CN106866630B - A kind of preparation method of R-lansoprazole - Google Patents
A kind of preparation method of R-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
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Abstract
The invention discloses a kind of preparation methods of R-lansoprazole：(1) prepare compound III；(2) R-lansoprazole crude product is prepared；(3) R-lansoprazole crude product is refined.The key point of the present invention is, in step 1 of the present invention, in the compound 2 that charcoal treated is added in 1~1.5 hour so that the reaction was complete, yield improves.In step 2 of the present invention, at 60~65 DEG C, makes to form enough complex compounds in isopropyl titanate (IV) or tert-butyl alcohol titanium are added in 10~15 minutes, content of isomer can be reduced to improve yield and purity.The technological operation of the present invention is simple, and product yield is higher, and purity is higher, conducive to commercially producing.
Description
Technical field
The present invention relates to a kind of preparation methods of R-lansoprazole, belong to pharmaceutical field.
Background technology
R-lansoprazole is proton pump inhibitor.Proton pump inhibitor is benzimidazoles derivative, specific and non-competing
Striving property acts on H+/K+-ATP enzymes, treats peptic ulcer.Proton pump inhibitor is mostly fat-soluble alkalescent, absorbed into serum
Entering afterwards in parietal cell secretory tubyle, small envelope chamber after acidic environment, activation products are generally active sulfenic acids and sulfenamide,
It is coupled to form an irreversible covalent disulfide bonds with H+-K+-ATP enzyme sulfydryls, H+-K+ transporting mechanisms is blocked, to inhibit
Gastric acid secretion.
Patent CN1150186 (patent families US6462058,6664276) discloses a kind of HPLC methods and prepares right Lan Suola
The method of azoles：That is, at room temperature, Lansoprazole racemic modification being dissolved in suitable solvent, then solution by portions is added
Chiralcel OD columns, are eluted with mobile phase, and eluent is checked in 285nm, are merged the shorter optical isomer of retention time and are evaporated
Point, concentration merges every batch of fraction, is dissolved in ethyl alcohol, is filtered by 0.45 μm of filter.Hexane is added, evaporation filtrate obtains to doing
The amorphous substance of R (+)-Lansoprazole.Obtained amorphous substance is crystallized in different solvents or water, obtains right Lan Suola
Azoles crystal or its hydrate (0.5 water~5.0 water).
Patent US6462058, CN95194956 discloses a kind of method that asymmetric oxidation is synthetically prepared R-lansoprazole：
That is, Lansoprazole is dissolved in toluene, water, (-)-D- ethyl tartrates and isopropyl titanate are then sequentially added into solution
(IV), 50 DEG C are warming up to, stirring is cooled to room temperature after sixty minutes, and diisopropylethylamine and cumene hydroperoxide, stirring is then added
16 hours.Toluene is added into the mixture, acquired solution ammonium hydroxide extracts three times, and combined water layer is by being added spirit acid
It neutralizes, by extraction, evaporation and the isolated Lansoprazole of flash chromatography.The residue acetonitrile treatment, obtains sediment,
Filtering, filtrate is evaporated, the optical purity grease being improved, and is repeated this process two or three times, is obtained requiredization of oily
Close object.
Patent WO97/02261 (11-JP508590) discloses one kind by a kind of enantiomer of enrichment to prepare optical voidness production
A kind of method of product, including will be enriched in the product of enantiomer and be added in another solvent, using the cleanliness factor of racemic compound,
A kind of racemic compound is settled out from the solvent；It is filtered to remove the racemic compound of precipitation；Then solvent is removed to obtain
The single enantiomer of high optical rotation.
Patent US7285668 (patent families CN1254473C), US6462058, WO2009113696 (patent families
US8222422), CN1254473C etc. is disclosed prepares R-lansoprazole crystal, R-lansoprazole by amorphous dexlansoprazole
The method of hydrate (0.5 water~5 water) and R-lansoprazole hydrate, is included in differential responses temperature, different solvents
Middle crystallization is to obtain the R-lansoprazole of expected crystal form.
The chiral column separation method right side of what patent CN1150186 was announced prepare R-lansoprazole is not only time-consuming but also cost
Height is unfavorable for commodity production.
The asymmetric oxidation method yield for preparing R-lansoprazole of patent US6462058, CN95194956 announcement is low, if oxygen
It is improper to change control, is also easy to produce excessive thioether and sulfone impurity.
The present invention is directed to develop the few R-lansoprazole production technology of a kind of easy to operate, high income, impurity.
Invention content
In view of the shortcomings of the prior art, the present invention relates to the few R-lansoprazole lifes of a kind of easy to operate, high income, impurity
Production. art.
