CN106045975A - A preparing method for high-purity ilaprazole sodium - Google Patents
A preparing method for high-purity ilaprazole sodium Download PDFInfo
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- CN106045975A CN106045975A CN201610307666.0A CN201610307666A CN106045975A CN 106045975 A CN106045975 A CN 106045975A CN 201610307666 A CN201610307666 A CN 201610307666A CN 106045975 A CN106045975 A CN 106045975A
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Abstract
A preparing method for high-purity ilaprazole sodium is provided. The method includes 1) dissolving a 2-[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfinyl-5-(1H-pyrrol-1-yl)-1H-benzimidazole crude product into an organic solvent, adding an inorganic alkali to form a salt, and filtering to obtain a 2-[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfinyl-5-(1H-pyrrol-1-yl)-1H-benzimidazole salt (A), 2) dissolving the A into an organic solvent, adjusting pH with an acid until reaching alkalescence to prepare high-purity 2-[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfinyl-5-(1H-pyrrol-1-yl)-1H-benzimidazole (B), and 3) reacting the prepared B with a sodium-containing compound in a water-containing solvent to prepare the ilaprazole sodium.
Description
Technical field
The present invention relates to pharmaceutical formulating art, be specifically related to the process for purification of Ilaprazole Sodium.
Background technology
Chinese patent CN94191913.7 describes 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-
2-pyridine radicals]-methyl] synthetic method of-sulfinyl-1 H-benzimidazole, this synthetic method with chloroform as solvent, m-chloro mistake
Oxybenzoic acid is oxidizing 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-mercapto
Base-1H-benzimidazole prepares 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-Asia sulphur
Acyl group-1H-benzimidazole.Synthetic route is as follows:
But, this route is susceptible to snperoxiaized side reaction in the middle of oxidizing process, causes generating peroxidating sulfonylation
Thing is difficult to remove.In current technology, can effectively not go the removal of impurity, obtain the preparation side of high-purity ilaprazole sodium salt
Method.
Summary of the invention
The present invention is to provide a kind of high yield, reaction condition easily manipulates, and the refined 5-(1H-pyrroles-1-of environmental protection
Base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole sodium (Ilaprazole Sodium)
Method.
For realizing object above, the present invention by the following technical solutions, including step:
(1) by 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-
1H-benzimidazole crude product is dissolved in organic solvent A, adds inorganic base and becomes salt, filter, prepares 5-(1H-pyrroles's-1-base)-2-[[(4-
Methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole salt；
(2) by 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-
1H-benzoglioxaline salt is dissolved in organic solvent B, uses pH adjusting agent acid to adjust pH to alkalescence, prepares high-purity 5-(1H-pyrroles-1-
Base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole；
(3) by prepared high-purity 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-first
Base]-sulfinyl-1 H-benzimidazole and compounds containing sodium, react in aqueous solvent, prepare Ilaprazole Sodium.
Concrete synthetic route is as follows:
Organic solvent A used in above-mentioned steps (1) includes methanol, ethanol, isopropanol, dimethylbenzene, toluene, tetrahydrochysene furan
Mutter, 1,2-dichloroethanes, acetone, ether, dichloromethane, acetonitrile, dimethyl sulfoxide, the one or many in N,N-dimethylacetamide
Kind.Preferentially select methanol, ethanol.
In above-mentioned steps (1), range of reaction temperature is 0-100 DEG C.Preferential selection room temperature 25 DEG C.
In above-mentioned steps (1) inorganic base used include sodium hydroxide, potassium hydroxide, Lithium hydrate one or more.Preferentially
Select sodium hydroxide, potassium hydroxide.
Organic solvent B used in above-mentioned steps (2) includes methanol, ethanol, isopropanol, dimethylbenzene, toluene, tetrahydrochysene furan
Mutter, 1,2-dichloroethanes, acetone, ether, dichloromethane, acetonitrile, dimethyl sulfoxide, the one or many in N,N-dimethylacetamide
Kind.Preferentially select ethanol.
