CN103265528A - Esomeprazole magnesium preparation method - Google Patents
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- CN103265528A CN103265528A CN2013101721737A CN201310172173A CN103265528A CN 103265528 A CN103265528 A CN 103265528A CN 2013101721737 A CN2013101721737 A CN 2013101721737A CN 201310172173 A CN201310172173 A CN 201310172173A CN 103265528 A CN103265528 A CN 103265528A
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Abstract
The invention discloses an esomeprazole preparation method and an esomeprazole magnesium preparation method. The esomeprazole preparation method is characterized in that a catalytic oxidation of omeprazole sulfide is carried out under the action of an added oxidant in the presence of bidentate chiral aminoalcohol and titanium alkoxide at room temperature to obtain a chiral proton pump inhibitor esomeprazole in a single enantiomer or enriched enantiomer form. The above preparation methods have the advantages of no need of the addition of an alkaline reagent, easy obtaining and reuse of the bidentate chiral aminoalcohol participating in the above reaction, increase of the utilization rate of the chiral aminoalcohol, substitution of expensive D-(-)-diethyl tartrate, and production cost reduction; and the chemical purity and the reaction overall yield of the prepared esomeprazole magnesium reach 99.7% and 66% respectively.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to a kind of new preparation process of esomeprazole magnesium.
Background technology
Esomeprazole magnesium (Esomeprazole magnesium), by name pair-S-5-methoxyl group-2{[(4-methoxyl group-3 of chemistry, 5-dimethyl-2-pyridyl) methyl] sulfonamido }-1H-benzoglyoxaline magnesium hydrate, be two hydrates among the present invention, molecular formula: (C
17H
18N
3O
3S)
2Mg2H
2O, molecular weight: 749.12, its structural formula is shown in following general formula 1, by omeprazole thioether (shown in the following general formula 2) salify gained behind asymmetric oxidation.
The S-enantiomorph of omeprazole is commonly called esomeprazole, has the pharmacokinetic property of improvement, and has improved result for the treatment of as lower interindividual variation degree (WO94/27988).Esomeprazole magnesium is known gastric proton pump inhibit, and can obtain from AstraZeneca is commercial from calendar year 2001, its commodity are called NEXIUM, can effectively prevent the disorder relevant with hydrochloric acid in gastric juice with treatment and inflammatory gastrointestinal illness (for example, stomach ulcer, duodenal ulcer, reflux esophagitis and gastritis).In addition, also can be used for the treatment of other stomach and intestine disorder, wherein cytoprotection and inhibition gastric secretion are also expected.
The method of synthetic S-omeprazole mainly contains following method in the prior art:
It is starting raw material with the piconol that CN102702172A discloses a kind of, adopt ultrasonic-microwave to coordinate Technology synthesis of nano esomeprazole sodium such as chemical reaction, decompression reaction, jet drying, the series reaction of this invention is to the requirement for experiment condition strictness, requirement to plant and instrument is also high, is not suitable for large-scale industrial production.
CN102633776A has invented a kind of with omeprazole thioether and D-(-)-chiral ligand that diethyl tartrate, titanium tetraisopropylate form, add N, the N-diisopropyl ethyl amine under the oxidation of oxygenant tertiary amyl hydrogen peroxide, obtains esomeprazole.This method is used the comparatively expensive D-(-of price)-diethyl tartrate.
CN102603261A has invented a kind of by raw material (((4-methoxyl group-3; 5-lutidine-2-yl) sulfinyl methyl)) oxygenant of bamic acid ethyl ester through providing for oneself obtains (S)-(((4-methoxyl group-3; 5-lutidine-2-yl) sulfinyl methyl)) the bamic acid ethyl ester again with the target product of the adjacent pentanoic back flow reaction of 4-methoxyl group; the selected raw material of this method is difficult to obtain; step is many, is not suitable for suitability for industrialized production.
A kind of Virahol of invention is made solvent among the CN102329302A, adds alkaline reagents, uses the mute piperazine compounds oxygenant oxidation omeprazole thioether of chirality camphor sulphur to make esomeprazole.The mute piperazine compounds of chirality camphor sulphur is difficult to obtain in this invention, and temperature of reaction requires also relatively stricter.
