CN109896987A - The preparation method of Glimepiride EP impurity D and EP impurity I - Google Patents
The preparation method of Glimepiride EP impurity D and EP impurity I Download PDFInfo
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- CN109896987A CN109896987A CN201910307646.7A CN201910307646A CN109896987A CN 109896987 A CN109896987 A CN 109896987A CN 201910307646 A CN201910307646 A CN 201910307646A CN 109896987 A CN109896987 A CN 109896987A
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Abstract
The present invention provides the preparation methods of Glimepiride EP impurity D and EP impurity I, using 3- ethyl -4- methyl -2- oxygen -3- pyrrolin-N- (2- phenethyl) formamide as raw material, successively reacted with chlorosulfonic acid, ammonium hydroxide, liquid phase preparation purifies and sulfonamide analog 1 and sulfonamide analog 2 is made again, then react obtained Glimepiride EP impurity D and EP impurity I with trans-1-isocyanato-4-methyl cyclohexane respectively；The present invention is by preparing Glimepiride EP impurity D and impurity I high-purity reference substance, purity, the production technology of optimization crude product that the major impurity in Glimepiride crude product can be not only belonged to, control Glimepiride crude product, more importantly pass through the purity of control Glimepiride crude product, achieve the purpose that control EP impurity D and impurity I content in Glimepiride finished product in advance, rather than it is simple control Glimepiride finished product impurity content by purification, to lose yield as cost, to make that Glimepiride is quality controllable, yield is higher, cost is relatively low.
Description
Technical field
The invention belongs to field of medicaments, and in particular to the preparation method of Glimepiride EP impurity D and EP impurity I.
Background technique
Glimepiride tablet is the third generation sulphonyl urine class antidiabetic drug of first listing, is applied to non-insulin-depending type glycosuria
The treatment of disease.Have many advantages, such as small dosage, long action time, bioavilability it is high be current clinical evaluation it is optimal sulphonyl class drop
Sugared medicine.
National requirements imitation medicine will grind drug quality and curative effect one with original in " national drug safety " 12 " planning "
It causes, including impurity spectrum is consistent, stability is consistent, inside and outside stripping law is consistent.As it can be seen that miscellaneous Quality Research is agreement
Important content.In addition, miscellaneous mass spectrographic research, can also be improved the controllability of pharmaceutical production.
1- [[3- [2- (3- ethyl -4- methyl -2- oxo -3- pyrrolin -1- formamido group) ethyl] phenyl] sulfonyl] -
3- (trans- -4- methylcyclohexyl) urea and 1- [[2- [2- (3- ethyl -4- methyl -2- oxo -3- pyrrolin -1- formamido group)
Ethyl] phenyl] sulfonyl] -3- (trans- -4- methylcyclohexyl) urea is Glimepiride European Pharmacopoeia EP impurity D and EP impurity I,
The two impurity are the major impurities in Glimepiride finished product, but EP impurity D and impurity the I preparation method of current Glimepiride are not
See document report.
Summary of the invention
It is composed by analysing impurity, it is possible to find the source of EP impurity D and EP impurity I is respectively: in key intermediate sulfonamide
Two major impurities ----analog 1 and analog 2.In the process for preparing sulfonamide by condensation product, due to the area of reaction
Field selectivity be not it is single-minded, not only sulfonation main reaction can occur in contraposition, can also in meta position, that sulfonation occurs for ortho position is secondary anti-
It answers, generates the analog 1 and sulfonamide analog 2 of sulfonamide respectively.
Two major impurities ----analog 1 and analog 2 in subsequent processing in --- -- crude product process, in sulfonamide
It is reacted with trans-1-isocyanato-4-methyl cyclohexane, is separately converted to Glimepiride major impurity --- -- EP impurity D and EP
Impurity I, reaction equation are as follows:
The present invention provides the preparation methods of Glimepiride EP impurity D and EP impurity I.With 3- ethyl -4- methyl -2- oxygen -
3- pyrrolin-N- (2- phenethyl) formamide (hereinafter referred to as condensation product) is raw material, is successively reacted with chlorosulfonic acid, ammonium hydroxide, liquid again
Mutually preparation, which purifies, is made sulfonamide analog 1 and sulfonamide analog 2, and then sulfonamide analog 1 and sulfonamide analog 2 divide
It is not reacted with trans-1-isocyanato-4-methyl cyclohexane and Glimepiride EP impurity D and EP impurity I is made, reaction equation is as follows:
Include the following steps:
(1) condensation product sulfonation: chlorosulfonic acid is cooled to 10-20 DEG C, condensation product, temperature reaction is added；Incline after reaction
Enter in ice water, is filtered, washed to obtain white solid A；
(2) ammonolysis: by step (1) white solid A；Ammonium hydroxide is added, is reacted between 20-25 DEG C；Then heating continues anti-
It answers；25 DEG C are cooled to hereinafter, being filtered, washed to obtain white solid B；
(3) liquid phase preparation purifying: by step (2) white solid B through high performance liquid preparative chromatography separate sulfonamides seemingly
Object 1 and sulfonamide analog 2；
(4) in step (3) sulfonamide analog 1 and sulfonamide analog 2 obtained respectively with trans- -4- methyl cyclohexane
Based isocyanate carries out condensation reaction, and Glimepiride EP impurity D and EP impurity I is made respectively.
