CN106543146A - 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
- 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 invention discloses a kind of preparation method of R-lansoprazole, belongs to organic synthesis field.Comprise the following steps:(1) 2 methylol, 3 methyl, 4 (2,2,2 trifluoro ethoxy) pyridine is reacted with thionyl chloride, synthesizes 2 chloromethyl, 3 methyl 4 (2,2,2 trifluoro ethoxy) pyridine;(2) 2 chloromethyl, 3 methyl 4 (2 for step (1) being obtained, 2,2 trifluoro ethoxies) pyridine, in 2 sulfydryl 1H benzimidazoles input aqueous solvent, add phase transfer catalyst and sodium hydroxide, obtain 2 [[3 methyl 4 (2,2,2 trifluoro ethoxy) 2 base of pyridine] methyl mercapto] 1H benzimidazoles;(3) 2 [[3 methyl 4 (2 that step (2) is obtained, 2,2 trifluoro ethoxies) 2 base of pyridine] methyl mercapto] 1H benzimidazoles make chiral adjuvant with L diethyl tartrate .s, titanium isopropoxide and diisopropylethylamine are catalyst, cumyl hydroperoxide is oxidant, and reaction at low temperature obtains R-lansoprazole.The present invention is a kind of simple, efficient, substantially can shorten the response time, the R-lansoprazole synthetic method of improve product quality on the premise of product yield is ensured.
Description
Technical field
The present invention relates to a kind of preparation method of R-lansoprazole, belongs to organic synthesis field.
Background technology
R-lansoprazole, English name:(R)-(+)-Lansoprazole (dexlansoprazole), chemical name:(R)-
(+) -2- [[3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- bases] methylsulfinyl] -1H- benzimidazoles, in molecule
With chiral sulfur atom, it is the enantiomer of proton pump inhibitor lansoprazole, be otherwise known as Dexlansoprazole, for controlling
The heartburn related to Non-erosive gastroesophageal reflux disease and different degrees of erosive esophagitis are treated, is by the field pharmacy of Japanese force
The esophagitis treatment new drug of company's research and development, on January 30th, 2009, approval was listed U.S. FDA.
R-lansoprazole is benzimidazole proton pump inhibitors.Specificity and noncompetitive act on H+/K+-ATP
Enzyme, treats peptic ulcer.Proton pump inhibitor mostly be fat-soluble alkalescence, after absorbed into serum enter parietal cell secretory tubyle,
In little envelope chamber after sour environment, activation products are generally active sulfenic acids and sulfenamide, with H+/K+- ATP enzyme sulfydryl is coupled
An irreversible covalent disulfide bonds are formed, H is blocked+/K+Transporting mechanism, so as to gastric acid secretion inhibiting.The structure of R-lansoprazole
It is as follows:
In prior art generally, for example the method being related in DE 4035455 and WO 94/27988 is all first to synthesize crucial
Intermediate 2- [[[3- methyl -4- (2,2,2- trifluoro ethoxy) -2- pyridine radicals) methyl) sulfenyl) -1H- benzimidazoles, then Jing oxygen
Change and raceme lansoprazole is obtained, then R-lansoprazole is obtained through fractionation.The method is needed through multiple inclusion resolution
The finished product of high light purity can be obtained, complex operation can produce substantial amounts of isomer garbage, be unfavorable for amplifying production.
WO2005054228 is adopted and with 2-mercaptobenzimidazole (3) and 2- chloromethyls -4- nitros -3- picolines (2) is
Raw material, nucleo philic substitution reaction are obtained 2- [[4- nitro -3- methyl -2- pyridine radicals] methyl mercapto] -1H- benzimidazoles (4).In L-
In the presence of (+)-diethyl tartrate., stereoselective oxidation reaction is carried out with cumyl hydroperoxide, generated in the middle of crucial
Body 2- [(R)-[[4- nitro -3- methyl -2- pyridine radicals] methyl] sulfinyl] -1H- benzimidazoles (5), then in alkaline bar
Under part, and 2,2,2, the reaction of-trifluoroethanol obtains Dexlansoprazole.The method is obtained by the asymmetric oxidation of sulphur atom
Optically pure key intermediate, then, the 4- positions nitro of trifluoro ethoxy substituted pyridines ring obtains the object of optical purity.
