CN103965166B - Rabeprazole intermediate impurities 2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl sulfur } preparation method of-1H-benzimidazole - Google Patents
Rabeprazole intermediate impurities 2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl sulfur } preparation method of-1H-benzimidazole Download PDFInfo
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Abstract
The preparation method of rabeprazole intermediate impurities 2 { [4 (3 methoxy propoxy) 3 oxide of mathylpyridine 2 base] methyl sulfur } the 1H benzimidazole that the present invention provides, comprise the following steps: 2 chloromethyl 4 (3 methoxy propoxy) 3 methyl pyridinium chloride are soluble in water, aqueous slkali adjusts pH, organic solvent extracts, and merges and concentrates organic facies；React after the organic solvent of dropping oxidant；Reactant liquor is placed in ice-water bath, drips mercaptobenzimidazole solution, maintains two-phase system room temperature reaction after dropping, and stratification, organic facies is dried；In the cryosel bath that organic facies is placed in, the organic solution of dropping oxidant, drip complete follow-up continuous reaction；Reactant liquor is placed in be poured in aqueous slkali, then is placed in stirring and evenly mixing in ice-water bath, stratification, and the acid of aqueous phase is adjusted to neutrality, and organic solvent extracts, and merges and concentrates organic facies, to obtain final product.The preparation method technique that the present invention provides is simple, high-efficiency and economic, product yield and purity high, be suitable for industrialized production.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly to a kind of rabeprazole intermediate impurities 2-{ [4-(3-methoxyl group
Propoxyl group)-3-oxide of mathylpyridine-2-base] methyl sulfur } preparation method of-1H-benzimidazole.
Background technology
The sickness rate of whole world digestive system accounts for the 10%～12% of human morbidity, China's cities and towns digestive system disease according to statistics
Sick sickness rate reaches 11.43%, and wherein gastroxia is the major reason of digestive system disease.Drug therapy is acid-related
The main purpose of disease is quick symptom relief, the complication of ease the pain, promote ulcer healing, prevention of recurrence and appearance.
Proton pump inhibitor (the proton pump that a kind of comparison that Wei Cai company of Japan lists in December, 1998 is new
Inhibitors, PPIs) medicine rabeprazole (Rabeprazole) has another name called Pariet.Rabeprazole bioavailability is high, onset
Hurry up, can in 24h the secretion of comprehensive gastric acid inhibitory and persistent.The phase interaction of medicine is seldom there is during Clinical practice
With.Rabeprazole treatment gastric ulcer, duodenal ulcer, the maintaining treatment of erosive stomach-esophageal reflux disease and
The aspects such as Zollinger-Ellison syndrome and HP infection have some superiority.The control of its impurity is for its quality control
System impact is the biggest.
2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl sulfinyl }-1H-benzo miaow
Azoles is an important impurity during this rabeprazole production of raw medicine.2-{ [4-(3-methoxy propoxy)-3-methyl pyrrole
Pyridine oxide-2-base] methyl sulfinyl }-1H-benzimidazole structure formula is as follows:
M/e:375.13 (100.0%), 376.13 (19.9%), 377.12 (4.5%), 377.13 (3.1%), 376.12
(1.9%)
C,57.58；H,5.64；N,11.19；O,17.05；S,8.54
Prior art literature (Synthetic Studies Connected with The Preparation of H+/K+-ATPase Inhibitors Rabeprazole and Lansoprazole.J.Heterocyclic Chem.,43,1447
(2006) .) report with patent (EP2022789A1) synthesize this compound method technique similar, all with 2-chloromethyl-4-
(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate is raw material, and sodium bicarbonate discharges 2-chloromethyl-4-through reaction a
(3-methoxy propoxy)-3-methvl-pyridinium, carries out reacting b and M-CPBA (metachloroperbenzoic acid) oxidation the most again and generates
Intermediate 3:1-oxo-2-chloromethyl-4-(3-methoxy-propoxyl)-3-methvl-pyridinium, intermediate 3 again with sulfydryl benzo miaow
Azoles: reaction generates intermediate 4:2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl sulfur }-1H-benzene
And imidazoles, intermediate 4 reacts generation target product 2-{ [4-(3-methoxy propoxy)-3-methyl more at low temperatures with M-CPBA
Pyridine-N-oxide-2-base] methyl sulfinyl }-1H-benzimidazole, reaction equation is as follows:
In document above and patent, method technique used is all to rotate reaction system post processing after reaction b terminates to steam
Obtain the thick product of intermediate 3 after dry, then reselection acetonitrile or acetone as solvent by intermediate 3 again with sulfydryl benzene
And imidazoles reacts in the basic conditions, reaction terminate after through concentrating, extraction, wash, be dried, recrystallization etc. 5 steps operation obtains
Intermediate 4.Last 4 react production end product 5 more at low temperatures with M-CPBA.Although this process route is feasible, but whole
Course of reaction needs separation of intermediates 3 and 4, simultaneously need to change different reaction dissolvents, relates to the concentration of multistep, extraction,
Washing, the operation such as recrystallization, operation is many, troublesome poeration, relatively costly and productivity is on the low side, and only 16.1%.Whole course of reaction
Lack economy, and do not meet the theory of environmental protection, be not suitable for industrial amplification production simultaneously.