A kind of preparation method of R-lansoprazole, its step are as follows：
(1) prepare compound III
At room temperature in input purified water (455L), sodium hydroxide (22.4kg) and compound 1 (35kg) to reaction kettle, then
In the compound 2 that charcoal treated is added in 1~1.5 hour, then reaction 1.5 hours, centrifugation is kept to use 35L in room temperature
Water rinses, and spin is about 1 hour dry, dry.Then dried material and toluene (315L) are put into reaction kettle, are warming up to reflux,
It maintains the reflux for about being cooled to room temperature after twenty minutes, be kept for about 30 minutes.Centrifugation is rinsed with 35L water, and spin is about 1.5 hours dry,
Dry compound 3.Yield about 96.0%；
The compound 2 of activated carbon processing：Check the cleanliness factor of reaction kettle, input purified water (350L) and compound 2
(67.6kg) makes compound 2 be completely dissolved in 90 minutes to reaction kettle, stir about, and input activated carbon (3.5kg), stir about 30 divides
Clock；
Reaction equation is as follows：
(2) R-lansoprazole crude product is prepared
It puts into toluene (375L) and compound 3 (75kg) to reaction kettle, be warming up to reflux and kept for about 60 minutes, in nitrogen
Cooling reaction mass puts into 0.6L water and L- (+)-ethyl tartrate (33.6kg) to room temperature under gas shielded, it is warming up to 60~
65 DEG C, in isopropyl titanate (IV) (21.6kg) or tert-butyl alcohol titanium (18.5kg) is added in 10~15 minutes after heat preservation about 15 minutes,
About 50 minutes postcoolings of insulation reaction to room temperature (is kept in a nitrogen environment until TLC results meet regulation), puts into diisopropyl
Cumene hydroperoxide (46.4kg) is then added in base ethamine (17.8kg) in about 30 minutes, keeps reaction about 3.5 hours.Room
Temperature is lower to be added hypo solution 1, and stir about stands 10 minutes after ten minutes, detaches bottom aqueous layer, continues to use thiosulfuric acid
Sodium solution 2 and 3 washs, and detaches bottom aqueous layer.
Hypo solution 1：At room temperature, input water (300L) and sodium thiosulfate (90kg), stir about make for 15 minutes
It is completely dissolved.
Hypo solution 2：At room temperature, input water (150L) and sodium thiosulfate (15kg), stir about make for 15 minutes
It is completely dissolved.
Hypo solution 3：At room temperature, input water (150L) and sodium thiosulfate (15kg), stir about make for 15 minutes
It is completely dissolved.
Above-mentioned organic layer is put into reaction kettle, is warming up to 30~35 DEG C, input water (94L), then in 10~15 minutes
Methyl tertiary butyl ether(MTBE) (187.5L) is added, hexamethylene (375L) is then added in 10~15 minutes, stirring is no more than 40 minutes.
Centrifugation, is washed with methyl tertiary butyl ether(MTBE) (75L), and spin is about 1.5 hours dry.It takes gained wet stock to reaction kettle, throws at room temperature
Enter acetone (375L), after ten minutes in putting into 1125L water in 30~45 minutes, stir about centrifuges stir about after 30 minutes, uses 75L
Water washing, spin obtain R-lansoprazole crude product in dry about 1.5 hours.Yield 83.0%.
(3) R-lansoprazole crude product is refined：
At room temperature, it puts into acetone (300L) and gained wet product to reaction kettle, stirring puts into ammonia spirit (1.5L) above,
Next input activated carbon (3.75kg).Filtering is rinsed with acetone (37.5L), is collected in filtrate to reaction kettle.It is molten to put into ammonium hydroxide
Then liquid (7.5L), centrifugation use 0.75L water washings with 75L water washings, drying of spinning.Put into dichloromethane (600L) and wet object
Material is stood to reaction kettle after stirring, detaches bottom organic layer, dry with sodium thiosulfate (37.5kg).It is distilled off organic molten
Agent, input acetone (60L), is distilled off solvent, and acetone (60L) is put into after being cooled to room temperature, and stirring makes to be completely dissolved.Input is just
Heptane (600L) filters after being warming up to 40~45 DEG C, stands about 30 minutes.Centrifugation, is washed with normal heptane (30L), drying of spinning
About 1.5 hours.Discharging is warming up to 35~40 DEG C, obtains R-lansoprazole within dry about 5 hours.
The key point of the present invention is, in step 1 of the present invention, in the chemical combination that charcoal treated is added in 1~1.5 hour
So that the reaction was complete, yield improves object 2.
