106543042 A CN 106543042A CN 201610973571 A CN201610973571 A CN 201610973571A CN 106543042 A CN106543042 A CN 106543042A
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- glipizide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation method of Glipizide impurity I, the method is with 4 for a kind of preparation method of Glipizide impurity I（2 aminoethyls）Benzsulfamide is raw material, is reacted with cyclohexyl isocyanate in two steps and is obtained.The method is simple, and the quality control for Glipizide provides satisfactory impurity I reference substances.
Description
Technical field
The present invention relates to a kind of preparation method of Glipizide impurity I, belongs to pharmaceutical technology field.
Background technology
Glipizide is second filial generation sulphanylureas oral hypoglycemic, is chiefly to facilitate islet β cell insulin, especially
It is the insulin secretion for promoting glucose to stimulate；And have enhancing insulin action, so as to be effectively reduced blood sugar concentration and glycosyl
Change hemoglobin；And hyperlipemia can be improved, triglyceride and cholesterol levels are reduced, HDL-C is improved and is existed
Ratio in T-CHOL；May also suppress platelet aggregation and promote fibrinolysiss, may have certain anti-to vascular lesion
Control effect.
Glipizide produces listing first by Pfizer, finds listing formulation products according to data check and Experimental comparison
And the impurity I in the EP 8.0 in crude drug（Formula II）Content is higher.Impurity I is that one main degraded of Glipizide is miscellaneous
Matter, can increase in storage and detection process, be one of topmost impurity in current commercialized product.
The content of the invention
It is an object of the invention to provide a kind of preparation method of Glipizide impurity I.
The technical scheme is that a kind of preparation method of Glipizide impurity I, it is characterised in that with 4-（2- ammonia second
Base）Benzsulfamide is raw material, is obtained with cyclohexyl isocyanate reaction.
According to the present invention, more specifically, a kind of preparation method of Glipizide impurity I is carried out in two steps：
The first step：4-（2- aminoethyls）Benzsulfamide prepares intermediate 1 with cyclohexyl isocyanate reaction；
Second step：In the case where acid binding agent is participated in, intermediate 1 prepares impurity I with cyclohexyl isocyanate reaction.
, according to the invention it is preferred to, the first step with aprotic reagent as solvent, selected from DMF
（DMF）, one kind in dichloromethane, more preferably DMF.
, according to the invention it is preferred to, the first step response time is 2h-8h, more preferably 2h.
According to the present invention, second step is reacted with intermediate 1 as raw material, with aprotic reagent as solvent, is joined in acid binding agent
With under, impurity I is prepared with cyclohexyl isocyanate reaction.The one kind of wherein described aprotic reagent in acetone, DMF,
The one kind of acid binding agent in potassium carbonate, sodium hydroxide.
According to the present invention, the preferred acetone of aprotic reagent, the preferred sodium hydroxide of acid binding agent used by second step reaction.
, according to the invention it is preferred to, the second step response time is 4h-8h.
According to products obtained therefrom of the present invention, the impurity I reference substances that HPLC purity is not less than 98.5% can be obtained through refined,
Described refining is carried out in organic solvent, the one kind in the preferred methanol of organic solvent, acetone, more preferably acetone.
The invention has the beneficial effects as follows there is provided a kind of preparation method of simple Glipizide impurity I, being lattice row
The quality control of pyrazine provides satisfactory impurity I reference substances.
Specific embodiment：
Content, is described further with reference to specific embodiment for a better understanding of the present invention, but the present invention is not only limited to
This.
The preparation of 1 intermediate compound I of embodiment
4- is added in reaction bulb（2- aminoethyls）Benzsulfamide 4.0g（20 mmol）, dichloromethane 100mL finishes room temperature and stirs
Mix 15 minutes.Ice salt bath cools to -4oC, adds cyclohexyl isocyanate 2.63g（21 mmol）, finish 0oC reacts 1h,
It is warmed to room temperature reaction 7h, TLC（DCM : MeOH = 20 : 1）After the completion of detection reaction, remove solvent under reduced pressure, obtain in 5.53g
Mesosome 1, HPLC methods determine content 92.2%, yield 85%.