Summary of the invention
Goal of the invention: in order to overcome above-mentioned the deficiencies in the prior art, it is an object of the invention to provide a kind of technique simple,
Rabeprazole intermediate impurities 2-{ [4-(3-the methoxy propoxy)-3-oxide of mathylpyridine-2-that with low cost, productivity is high
Base] methyl sulfur } preparation method of-1H-benzimidazole.
Technical scheme: rabeprazole intermediate impurities 2-{ [4-(3-the methoxy propoxy)-3-methyl that the present invention provides
Pyridine-N-oxide-2-base] methyl sulfur } preparation method of-1H-benzimidazole, comprise the following steps:
(1) as raw material, raw material is dissolved in water with 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate
In, adjust pH to 6.5-8.5 with aqueous slkali, organic solvent extracts, and merges and concentrates organic facies；Organic facies drips the organic of oxidant
20-50 DEG C of reaction 3-10h after solvent；
(2) reactant liquor of step (1) is placed in 5-25 DEG C of ice-water bath, drips mercaptobenzimidazole solution, after dropping
Maintaining two-phase system room temperature reaction 2-5h, stratification, organic facies is dried；
(3) organic facies of step (2) be placed in-20～-10 DEG C cryosel bath in, dropping oxidant organic solution, dropping
After continue reaction 1-5h；
(4) reactant liquor of step (3) is placed in and pours in aqueous slkali, then is placed in stirring and evenly mixing in 5-25 DEG C of ice-water bath, stands
Layering, aqueous phase is adjusted to neutrality with the acid of 10%～50%, and organic solvent extracts, and merges and concentrates organic facies, to obtain final product.
In this preparation method, described organic solvent is same, selected from dichloromethane, chloroform, ether, acetic acid second
One in ester, furan, toluene and diethyl ether, preferably dichloromethane or chloroform.
In step (1), described oxidant is selected from M-CPBA, H2O2, tBuOOH, peroxy acid, OXONE, NaIO4, N-methyl oxygen
Change the one in morpholine；Alkali be selected from TEA, N, N-diisopropyl ethylenediamine, N-methylmorpholine, DBU, sodium bicarbonate, sodium hydroxide,
One or more in potassium carbonate, potassium hydroxide；2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate and
The mol ratio of oxidant is 1:1～1:5.
In step (2), mercaptobenzimidazole and 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate
Mol ratio be 1:1～1:5.
In step (3), oxidant is selected from M-CPBA, H2O2, tBuOOH, peroxy acid, OXONE, NaIO4, N-methyl oxidation
One in quinoline；The mol ratio of oxidant and 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate is
0.5:1～5:1.
In step (4), alkali is selected from TEA, N, N-diisopropyl ethylenediamine, N-methylmorpholine, DBU, sodium bicarbonate, hydroxide
One or more in sodium, potassium carbonate, potassium hydroxide, the pH of aqueous slkali is 10～14；Acid is selected from hydrochloric acid, acetic acid, nitric acid, sulphuric acid
With one or more in phosphoric acid.
Beneficial effect: rabeprazole intermediate impurities 2-{ [4-(3-the methoxy propoxy)-3-methyl that the present invention provides
Pyridine-N-oxide-2-base] methyl sulfur the preparation method of-1H-benzimidazole without the intermediate during separating step 2 and 3,
Without changing solvent, substantially reduce the processing step of prior art, technique is simple, high-efficiency and economic, environmental protection, product yield
High with purity, it is suitable for industrialized production.
