CN113072539A - Chemical synthesis method of pantoprazole dimer - Google Patents
Chemical synthesis method of pantoprazole dimer Download PDFInfo
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- CN113072539A CN113072539A CN202110333577.4A CN202110333577A CN113072539A CN 113072539 A CN113072539 A CN 113072539A CN 202110333577 A CN202110333577 A CN 202110333577A CN 113072539 A CN113072539 A CN 113072539A
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- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/14—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 three or more hetero rings
Abstract
The invention discloses a chemical synthesis method of pantoprazole dimer. The method disclosed by the invention starts from 3- (difluoromethoxy) nitrobenzene, the pantoprazole dimer is obtained through 8-step reaction, the synthesis operation is simple, the method is economic and environment-friendly, the total yield is high, and a qualified, cheap and easily-obtained reference substance can be provided for the quality control of pantoprazole.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a chemical synthesis method of pantoprazole dimer.
Background
Pantoprazole sodium is an antacid and antiulcer drug, is marketed in injection and enteric tablets at present, can eradicate helicobacter pylori infection when used together with other antibacterial drugs (clarithromycin, amoxicillin and metronidazole), has good treatment effect on duodenal ulcer, gastric ulcer and moderate and severe reflux esophagitis, and can also be used for preventing stress ulcer caused by major operation or severe trauma.
When the pantoprazole product is prepared, the pantoprazole dimer is required to be used as a standard substance contrast, but the pantoprazole dimer is high in synthesis difficulty, mainly depends on import, is high in price (more than 10mg/3500 memantine), and brings inconvenience to domestic related medicine production enterprises. Therefore, there is a need to develop a method for synthesizing pantoprazole dimer.
Disclosure of Invention
Aiming at the prior art, the invention provides a chemical synthesis method of pantoprazole dimer, which aims to solve the problem that pantoprazole dimer is difficult to obtain.
In order to achieve the purpose, the invention adopts the technical scheme that: the chemical synthesis method of pantoprazole dimer comprises the following steps:
s1: dissolving 3- (difluoromethoxy) nitrobenzene and zinc powder in a solvent according to a mass ratio of 1: 1-3, adding alkali, heating to 80-100 ℃, reacting for 10-20 hours while keeping the temperature, adding concentrated hydrochloric acid into the reaction system, and reacting for 40-60 hours at 80-100 ℃ to obtain a product M1;
s2: dissolving M1 in a mixed solution of acetic anhydride and N, N-dimethylformamide, and reacting for 2-5 h at 20-40 ℃ to obtain a product M2;
s3: dissolving M2 in acetic anhydride, adding concentrated nitric acid, and reacting at 20-30 ℃ for 1-5 h to obtain a product M3;
s4: dissolving M3 in a solvent, adding concentrated hydrochloric acid, and reacting at 80-100 ℃ for 10-20 h to obtain a product M4;
s5: dissolving M4 in a solvent, adding a catalyst, introducing hydrogen to react for 5-20 h to obtain a product M5, wherein the catalyst is 10% palladium carbon, 5% palladium carbon, Raney nickel or platinum carbon;
s6: dissolving M5 in a mixed solution of alkali and an organic solvent, adding carbon disulfide, and performing reflux reaction at 70-90 ℃ for 5-10 hours to obtain a product M6;
s7: dissolving M6 in a mixed solution of alkali and an organic solvent, adding a compound shown as a formula I, and reacting at 40-60 ℃ for 5-10 h to obtain a product M7;
s8: dissolving M7 in an organic solvent, adding M-chloroperoxybenzoic acid, and reacting at-40 to-10 ℃ for 1 to 5 hours to obtain the compound.
On the basis of the technical scheme, the invention can be further improved as follows.
Further, the alkali in the S1 is sodium hydroxide, and the mass ratio of the sodium hydroxide to the 3- (difluoromethoxy) nitrobenzene is 2-2.5: 1; the alkali in S6 and S7 is sodium hydroxide, potassium carbonate or sodium carbonate, the mass ratio of the alkali in S6 to M5 is 1.5-3: 1, and the mass ratio of the alkali in S7 to M6 is 1.5-3: 1.
Furthermore, after M1 in S2 is dissolved in a mixed solution of acetic anhydride and N, N-dimethylformamide, the mass ratio of M1 to acetic anhydride in a mixed system is 1: 0.5-2.
Further, the volume ratio of acetic anhydride to N, N-dimethylformamide in the mixed solution of acetic anhydride and N, N-dimethylformamide is 1: 1-5.
Further, the mass ratio of the concentrated nitric acid added in the S3 to the M2 is 0.5-1: 1.
Furthermore, the mass ratio of the concentrated hydrochloric acid added in the S4 to the M3 is 2-5: 1.
Further, the mass ratio of the compound shown in the formula I added in the S6 to the M6 is 0.5-2: 1.
Further, the mass ratio of the carbon disulfide added in the S7 to the M5 is 2-10: 1
Furthermore, the mass ratio of the M-chloroperoxybenzoic acid added in the S8 to the M7 is 0.4-1: 1.