Invented a kind of at traditional method mineral alkali (salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide) replacement organic bases among the CN102321071A, but other metal ions (sodium or potassium) in reaction, have been introduced, also can generate corresponding esomeprazole salt, the magnesium salts content that obtains is later had certain influence.
Adopt (S among the CN102807560A, S)-6,6 '-dihydroxyl-2,2 '-biphenyl dicarboxylic acid diethyl ester are the chiral ligand inductor, having adopted the compound that contains molybdenum simultaneously is catalyzer, is that oxidizer catalytic oxidation omeprazole thioether obtains esomeprazole with the hyperis.The consumption of the chiral ligand inductor that this method is used is big, be difficult to obtain, and uses the toluene that toxicity is big, boiling point is high.
Invented a kind ofly under tetrahydrofuran solvent among the CN101914090A, with under (S)-binaphthol and the titanium tetraisopropylate reflux conditions, adding tertbutyl peroxide decane solution does not add any organic bases oxidation omeprazole thioether and obtains esomeprazole.Wherein (S)-binaphthol is expensive.
Invented a kind of usefulness (1R among the CN102408412A, 2S)-1-amino-traditional D-(-of 2-indanol replacement)-diethyl tartrate, acetonitrile is made solvent, the product postprocessing 4-methyl-2 pentanone, yield is lower, acetonitrile toxicity is bigger, and 4-methyl-2 pentanone has increased production cost, is not suitable for suitability for industrialized production.
That CN1810803A has invented is a kind of (R, R) or (S, S)-1,2-diaryl-1,2-glycols compound (especially (R, R) or (S, S)-1,2-two (2-bromo-phenyl)-1, the 2-glycol) with metal titanium reagent in the presence of the oxygenant tertbutyl peroxide, selective catalytic oxidation omeprazole thioether, but chemical purity does not reach the pharmacopeia requirement, and the cost height of chirality bidentate ligand, adopt the bigger solvent toluene of toxicity in the reaction.
WO9427988 has mentioned among the WO04/002982 and has adopted the method for chiral selectors that the raceme omeprazole is split, effectively the free alkali of omeprazole split but traditional method for splitting is very difficult, and the too much raw material of this method waste.
WO9617076 mentions among the WO9617077 with biological enzyme and the omeprazole thioether is carried out oxidation or the omeprazole sulfone is reduced, and obtain the single enantiomer of omeprazole, but this method suitability for industrialized production early investment is bigger.
Disclose among the CN101012141A a kind of in the presence of the pure and mild zirconium alkoxide of chiral amino or alkoxy titanium compound catalyzed oxidation omeprazole thioether obtain the method for esomeprazole, wherein chiral amino alcohol is the S-2-aminopropanol, S-2-amino-1-butanols, S-3-amino-1-butanols, S-benzene glycinol, the S-phenylalaninol, S-leucinol, S-glycinol, S-egg ammonia alcohol, the S-tryptosol, S-asparagine alcohol, S-arm ammonia alcohol, S-dried meat ammonia alcohol, the S-valerian ammonia alcohol, S-isoleucine alcohol, S-serinol, S-hydroxyl dried meat ammonia alcohol, S-Soviet Union ammonia alcohol, the smart ammonia alcohol of S-, this method yield is lower.
Invented a kind of employing 1-hydroxyl-1 among the CN101070315A, 2-benzenesulfonyl-3(1 hydrogen)-ketone-1-oxide compound is oxygenant, quaternary ammonium compound is the synthetic omeprazole raceme of catalyzer, the unresolved problem that obtains the single enantiomer esomeprazole.
That mentions among the WO2008/018091 is the synthetic method of traditional esomeprazole, but strict to the requirement of temperature, the solvent of employing still is the bigger toluene of toxicity.
Adopt among the WO2009114981 (+)-or (-)-tartrate diamide ligand exist down with the complex compound catalyst that titanium forms, the use oxygenant directly becomes esomeprazole with omeprazole thioether asymmetric oxidation.But still do not solve the problem of toxic solvents toluene.
Adopt among the WO2010043601 under the existence of the comparatively complicated metal complex of structure and hydrogen peroxide, in solvent acetonitrile, obtain esomeprazole salt, but chemical purity is not high.