Specifically, the present invention has an advantage highlighted below relative to prior art:
(1) preparation technology of the present invention is simple, and whole preparation process is without separation of intermediates, it is not necessary to changes solvent, not only drops
Low cost, and efficiency is high；
(2) the second step reaction of the present invention is two phase reaction, is made product and the sulfydryl benzo of step (1) by two phase reaction
Imidazoles reacts, and not only reaction rate is controlled, and product and reactant can natural separation, simple to operate, economic and environment-friendly；
(3) the inventive method productivity is high, be up to more than 80%, and purity is high.
Accompanying drawing explanation
Fig. 1 is the inventive method process chart, and Fig. 1 is raw material, and 2 is the intermediate obtained after step (1) adjusts pH, and 3 are
The intermediate of step (1), 4 is the intermediate of step (2), and 5 is the intermediate of step (3).
Fig. 2 is 2-{ [4-(3-the methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl that the present invention prepares
Sulfur }-1H-benzimidazole hydrogen spectrum.
Detailed description of the invention
Below in conjunction with the accompanying drawings the present invention is made and further illustrating.
Embodiment 1
Rabeprazole intermediate impurities 2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl
Sulfur } preparation of-1H-benzimidazole, comprise the following steps:
(1), it is dissolved in water as raw material with 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate
Colorless clear liquid, with TEA regulation pH value of solution to for 7.5 (accurate pH test paper pH=5.5-9)), dichloromethane extraction, organic be harmonious
And, wash, be dried；Dried organic facies is transferred in three-neck flask, slowly drips the dichloromethane solution of M-CPBA, drip
Adding and continue reaction 6 hours after end, reaction terminates rear reactant liquor and does not process and be directly used in the next step；Wherein, the 2-of addition
The mol ratio of chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate and M-CPBA is 1:3；
(2) the reactant liquor frozen water of step (1) being cooled to 15 DEG C, the TEA then starting to drip mercaptobenzimidazole is molten
Liquid, exothermic heat of reaction, dropping process temperature is maintained at 15 DEG C, and about 30min dropping is complete；Remove ice-water bath, under room temperature, continue reaction 3
Hour, reactant liquor stratification, separate organic facies washing, be dried, be not further processed, direct plunge into next step reaction；Its
In, the mercaptobenzimidazole of addition and the mol ratio of 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate
For 1:3；
(3) by the reactant liquor of step (2) cryosel bath cooling solution to-15 DEG C, the dichloromethane of M-CPBA is then dripped
Solution, dropping process reaction temperature controls at-15 DEG C, drips complete follow-up continuous reaction 3 hours at this temperature, and TLC shows
Reaction is complete, stopped reaction；Wherein, M-CPBA and 2-chloromethyl-4-(3-the methoxy propoxy)-3-methvl-pyridinium of addition
The mol ratio of hydrochlorate is 1:1；
(4) reactant liquor is poured in the TEA solution that pH is 12, stirring mixing, stratification, TLC under 15 DEG C of ice-water baths
Analyzing, separate aqueous phase and be about neutrality with the phosphorus acid for adjusting pH value of 30%, extraction, organic facies merges, washs, is dried, concentrates, to obtain final product
Product, productivity is 86%；Acetone recrystallization obtains sterling, and productivity is 80%.
Product through nucleus n-ness spectrum be defined as target product 2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-
2-yl] methyl sulfinyl }-1H-benzimidazole, hydrogen spectrum is shown in that Fig. 2, HPLC display purity is 97.28%.