Optically pure intermediate 2- [(R)-[[4- nitro -3- methyl -2- pyridine radicals] methyl] the sulfinyl] -1H- in substitution reaction
Benzimidazole (5) has certain loss, improves can cost.
Kagan and partner report (Pitchen, P.;Deshmukh, M.;Dunach, E.;Kagan,
H.B.J.Am.Chem.Soc.106 (1984), 8188) excessive 30%, the Jing of the enantiomer of sulphur atom chiral oxidization crude product
Repeated recrystallize purification optical purity reaches 95%.
Knowable to analysis prior art route, Jing first step synthetic intermediate 2- chloromethyl -3- methyl -4- (2,2,2- trifluoros
Ethyoxyl) after pyridine, synthesize 2- [[2- (3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine radicals) methyl]-sulfenyl] -1H- benzene
And imidazoles is one of key technology of whole synthesis technique.This step reaction type belongs to nucleophilic substitution, and response speed is slow,
With the rising and the prolongation in response time of reaction temperature, by-product substantially can increase, and the yield and purity of finished product is received
To impact.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of R-lansoprazole, and the present invention is a kind of letter
R-lansoprazole synthetic method that is single, being suitable for industrialized production.
The technical solution used in the present invention is:A kind of preparation method of R-lansoprazole, comprises the following steps:
(1) 2- methylol -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridines are reacted with thionyl chloride, synthesizes 2- chlorine
Methyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine;
(2) 2- chloromethyl -3- methyl -4- (2,2, the 2- trifluoro ethoxy) pyridines for step (1) being obtained, with 2- sulfydryls -
In 1H- benzimidazoles input aqueous solvent, phase transfer catalyst and sodium hydroxide are added, 2- [[3- methyl -4- (2,2,2- tri- are obtained
Fluorine ethyoxyl) pyridine -2- bases] methyl mercapto] -1H- benzimidazoles;
(3) 2- [[3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine -2- bases] methyl mercapto] for step (2) being obtained -
1H- benzimidazoles L- (+)-diethyl tartrate. makees chiral adjuvant, and titanium isopropoxide and diisopropylethylamine are catalyst,
Cumyl hydroperoxide is oxidant, and reaction at low temperature obtains R-lansoprazole.
Preferred phase transfer catalyst is quaternary ammonium salt, and formula is R4N+X-, R is C1-C16Chain alkylene, alicyclic hydrocarbon radical or virtue
One or more in alkyl, X are Cl, Br, I or HSO4In one kind.
Preferred quaternary ammonium salt-type phase transfer catalyst is tetrabutyl ammonium bromide, cetyl trimethylammonium bromide, benzyl three
One kind in ethyl ammonium chloride or benzyl tributyl ammonium chloride.
Preferred quaternary ammonium salt-type phase transfer catalyst is benzyl tributyl ammonium chloride.
Preferred phase transfer catalyst is crown ether-like, and formula is (- C2H4O-)n, n is 1,2,3,4,5 or 6.
Preferred crown ether-like phase transfer catalysts are 15- crown ethers-5, hexaoxacyclooctadecane-6-6,12- crown ethers-4, dicyclohexyl 18- hats
One kind in ether-6 or dibenzo hexaoxacyclooctadecane-6-6.
Preferred crown ether-like phase transfer catalysts are hexaoxacyclooctadecane-6-6.
Preferred lower alcohol is the one kind in methanol, ethanol or isopropanol.
Preferred phase transfer catalyst is polyethylene glycols, be PEG-400, PEG-600, PEG-1000, PEG-1500,
One kind in PEG-4000 or PEG-6000.
Preferred phase transfer catalyst is 0.005~0.014 with the mol ratio of 2- sulfydryl -1H- benzimidazoles:1.
Lower alcohol is miscible with water in theory, and 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridines, 2- mercaptos
Base -1H- benzimidazoles and sodium hydroxide are suspended in lower alcohol in lower alcohol, and response speed is slower, and require in certain alkali
Property environment carry out, if be in suspension, be unfavorable for contacting with hydroxide ion between reaction raw materials, under causing reaction rate further
Drop, therefore, the response time extends, and by-product increases.With hydroxide ion between addition phase transfer catalyst increase reaction raw materials
Contact area, so as to accelerate response speed.