The preparation method of the Glimepiride EP impurity D and EP impurity I, it is characterised in that:
1/ analog 2 of analog: trans-1-isocyanato-4-methyl cyclohexane=1:0.4-0.8 (W/W)；
Reaction temperature is 50-60 DEG C；
Reaction time is 5-10 hours.
We use homemade sulfonamide analog 1 and sulfonamide analog 2 for raw material, respectively with trans- -4- methyl ring
Hexyl isocyanates carries out condensation reaction, and Glimepiride EP impurity D and impurity I is made respectively.EP impurity D and impurity I are as lattice
The reference substance for arranging the related substance detection of U.S. urea, can be used for the Pureness control of glimepiride raw material or preparation.
It, not only can be in Glimepiride crude product by preparing Glimepiride EP impurity D and impurity I high-purity reference substance
Major impurity is belonged to, preferably controls the purity of Glimepiride crude product, optimizes the production technology of Glimepiride crude product, heavier
What is wanted is the purity by controlling Glimepiride crude product, reaches and controls EP impurity D and impurity I content in Glimepiride finished product in advance
Purpose, rather than simple contain by purification, to lose yield as cost to control Glimepiride finished product EP impurity D and impurity I
Amount, to make that Glimepiride is quality controllable, yield is higher, cost is relatively low.
Specific embodiment
The preparation of embodiment 1 sulfonamide analog 1 and sulfonamide analog 2
Chlorosulfonic acid 180g is added into 250ml reaction flask, is cooled to 20 DEG C hereinafter, being slowly added under the conditions of 10-20 DEG C
Condensation product 30g then heats to 40 DEG C, reacts 7 hours between 40 ± 2 DEG C.After reaction, reaction solution is slowly poured into
In 1000ml ice water.Then it filters, wash to get white solid.
White solid is added in 100ml reaction flask, 800ml concentrated ammonia liquor is added, reacts 4 hours between 20-25 DEG C, so
After be warming up to 40 ± 2 DEG C, the reaction was continued 4 hours.After reaction, 25 DEG C are cooled to hereinafter, filtering, washing to obtain white solid.
White solid is finally used into high performance liquid preparative chromatography, chromatographic condition: chromatographic column: C18,300*50.0mm, grain
10 μm of diameter, aperture 120A, wavelength: 225nm, mobile phase A: methanol, Mobile phase B: water, isocratic elution, A80%, B20% (V/V)
Separation, respectively obtains 2.4g sulfonamide analog 1 and 1.9g sulfonamide analog 2.
The preparation of embodiment 2, EP impurity D
1.0g compound 1,0.51g Anhydrous potassium carbonate, 16ml acetone are added into the reaction flask of 50ml, is warming up to 50 DEG C,
It is reacted at a temperature of this, after 0.5 hour, the mixed solution of trans-4-methylcyclohexane isocyanate 0.40g and 4ml acetone is added dropwise,
The reaction was continued 5 hours.End of reaction is down to room temperature, is filtered, washed up to EP impurity D1.10g.
The preparation of embodiment 3, EP impurity D
1.0g compound 1,0.51g Anhydrous potassium carbonate, 16ml acetone are added into the reaction flask of 50ml, is warming up to 55 DEG C,
It is reacted at a temperature of this, after 0.5 hour, the mixed solution of trans-4-methylcyclohexane isocyanate 0.60g and 4ml acetone is added dropwise,
The reaction was continued 8 hours.End of reaction is down to room temperature, is filtered, washed up to EP impurity D1.35g.
The preparation of embodiment 4, EP impurity D
1.0g compound 1,0.51g Anhydrous potassium carbonate, 16ml acetone are added into the reaction flask of 50ml, is warming up to 60 DEG C,
It is reacted at a temperature of this, after 0.5 hour, the mixed solution of trans-4-methylcyclohexane isocyanate 0.80g and 4ml acetone is added dropwise,
The reaction was continued 10 hours.End of reaction is down to room temperature, is filtered, washed up to EP impurity D1.41g.
The preparation of embodiment 5, EP impurity I
1.0g compound 2,0.51g Anhydrous potassium carbonate, 16ml acetone are added into the reaction flask of 50ml, is warming up to 50 DEG C,
It is reacted at a temperature of this 0, after 0.5 hour, the mixing that trans-4-methylcyclohexane isocyanate 0.40g and 4ml acetone is added dropwise is molten
Liquid, the reaction was continued 5 hours.End of reaction is down to room temperature, is filtered, washed up to EP impurity I1.02g.
