CN104447696B - The synthesis technique of lansoprazole - Google Patents
The synthesis technique of lansoprazole Download PDFInfo
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- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to the synthesis technique of a kind of lansoprazole, comprise the following steps: 2 chloromethyl 3 methyl 4 trifluoro ethoxy pyridine hydrochlorates and 2 mercaptobenzimidazoles are reacted in sodium carbonate methanol solution and post-treated off-white color solid；Aoxidize above-mentioned off-white color solid with the combination of cumyl hydroperoxide tetraisopropyl titanate, obtain the lansoprazole crude product being rendered as yellow solid through post processing；Lansoprazole crude product uses organic solvent to obtain lansoprazole fine work after being purified under the conditions of temperature 52 56 DEG C.Emphasis of the present invention is by the lansoprazole purifying crude condition improved and in optimization step three, the purification making final step, the yield concentrating, being dried link are brought up to 98% by the 90% of prior art, thus improve total recovery, the most industrial large-scale production and application.
Description
Technical field
The present invention relates to the synthesis technique of a kind of proton pump inhibitor, be specifically related to the synthesis technique of a kind of lansoprazole.
Background technology
Because of the development of society, rhythm of life is accelerated, and the sickness rate of gastrointestinal disease also has the trend raised year by year, this type of disease
Pharmaceutical market also by steady-state growth.
Lansoprazole is as a kind of novel proton pump inhibitor, and it is second novel proton pump after omeprazole exploitation
Inhibitor, it is by acting on the H of parietal cell+-K+-ATP enzyme, makes the H of parietal cell+Can not be transported in stomach, with
The gastric acid amount in gastric juice that causes is greatly reduced, thus gastric acid secretion inhibiting, to basal gastric acid secretion and by histamine, pentagastrin,
The gastric acid that dibutyl cyclic AMP, choline and food etc. cause is formed has, with secretion, the inhibitory action that strength is lasting, and it suppresses to make
With being substantially better than the effect protected to gastrointestinal mucosa simultaneously of H2 receptor blocking agent, burst for duodenal ulcer, stomach clinically
Infections, reflux esophagitis, the treatment of Zuo-Chinese mugwort (Zollinger-Ellison) syndrome (gastrinoma), evident in efficacy,
Helicobacter pylori is also had inhibitory action, therefore, the synthesis technique of lansoprazole is carried out in-depth study there is important meaning
Justice.
The patent documentation (publication date is on 08 01st, 2012) of Publication No. CN102617555A discloses a kind of blue rope
Draw the preparation method of azoles, comprise the following steps: by 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine hydrochlorate and 2-sulfydryl
-benzimidazole reacts [[[3-methyl-4-(2,2,2-trifluoro ethoxy)-pyridine-2-base] methyl] in sodium carbonate methanol solution
Sulfenyl]-1H-benzimidazole, with the combination of cumyl hydroperoxide-tetraisopropyl titanate, aoxidize [[[3-methyl-4-(2,2,
2-trifluoro ethoxy)-pyridine-2-base] methyl] sulfenyl]-1H-benzimidazole, obtain lansoprazole crude product, last lansoprazole
Crude product use mixed solvent in temperature less than purification under the conditions of 50 DEG C, concentrate, be dried, obtain lansoprazole.
Although the above-mentioned synthetic method that prior art discloses a kind of lansoprazole, it is possible to meet certain needs, but above-mentioned
Preparation method still suffers from certain defect: such as, lansoprazole crude product final step purification, concentrate, be dried link
Yield be 90%, total recovery only has about 70%, and yield is on the low side can affect industrial large-scale production and application.
Therefore, there is further improvement and optimize demand in the synthetic method for above-mentioned lansoprazole, this is also this technology
One of study hotspot in field and emphasis, the present invention is accomplished especially power and starting point place.
Summary of the invention
For the technical problem that the lansoprazole total recovery overcoming prior art to exist is on the low side, the present inventor is being carried out in a large number
Further investigation after, thus complete the present invention.