Adopt 1 among the derivative of employing S-amygdalic acid and the WO2007074099 among the WO2011120475,1,2-triphenyl-1, the 2-glycol replaces D-(-)-diethyl tartrate, product chemical purity height, but productive rate is very low, and also aftertreatment also requires column chromatography that crude product is purified, complicated operation has also increased production cost simultaneously.
That mentions among the WO2011012957 also is the synthetic method of traditional esomeprazole, but the experiment condition harshness needs the nitrogen protection reaction.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, a kind of easy high chemical purity of preparation of research and design, esomeprazole and the esomeprazole magnesium method of high yield, make that this method is simple, reduce production costs, be applicable to suitability for industrialized production.
Above-mentioned purpose of the present invention is achieved by the following scheme:
According to an aspect of the present invention, a kind of preparation method of esomeprazole is provided, it is characterized in that: in organic solvent, in the presence of bidentate chiral amino alcohol and titan-alkoxide, utilize oxygenant that 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline (being the omeprazole thioether) oxidation is obtained esomeprazole.
Wherein,
Preferably, described organic solvent is that esters solvent (as ethyl acetate), ether solvent are (as diethyl ether, tetrahydrofuran (THF)), halogenated hydrocarbon solvent is (as methylene dichloride, chloroform), in the aromatic solvent (as toluene), ketones solvent (as acetone), nitrile solvents (as acetonitrile) any one, most preferably methylene dichloride.Raw material and other reagent normal-temperature dissolution degree in methylene dichloride is big, does not need heating for dissolving.
Preferably, the bidentate chiral amino alcohol can be for containing the bidentate chiral amino alcohol of phenyl, be more preferably the bidentate chiral amino alcohol that contains two or three phenyl.Usually have 8-30 carbon atom altogether, more preferably have 14-26 carbon atom, and at least one hydroxyl and at least one amino, for example a hydroxyl and an amino.More preferably, described bidentate chiral amino alcohol structure is:
Wherein, R
1Can be in hydrogen, phenyl, benzyl, C1～4 alkyl, 1H-indoles-3-alkyl, C1～4 alkyl any one.
Particularly preferably be, the bidentate chiral amino alcohol can be (2R)-2-amino-1,1,2-triphenyl-ethanol, (2R)-2-amino-1,1,3-triphenyl-1-propyl alcohol, (2R)-2-amino-4-methyl isophthalic acid, 1-phenylbenzene-1-amylalcohol, (2R)-and 2-amino-3-(1H-indol-3-yl)-1,1-phenylbenzene-1-propyl alcohol, (2R)-2-amino-1,1-phenylbenzene-ethanol, or (2R)-2-amino-1,1-phenylbenzene-1, any one in the 4-pentanediol.
Preferably, described bidentate chiral amino alcohol is that D type amino acid and halogeno-benzene (for example bromobenzene) are at the product that obtains after the grignard reaction under organic solvent (for example ether) condition.
The bidentate chiral amino alcohol is introduced phenyl ring through format, and purpose is to utilize the sterically hindered stereoselectivity that improves chiral amino alcohol of phenyl ring.Selected bidentate chiral amino alcohol can also recycle and reuse.And itself has amino chiral amino alcohol, has alkalescence, need not additionally to add alkaloids, reduces the formation of impurity and minimizing by product.
Preferably, the consumption mol ratio of bidentate chiral amino alcohol and omeprazole thioether is 0.02:1.0～1.2:1.0, further preferred 0.05:1.0～1.0:1.0, or 0.1:1.0～0.8:1.0; More preferably 0.3:1.0～0.7:1.0, for example 0.5:1.0.
Preferably, described titan-alkoxide is four (C1-C10) titan-alkoxide, more preferably four (C1-C6) titan-alkoxide, be more preferably the tetramethoxy titanium, purity titanium tetraethoxide, four titanium propanolates, four titanium butoxide, tetraisopropoxy titanium, four isobutoxy titaniums, any one in the four tert.-butoxy titaniums or two or more combinations.The consumption mol ratio of titan-alkoxide and omeprazole thioether is 0.1:1.0～1.5:1.0, more preferably 0.15:1.0～1.2:1.0, preferably 0.2:1.0～0.8:1.0, preferably 0.3:1.0～0.7:1.0; More preferably 0.4:1.0～0.6:1.0 0.5:1.0 for example.