Further, the solvent in S1 is ethanol, methanol or isopropanol; the solvent in S4 is dioxane, acetone or N, N-dimethylformamide; the solvent in S5 is ethanol, methanol or isopropanol; the organic solvent in S6 and S7 is ethanol, methanol, isopropanol or dioxane; the organic solvent in S8 is dichloromethane or trichloromethane.
The invention has the beneficial effects that: the method disclosed by the invention is simple in synthesis operation, economic and environment-friendly, high in total yield, and capable of providing a qualified, cheap and easily-obtained reference substance for the quality control of pantoprazole.
Drawings
FIG. 1 is a schematic diagram of the synthesis of pantoprazole dimer;
FIG. 2 is a hydrogen spectrum of product M6;
FIG. 3 is a hydrogen spectrum of product M8;
fig. 4 is a carbon spectrum of product M8.
Detailed Description
The following examples are provided to illustrate specific embodiments of the present invention.
Example 1
A chemical synthesis method of pantoprazole dimer comprises the following steps:
the first step is as follows: the reaction process is shown as the formula (1-1)
Adding 10g of 3- (difluoromethoxy) nitrobenzene and 20g of zinc powder into 250ml of ethanol, dropwise adding 50ml of NaOH solution with the concentration of 12mol/L under ice bath, and reacting at 90 ℃ for 15h after dropwise adding; then 100ml of concentrated hydrochloric acid (37 wt%) is added dropwise in an ice bath, after the dropwise addition, the reaction is carried out for 50h at 90 ℃, after the cooling, NaOH is added to adjust the pH value to 12, the ethyl acetate is used for extraction, and after the evaporation, the column chromatography is carried out to obtain a product M14 g.
The second step is that: the reaction process is shown as the formula (1-2)
Adding 12g M1 into a mixed solution of 20ml acetic anhydride and 60ml DMF, stirring and reacting for 2h at 25 ℃, adding 200ml water, extracting ethyl ester and evaporating to dryness to obtain a product M212 g.
The third step: the reaction process is shown as the formula (1-3)
Adding 12g M2 into 80ml acetic anhydride, dripping 8g concentrated nitric acid (68 wt%) at 10 ℃, reacting for 4h at 25 ℃ after finishing dripping, adding 200ml ice water after TLC detection reaction, extracting ethyl acetate and evaporating to dryness to obtain 10g yellow solid M3.
The fourth step: the reaction process is shown as the formula (1-4)
10g M3 was added to 50ml dioxane, 50ml concentrated hydrochloric acid (37 wt%) was added and the mixture was refluxed at 100 ℃ for 10 hours, and then added to 100ml water to precipitate a solid, which was washed with filtered water to obtain 7g orange solid M4.
The fifth step: the reaction process is shown as the formula (1-5)
Adding 7g M5 into 150ml methanol, adding 2g 10% palladium carbon, reacting at 30 deg.C with hydrogen for 10h, filtering to remove Pd/C, and evaporating to dryness to obtain 6g brown oily matter M5.
And a sixth step: the reaction process is shown as the formula (1-6)
Adding 10g of KOH into 50ml of ethanol, stirring and dissolving to obtain a mixed solution, then adding 6g M5 and 20ml of carbon disulfide into the mixed solution, carrying out reflux reaction for 6 hours at 80 ℃, cooling the reaction solution, pouring into 500ml of ice water to separate out a gray solid, extracting and evaporating to dryness by using 200ml of ethyl acetate to obtain 8g of gray solid M6, wherein a hydrogen spectrum of M6 is shown in figure 2.
The seventh step: the reaction process is shown as the formula (1-7)
Adding 5g of NaOH into a mixed solvent of 100ml of ethanol and 50ml of water, stirring and dissolving to obtain a mixed solution, then adding 8g M6 into the mixed solution, adding 10g of a compound shown as the formula I in batches at 50 ℃, keeping the temperature for reacting for 8 hours, adding 50ml of water, extracting with DCM, washing with water, washing with saturated saline solution, drying and evaporating to obtain 15g of a crude product, and purifying by chromatography to obtain 3g M7.
Eighth step: the reaction process is shown as the formula (1-8)
3g M7 is dissolved in 100ml dichloromethane, the temperature is reduced to-10 ℃, 2g M-chloroperoxybenzoic acid dissolved in 50ml dichloromethane is slowly dripped into the dichloromethane, TLC shows that the reaction is finished, 100ml saturated sodium bicarbonate is used for washing, drying and evaporating to dryness, and column chromatography is carried out to obtain a product M82 g, the hydrogen spectrum and the carbon spectrum of M8 are respectively shown in figure 3 and figure 4, and M8, namely pantoprazole dimer can be seen from the figure.
While the present invention has been described in detail with reference to the embodiments, it should not be construed as limited to the scope of the patent. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.