The preparation of 2 intermediate compound I of embodiment
4- is added in reaction bulb（2- aminoethyls）Benzsulfamide 4.0g（20 mmol）, DMF 80mL finish and are stirred at room temperature 15 points
Clock.Ice salt bath cools to -4oC, adds cyclohexyl isocyanate 2.63g（21 mmol）, finish 0oC reacts 0.5h, rises to
Room temperature reaction 1.5h, TLC（DCM : MeOH = 20 : 1）After the completion of detection reaction, temperature control<15oC is added in reaction system
Water 300mL, separates out a large amount of white solids.5～15oC stirs 0.5h, filters, and filter cake is washed with water 20mL, and 60oC dries to obtain 6.2g
Intermediate 1, HPLC methods determine content 99.1%, yield 90%.
The preparation of 3 impurity I crude products of embodiment
1 3.25g of intermediate is added in reaction bulb（10 mmol）, DMF 40mL, potassium carbonate 2.76g（20 mmol）, finish room
Temperature stirring 10 minutes, after detection 1 one-tenth salt of intermediate is complete, adds cyclohexyl isocyanate 1.25g（10 mmol）, finish intensification
To 60oC reacts 3h；Add cyclohexyl isocyanate 1.25g（10 mmol）, continue 60oC reacts 5h.TLC（DCM : MeOH =
20 : 1）After the completion of detection reaction, in reaction system water 160mL, most of solid dissolving is added to be filtered to remove insoluble matter,
Filtrate with 10% hydrochloric acid adjust pH=5～6,5～15oC stirring and crystallizings 1h, filter, and filter cake is washed with water 20mL, and 60oC dries to obtain impurity I
Crude product 3.38g, HPLC method determines content 95.3%, yield 75%.
The preparation of 4 impurity I crude products of embodiment
1 3.25g of intermediate is added in reaction bulb（10 mmol）, acetone 60mL, potassium carbonate 2.76g（20 mmol）, finish
It is stirred at room temperature 10 minutes, after detection 1 one-tenth salt of intermediate is complete, adds cyclohexyl isocyanate 1.25g（10 mmol）, finish liter
Temperature is to back flow reaction 3h；Add cyclohexyl isocyanate 1.25g（10 mmol）, continue 60oC reacts 5h.TLC（DCM : MeOH
= 20 : 1）After the completion of detection reaction, in reaction system water 180mL, most of solid dissolving is added to be filtered to remove insoluble
Thing, filtrate with 10% hydrochloric acid adjust pH=5～6,5～15oC stirring and crystallizings 1h, filter, and filter cake is washed with water 20mL, and 60oC is dried miscellaneous
Matter I crude product 3.69g, HPLC methods determine content 96.9%, yield 82%.
The preparation of 5 impurity I crude products of embodiment
1 3.25g of intermediate is added in reaction bulb（10 mmol）, acetone 60mL, sodium hydroxide 0.80g（20 mmol）, plus
Finish and be stirred at room temperature 10 minutes, after detection 1 one-tenth salt of intermediate is complete, add cyclohexyl isocyanate 1.25g（10 mmol）, finish
It is warming up to back flow reaction 3h；Add cyclohexyl isocyanate 1.25g（10 mmol）, continue 60oC reacts 5h.TLC（DCM :
MeOH = 20 : 1）After the completion of detection reaction, in reaction system water 180mL, most of solid dissolving is added to be filtered to remove
Insoluble matter, filtrate with 10% hydrochloric acid adjust pH=5～6,5～15oC stirring and crystallizings 1h, filter, and filter cake is washed with water 20mL, and 60oC is dried
Impurity I crude product 3.97g are obtained, HPLC methods determine content 97.5%, yield 88%.