Embodiment 2
Rabeprazole intermediate impurities 2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl
Sulfur } preparation of-1H-benzimidazole, comprise the following steps:
(1), it is dissolved in water as raw material with 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate
Colorless clear liquid, with N, N-diisopropyl ethylenediamine regulation pH value of solution to for 6.5 (accurate pH test paper pH=5.5-9)), three chloromethanes
Alkane extracts, and organic facies merges, washs, is dried；Dried organic facies is transferred in three-neck flask, slowly drips the three of H2O2
Chloromethanes solution, continues reaction 10 hours after completion of dropwise addition, reaction terminates rear reactant liquor and do not processes and be directly used in the next step；
Wherein, 2-chloromethyl-4-(3-the methoxy propoxy)-3-methvl-pyridinium hydrochlorate of addition and the mol ratio of H2O2 are 1:5；
(2) the reactant liquor frozen water of step (1) is cooled to 25 DEG C, then starts to drip the N, N-bis-of mercaptobenzimidazole
Isopropyl ethylenediamine solution, exothermic heat of reaction, dropping process temperature is maintained at 25 DEG C, and about 60min dropping is complete；Remove ice-water bath,
Continue reaction 5 hours, reactant liquor stratification under room temperature, separate organic facies washing, be dried, be not further processed, directly throw
Enter next step reaction；Wherein, the mercaptobenzimidazole of addition and 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium
The mol ratio of hydrochlorate is 1:1；
(3) by the reactant liquor of step (2) cryosel bath cooling solution to-10 DEG C, the chloroform then dripping H2O2 is molten
Liquid, dropping process reaction temperature controls at-10 DEG C, drips complete follow-up continuous reaction 1 hour at this temperature, and TLC shows instead
Should be complete, stopped reaction；Wherein, H2O2 and 2-chloromethyl-4-(3-the methoxy propoxy)-3-methvl-pyridinium hydrochloric acid of addition
The mol ratio of salt is 0.5:1；
(4) reactant liquor being poured into the N that pH is 10, in N-diisopropyl ethylenediamine solution, under 25 DEG C of ice-water baths, stirring is mixed
Closing, stratification, TLC analyzes, and separates aqueous phase and is about neutrality, extraction with the sulfur acid for adjusting pH value of 50%, and organic facies merges, washes
Washing, be dried, concentrate, obtain product, productivity is 87%；Acetone recrystallization obtains sterling, and productivity is 82%.Embodiment 3
Rabeprazole intermediate impurities 2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl
Sulfur } preparation of-1H-benzimidazole, comprise the following steps:
(1), it is dissolved in water as raw material with 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate
Colorless clear liquid, with N-methylmorpholine regulation pH value of solution to for 8.5 (accurate pH test paper pH=5.5-9)), ether extraction, organic
Merge mutually, wash, be dried；Dried organic facies is transferred in three-neck flask, slowly drips the diethyl ether solution of tBuOOH, drip
Adding and continue reaction 3 hours after end, reaction terminates rear reactant liquor and does not process and be directly used in the next step；Wherein, the 2-of addition
The mol ratio of chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate and tBuOOH is 1:1；
(2) the reactant liquor frozen water of step (1) is cooled to 5 DEG C, then starts to drip the N-methyl of mercaptobenzimidazole
Morpholine solution, exothermic heat of reaction, dropping process temperature is maintained at 5 DEG C, and about 10min dropping is complete；Remove ice-water bath, continue under room temperature
React 2 hours, reactant liquor stratification, separate organic facies washing, be dried, be not further processed, direct plunge into next step anti-
Should；Wherein, the mercaptobenzimidazole of addition and rubbing of 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate
That ratio is 1:5；
(3) by the reactant liquor of step (2) cryosel bath cooling solution to-20 DEG C, the diethyl ether solution of tBuOOH is then dripped,
Dropping process reaction temperature controls at-20 DEG C, drips complete follow-up continuous reaction 5 hours at this temperature, and TLC display has been reacted
Entirely, stopped reaction；Wherein, tBuOOH and 2-chloromethyl-4-(3-the methoxy propoxy)-3-methvl-pyridinium hydrochlorate of addition
Mol ratio be 5:1；
(4) reactant liquor is poured in the N-methylmorpholine solution that pH is 14, stirring mixing under 5 DEG C of ice-water baths, stands and divide
Layer, TLC analyzes, and separates aqueous phase and is about neutrality with the salt acid for adjusting pH value of 10%, extracts, and organic facies merges, washs, is dried, dense
Contracting, obtains product, and productivity is 86%；Acetone recrystallization obtains sterling, and productivity is 81%.
Embodiment 4
Substantially the same manner as Example 1, the difference is that only: use ethyl acetate to replace dichloromethane molten as reaction
Agent, uses peracetic acid to replace M-CPBA as oxidant, uses DBU, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium hydroxide
Replace TEA as the alkali used in preparation process, use the phosphoric acid that the acetic acid of 10% replaces 30%.
Embodiment 5
Substantially the same manner as Example 1, the difference is that only: use furan to replace dichloromethane as reaction dissolvent, adopt
Use NaIO4Replace M-CPBA as oxidant, use DBU to replace TEA as the alkali used in preparation process.