Preferably, the required oxygenant of oxidation is inorganic peroxide type oxygenant or organo-peroxide type oxygenant, be more preferably the hydrogen peroxide form of hydrogen peroxide (for example with), Potassium Persulphate or Sodium Persulfate or C1-C20 organic radical peroxide type oxygenant, further hydrogen peroxide preferably, C1～9 alkyl peroxides (C2～8 alkyl peroxides preferably, more preferably C3～6 alkyl peroxides, as tertbutyl peroxide), among the C1～6 alkyl phenyl superoxide (preferred C3～5 alkyl phenyl superoxide is as hydrogen phosphide cumene) any one or two or more combinations.Hydrogen phosphide cumene especially preferably.The mol ratio of oxygenant and omeprazole thioether is preferably 0.6:1.0～3.5:1.0,0.7:1.0～3.0:1.0 more preferably, 0.75:1.0～2.5:1.0 more preferably, more preferably 0.8:1.0～2.0:1.0, more preferably 0.9:1.0～1.6:1.0, or 1.0:1.0～1.4:1.0, or 1.1:1.0～1.2:1.0.
Preferably, described 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline (being the omeprazole thioether) is by 2-sulfydryl-5-methoxyl group benzo imidazoles and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride is in solvent, and reaction obtains under dropping alkaline solution condition.
Wherein, solvent and above-described organic solvent described here can be identical or different.Solvent described here is organic alcohols solvent (the organic alcohol of C1-C6 for example preferably, as methyl alcohol, ethanol, Virahol), any one or two or more combinations in nitrile solvents (as acetonitrile), esters solvent (as ethyl acetate) etc., particular methanol, the solubleness of raw material in methyl alcohol is big, and boiling point is on the low side.
Described alkaline solution is any one inorganic alkali solution, and mineral alkali can be in sodium hydroxide, potassium hydroxide, sodium bicarbonate, the yellow soda ash any one or a few, preferred aqueous sodium hydroxide solution.
2-sulfydryl-5-methoxyl group benzo imidazoles, 2-chloromethyl-3, the reaction mol ratio of 5-dimethyl-4-methoxypyridine hydrochloride and mineral alkali is preferably (0.7～2.0): (0.7～3.5): (1.4～7), preferably (0.8～1.8): (0.9～3.0): (1.6～5), preferably (1.0～1.6): (1.0～2.5): (1.8～4), preferably (1.0～1.6): (1.1～2.2): (2.0～3.5), preferred 1.0:0.9:1.0～1.0:1.5:3.0, more preferably ratio is 1.0:1.05:2.15.Temperature of reaction is 40～100 ℃, preferred 45～95 ℃, or 50～90 ℃, more preferably 55～85 ℃, or 60～80 ℃, or 65～75 ℃, for example 70 ℃.Reaction times is 3～10h, preferred 4～8h, further preferred 5～7h, for example 6h.
According to another aspect of the present invention, provide the preparation method of esomeprazole magnesium, this method comprises that the esomeprazole that above method is obtained joins in the alcoholic solution that is formed by magnesium alkoxide and reacts in organic alcohol solvent (as the C1-C6 alcoholic solvent).This magnesium alkoxide can be C1-C6 magnesium alkoxide, preferred C1-C4 magnesium alkoxide.Particular methanol magnesium, magnesium ethylate, magnesium propylate, butanols magnesium or amylalcohol magnesium etc., particular methanol magnesium.The consumption mol ratio of magnesium alkoxide and omeprazole thioether is preferably 0.3:1.0～2.5:1.0, preferred 0.4:1.0～2.0:1.0, preferred 0.5:1.0～1.5:1.0, more preferably 0.7:1.0～1.4:1.0, or 0.8:1.0～1.2:1.0.The organic alcohol of solvent is methyl alcohol, ethanol, propyl alcohol, ethylene glycol etc., particular methanol.The one, the solubleness of esomeprazole magnesium in methyl alcohol is big, and the 2nd, there is methyl alcohol to generate behind magnesium methylate and the esomeprazole salify, select the solvent of coupling.Normal-temperature reaction 0.5-8h, preferred 1～4h, preferred 2h.Reaction can be carried out 0.5-8h under conditions such as normal temperature, intensification, 1～4h, preferred 2h.