The preparation of 6 impurity I fine work of embodiment
5 product 3.60g of embodiment is added in reaction bulb（8.0 mmol）, acetone（200ml）, temperature rising reflux beating 1h, cooling
To 10 ~ 25 DEG C, continue stirring 1h, filter, 60oC dryings are received to impurity I fine work 3.24g, HPLC methods measure content 99.2%
Rate 90%.
The preparation of 7 impurity I fine work of embodiment
5 product 3.60g of embodiment is added in reaction bulb（8.0 mmol）, methanol（200ml）, temperature rising reflux beating 1h, cooling
To 10 ~ 25 DEG C, continue stirring 1h, filter, 60oC dryings are received to impurity I fine work 3.13g, HPLC methods measure content 98.5%
Rate 87%.
Claims (6)
1. the preparation method of Glipizide impurity I shown in a kind of Formula II, it is characterised in that with 4-（2- aminoethyls）Benzsulfamide is
Raw material, is obtained with cyclohexyl isocyanate reaction：
。
2. preparation method according to claim 1, it is characterised in that reaction is carried out in two steps：
The first step：4-（2- aminoethyls）Benzsulfamide prepares intermediate 1 with cyclohexyl isocyanate reaction；
Second step：In the case where acid binding agent is participated in, intermediate 1 prepares impurity I with cyclohexyl isocyanate reaction.
3. preparation method according to claim 2, it is characterised in that two-step reaction is with aprotic reagent as solvent.
4. preparation method according to claim 3, it is characterised in that the preferred N of aprotic reagent used by first step reaction,
Dinethylformamide, dichloromethane；The preferred acetone of aprotic reagent, N,N-dimethylformamide used by second step reaction.
5. preparation method according to claim 2, it is characterised in that the acid binding agent described in second step reaction is selected from carbonic acid
One kind in potassium, sodium hydroxide.
6. the preparation method according to claim 1-5 any claim, products obtained therefrom can by it is refined come it is further
Improve purity, the one kind of refining solvent in methanol, acetone, preferred acetone.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610973571.2A CN106543042A (en) | 2016-11-07 | 2016-11-07 | A kind of preparation method of Glipizide impurity I |
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| CN201610973571.2A CN106543042A (en) | 2016-11-07 | 2016-11-07 | A kind of preparation method of Glipizide impurity I |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109836360A (en) * | 2019-03-19 | 2019-06-04 | 南京恩泰医药科技有限公司 | A kind of preparation method and midbody compound of toluenesulfonic acid Yi Dushaban intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3709908A (en) * | 1969-02-14 | 1973-01-09 | Hoechst Ag | Benzenesulfonyl ureas having hypoglycemic activity |
| CN102993106A (en) * | 2012-12-24 | 2013-03-27 | 武汉武药制药有限公司 | Novel synthesis route of glipizide |
-
2016
- 2016-11-07 CN CN201610973571.2A patent/CN106543042A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3709908A (en) * | 1969-02-14 | 1973-01-09 | Hoechst Ag | Benzenesulfonyl ureas having hypoglycemic activity |
| CN102993106A (en) * | 2012-12-24 | 2013-03-27 | 武汉武药制药有限公司 | Novel synthesis route of glipizide |
Non-Patent Citations (1)
| Title |
|---|
| MONICA ALBU ET AL.: ""HPLC/DAD ASSAY OF CYCLOHEXANAMINE AS RELATED IMPURITY IN GLIPIZIDE THROUGH DERIVATIZATION WITH O-PHTALDIALDEHYDE"", 《ANALYTICAL LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109836360A (en) * | 2019-03-19 | 2019-06-04 | 南京恩泰医药科技有限公司 | A kind of preparation method and midbody compound of toluenesulfonic acid Yi Dushaban intermediate |
| CN109836360B (en) * | 2019-03-19 | 2021-08-13 | 南京恩泰医药科技有限公司 | Preparation method of edoxaban tosylate intermediate and intermediate compound |
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Application publication date: 20170329 |