The present invention is achieved through the following technical solutions, the synthesis technique of a kind of lansoprazole, comprises the steps:
Step one, takes natrium carbonicum calcinatum and adds in absolute methanol, open stirring, add 2-chloromethyl-3-methyl-4-trifluoro second
Epoxide pyridine hydrochloride and 2-mercapto-benzimidazole, be heated to 60-70 DEG C of reaction, stops heating and be cooled to room temperature after 2-4h,
Filtering, filtrate reduced in volume, filter, filter cake absolute methanol washs, and filtrate is concentrated into no liquid and oozes, to residue Huang
Adding toluene in color dope, stirring, to muddy, concentrates, room temperature crystallize, filters after 5-8h, and filter cake toluene washs,
Obtain off-white color solid；
Step 2, takes toluene, ethyl acetate or dichloromethane and is heated to 26-30 DEG C, adds tetraisopropyl titanate, stirs,
Add above-mentioned off-white color solid and water, continue 26-30 DEG C stir 15-25 minute, after be warming up to 54-56 DEG C reaction 1-1.5h,
Stop heating, be cooled to 26-30 DEG C, add DIPEA or triethylamine, then drip cumene hydroperoxide,
Continuing after adding to react 1-1.5h at 26-30 DEG C, then add ammonia in reactant liquor, separatory, organic facies extracts with ammonia again
Taking, merge aqueous phase, be neutralized to pH6.5-7.5 with acetic acid, extract with dichloromethane, water layer extracts with dichloromethane again, closes
And organic facies, organic facies is 0.05-0.08MPa in vacuum, temperature be 35-50 DEG C at reclaim organic solvent, then
It is dried at 30-35 DEG C, obtains yellow solid；
Step 3, takes above-mentioned yellow solid and acetone mixing is complete, is heated to 52-56 DEG C, and insulated and stirred is to all
Dissolving, heat filtering, heat filtering terminates, filtrate added drop-wise water, adds and is cooled to 5-15 DEG C, is incubated 2-3h, obtains white solid
Body precipitate, filters, filter cake ice acetone drip washing, drains, be dried to constant weight, it is thus achieved that lansoprazole at 30-35 DEG C.
In described step 3, temperature range 52-56 DEG C of heat temperature raising includes and belongs to any concrete point value therein,
Such as 52 DEG C, 53 DEG C, 54 DEG C, 55 DEG C, 56 DEG C, most preferably 54 DEG C, also include in these concrete point values is any
The scope that two point values are constituted, more preferably 53～55 DEG C.
In described step one, temperature range 60-70 DEG C of heating includes and belongs to any concrete point value therein, such as
60 DEG C, 61 DEG C, 62 DEG C, 63 DEG C, 64 DEG C, 65 DEG C, 66 DEG C, 67 DEG C, 68 DEG C, 69 DEG C, 70 DEG C, most preferably 64 DEG C,
Also include the scope that any two point value in these concrete point values is constituted, more preferably 62～65 DEG C.
Compared with prior art, beneficial effects of the present invention is as follows: emphasis of the present invention is by improving and in optimization step three
Lansoprazole purifying crude condition so that the purification of final step, concentrate, be dried the yield of link by the 90% of prior art
Bringing up to 98%, it is possible to significantly improve yield in final step, this is for making full use of the intermediate of prior step, raising
Total recovery, reduces the large-scale production and application that cost is most important, the most industrial.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in detail.Following example will assist in those skilled in the art
Member is further appreciated by the present invention, but limits the present invention the most in any form.It should be pointed out that, the common skill to this area
For art personnel, without departing from the inventive concept of the premise, it is also possible to make some deformation and improvement.These broadly fall into
Protection scope of the present invention.