In step 2 of the present invention, at 60~65 DEG C, make shape in isopropyl titanate (IV) or tert-butyl alcohol titanium are added in 10~15 minutes
At enough complex compounds, content of isomer can be reduced to improve yield and purity.
Advantages of the present invention：
The technological operation of the present invention is simple, and product yield is higher, and purity is higher, conducive to commercially producing.
Specific implementation mode
The embodiment of the present invention is described below in detail, the embodiment is only used for explaining the present invention, and should not be understood as pair
The limitation of the present invention.
Specific embodiments of the present invention are as described below.
Embodiment 1
A kind of preparation method of R-lansoprazole, its step are as follows：
(1) prepare compound III
At room temperature in input purified water (455L), sodium hydroxide (22.4kg) and compound 1 (35kg) to reaction kettle, then
In the compound 2 that charcoal treated is added in 1~1.5 hour, then reaction 1.5 hours, centrifugation is kept to use 35L in room temperature
Water rinses, and spin is about 1 hour dry, dry.Then dried material and toluene (315L) are put into reaction kettle, are warming up to reflux,
It maintains the reflux for about being cooled to room temperature after twenty minutes, be kept for about 30 minutes.Centrifugation is rinsed with 35L water, and spin is about 1.5 hours dry,
Dry compound 3.Yield about 96.0%；
The compound 2 of activated carbon processing：Check the cleanliness factor of reaction kettle, input purified water (350L) and compound 2
(67.6kg) makes compound 2 be completely dissolved in 90 minutes to reaction kettle, stir about, and input activated carbon (3.5kg), stir about 30 divides
Clock；
Reaction equation is as follows：
(2) R-lansoprazole crude product is prepared
It puts into toluene (375L) and compound 3 (75kg) to reaction kettle, be warming up to reflux and kept for about 60 minutes, in nitrogen
Cooling reaction mass puts into 0.6L water and L- (+)-ethyl tartrate (33.6kg) to room temperature under gas shielded, it is warming up to 60~
65 DEG C, in isopropyl titanate (IV) (21.6kg) is added in 10~15 minutes after keeping the temperature about 15 minutes, insulation reaction is after about 50 minutes
It is cooled to room temperature and (keeps in a nitrogen environment until TLC results meet regulation), input diisopropylethylamine (17.8kg), then
Cumene hydroperoxide (46.4kg) is added in about 30 minutes, keeps reaction about 3.5 hours.It is molten that sodium thiosulfate is added at room temperature
Liquid 1, stir about stand 10 minutes after ten minutes, detach bottom aqueous layer, continue to be washed with hypo solution 2 and 3, detach bottom
Portion's water layer.
Hypo solution 1：At room temperature, input water (300L) and sodium thiosulfate (90kg), stir about make for 15 minutes
It is completely dissolved.
Hypo solution 2：At room temperature, input water (150L) and sodium thiosulfate (15kg), stir about make for 15 minutes
It is completely dissolved.
Hypo solution 3：At room temperature, input water (150L) and sodium thiosulfate (15kg), stir about make for 15 minutes
It is completely dissolved.
Above-mentioned organic layer is put into reaction kettle, is warming up to 30~35 DEG C, input water (94L), then in 10~15 minutes
Methyl tertiary butyl ether(MTBE) (187.5L) is added, hexamethylene (375L) is then added in 10~15 minutes, stirring is no more than 40 minutes.
Centrifugation, is washed with methyl tertiary butyl ether(MTBE) (75L), and spin is about 1.5 hours dry.It takes gained wet stock to reaction kettle, throws at room temperature
Enter acetone (375L), after ten minutes in putting into 1125L water in 30~45 minutes, stir about centrifuges stir about after 30 minutes, uses 75L
Water washing, spin obtain R-lansoprazole crude product in dry about 1.5 hours.Yield 83.0%.
(3) R-lansoprazole crude product is refined：
At room temperature, it puts into acetone (300L) and gained wet product to reaction kettle, stirring puts into ammonia spirit (1.5L) above,
Next input activated carbon (3.75kg).Filtering is rinsed with acetone (37.5L), is collected in filtrate to reaction kettle.It is molten to put into ammonium hydroxide
Then liquid (7.5L), centrifugation use 0.75L water washings with 75L water washings, drying of spinning.Put into dichloromethane (600L) and wet object
Material is stood to reaction kettle after stirring, detaches bottom organic layer, dry with sodium thiosulfate (37.5kg).It is distilled off organic molten
Agent, input acetone (60L), is distilled off solvent, and acetone (60L) is put into after being cooled to room temperature, and stirring makes to be completely dissolved.Input is just
Heptane (600L) filters after being warming up to 40~45 DEG C, stands about 30 minutes.Centrifugation, is washed with normal heptane (30L), drying of spinning
About 1.5 hours.Discharging is warming up to 35~40 DEG C, obtains R-lansoprazole within dry about 5 hours.Yield 38.0%.