2- methylol -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridines are reacted with thionyl chloride, synthesizes 2- chloromethanes
Base -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine;2- chloromethyl -3- methyl -4- (the 2,2,2- tri- that step (1) is obtained
Fluorine ethyoxyl) pyridine, put in aqueous solvent with 2- sulfydryl -1H- benzimidazoles, add catalyst and sodium hydroxide, obtain 2-
[[3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine -2- bases] methyl mercapto] -1H- benzimidazoles;The 2- that step (2) is obtained
[[3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine -2- bases] methyl mercapto] -1H- benzimidazoles L- (+)-tartaric acid diethyl
Ester makees chiral adjuvant, and titanium isopropoxide and diisopropylethylamine are catalyst, and cumyl hydroperoxide is oxidant, in low temperature
Lower reaction obtains R-lansoprazole.Synthetic route is as follows:
Using the beneficial effect produced by above-mentioned technical proposal it is:The present invention is a kind of simple, efficient, can ensure to produce
Shorten the response time on the premise of product yield, the R-lansoprazole synthetic method of improve product quality.Right orchid disclosed by the invention
Rope draws the optical purity of the R-lansoprazole of the preparation method preparation of azoles to can reach 100%.
Specific embodiment
Embodiment 1
A kind of preparation method of R-lansoprazole, comprises the following steps:
(1) preparation of 2- chloromethyls -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine
Under room temperature, the dioxy six of 2- methylols -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine (250g, 1.13mol)
Thionyl chloride (0.11L, 1.47mol) is added in ring (2.5L) solution.By mixed liquor in 50 DEG C of stirring reactions 3h, room is cooled to
Temperature.With dchloromethane, successively with saturated sodium bicarbonate solution and aqueous salt solu-tion.Anhydrous magnesium sulfate is dried, and filters, subtracts
Pressure is evaporated off solvent, obtains 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine 245g, yield 90.5%.1H-NMR
(CDCl3, 300MHz) and δ 8.34 (d, J=5.6Hz, 1H), 6.67 (d, J=5.6Hz, 1H), 4.68 (s, 2H), 4.38 (q, J=
7.8Hz, 2H), 2.31 (s, 3H).
(2) 2- [[2- (3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine radicals) methyl]-sulfenyl] -1H- benzimidazoles
Prepare
2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridines (91g, 0.38mol), 2-mercaptobenzimidazole
(57g, 0.38mol), is suspended in methanol (1L), benzyl tributyl ammonium bromide (2.15g, 0.006mol), Deca in 1 hour
30%NaOH solution (65mL), room temperature reaction 2h.300mL water is added in mixture, is stirred 30 minutes.10 DEG C are adjusted with 35%HCl
PH 9, separates out precipitation.Filter, successively with 50% methanol and water washing.It is vacuum dried in 50 DEG C, obtains 2- [[2- (3- methyl -4-
(2,2,2- trifluoro ethoxy) pyridine radicals) methyl]-sulfenyl] -1H- benzimidazole 129g, yield 96%.1H-NMR(CDCl3,
300MHz) δ 8.40 (d, J=5.7Hz, 1H), 7.53 (dd, J=6.0Hz, J=3.2Hz, 2H), 7.18 (dd, J=6.0Hz, J
=3.2Hz, 2H), 6.72 (d, J=5.7Hz, 1H), 4.41 (q, J=7.7Hz, 2H), 4.40 (s, 2H), 2.31 (s, 3H).
(3) (R)-(+) -2- [[3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine -2- bases] methylsulfinyl] -1H-
The preparation of benzimidazole (R-lansoprazole)
Under the protection of example one, nitrogen, 2- [[2- (3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine radicals) methyl]-sulfenyl] -
1H- benzimidazoles (50.0g, 0.142mol), toluene (250mL) and L- (+)-diethyl tartrate. (5.5mL, 0.038mol) are mixed
Close, stir 30 minutes in 50 DEG C~55 DEG C.Under nitrogen protection, tetraisopropoxy titanium (4.15mL, 0.0143mol), mixing are added
Thing is stirred 1 hour in 50 DEG C~55 DEG C.Diisopropylethylamine (8.13mL, 0.048mol), 0 DEG C~10 DEG C drops are added under cooling
Plus 82% dicumyl peroxide (76.5mL, 0.425mol), insulated and stirred 3.5 hours.