Embodiment 1
The present embodiment relates to the synthesis technique of a kind of lansoprazole, comprises the steps:
Step one, takes 105.3g natrium carbonicum calcinatum and adds in 1.2L absolute methanol, open stirring, add 124.3g 2-chloromethane
Base-3-methyl-4-trifluoro ethoxy pyridine hydrochlorate and 66.75g 2-mercapto-benzimidazole, add post-heating to 64 DEG C of reactions,
Stop heating after 3h and be cooled to room temperature (25 DEG C), be filtered to remove insoluble matter, filtrate reduced in volume to about 200g, filters, filter
Cake washs with a small amount of absolute methanol, and filtrate is concentrated into no liquid and oozes, and adds 200ml toluene in residue clear yellow viscous thing,
Under room temperature (25 DEG C), stirring is to muddy, and solution decompression is concentrated into 251g, continues room temperature (25 DEG C) stirring and crystallizing, after 6h
Filtering, filter cake 70ml toluene washs, and obtains 146.2g off-white color solid, yield 92%；
Step 2, takes 570ml toluene and is heated to 28 DEG C, adds 44.29g tetraisopropyl titanate, stirs 30 minutes, adds
118g above-mentioned off-white color solid and water, continue 28 DEG C stir 20 minutes, after be warming up to 55 DEG C reaction 1h, stop heating,
It is cooled to 28 DEG C, adds 21.41g DIPEA, dropping 66.49ml 70% (mass percent concentration)
Cumene hydroperoxide, continues after adding to react 1.2h at 28 DEG C, adds 570ml 12.5% after stopped reaction in reactant liquor
The ammonia of (mass percent), separatory, organic facies is again with the ammonia of 2*570ml 12.5% (mass percent concentration)
Extraction, merges aqueous phase, is neutralized to pH about 7.0 with 398.0ml acetic acid, extracts with 500ml dichloromethane, and water layer uses 2*250 again
Ml dichloromethane extract, merge organic facies, organic facies is 0.06MPa in vacuum, temperature be reclaim at 45 DEG C organic molten
Agent is to most, then is dried at 35 DEG C, obtains 112.3g yellow solid, yield 91%；
Step 3, at 500mL equipped with sealing stirring, reflux condensing tube, Dropping funnel and the clean four-necked bottle of thermometer
In, adding above-mentioned 25g yellow solid and 125mL acetone, mixing completely, is heated to 54 DEG C, insulated and stirred 30min,
Not dissolving minimizing, heat filtering to solid, heat filtering terminates, filtrate added drop-wise 75mL purified water, adds and is cooled to 10 DEG C,
Insulation 2h, obtain white solid precipitates, filter, filter cake 24mL ice acetone drip washing, drain lansoprazole refine
Wet product, is dried to constant weight at 32 DEG C, obtains lansoprazole fine work 21.9g, HPLC purity 99.89%, yield 98%.
1H-NMR(CDCl3, 500MHz) and δ: 11.84 (bs, 1H), 8.22 (d, J=5.7Hz, 1H), 7.64 (bs, 1H),
7.36 (bs, 1H), 7.21～7.16 (m, 2H), 6.53 (d, J=5.7Hz, 1H), 4.66 (q, 2H), 4.23-4.18 (m,
2H), 2.06 (s, 3H).