In triplicate, average result is taken：
Sulfone impurity：Less than 0.15%
Sulphur impurity：Less than 0.15%
Any nonspecific impurity：Less than 0.10%
S- isomer impurities：0.13%
Content：98.0%~102.0%.
Embodiment 2
With embodiment 1, but step 2 is added without isopropyl titanate.
In triplicate, average result is taken：
The yield 65.3% of step 2.
Sulfone impurity：Less than 0.15%
Sulphur impurity：Less than 0.15%
Any nonspecific impurity：Less than 0.10%
S- isomer impurities：0.19%
Content：93.1%
Embodiment 3：
With embodiment 1, but isopropyl titanate changes tert-butyl alcohol titanium (18.5kg) into.
In triplicate, average result is taken：
The yield 71.6% of step 2.
Sulfone impurity：Less than 0.15%
Sulphur impurity：Less than 0.15%
Any nonspecific impurity：Less than 0.10%
S- isomer impurities：0.21%
Content：89.5%
Embodiment 4
With embodiment 1, but isopropyl titanate changes tert-butyl alcohol titanium (5kg) and isopropyl titanate (18.3kg) into.
In triplicate, average result is taken：
The yield 96.3% of step 2.
Sulfone impurity：Less than 0.15%
Sulphur impurity：Less than 0.15%
Any nonspecific impurity：Less than 0.10%
S- isomer impurities：0.08%
Content：101.1%
As it can be seen that under the proportioning of this tert-butyl alcohol titanium and isopropyl titanate, yield is greatly improved.
Embodiment 5
With embodiment 1, but isopropyl titanate changes tert-butyl alcohol titanium (16.8kg) and isopropyl titanate (9.3kg) into.
In triplicate, average result is taken：
The yield 87.6% of step 2.
Sulfone impurity：Less than 0.15%
Sulphur impurity：Less than 0.15%
Any nonspecific impurity：Less than 0.10%
S- isomer impurities：0.01%
Content：101.1%.
As it can be seen that under the proportioning of this tert-butyl alcohol titanium and isopropyl titanate, yield raising is relatively limited, but S- isomer impurities
It is greatly lowered.
It should be noted that the foregoing is merely the preferred specific embodiment of the present invention,
If conception under this invention changes, the function generated, the spirit still covered without departing from specification
When, it should all be within the scope of the invention.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example
Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not
Centainly refer to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any
One or more embodiments or example in can be combined in any suitable manner.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that：Not
In the case of being detached from the principle of the present invention and objective a variety of change, modification, replacement and modification can be carried out to these embodiments, this
The range of invention is limited by claim and its equivalent.
Claims (2)
1. a kind of preparation method of R-lansoprazole, its step are as follows：
(1) prepare compound 3
It puts into purified water, sodium hydroxide and compound 1 to reaction kettle at room temperature, then in addition in 1~1.5 hour through activity
The compound 2 of charcoal processing then keeps reaction 1.5 hours, centrifugation to be rinsed with 35L water in room temperature, and spin is about 1 hour dry, does
It is dry；Then dried material and toluene are put into reaction kettle, is warming up to reflux, maintains the reflux for about being cooled to room temperature after twenty minutes, protected
It holds about 30 minutes；Centrifugation is rinsed with 35L water, dry about 1.5 hours of spin, dry compound 3；
The compound 2 of activated carbon processing：It checks the cleanliness factor of reaction kettle, puts into purified water and compound 2 to reaction kettle, stir about
So that compound 2 is completely dissolved within 90 minutes, puts into activated carbon, stir about 30 minutes；The compound 1 is 2- mercapto-benzimidazoles,
Molecular formula is C7H6N2S；Structural formula is：
The compound 2 is 2- (chloromethyl) -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine hydrochloride, and molecular formula is
C9H10Cl2F3NO；Structural formula is：
The compound 3 is 2- [[[3- methyl -4- (2,2,2- trifluoro ethoxies) -2- pyridyl groups] methyl] is thio] -1H- benzos
Imidazoles, molecular formula C16H14F3N3OS, structural formula are：
(2) R-lansoprazole crude product is prepared
It puts into toluene and compound 3 to reaction kettle, be warming up to reflux and kept for about 60 minutes, cooling reaction under nitrogen protection