In a preferred implementation, the preparation method of esomeprazole magnesium comprises the steps:
(1) with 2-sulfydryl-5-methoxyl group benzo imidazoles and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride adds in the solvent, drip alkaline solution, react (for example under agitation reacting under the situation of reflux), obtain omeprazole thioether (5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline) through aftertreatment (for example crystallization, suction filtration, washing etc.).Preferably, solvent described here is organic alcohols solvent (for example the organic alcohol of C1-C6, as methyl alcohol, ethanol, Virahol), nitrile solvents (as acetonitrile), esters solvent (as ethyl acetate).
(2) the omeprazole thioether that obtains in the step (1) is dissolved in acquisition reaction system in the organic solvent (as methylene dichloride).Solvent in this organic solvent and the step (1) can be identical or different.Preferably, this organic solvent is that esters solvent (as ethyl acetate), ether solvent are (as diethyl ether, tetrahydrofuran (THF)), any one in halogenated hydrocarbon solvent (as methylene dichloride, chloroform), aromatic solvent (as toluene), ketones solvent (as acetone), the nitrile solvents (as acetonitrile).
(3) adding the bidentate chiral amino alcohol (as previously discussed) and the titan-alkoxide (as previously discussed) that contain phenyl in the reaction system of step (2) reacts, (for example under 10-50 ℃, preferably under 15-40 ℃, more preferably at room temperature react), for example reacted 70～250 minutes, preferred 90～180 minutes, preferred 100～120 minutes;
(4) dropping oxidizing agent (as mentioned above) in the reaction system of step (3), continue reaction (normal-temperature reaction for example, as under 10-50 ℃, preferably under 15-40 ℃, more preferably at room temperature react), for example react 4～35h, 5～24h, preferred 8～20h, or 10～18h, further preferred 12～16h;
(5) after step (4) reaction finishes, drip reductive agent (for example aqueous solution of sulphite such as S-WAT or potassium sulfite) cancellation reaction; Preferably the consumption mol ratio of sulphite and omeprazole thioether is 0.6:1.0～1.8:1.0, preferred 0.8:1.0～1.6:1.0;
(6) solution that obtains in the step (5) is carried out separatory, wherein organic phase extracts with ammoniacal liquor, and gained ammoniacal liquor is used organic solvent extraction mutually again, obtains the extract organic phase;
(7) solvent in the extract organic phase that obtains in the step (6) is removed, in the gained residue, add the alcoholic solution (as previously discussed) that in organic alcohol, is formed by magnesium alkoxide, react (as the normal temperature reaction), for example react 0.5～7h, preferred 1～4h, preferred 2～3h;
(8) after step (7) reaction finished, with reacting liquid filtering, filtrate was removed (for example rotary evaporation removes) alcoholic solvent, gets the esomeprazole magnesium crude product;
(9) with the esomeprazole magnesium crude product organic solvent recrystallization that obtains in the step (8), purifying obtains esomeprazole magnesium.
Preferably, the condition of each step as previously discussed.In addition, the consumption of the various raw materials in the aforesaid method or relative consumption are as previously discussed.
Preferably, the consumption mol ratio of bidentate chiral amino alcohol and omeprazole thioether is 0.02:1.0～1.2:1.0, further preferred 0.05:1.0～1.0:1.0, or 0.1:1.0～0.8:1.0; More preferably 0.3:1.0～0.7:1.0, for example 0.5:1.0.
Preferably, the consumption mol ratio of titan-alkoxide and omeprazole thioether is 0.1:1.0～1.5:1.0, more preferably 0.15:1.0～1.2:1.0, preferably 0.2:1.0～0.8:1.0, preferably 0.3:1.0～0.7:1.0; More preferably 0.4:1.0～0.6:1.0 0.5:1.0 for example.
Preferably, the mol ratio of oxygenant and omeprazole thioether is preferably 0.6:1.0～3.5:1.0,0.7:1.0～3.0:1.0 more preferably, 0.75:1.0～2.5:1.0 more preferably, more preferably 0.8:1.0～2.0:1.0, more preferably 0.9:1.0～1.6:1.0, or 1.0:1.0～1.4:1.0, or 1.1:1.0～1.2:1.0.