Embodiment 2
The present embodiment relates to the synthesis technique of a kind of lansoprazole, comprises the steps:
Step one, takes 105.3g natrium carbonicum calcinatum and adds in 1.2L absolute methanol, open stirring, add 124.3g 2-chlorine
Methyl-3-methyl-4-trifluoro ethoxy pyridine hydrochlorate and 66.75g 2-mercapto-benzimidazole, add post-heating anti-to 60 DEG C
Should, stop heating after 4h and be cooled to room temperature (25 DEG C), be filtered to remove insoluble matter, filtrate reduced in volume to about 200g, filter,
Filter cake washs with a small amount of absolute methanol, and filtrate is concentrated into no liquid and oozes, and adds 200ml first in residue clear yellow viscous thing
Benzene, under room temperature (25 DEG C), stirring is to muddy, and solution decompression is concentrated into 251g, continues room temperature (25 DEG C) stirring and crystallizing, and 5
Filtering after h, filter cake 70ml toluene washs, and obtains 146.1g off-white color solid, yield 91.9%；
Step 2, takes 570ml ethyl acetate and is heated to 29 DEG C, adds 44.29g tetraisopropyl titanate, stirs 30 minutes,
Add 118g above-mentioned off-white color solid and water, continue 29 DEG C and stir 15 minutes, after be warming up to 56 DEG C and react 1.5h, stop adding
Heat, is cooled to 29 DEG C, adds 21.41g triethylamine, drips 66.49ml 70% cumene hydroperoxide, continues after adding
Reacting 1.5h at 29 DEG C, add the ammonia of 570ml 12.5% after stopped reaction in reactant liquor, separatory, organic facies is used again
2*570ml 12.5% ammonia extracts, and merges aqueous phase, is neutralized to pH about 7.5 with 398.0ml acetic acid, uses 500ml dichloromethane
Alkane extracts, and water layer extracts with 2*250ml dichloromethane again, merges organic facies, and organic facies is 0.05MPa in vacuum,
Temperature is that at 40 DEG C, recovery organic solvent is to most drier at 30 DEG C, obtains 112.5g yellow solid, yield 91.2%；
Step 3, at 500mL equipped with sealing stirring, reflux condensing tube, Dropping funnel and the clean four-necked bottle of thermometer
In, adding above-mentioned 25g yellow solid and 125mL acetone, mixing completely, is heated to 55 DEG C, insulated and stirred 30min,
Not dissolving minimizing, heat filtering to solid, heat filtering terminates, filtrate added drop-wise 75mL purified water, adds and is cooled to 5 DEG C,
Insulation 3h, obtain white solid precipitates, filter, filter cake 24mL ice acetone drip washing, drain lansoprazole refine
Wet product, is dried to constant weight at 34 DEG C, obtains lansoprazole fine work 21.8g, HPLC purity 99.86%, yield 97.6%.
1H-NMR(CDCl3, 500MHz) and δ: 11.82 (bs, 1H), 8.22 (d, J=5.7Hz, 1H), 7.63 (bs, 1H),
7.36 (bs, 1H), 7.20～7.15 (m, 2H), 6.53 (d, J=5.7Hz, 1H), 4.68 (q, 2H), 4.21-4.18 (m,
2H), 2.06 (s, 3H)；
Embodiment 3
The present embodiment relates to the synthesis technique of a kind of lansoprazole, comprises the steps:
Step one, takes 105.3g natrium carbonicum calcinatum and adds in 1.2L absolute methanol, open stirring, add 124.3g 2-chloromethane
Base-3-methyl-4-trifluoro ethoxy pyridine hydrochlorate and 66.75g 2-mercapto-benzimidazole, add post-heating to 62 DEG C of reactions,
Stop heating after 2h and be cooled to room temperature (25 DEG C), be filtered to remove insoluble matter, filtrate reduced in volume to about 200g, filter,
Filter cake washs with a small amount of absolute methanol, and filtrate is concentrated into no liquid and oozes, and adds 200ml first in residue clear yellow viscous thing
Benzene, under room temperature (25 DEG C), stirring is to muddy, and solution decompression is concentrated into 251g, continues room temperature (25 DEG C) stirring and crystallizing,
Filtering after 6h, filter cake 70ml toluene washs, and obtains 146.3g off-white color solid, yield 92.1%；
Step 2, takes 570ml dichloromethane and is heated to 30 DEG C, adds 44.29g tetraisopropyl titanate, stirs 30 minutes,
Add 118g above-mentioned off-white color solid and water, continue 30 DEG C and stir 20 minutes, after be warming up to 54 DEG C and react 1h, stop adding