Material puts into water and L- (+)-ethyl tartrate to room temperature, is warming up to 60~65 DEG C, in 10~15 points after keeping the temperature about 15 minutes
Be added isopropyl titanate and tert-butyl alcohol titanium in clock, about 50 minutes postcoolings of insulation reaction to room temperature, keep in a nitrogen environment until
TLC results meet regulation, put into diisopropylethylamine, and cumene hydroperoxide is then added in about 30 minutes, keep reaction about
3.5 hour；Hypo solution 1 is added at room temperature, stir about stands 10 minutes after ten minutes, detaches bottom aqueous layer, continues
It is washed with hypo solution 2 and 3, detaches bottom aqueous layer；Reaction terminates to obtain R-lansoprazole；
Above-mentioned organic layer is put into reaction kettle, is warming up to 30~35 DEG C, water is put into, methyl- tert then is added in 10~15 minutes
Butyl ether, is then added hexamethylene in 10~15 minutes, and stirring is no more than 40 minutes；Centrifugation, is washed with methyl tertiary butyl ether(MTBE),
Spin is about 1.5 hours dry；It takes gained wet stock to reaction kettle, puts into acetone at room temperature, stir about is after ten minutes in 30~45
1125L water is put into minute, stir about centrifuges after 30 minutes, and with 75L water washings, spin obtains right Lan Suola in dry about 1.5 hours
Azoles crude product；
Wherein, the hypo solution 1：At room temperature, put into 300L water and 90kg sodium thiosulfate, stir about makes for 15 minutes
It is completely dissolved；
Hypo solution 2：At room temperature, put into 150L water and 15kg sodium thiosulfate, stir about makes to be completely dissolved for 15 minutes；
Hypo solution 3：At room temperature, put into 150L water and 15kg sodium thiosulfate, stir about makes to be completely dissolved for 15 minutes.
2. method described in claim 1, it is characterised in that：
Still further comprise the refined of (3) R-lansoprazole crude product：
At room temperature, it puts into acetone and gained wet product to reaction kettle, stirring puts into ammonia spirit, next put into activated carbon above；
Filtering is collected with acetone rinsing in filtrate to reaction kettle, and ammonia spirit is put into, and centrifugation with 75L water washings, then uses 0.75L
Water washing, drying of spinning；Dichloromethane and wet stock are put into reaction kettle, is stood after stirring, bottom organic layer is detached, use is thio
Sodium sulphate is dried；Organic solvent is distilled off, puts into acetone, solvent is distilled off, acetone is put into after being cooled to room temperature, stirring makes
It is completely dissolved；Normal heptane is put into, filtered after being warming up to 40~45 DEG C, stand about 30 minutes；Centrifugation, is washed with normal heptane, is spinned
It is about 1.5 hours dry；Discharging is warming up to 35~40 DEG C, must refine R-lansoprazole within dry about 5 hours.
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| CN107141280A (en) * | 2017-07-10 | 2017-09-08 | 长沙康普大药房有限责任公司 | A kind of preparation method of Dexlansoprazole |
| CN108440501A (en) * | 2018-04-19 | 2018-08-24 | 湖北省医药工业研究院有限公司 | The preparation method of proton pump inhibitor R-lansoprazole |
| CN114163419A (en) * | 2021-12-24 | 2022-03-11 | 辰欣药业股份有限公司 | Preparation method of lansoprazole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1157614A (en) * | 1994-07-15 | 1997-08-20 | 阿斯特拉公司 | Process for synthesis of substituted sulphoxides |
| CN102558148A (en) * | 2010-12-15 | 2012-07-11 | 山东方明药业股份有限公司 | Synthesis process of lansoprazole important intermediate |
| CN106543146A (en) * | 2016-11-10 | 2017-03-29 | 石家庄市度智医药科技有限公司 | A kind of preparation method of R-lansoprazole |
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| TWI289557B (en) * | 1999-06-17 | 2007-11-11 | Takeda Chemical Industries Ltd | A crystal of a hydrate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1157614A (en) * | 1994-07-15 | 1997-08-20 | 阿斯特拉公司 | Process for synthesis of substituted sulphoxides |
| CN102558148A (en) * | 2010-12-15 | 2012-07-11 | 山东方明药业股份有限公司 | Synthesis process of lansoprazole important intermediate |
| CN106543146A (en) * | 2016-11-10 | 2017-03-29 | 石家庄市度智医药科技有限公司 | A kind of preparation method of R-lansoprazole |
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| Title |
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| 右兰索拉唑的合成及精制工艺研究;李玉龙 等;《中国药物化学杂志》;20160430;第26卷(第2期);第136-138页 * |
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