Preferably, 2-sulfydryl-5-methoxyl group benzo imidazoles, 2-chloromethyl-3, the reaction mol ratio of 5-dimethyl-4-methoxypyridine hydrochloride and mineral alkali is preferably (0.7～2.0): (0.7～3.5): (1.4～7), preferably (0.8～1.8): (0.9～3.0): (1.6～5), preferably (1.0～1.6): (1.0～2.5): (1.8～4), preferably (1.0～1.6): (1.1～2.2): (2.0～3.5), preferred 1.0:0.9:1.0～1.0:1.5:3.0, more preferably ratio is 1.0:1.05:2.15.
Preferably, the consumption mol ratio of magnesium alkoxide and omeprazole thioether is preferably 0.3:1.0～2.5:1.0, preferred 0.4:1.0～2.0:1.0, preferred 0.5:1.0～1.5:1.0, more preferably 0.7:1.0～1.4:1.0, or 0.8:1.0～1.2:1.0.
Further preferred embodiment is following embodiment:
In step (1), the solvent that reaction is adopted be in methyl alcohol, ethanol, ethyl acetate, Virahol, the acetonitrile etc. any one or two or more, particular methanol, the solubleness of raw material in methyl alcohol is big, and boiling point is on the low side; Alkali is any one or the two or more combinations in sodium hydroxide, potassium hydroxide, sodium bicarbonate, the yellow soda ash etc., preferred sodium hydroxide, raw material easily obtain and price suitable.2-sulfydryl-5-methoxyl group benzo imidazoles, 2-chloromethyl-3, the reaction mol ratio of 5-dimethyl-4-methoxypyridine hydrochloride and sodium hydroxide is 1.0:0.9:1.0～1.0:1.5:3.0, preferred proportion 1.0:1.05:2.15; Temperature is 40～100 ℃, preferred 85 ℃; Reaction times is 3～10h, preferred 5h.
The solvent that adopts in step (2) is one or more in ethyl acetate, methylene dichloride, toluene, acetone, chloroform, tetrahydrofuran (THF), the acetonitrile etc., preferred methylene dichloride, because raw material and other reagent normal-temperature dissolution degree in methylene dichloride is big, do not need heating for dissolving.
The bidentate chiral amino alcohol that adopts in step (3) is D type amino acid and bromobenzene at the product that obtains under the ether condition after the grignard reaction, its structure is:
Wherein, R
1Can be in hydrogen, phenyl, benzyl, C1～4 alkyl, 1H-indoles-3-methyl, C1～4 alkyl alcohols any one.The bidentate chiral amino alcohol can be (2R)-2-amino-1,1,2-triphenyl-ethanol, (2R)-and 2-amino-1,1,3-triphenyl-1-propyl alcohol, (2R)-and 2-amino-4-methyl isophthalic acid, 1-phenylbenzene-1-amylalcohol, (2R)-2-amino-3-(1H-indol-3-yl)-1,1-phenylbenzene-1-propyl alcohol, (2R)-and 2-amino-1,1-phenylbenzene-ethanol, (2R)-2-amino-1,1-phenylbenzene-1, one or more in the 4-pentanediol etc.The mol ratio of bidentate chiral amino alcohol and omeprazole thioether is 0.02:1.0～0.8:1.0, preferred 0.5:1.0.The bidentate chiral amino alcohol is introduced phenyl ring through format, and purpose is to utilize the sterically hindered stereoselectivity that improves chiral amino alcohol of phenyl ring.Selected bidentate chiral amino alcohol can also recycle and reuse.And itself has amino chiral amino alcohol, has alkalescence, need not additionally to add alkaloids.The titan-alkoxide that adopts is the tetramethoxy titanium, purity titanium tetraethoxide, four titanium propanolates, four titanium butoxide, tetraisopropoxy titanium, four isobutoxy titaniums, one or more in the four tert.-butoxy titaniums.The mol ratio of titan-alkoxide and omeprazole thioether is 0.2:1.0～0.8:1.0, preferred 0.5:1.0.
The oxygenant that adopts in step (4) is hydrogen peroxide, the alkyl phenyl superoxide of the alkyl peroxide of C1～4 or C1～4, preferred hydrogen phosphide cumene.The mol ratio of oxygenant and omeprazole thioether is 1.0:1.0～1.5:1.0, preferred 1.0:1.0.Normal-temperature reaction 5～24h, preferred 12h.