Heat, is cooled to 30 DEG C, adds 21.41g DIPEA, drips 66.49ml 70% cumene hydroperoxide,
Continue after adding 30 DEG C react 1.0h, after stopped reaction in reactant liquor add 570ml 12.5% ammonia, separatory,
Organic facies with the 12.5% ammonia extraction of 2*570ml, merges aqueous phase, is neutralized to pH about 6.5 with 398.0ml acetic acid, use again
500ml dichloromethane extracts, and water layer extracts with 2*250ml dichloromethane again, merges organic facies, and organic facies is in vacuum
For 0.08MPa, temperature is that at 50 DEG C, recovery organic solvent is to most drier at 32 DEG C, obtains 112.1g yellow solid, receives
Rate 90.8%；
Step 3, at 500mL equipped with sealing stirring, reflux condensing tube, Dropping funnel and the clean four-necked bottle of thermometer
In, adding above-mentioned 25g yellow solid and 125mL acetone, mixing completely, is heated to 56 DEG C, insulated and stirred 30min,
Not dissolving minimizing, heat filtering to solid, heat filtering terminates, filtrate added drop-wise 75mL purified water, adds and is cooled to 15 DEG C,
Insulation 2h, obtain white solid precipitates, filter, filter cake 24mL ice acetone drip washing, drain lansoprazole refine
Wet product, is dried to constant weight at 30 DEG C, obtains lansoprazole fine work 21.7g, HPLC purity 99.85%, yield 97.1%.
1H-NMR(CDCl3, 500MHz) and δ: 11.83 (bs, 1H), 8.20 (d, J=5.7Hz, 1H), 7.61 (bs, 1H),
7.34 (bs, 1H), 7.21～7.15 (m, 2H), 6.53 (d, J=5.7Hz, 1H), 4.66 (q, 2H), 4.21-4.18 (m,
2H), 2.05 (s, 3H).
Embodiment 4
The present embodiment relates to the synthesis technique of a kind of lansoprazole, comprises the steps:
Step one, takes 105.3g natrium carbonicum calcinatum and adds in 1.2L absolute methanol, open stirring, add 124.3g 2-chloromethane
Base-3-methyl-4-trifluoro ethoxy pyridine hydrochlorate and 66.75g 2-mercapto-benzimidazole, add post-heating to 70 DEG C of reactions,
Stop heating after 3h and be cooled to room temperature (25 DEG C), be filtered to remove insoluble matter, filtrate reduced in volume to about 200g, filter,
Filter cake washs with a small amount of absolute methanol, and filtrate is concentrated into no liquid and oozes, and adds 200ml first in residue clear yellow viscous thing
Benzene, under room temperature (25 DEG C), stirring is to muddy, and solution decompression is concentrated into 251g, continues room temperature (25 DEG C) stirring and crystallizing, and 7
Filtering after h, filter cake 70ml toluene washs, and obtains 146.2g off-white color solid, yield 92.0%；
Step 2, takes 570ml toluene and is heated to 26 DEG C, adds 44.29g tetraisopropyl titanate, stirs 30 minutes, adds
118g above-mentioned off-white color solid and water, continue 26 DEG C stir 25 minutes, after be warming up to 55 DEG C reaction 1.5h, stop heating,
It is cooled to 26 DEG C, adds 21.41g triethylamine, drip 66.49ml 70% cumene hydroperoxide, continue after adding at 26 DEG C
Reaction 1.2h, adds the ammonia of 570ml 12.5% in reactant liquor after stopped reaction, separatory, organic facies uses 2*570ml again
12.5% ammonia extraction, merges aqueous phase, is neutralized to pH about 7.0 with 398.0ml acetic acid, then extracts with 500ml dichloromethane,
Water layer extracts with 2*250ml dichloromethane again, merges organic facies, and organic facies is 0.07MPa in vacuum, and temperature is 35 DEG C
Lower recovery organic solvent is to most, then is dried at 33 DEG C, obtains 112.0g yellow solid, yield 90.8%；
Step 3, at 500mL equipped with sealing stirring, reflux condensing tube, Dropping funnel and the clean four-necked bottle of thermometer
In, adding above-mentioned 25g yellow solid and 125mL acetone, mixing completely, is heated to 52 DEG C, insulated and stirred 30min,
Not dissolving minimizing, heat filtering to solid, heat filtering terminates, filtrate added drop-wise 75mL purified water, adds and is cooled to 10 DEG C,
Insulation 3h, obtain white solid precipitates, filter, filter cake 24mL ice acetone drip washing, drain lansoprazole refine
Wet product, is dried to constant weight at 33 DEG C, obtains lansoprazole fine work 21.6g, HPLC purity 99.87%, yield 96.7%.