Reactant liquor HPLC (CHIRALCEL OD, mobile phase:Normal hexane/ethanol=90/10, flow velocity:1.0mL/min, inspection
Survey wavelength:285nm) testing result:Thioether 1.26%, sulfone compound 1.01%.Other related substanceses are not detected.Enantiomerism health check-up
Survey:98.0%ee.
Under the protection of example two, nitrogen, 2- [[2- (3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine radicals) methyl]-sulfenyl] -
1H- benzimidazoles (4.5kg, 12.7mol), toluene (22L) and L- (+)-diethyl tartrate. (958mL, 5.6mol) mixing.Nitrogen
Under gas shielded, tetraisopropoxy titanium (7.47L, 2.53mol), mixture insulated and stirred 30 minutes are added in 50 DEG C~60 DEG C.
Add diisopropylethylamine (0.733L, 4.44mol) under room temperature, -5 DEG C~5 DEG C 82% dicumyl peroxides of Deca (6.88L,
37.5mol), insulated and stirred 1.5 hours.In above-mentioned reactant liquor, 30% sodium thiosulfate solution, the peroxide of decomposing excessive are added
Change isopropylbenzene.Separate organic faciess, sequentially add water (4.5L), petroleum ether (60~90 DEG C) (13.5L), t-butyl methyl ether
(18L) with petroleum ether (27L), stirring and crystallizing.Filter, with t-butyl methyl ether-toluene (4:1) (4L) washing, obtains right Lan Suola
Azoles.
With HPLC detection crystallization (CHIRALCEL OD, mobile phase:Normal hexane: ethanol=90: 10, flow velocity:1.0mL/min,
Detection wavelength:285nm), testing result:Sulfone compound 0.9%, does not detect sulfide and other related substanceses.Enantiomerism health check-up
Survey:100%ee.
(decompose) mp.147.0~148.0 DEG C;1H-NMR (400MHz, CDCl3):2.24 (3H, s), 4.38 (2H, q, J=
7.8Hz), 4.74 (1H, d, J=13.6Hz), 4.87 (1H, d, J=13.6Hz), 6.68 (1H, d, J=5.8Hz), 7.26~
7.36 (2H, m), 7.45 (1H, m), 7.78 (1H, m), 8.35 (1H, d, J=5.8Hz).
Embodiment 2
(1) the step of synthesizing 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridines is with embodiment 1.
(2) 2- chloromethyls -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine (91g, 0.38mol), 2- sulfydryl benzo miaows
Azoles (57g, 0.38mol), is suspended in methanol (1L), benzyl tributyl ammonium chloride (1.87g, 0.006mol), Deca in 1 hour
30%NaOH solution (65mL), room temperature reaction 2h.300mL water is added in mixture, is stirred 30 minutes.10 DEG C are adjusted with 35%HCl
PH 9, separates out precipitation.Filter, successively with 50% methanol and water washing.It is vacuum dried in 50 DEG C, obtains 2- [[2- (3- methyl -4-
(2,2,2- trifluoro ethoxy) pyridine radicals) methyl]-sulfenyl] -1H- benzimidazole 121.7g, yield 90.6%.
(3) the step of synthesizing target product R-lansoprazole is with embodiment 1.
Embodiment 3
(1) the step of synthesizing 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridines is with embodiment 1.
(2) 2- chloromethyls -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine (91g, 0.38mol), 2- sulfydryl benzo miaows
Azoles (57g, 0.38mol), is suspended in methanol (1L), tetrabutyl ammonium bromide (3.87g, 0.012mol), Deca 30% in 1 hour
NaOH solution (65mL), room temperature reaction 2.5h.300mL water is added in mixture, is stirred 30 minutes.10 DEG C are adjusted pH with 35%HCl
9, separate out precipitation.Filter, successively with 50% methanol and water washing.In 50 DEG C be vacuum dried, obtain 2- [[2- (3- methyl -4- (2,2,
2- trifluoro ethoxies) pyridine radicals) methyl]-sulfenyl] -1H- benzimidazole 115.5g, yield 86%.