In above-mentioned steps (2), range of reaction temperature is 0-100 DEG C.Preferential selection 25 DEG C.
Regulation pH to 7.5-9.5 in above-mentioned steps (2), optimum is 9.0；The acid of pH adjusting agent can use benzoic acid, hydrochloric acid, sulfur
One or more in acid, phosphoric acid, nitric acid, acetic acid, monoxone, isooctyl acid, butanoic acid, pyrovinic acid, preferentially select ethanol acetate
Solution.In the present reaction, the regulation of pH is particularly significant with regulations speed, and the too high meeting of pH value after acid adjustment causes there is part Ai Pula
Azoles sodium salt separates out, and reduces product yield；And the too low meeting of pH value causes catabolite to generate, form impurity.Acetic acid and other acid phases
Ratio, obtains will not produce in the middle of process at regulation pH value and destroys ilaprazole because local ph is too low.
The process for purification of the present invention can effectively remove the peroxidating sulfonyl compound that side reaction produces, and makes the 5-prepared
The product of (1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole
Product purity is high；Process for refining is simple, and yield is high；Environmental protection, environmentally safe.
Specifically, patent of the present invention has the advantage that
1, product quality is high.Product purity is more than 99.5%, can effectively remove 5-(1H-pyrroles's-1-base)-2-[[(4-
Methoxyl group-3-methyl)-2-pyridine radicals]-methyl] middle 5-(the 1H-pyrrole produced of-sulfinyl-1 H-benzimidazole preparation process
Cough up-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfonyl-1H-benzimidazole and other are miscellaneous
Matter.
2, reaction condition is gentle, simple to operate.In process for refining, reacting temperature required for room temperature, technological operation is simple.
3, environmental protection.Subtractive process does not use the reagent that toxicity is big, and the reagent environmental pollution of use is little, it is easy to place
Reason.
Therefore, patent of the present invention can effectively improve 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-
2-pyridine radicals]-methyl] quality of-sulfinyl-1 H-benzimidazole, tool has significant practical applications.
Specific embodiment
Embodiment 1:5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfenyl
The preparation of base-1H-benzimidazole potassium salt
Adding methanol (110mL), potassium hydroxide (3.1g) in the there-necked flask of 250mL, stirring and dissolving is clarified, is added afterwards
5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole
(20g), mixture is stirred 18 hours at 25 DEG C.Being filtered by mixture, filter cake methanol (20mL*2) washs, and collects solid
It is dried 4 hours at 40 DEG C, obtains 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-Asia
Sulfonyl-1H-benzimidazole potassium salt (20.0g), yield: 90%.
Embodiment 2:5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfenyl
The preparation of base-1H-benzimidazole sodium salt
Adding organic solvent A (110mL), sodium hydroxide (2.2g) in the there-necked flask of 250mL, stirring and dissolving is clarified, it
Rear addition 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1H-benzo
Imidazoles (20g), stirs at a certain temperature by mixture 18 hours.Being filtered by mixture, filter cake methanol (20mL*2) washs,
Collect solid at 40 DEG C be dried 4 hours, obtain 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-
Methyl]-sulfinyl-1 H-benzimidazole sodium salt, the most as shown in table 1:
Table 1: organic solvent A, reaction temperature Comparison of experiment results
| Sequence number | Organic solvent A | Reaction temperature (DEG C) | Product yield (%) |
| 1 | Methanol | 25 | 92 |
| 2 | Ethanol | 25 | 91.3 |
| 3 | Dimethyl sulfoxide | 40 | 61 |
As shown above, the preferred methanol of organic solvent A, ethanol, reaction temperature preferably 25 DEG C.