1H-NMR(CDCl3, 500MHz) and δ: 11.83 (bs, 1H), 8.23 (d, J=5.7Hz, 1H), 7.63 (bs, 1H),
7.34 (bs, 1H), 7.18～7.15 (m, 2H), 6.53 (d, J=5.7Hz, 1H), 4.66 (q, 2H), 4.22-4.19 (m,
2H), 2.06 (s, 3H).
Embodiment 5
The present embodiment relates to the synthesis technique of a kind of lansoprazole, comprises the steps:
Step one, takes 105.3g natrium carbonicum calcinatum and adds in 1.2L absolute methanol, open stirring, add 124.3g 2-chloromethane
Base-3-methyl-4-trifluoro ethoxy pyridine hydrochlorate and 66.75g 2-mercapto-benzimidazole, add post-heating to 65 DEG C of reactions,
Stop heating after 4h and be cooled to room temperature (25 DEG C), be filtered to remove insoluble matter, filtrate reduced in volume to about 200g, filters, filter
Cake washs with a small amount of absolute methanol, and filtrate is concentrated into no liquid and oozes, and adds 200ml toluene in residue clear yellow viscous thing,
Under room temperature (25 DEG C), stirring is to muddy, and solution decompression is concentrated into 251g, continues room temperature (25 DEG C) stirring and crystallizing, after 8h
Filtering, filter cake 70ml toluene washs, and obtains 146.0g off-white color solid, yield 91.9%；
Step 2, takes 570ml ethyl acetate and is heated to 28 DEG C, adds 44.29g tetraisopropyl titanate, stirs 30 minutes,
Add 118g above-mentioned off-white color solid and water, continue 28 DEG C and stir 15 minutes, after be warming up to 56 DEG C and react 1h, stop adding
Heat, is cooled to 28 DEG C, adds 21.41g DIPEA, drips 66.49ml 70% cumene hydroperoxide,
Continue after adding 28 DEG C react 1.5h, after stopped reaction in reactant liquor add 570ml 12.5% ammonia, separatory,
Organic facies extracts with 2*570ml 12.5% ammonia again, merges aqueous phase, is neutralized to pH about 7.5 with 398.0ml acetic acid, with 500
Ml dichloromethane extracts, and water layer extracts with 2*250ml dichloromethane again, merges organic facies, and organic facies is 0.06 in vacuum
MPa, temperature is that at 50 DEG C, recovery organic solvent is to most drier at 34 DEG C, obtains 112.4g yellow solid, yield 91.1%；
Step 3, at 500mL equipped with sealing stirring, reflux condensing tube, Dropping funnel and the clean four-necked bottle of thermometer
In, adding above-mentioned 25g yellow solid and 125mL acetone, mixing completely, is heated to 53 DEG C, insulated and stirred 30min,
Not dissolving minimizing, heat filtering to solid, heat filtering terminates, filtrate added drop-wise 75mL purified water, adds and is cooled to 5 DEG C,
Insulation 2h, obtain white solid precipitates, filter, filter cake 24mL ice acetone drip washing, drain lansoprazole refine
Wet product, is dried to constant weight at 35 DEG C, obtains lansoprazole fine work 21.8g, HPLC purity 99.88%, yield 97.6%.