(3) the step of synthesizing target product R-lansoprazole is with embodiment 1.
Embodiment 4
(1) the step of synthesizing 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridines is with embodiment 1.
(2) 2- chloromethyls -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine (91g, 0.38mol), 2- sulfydryl benzo miaows
Azoles (57g, 0.38mol), is suspended in methanol (1L), tetrabutylammonium chloride (3.34g, 0.012mol), Deca 30% in 1 hour
NaOH solution (65mL), room temperature reaction 2.5h.300mL water is added in mixture, is stirred 30 minutes.10 DEG C are adjusted pH with 35%HCl
9, separate out precipitation.Filter, successively with 50% methanol and water washing.In 50 DEG C be vacuum dried, obtain 2- [[2- (3- methyl -4- (2,2,
2- trifluoro ethoxies) pyridine radicals) methyl]-sulfenyl] -1H- benzimidazole 114.4g, yield 85.2%.
(3) the step of synthesizing target product R-lansoprazole is with embodiment 1.
Embodiment 5
(1) the step of synthesizing 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridines is with embodiment 1.
(2) 2- chloromethyls -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine (91g, 0.38mol), 2- sulfydryl benzo miaows
Azoles (57g, 0.38mol), is suspended in methanol (1L), hexadecyltrimethylammonium chloride (6.84g, 0.01mol), in 1 hour
Deca 30%NaOH solution (65mL), room temperature reaction 2.5h.300mL water is added in mixture, is stirred 30 minutes.10 DEG C with 35%
HCl adjusts pH 9, separates out precipitation.Filter, successively with 50% methanol and water washing.It is vacuum dried in 50 DEG C, obtains 2- [[2- (3- first
Base -4- (2,2,2- trifluoro ethoxy) pyridine radicals) methyl]-sulfenyl] -1H- benzimidazole 118.2g, yield 88%.
(3) the step of synthesizing target product R-lansoprazole is with embodiment 1.
Embodiment 6
(1) the step of synthesizing 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridines is with embodiment 1.
(2) 2- chloromethyls -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine (31.87g, 0.133mol), 2- sulfydryl benzene
And imidazoles (20g, 0.133mol), it is suspended in methanol (350mL), hexaoxacyclooctadecane-6-6 (0.11g), Deca 30%NaOH in 1 hour
Solution (25mL), room temperature reaction 2h.100mL water is added in mixture, is stirred 30 minutes.10 DEG C are adjusted pH 9 with 35%HCl, are separated out
Precipitation.Filter, successively with 50% methanol and water washing.It is vacuum dried in 50 DEG C, obtains 2- [[2- (3- methyl -4- (2,2,2- trifluoros
Ethyoxyl) pyridine radicals) methyl]-sulfenyl] -1H- benzimidazole 38.5g, yield 82%.
(3) the step of synthesizing target product R-lansoprazole is with embodiment 1.
Each data see the table below.
Different crown ether-like phase transfer catalysts, other reactions steps and each parameter are added with embodiment 5.
Embodiment 11
(1) the step of synthesizing 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridines is with embodiment 1.
(2) 2- chloromethyls -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine (31.87g, 0.133mol), 2- sulfydryl benzene
And imidazoles (20g, 0.133mol), it is suspended in methanol (350mL), PEG-6000 (5.78g), Deca 30%NaOH in 1 hour
Solution (25mL), room temperature reaction 3.5h.100mL water is added in mixture, is stirred 30 minutes.10 DEG C are adjusted pH 9, analysis with 35%HCl
Go out precipitation.Filter, successively with 50% methanol and water washing.It is vacuum dried in 50 DEG C, obtains 2- [[2- (3- methyl -4- (2,2,2- tri-
Fluorine ethyoxyl) pyridine radicals) methyl]-sulfenyl] -1H- benzimidazole 37.36g, yield 79.5%.