Embodiment 3:5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfenyl
The preparation of base-1H-benzimidazole
Ethanol (200mL), 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-is added in the there-necked flask of 500mL
Methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole potassium salt (10g), drip 10% ethanol acetate at 25 DEG C molten
Liquid regulation pH value, to 9.0, filters after standing 30 minutes, and filter cake ethanol water (50%, 30mL*2) washs, afterwards at 30 DEG C
5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-the pyridine radicals]-methyl]-sulfinyl-1H-benzene of lower drying
And imidazoles (7.4g, white solid), yield: 82%, purity is 99.2%.
Embodiment 4:5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfenyl
The preparation of base-1H-benzimidazole
Organic solvent B (200mL), 5-(1H-pyrroles's-1-base)-2-[[(4-methoxy is added in the there-necked flask of 500mL
Base-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole potassium salt (10g), drip pH adjusting agent at 25 DEG C,
Regulation pH value, to 9.0, filters after standing 30 minutes, and filter cake ethanol water (50%, 30mL*2) washs, afterwards at 30 DEG C
5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-the pyridine radicals]-methyl]-sulfinyl-1H-benzo dried
Imidazoles, the most as shown in table 2:
Table 2: organic solvent B, pH adjusting agent Comparison of experiment results
| Sequence number | Organic solvent B | PH adjusting agent | Product yield (%) | Product yield (%) |
| 1 | Ethanol | 10% ethanol acetate solution | 82 | 99.2 |
| 2 | Ethanol | 10% ethanol solution of sulfuric acid | 78 | 93.1 |
| 3 | Ethanol | 10% ethanol solution hydrochloride | 68 | 92.5 |
| 4 | Methanol | 10% ethanol acetate solution | 75 | 99.0 |
| 5 | Acetonitrile | 10% ethanol acetate solution | 72 | 98.5 |
As shown above, organic solvent B preferred alcohol, pH adjusting agent preferred ethanol acetate solution.
The embodiment 5:pH regulation impact on experimental result
Ethanol (200mL), 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-is added in the there-necked flask of 500mL
Methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole sodium salt (10g), drip 10% ethanol acetate under room temperature molten
Liquid regulation pH value, filters after standing 30 minutes afterwards, and filter cake ethanol water (50%, 30mL*2) washs, afterwards at 30 DEG C
5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-the pyridine radicals]-methyl]-sulfinyl-1H-benzene of lower drying
And imidazoles (7.3g, white solid), the most as shown in table 3:
Table 3: pH value and the comparison of experimental result after regulation
Conclusion: by the result of upper table it can be seen that when regulation after pH as little as 6.5 time, product yield and product purity are all
On the low side；When regulation after pH up to 10.5 time, the yield of product ought significantly decline.And the pH after regulating is when 7.5-9.5, produce
The yield of product and the purity of product, all in the range of preferably, meet production requirement.
The preparation of embodiment 6 ilaprazole sodium salt
Take the preparation-obtained product of above-described embodiment 4: 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-
2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole 10.0g (0.0273mol), add in 50ml methanol, add hydrogen-oxygen
Changing sodium 1.09g (0.0273mol), be stirred at room temperature 2 hours, concentrate, add n-butyl alcohol, add diisopropyl ether crystallizing at room temperature, gained produces
Product obtain white crystals in 60 DEG C of drying under reduced pressure, i.e. Ilaprazole Sodium 9.5g, yield: 90%, content: 99.8%.
The preparation of embodiment 7 ilaprazole sodium salt
Take the preparation-obtained product of above-described embodiment 5: 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-
2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole 10.0g (0.0273mol), add in 50ml methanol, be warming up to 50
DEG C, add the methanol solution 4.92g (0.0273mol) comprising 30% (weight) Feldalat NM, stir 2 hours, be cooled to 0 DEG C, mistake
Filter, products obtained therefrom obtains white crystals in 60 DEG C of drying under reduced pressure, i.e. Ilaprazole Sodium 9.33g, yield: 88%, content: 99.9%.