The sulphite that adopts in step (5) is S-WAT; Preferably, the consumption mol ratio of sulphite and omeprazole thioether is 0.6:1.0～1.8:1.0, preferred 0.8:1.0～1.6:1.0; Preferred 1.0:1.0～1.5:1.0, preferred 1.1:1.0～1.4:1.0, or 1.2:1.0～1.3:1.0.
The organic solvent that adopts in step (6) is ethyl acetate, toluene, one or more in the ether etc., ethyl acetate.The one, effect of extracting is good, avoids using expensive extraction agent; The 2nd, boiling point is lower, easily reclaims.The magnesium alkoxide that adopts in step (7) can be magnesium methylate, magnesium ethylate, particular methanol magnesium.The consumption mol ratio of magnesium alkoxide and omeprazole thioether is preferably 0.5:1.0～1.5:1.0, more preferably 0.7:1.0～1.4:1.0, or 0.8:1.0～1.2:1.0.Solvent alcohol is methyl alcohol, ethanol etc., and particular methanol, the one, the solubleness of esomeprazole magnesium in methyl alcohol is big, and the 2nd, there is methyl alcohol to generate behind magnesium methylate and the esomeprazole salify, select the solvent of coupling.Normal-temperature reaction 1～4h, preferred 2h.
After reaction finishes in step (8), adopt membrane filtration, be spin-dried for alcoholic solvent, get light yellow solid esomeprazole magnesium crude product;
Can be earlier with dissolving crude product in step (9), the solvent of dissolving crude product can select in methyl alcohol, ethanol, acetone, the acetonitrile etc. any one or two or more, particular methanol.Crude product is 1:1～1:10(quality/g with the dissolution solvent ratio: volume/ml), preferred 1:3～1:8, or 1:4～1:6.
Described recrystallization solvent can be selected ethyl acetate, N, and dinethylformamide, N,N-dimethylacetamide, any one or a few in the acetone, ethyl acetate, the solubleness of product in ethyl acetate is little, and can remove other impurity.Dissolution solvent and recrystallisation solvent volume ratio are 1:5～1:20, preferred 1:8～1:15, or 1:10～1:12.Tc is 20～35 ℃, preferred 22～32 ℃, or 25～28 ℃.Crystallization time is 1～2h, preferred 2h.Suction filtration behind the recrystallization, 50 ℃ of vacuum-dryings of solid.Also can repeat for example to repeat 1,2 or 3 time in above ratio recrystallization purifying, the purity of the esomeprazole magnesium of gained purifying can reach 95～99.9wt%, preferred 97～99.9wt%, even 99.95%.
Described esomeprazole magnesium preparation method's synthetic route is:
As a preferred embodiment of the present invention, the synthetic method of esomeprazole magnesium is:
2-sulfydryl-5-methoxyl group benzo imidazoles adds dissolve with methanol, the dropping sodium aqueous solution, drip to clear liquor, stop dropping sodium, add 2-chloromethyl-3 in batches, 5-dimethyl-4-methoxypyridine hydrochloride, and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution dichloromethane extraction three times, and the reclaim under reduced pressure methylene dichloride adds an amount of ethyl acetate backflow, cooling, stirring at room crystallization.Suction filtration, the ethyl acetate washing gets omeprazole thioether white solid.
Get reaction flask, add the omeprazole thioether, with the methylene dichloride dissolving, add bidentate chiral amino alcohol and titan-alkoxide, continue reaction 2h under this temperature, dropping oxidizing agent is dripped and is finished, thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, and the aqueous solution cancellation that drips S-WAT is reacted.Separatory, methylene dichloride extracts three times with ammoniacal liquor, and the aqueous solution is used ethyl acetate extraction three times again, the combined ethyl acetate phase, the reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter, i.e. esomeprazole.Add magnesium methylate, make solvent with methyl alcohol, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved methyl alcohol through decompression, gets light yellow solid (esomeprazole magnesium crude product).
Above-mentioned Omeprazole magnesium dissolving crude product in amount of methanol, is dripped a certain amount of ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get white or canescence esomeprazole magnesium pressed powder.