Claims (10)
1. A chemical synthesis method of pantoprazole dimer is characterized by comprising the following steps:
s1: dissolving 3- (difluoromethoxy) nitrobenzene and zinc powder in a solvent according to a mass ratio of 1: 1-3, adding alkali, heating to 80-100 ℃, reacting for 10-20 hours while keeping the temperature, adding concentrated hydrochloric acid into the reaction system, and reacting for 40-60 hours at 80-100 ℃ to obtain a product M1;
s2: dissolving M1 in a mixed solution of acetic anhydride and N, N-dimethylformamide, and reacting for 2-5 h at 20-40 ℃ to obtain a product M2;
s3: dissolving M2 in acetic anhydride, adding concentrated nitric acid, and reacting at 20-30 ℃ for 1-5 h to obtain a product M3;
s4: dissolving M3 in a solvent, adding concentrated hydrochloric acid, and reacting at 80-100 ℃ for 10-20 h to obtain a product M4;
s5: dissolving M4 in a solvent, adding a catalyst, introducing hydrogen to react for 5-20 h to obtain a product M5, wherein the catalyst is 10% palladium carbon, 5% palladium carbon, Raney nickel or platinum carbon;
s6: dissolving M5 in a mixed solution of alkali and an organic solvent, adding carbon disulfide, and performing reflux reaction at 70-90 ℃ for 5-10 hours to obtain a product M6;
s7: dissolving M6 in a mixed solution of alkali and an organic solvent, adding a compound shown as a formula I, and reacting at 40-60 ℃ for 5-10 h to obtain a product M7;
s8: dissolving M7 in an organic solvent, adding M-chloroperoxybenzoic acid, and reacting at-40 to-10 ℃ for 1 to 5 hours to obtain the compound.
2. The chemical synthesis process of pantoprazole dimer according to claim 1, characterized in that: the alkali in the S1 is sodium hydroxide, and the mass ratio of the alkali to 3- (difluoromethoxy) nitrobenzene is 2-2.5: 1; the alkali in S6 and S7 is sodium hydroxide, potassium carbonate or sodium carbonate, the mass ratio of the alkali in S6 to M5 is 1.5-3: 1, and the mass ratio of the alkali in S7 to M6 is 1.5-3: 1.
3. The chemical synthesis process of pantoprazole dimer according to claim 1, characterized in that: after M1 in S2 is dissolved in a mixed solution of acetic anhydride and N, N-dimethylformamide, the mass ratio of M1 to acetic anhydride in a mixed system is 1: 0.5-2.
4. A chemical synthesis process of pantoprazole dimer according to claim 1 or 3, characterized in that: the volume ratio of acetic anhydride to N, N-dimethylformamide in the mixed solution of acetic anhydride and N, N-dimethylformamide is 1: 1-5.
5. The chemical synthesis process of pantoprazole dimer according to claim 1, characterized in that: the mass ratio of the concentrated nitric acid added in the S3 to the M2 is 0.5-1: 1.
6. The chemical synthesis process of pantoprazole dimer according to claim 1, characterized in that: the mass ratio of the concentrated hydrochloric acid added in the S4 to the M3 is 2-5: 1.
7. The chemical synthesis process of pantoprazole dimer according to claim 1, characterized in that: the mass ratio of the compound shown in the formula I added in the S6 to the M6 is 0.5-2: 1.
8. The chemical synthesis process of pantoprazole dimer according to claim 1, characterized in that: the mass ratio of the carbon disulfide added in the S7 to the M5 is 2-10: 1.
9. The chemical synthesis process of pantoprazole dimer according to claim 1, characterized in that: the mass ratio of M-chloroperoxybenzoic acid added in the S8 to M7 is 0.4-1: 1.
10. The chemical synthesis process of pantoprazole dimer according to claim 1, characterized in that: the solvent in S1 is ethanol, methanol or isopropanol; the solvent in S4 is dioxane, acetone or N, N-dimethylformamide; the solvent in S5 is ethanol, methanol or isopropanol; the organic solvent in S6 and S7 is ethanol, methanol, isopropanol or dioxane; the organic solvent in S8 is dichloromethane or trichloromethane.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163419A (en) * | 2021-12-24 | 2022-03-11 | 辰欣药业股份有限公司 | Preparation method of lansoprazole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101475561A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Method for synthesizing pantoprazole and salt thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101475561A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Method for synthesizing pantoprazole and salt thereof |
Non-Patent Citations (2)
| Title |
|---|
| D. V. KRYL’SKII等: "Arylbiguanides in Heterocyclization Reactions", 《RUSSIAN JOURNAL OF GENERAL CHEMISTRY》 * |
| YARI, AHMAD等: "On the Mechanism of Formation and the Synthesis of Pantoprazole Sodium Sesquihydrate-Related Compound E: A Phantom Chemical Entity", 《ACS OMEGA》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163419A (en) * | 2021-12-24 | 2022-03-11 | 辰欣药业股份有限公司 | Preparation method of lansoprazole |
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