1H-NMR(CDCl3, 500MHz) and δ: 11.81 (bs, 1H), 8.20 (d, J=5.7Hz, 1H), 7.61 (bs, 1H),
7.34 (bs, 1H), 7.21～7.15 (m, 2H), 6.51 (d, J=5.7Hz, 1H), 4.66 (q, 2H), 4.22-4.18 (m,
2H), 2.05 (s, 3H).
Comparative example 1
In addition to the yellow solid in step 3 and acetone being mixed complete post-heating and is warming up to 38 DEG C, with the phase with embodiment 1
Comparative example 1 is implemented with mode, the lansoprazole fine work 20.2g that step 3 obtains, HPLC purity 99.3%, step
The yield 90% of three.
1H-NMR(CDCl3, 500MHz) and δ: 11.83 (bs, 1H), 8.21 (d, J=5.7Hz, 1H), 7.62 (bs, 1H),
7.35 (bs, 1H), 7.20～7.15 (m, 2H), 6.52 (d, J=5.7Hz, 1H), 4.67 (q, 2H), 4.22-4.18 (m,
2H), 2.06 (s, 3H).
Comparative example 2
In addition to the yellow solid in step 3 and acetone being mixed complete post-heating and is warming up to 41 DEG C, with the phase with embodiment 1
Comparative example 2 is implemented with mode, the lansoprazole fine work 19.7g that step 3 obtains, HPLC purity 99.1%, step
The yield 87.3% of three.
1H-NMR(CDCl3, 500MHz) and δ: 11.82 (bs, 1H), 8.20 (d, J=5.7Hz, 1H), 7.61 (bs, 1H),
7.34 (bs, 1H), 7.21～7.15 (m, 2H), 6.51 (d, J=5.7Hz, 1H), 4.66 (q, 2H), 4.23-4.18 (m,
2H), 2.05 (s, 3H).
Comparative example 3
In addition to the yellow solid in step 3 and acetone being mixed complete post-heating and is warming up to 45 DEG C, with the phase with embodiment 1
Comparative example 3 is implemented with mode, the lansoprazole fine work 20.1g that step 3 obtains, HPLC purity 98.9%, step
The yield 89.1% of three.
1H-NMR(CDCl3, 500MHz) and δ: 11.82 (bs, 1H), 8.22 (d, J=5.7Hz, 1H), 7.63 (bs, 1H),
7.35 (bs, 1H), 7.20～7.16 (m, 2H), 6.54 (d, J=5.7Hz, 1H), 4.68 (q, 2H), 4.23-4.18 (m,
2H), 2.04 (s, 3H).
Comparative example 4
In addition to the yellow solid in step 3 and acetone being mixed complete post-heating and is warming up to 49 DEG C, with the phase with embodiment 1
Comparative example 4 is implemented with mode, the lansoprazole fine work 19.9g that step 3 obtains, HPLC purity 98.6%, step
The yield 88.2% of three.
1H-NMR(CDCl3, 500MHz) and δ: 11.85 (bs, 1H), 8.20 (d, J=5.7Hz, 1H), 7.61 (bs, 1H),
7.36 (bs, 1H), 7.20～7.14 (m, 2H), 6.51 (d, J=5.7Hz, 1H), 4.68 (q, 2H), 4.23-4.18 (m,
2H), 2.02 (s, 3H).
Comparative example 5
In addition to the yellow solid in step 3 and acetone being mixed complete post-heating and is warming up to 35 DEG C, with the phase with embodiment 1
Comparative example 5 is implemented with mode, the lansoprazole fine work 20.0g that step 3 obtains, HPLC purity 99.1%, step
The yield 88.7% of three.
1H-NMR(CDCl3, 500MHz) and δ: 11.81 (bs, 1H), 8.20 (d, J=5.7Hz, 1H), 7.61 (bs, 1H),
7.33 (bs, 1H), 7.22～7.15 (m, 2H), 6.53 (d, J=5.7Hz, 1H), 4.66 (q, 2H), 4.24-4.18 (m,
2H), 2.04 (s, 3H).