(3) the step of synthesizing target product R-lansoprazole is with embodiment 1.
Embodiment 12~15
Each data see the table below.
Different polyethylene glycols phase transfer catalysts, other reactions steps and each parameter are added with embodiment 10.
Claims (10)
1. a kind of preparation method of R-lansoprazole, it is characterised in that comprise the following steps:
(1) 2- methylol -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridines are reacted with thionyl chloride, synthesis 2- chloromethyls -
3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine;
(2) 2- chloromethyl -3- methyl -4- (2,2, the 2- trifluoro ethoxy) pyridines for step (1) being obtained, with 2- sulfydryl -1H- benzene
And in imidazoles input aqueous solvent, add phase transfer catalyst and sodium hydroxide, obtain 2- [[3- methyl -4- (2,2,2- trifluoro second
Epoxide) pyridine -2- bases] methyl mercapto] -1H- benzimidazoles;
(3) 2- [[3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine -2- bases] the methyl mercapto] -1H- benzene for step (2) being obtained
And imidazoles L- (+)-diethyl tartrate. makees chiral adjuvant, titanium isopropoxide and diisopropylethylamine are catalyst, peroxide
It is oxidant to change hydrogen isopropylbenzene, and reaction at low temperature obtains R-lansoprazole.
2. a kind of preparation method of R-lansoprazole according to claim 1, it is characterised in that described phase transfer catalysis
Agent is quaternary ammonium salt, and formula is R4N+X-, R is C1-C16One or more in chain alkylene, alicyclic hydrocarbon radical or aryl, X
For Cl, Br, I or HSO4In one kind.
3. the preparation method of a kind of R-lansoprazole according to claim 2, it is characterised in that the quaternary ammonium salt phase turns
Shifting catalyst is tetrabutyl ammonium bromide, cetyl trimethylammonium bromide, benzyltriethylammoinium chloride or benzyl tributyl chlorination
One kind in ammonium.
4. a kind of preparation method of R-lansoprazole according to claim 3, it is characterised in that described quaternary ammonium salt phase
Transfer catalyst is benzyltriethylammoinium chloride.
5. a kind of preparation method of R-lansoprazole according to claim 1, it is characterised in that described phase transfer catalysis
Agent is crown ether-like, and formula is (- C2H4O-)n, n is 1,2,3,4,5 or 6.
6. the preparation method of a kind of R-lansoprazole according to claim 5, it is characterised in that described crown ether-like phase turns
Shifting catalyst is 15- crown ethers-5, hexaoxacyclooctadecane-6-6,12- crown ethers-4, dicyclohexyl-hexaoxacyclooctadecane-6-6 or dibenzo-18-crown-6 (DB18C6)
In one kind.
7. the preparation method of a kind of R-lansoprazole according to claim 6, it is characterised in that described crown ether-like phase turns
Shifting catalyst is hexaoxacyclooctadecane-6-6.
8. the preparation method of a kind of R-lansoprazole according to claim 1, it is characterised in that the lower alcohol is first
One kind in alcohol, ethanol or isopropanol.
9. a kind of preparation method of R-lansoprazole according to claim 1, it is characterised in that described phase transfer catalysis
Agent is polyethylene glycols, is in PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000 or PEG-6000
Kind.
10. the preparation method of a kind of R-lansoprazole according to claim 1, it is characterised in that phase transfer catalyst with
The mol ratio of 2- sulfydryl -1H- benzimidazoles is 0.005~0.014:1.
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Cited By (4)
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CN106866630A (en) * | 2017-04-01 | 2017-06-20 | 上海华源医药科技发展有限公司 | A kind of preparation method of R-lansoprazole |
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 |
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CN106866630A (en) * | 2017-04-01 | 2017-06-20 | 上海华源医药科技发展有限公司 | A kind of preparation method of R-lansoprazole |
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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 |
CN111320570A (en) * | 2020-03-24 | 2020-06-23 | 迪嘉药业集团有限公司 | Preparation method of lansoprazole key intermediate |
CN111320570B (en) * | 2020-03-24 | 2022-02-08 | 迪嘉药业集团有限公司 | Preparation method of lansoprazole key intermediate |
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