Embodiment 6
Substantially the same manner as Example 1, the difference is that only: use toluene to replace dichloromethane as reaction dissolvent, adopt
Replace M-CPBA as oxidant with OXONE, use sodium bicarbonate to replace TEA as the alkali used in preparation process, use
The nitric acid of 10% replaces the phosphoric acid of 30%.
Embodiment 7
Substantially the same manner as Example 1, the difference is that only: use diethyl ether replace dichloromethane as reaction dissolvent,
Use N-methyl morpholine oxide to replace M-CPBA as oxidant, use sodium hydroxide to replace TEA to use as in preparation process
Alkali.
Claims (1)
1. rabeprazole intermediate impurities 2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl sulfur }-
The preparation method of 1H-benzimidazole, it is characterised in that: comprise the following steps:
It is (1) with 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate as raw material, raw material is soluble in water,
Adjusting pH to 6.5-8.5 with aqueous slkali, organic solvent extracts, and merges and concentrates organic facies；Organic facies drips the organic molten of oxidant
3-10h is reacted in 20-50 DEG C after agent；
(2) reactant liquor of step (1) is placed in 5-25 DEG C of ice-water bath, drips mercaptobenzimidazole solution, maintains after dropping
Two-phase system room temperature reaction 2-5h, stratification, organic facies is dried；
(3) organic facies of step (2) be placed in-20～-10 DEG C cryosel bath in, dropping oxidant organic solution, drip complete
Rear continuation reacts 1-5h；
(4) reactant liquor of step (3) is poured in aqueous slkali, then is placed in stirring and evenly mixing in 5-25 DEG C of ice-water bath, stratification, aqueous phase
Being adjusted to neutrality with the acid of 10%～50%, organic solvent extracts, and merges and concentrates organic facies, to obtain final product；
In this preparation method, described organic solvent is same, the one in dichloromethane, chloroform and ether；Step
Suddenly, in (1), described oxidant is selected from M-CPBA, H2O2, one in tBuOOH；Alkali be selected from TEA, N, N-diisopropyl ethylenediamine,
One in N-methylmorpholine；Rubbing of 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate and oxidant
That ratio is 1:1～1:5；
The mol ratio of mercaptobenzimidazole and 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate is 1:1
～1:5；
In step (3), oxidant is selected from M-CPBA, H2O2, tBuOOH, peroxy acid, OXONE, NaIO4, in N-methyl morpholine oxide
One；The mol ratio of oxidant and 2-chloromethyl-4-(3-methoxy propoxy)-3-methvl-pyridinium hydrochlorate be 0.5:1～
5:1；
In step (4), alkali be selected from TEA, N, N-diisopropyl ethylenediamine, N-methylmorpholine, DBU, sodium bicarbonate, sodium hydroxide,
One or more in potassium carbonate, potassium hydroxide, the pH of aqueous slkali is 10～14；Acid selected from hydrochloric acid, acetic acid, nitric acid, sulphuric acid and
One or more in phosphoric acid.
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| CN201410214547.1A CN103965166B (en) | 2014-05-20 | 2014-05-20 | Rabeprazole intermediate impurities 2-{ [4-(3-methoxy propoxy)-3-oxide of mathylpyridine-2-base] methyl sulfur } preparation method of-1H-benzimidazole |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2022789A1 (en) * | 2007-08-06 | 2009-02-11 | Farmaprojects, S.A. | Process for the preparation of a gastric acid secretion inhibitor |
-
2014
- 2014-05-20 CN CN201410214547.1A patent/CN103965166B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2022789A1 (en) * | 2007-08-06 | 2009-02-11 | Farmaprojects, S.A. | Process for the preparation of a gastric acid secretion inhibitor |
Non-Patent Citations (3)
| Title |
|---|
| Efficient Synthesis of N-Oxide Derivatives: Substituted 2-(2-(Pyridyl-Noxide)methylsulphinyl)benzimidazoles;Purna C. Ray et al.;《Synthetic Communications》;20070830;第37卷;第2861-2868页 * |
| Synthesis of Metabolites and Related Substances of Rabeprazole, an Anti-Ulcerative Drug;Ganta Madhusudhan Reddy et al.;《Synthetic Communications》;20081222;第39卷;第278-290页 * |
| Synthetic Studies Connected with The Preparation of H+/K+- ATPase Inhibitors Rabeprazole and Lansoprazole;Stanislav Radl et al.;《J. Heterocyclic Chem.》;20061231;第43卷;第1447-1453页 * |
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