Implementation result
Implement above-described embodiment 1-5 and comparative example 1-5 respectively, and respectively according to the lansoprazole fine work pair obtained in step 3
The yield of step 3 is added up.In rapid three, when yellow solid and the acetone complete post-heating of mixing are warming up to 52-56 DEG C,
In step 3, the yield of lansoprazole fine work is 96.7-98.0% (see embodiment 1-5), and when this temperature is less than 50 DEG C of conditions
Time, in step 3, the yield of lansoprazole fine work is reduced to 88.7-90.0% (see comparative example 1-5), and the range of decrease is obvious, explanation
Above-mentioned yellow solid and acetone mix temperature that complete post-heating heats up in step 3 lansoprazole fine work yield and
Total recovery has appreciable impact.
Above the specific embodiment of the present invention is described.It is to be appreciated that the invention is not limited in above-mentioned spy
Determining embodiment, those skilled in the art can make various deformation or amendment within the scope of the claims, this not shadow
Ring the flesh and blood of the present invention.
Claims (1)
1. the synthesis technique of a lansoprazole, it is characterised in that comprise the steps:
Step one, takes natrium carbonicum calcinatum and adds in absolute methanol, open stirring, add 2-chloromethyl-3-methyl-4-
Trifluoro ethoxy pyridine hydrochlorate and 2-mercapto-benzimidazole, be heated to 60-70 DEG C of reaction, stops adding after 2-4h
Heat is cooled to room temperature, filters, filtrate reduced in volume, filters, and filter cake absolute methanol washs, and filtrate is concentrated into
No liquid oozes, and adds toluene in residue clear yellow viscous thing, and stirring, to muddy, concentrates, room temperature crystallize, 5-8
Filtering after h, filter cake toluene washs, and obtains off-white color solid；
Step 2, takes toluene, ethyl acetate or dichloromethane and is heated to 26-30 DEG C, adds tetraisopropyl titanate,
Stirring, add above-mentioned off-white color solid and water, continues 26-30 DEG C stirring 15-25 minute, after be warming up to 54-56 DEG C
Reaction 1-1.5h, stops heating, is cooled to 26-30 DEG C, adds DIPEA or triethylamine, connects
Dropping cumene hydroperoxide, continue after adding to react 1-1.5h at 26-30 DEG C, then add in reactant liquor
Ammonia, separatory, organic facies extracts with ammonia again, merges aqueous phase, is neutralized to pH6.5-7.5 with acetic acid, uses dichloro
Methane extracts, and water layer extracts with dichloromethane again, merges organic facies, and organic facies is 0.05-0.08 in vacuum
MPa, temperature reclaims organic solvent, then is dried at 30-35 DEG C, obtains yellow solid at being 35-50 DEG C；
Step 3, takes above-mentioned yellow solid and acetone mixing is complete, is heated to 54 DEG C, and insulated and stirred is to entirely
Portion dissolves, heat filtering, and heat filtering terminates, filtrate added drop-wise water, adds and is cooled to 5-15 DEG C, is incubated 2-3h,
To white solid precipitates, filter, filter cake ice acetone drip washing, drain, be dried to constant weight at 30-35 DEG C,
Obtain lansoprazole.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006074952A1 (en) * | 2005-01-14 | 2006-07-20 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing lansoprazole |
| CN102267979A (en) * | 2011-06-15 | 2011-12-07 | 扬州天和药业有限公司 | Method for preparing lansoprazole |
| CN102617555A (en) * | 2012-03-20 | 2012-08-01 | 西藏易明西雅生物医药科技有限公司 | Preparation method of lansoprazole |
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| WO2006074952A1 (en) * | 2005-01-14 | 2006-07-20 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing lansoprazole |
| CN102267979A (en) * | 2011-06-15 | 2011-12-07 | 扬州天和药业有限公司 | Method for preparing lansoprazole |
| CN102617555A (en) * | 2012-03-20 | 2012-08-01 | 西藏易明西雅生物医药科技有限公司 | Preparation method of lansoprazole |
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