Claims (10)
1. a preparation method for high-purity Ilaprazole Sodium, comprises the steps:
1) by 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1H-benzene
And imidazoles crude product is dissolved in organic solvent A, adds inorganic base and become salt, filter, prepare 5-(1H-pyrroles's-1-base)-2-[[(4-methoxy
Base-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole salt；
2) by 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1H-benzene
Benzimidazole salt be dissolved in organic solvent B, use pH adjusting agent, acid adjust pH to alkalescence, prepare high-purity 5-(1H-pyrroles's-1-base)-
2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-sulfinyl-1 H-benzimidazole；
3) by prepared high-purity 5-(1H-pyrroles's-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl]-Asia
Sulfonyl-1H-benzimidazole and compounds containing sodium react in aqueous solvent, prepare Ilaprazole Sodium.
Preparation method the most according to claim 1, it is characterised in that described step 1) used in organic solvent A bag
Include methanol, ethanol, isopropanol, dimethylbenzene, toluene, oxolane, 1,2-dichloroethanes, acetone, ether, dichloromethane, acetonitrile,
One or more in dimethyl sulfoxide, N,N-dimethylacetamide.
Preparation method the most according to claim 2, it is characterised in that described step 1) used in organic solvent A choosing
One or both in methanol, ethanol.
Preparation method the most according to claim 3, it is characterised in that described step 1) in inorganic base used selected from hydroxide
Sodium, potassium hydroxide, Lithium hydrate one or more.
Preparation method the most according to claim 4, it is characterised in that described step 1) in inorganic base used be hydroxide
Sodium.
Preparation method the most according to claim 5, it is characterised in that described step 2) used in organic solvent B bag
Include methanol, ethanol, isopropanol, dimethylbenzene, toluene, oxolane, 1,2-dichloroethanes, acetone, ether, dichloromethane, acetonitrile,
One or more in dimethyl sulfoxide, N,N-dimethylacetamide.
Preparation method the most according to claim 6, it is characterised in that described step 2) used in organic solvent B be
Ethanol.
Preparation method the most according to claim 7, it is characterised in that described step 2) middle regulation pH to 7.5-9.5.
Preparation method the most according to claim 8, it is characterised in that described step 2) in the acid of pH adjusting agent can use benzene first
One or more in acid, hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, acetic acid, monoxone, isooctyl acid, butanoic acid, pyrovinic acid.
Preparation method the most according to claim 9, it is characterised in that described step 2) in the acid of pH adjusting agent be acetic acid.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749191A (en) * | 2016-12-10 | 2017-05-31 | 珠海保税区丽珠合成制药有限公司 | Ilaprazole crystal form II and preparation method thereof |
| CN110128412A (en) * | 2019-06-21 | 2019-08-16 | 丽珠医药集团股份有限公司 | The preparation method of dextrorotation Iprazole sylvite mother liquor, dextrorotation Iprazole and preparation method thereof |
| CN111187255A (en) * | 2020-01-13 | 2020-05-22 | 丽珠医药集团股份有限公司 | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole |
-
2016
- 2016-05-05 CN CN201610307666.0A patent/CN106045975A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749191A (en) * | 2016-12-10 | 2017-05-31 | 珠海保税区丽珠合成制药有限公司 | Ilaprazole crystal form II and preparation method thereof |
| CN110128412A (en) * | 2019-06-21 | 2019-08-16 | 丽珠医药集团股份有限公司 | The preparation method of dextrorotation Iprazole sylvite mother liquor, dextrorotation Iprazole and preparation method thereof |
| CN110128412B (en) * | 2019-06-21 | 2020-03-31 | 丽珠医药集团股份有限公司 | Preparation method of dextro-ilaprazole potassium salt mother liquor, dextro-ilaprazole and preparation method thereof |
| CN111187255A (en) * | 2020-01-13 | 2020-05-22 | 丽珠医药集团股份有限公司 | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole |
| CN111187255B (en) * | 2020-01-13 | 2021-07-20 | 丽珠医药集团股份有限公司 | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole |
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Application publication date: 20161026 |