The preparation of embodiment 6, EP impurity I
1.0g compound 2,0.51g Anhydrous potassium carbonate, 16ml acetone are added into the reaction flask of 50ml, is warming up to 55 DEG C,
It is reacted at a temperature of this, after 0.5 hour, the mixed solution of trans-4-methylcyclohexane isocyanate 0.60g and 4ml acetone is added dropwise,
The reaction was continued 8 hours.End of reaction is down to room temperature, is filtered, washed up to EP impurity I1.18g.
The preparation of embodiment 7, EP impurity I
1.0g compound 2,0.51g Anhydrous potassium carbonate, 16ml acetone are added into the reaction flask of 50ml, is warming up to 60 DEG C,
It is reacted at a temperature of this, after 0.5 hour, the mixed solution of trans-4-methylcyclohexane isocyanate 0.80g and 4ml acetone is added dropwise,
The reaction was continued 10 hours.End of reaction is down to room temperature, is filtered, washed up to EP impurity I1.25g.
Claims (4)
1. the preparation method of Glimepiride EP impurity D and EP impurity I, it is characterised in that: with 3- ethyl -4- methyl -2- oxygen -3- pyrrole
Cough up quinoline-N- (2- phenethyl) formamide (lower abbreviation condensation product) be raw material, successively react with chlorosulfonic acid, ammonium hydroxide again liquid phase preparation
It purifies and sulfonamide analog 1 and sulfonamide analog 2 is made, then sulfonamide analog 1 and sulfonamide analog 2 be respectively and instead
Formula -4- isocyanatomethyl, which is reacted, is made Glimepiride EP impurity D and EP impurity I, and equation is as follows:
2. the preparation method of Glimepiride EP impurity D and EP impurity I according to claim 1, its step are as follows:
(1) condensation product sulfonation: chlorosulfonic acid is cooled to 10-20 DEG C, condensation product, temperature reaction is added；It is poured into ice after reaction
In water, it is filtered, washed to obtain white solid A；
(2) ammonolysis: by step (1) white solid A；Ammonium hydroxide is added, is reacted between 20-25 DEG C；Then the reaction was continued for heating；Drop
Temperature is to 25 DEG C hereinafter, being filtered, washed to obtain white solid B；
(3) step (2) white solid B liquid phase preparation purifying: is separated into obtain 1 He of sulfonamide analog through high performance liquid preparative chromatography
Sulfonamide analog 2；
(4) sulfonamide analog 1 and sulfonamide analog 2 obtained are different with trans- -4- methylcyclohexyl respectively in step (3)
Cyanate carries out condensation reaction, and Glimepiride EP impurity D and EP impurity I is made respectively.
3. the preparation method of Glimepiride EP impurity D according to claim 1, its feature is as follows:
(1) analog 1: trans-1-isocyanato-4-methyl cyclohexane=1:0.4-0.8 (W/W)；
(2) reaction temperature is 50-60 DEG C；
(3) reaction time is 5-10 hours
4. the preparation method of Glimepiride EP impurity I according to claim 1, its feature is as follows:
(1) analog 2: trans-1-isocyanato-4-methyl cyclohexane=1:0.4-0.8 (W/W)；
(2) reaction temperature is 50-60 DEG C；
(3) reaction time is 5-10 hours.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113281423A (en) * | 2021-03-31 | 2021-08-20 | 石药集团欧意药业有限公司 | Glimepiride impurity and analysis method thereof in Glimepiride bulk drug and preparation |
| CN113277971A (en) * | 2021-03-31 | 2021-08-20 | 石药集团欧意药业有限公司 | Glimepiride impurity and preparation method thereof |
| CN114264765A (en) * | 2020-09-16 | 2022-04-01 | 徐州万邦金桥制药有限公司 | Analysis method for determining related substances in glimepiride intermediate by using HPLC |
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2019
- 2019-04-17 CN CN201910307646.7A patent/CN109896987A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114264765A (en) * | 2020-09-16 | 2022-04-01 | 徐州万邦金桥制药有限公司 | Analysis method for determining related substances in glimepiride intermediate by using HPLC |
| CN114264765B (en) * | 2020-09-16 | 2023-10-03 | 徐州万邦金桥制药有限公司 | Analytical method for determining related substances in glimepiride intermediate by utilizing HPLC |
| CN113281423A (en) * | 2021-03-31 | 2021-08-20 | 石药集团欧意药业有限公司 | Glimepiride impurity and analysis method thereof in Glimepiride bulk drug and preparation |
| CN113277971A (en) * | 2021-03-31 | 2021-08-20 | 石药集团欧意药业有限公司 | Glimepiride impurity and preparation method thereof |
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Application publication date: 20190618 |