Preparation method of the present invention has the following advantages:
1, the bidentate chiral amino alcohol of preparation method's employing of the present invention replaces D-(-)-diethyl tartrate of traditional method, the bidentate chiral amino alcohol that uses is D type amino acid and bromobenzene at the product that obtains under the ether condition after grignard reacts, be simple and easy to.Secondly, selected bidentate chiral amino alcohol can also recycle and reuse, and chiral amino alcohol itself has amino, has alkalescence, need not additionally to add alkaloids, greatly reduces production cost.
2, the product chemical purity that utilizes the method for the invention to make reaches 99.7%, and the three-step reaction overall yield of reaction is suitable for suitability for industrialized production up to 66%.
Wherein step (1) adopts 2-sulfydryl-5-methoxyl group benzo imidazoles and 2-chloromethyl-3, and 5-dimethyl-4-methoxypyridine hydrochloride drips alkaline solution in alcoholic solvent, reflux, and obtains the omeprazole thioether through aftertreatment, and purity is up to 99.8%, and yield is up to 96%.
3, in the described method for preparing esomeprazole magnesium, gained organic phase esomeprazole does not need to do drying treatment, directly adds the esomeprazole magnesium that the magnesium methylate reaction obtains highly selective, and the ee value reaches 99.7%, and overall yield of reaction is up to 66%.
4, preparation method of the present invention all adopts normal-temperature reaction, do not need at low temperatures or nitrogen protection under react, reduced the requirement to plant and instrument; And the reaction conditions gentleness, reaction is polluted little than being easier to control.
5, reaction conditions gentleness, reaction is polluted little than being easier to control; Bidentate chiral amino alcohol of the present invention can also recycle and reuse (methylene dichloride after methylene dichloride has extracted with ammoniacal liquor is direct reclaim under reduced pressure methylene dichloride mutually, and residue is the bidentate chiral amino alcohol), has reduced production cost; With the bidentate chiral amino alcohol selectivity height that lower cost synthesized, the ee value of end product even reach 99.9%.
Description of drawings
Fig. 1 is the IR spectrogram of the intermediate omeprazole thioether of embodiment 1.
Fig. 2 is the HPLC figure of the end product esomeprazole magnesium of embodiment 1.
Fig. 3 is the IR spectrogram of the end product esomeprazole magnesium of embodiment 1.
Fig. 4 is the end product esomeprazole magnesium of embodiment 1
1The H-NMR spectrogram.
Embodiment
In order further to understand the present invention, the present invention will be further described below in conjunction with specific embodiment.Specify as nothing, various raw materials of the present invention all can obtain by commercially available; Or prepare according to the ordinary method of this area.The raw materials used technical grade that is of the method for the invention, equipment used is the experiment common equipment.Unless otherwise defined or explanation, same meanings of being familiar with of all specialties used herein and scientific words and those skilled in the art.Any method similar or impartial to described content and priming paint all can be applicable in the inventive method in addition.But should be appreciated that these describe just to further specifying the features and advantages of the present invention, rather than to the restriction of claim of the present invention.
The 2-sulfydryl of 1kg-5-methoxyl group benzo imidazoles (5.56mol) adds the 12L dissolve with methanol, drip 478g sodium hydroxide (12mol) aqueous solution, drip to clear liquor, stop dropping sodium, add the 2-chloromethyl-3 of 1.08kg in batches, 5-dimethyl-4-methoxypyridine hydrochloride (5.84mol), and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution 3L dichloromethane extraction three times, and the reclaim under reduced pressure methylene dichloride carries out reflux, cooling, stirring at room crystallization after the interpolation 1.1L ethyl acetate in resistates.Suction filtration, ethyl acetate washing gets 1.76kg omeprazole thioether white solid, yield 96%, purity 99.8%, m.p.121～122 ℃.IR (KBr), v/cm
-1: 3120,2995,2958,2900,1634,1593,1480,1466,1264,1154,1078,1026,805(sees accompanying drawing 1).
Get reaction flask, add 100g omeprazole thioether (0.304mol) under the normal temperature, with the dissolving of 500ml methylene dichloride, add (2R)-2-amino-1 of 43.9g, 1,2-triphenyl-ethanol (0.152mol) and 43.2g tetraisopropoxy titanium (0.152mol) continue reaction 2h, dropping oxidizing agent 46.9g hydrogen phosphide cumene (0.304mol) under this temperature, drip and finish, thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, and the 100ml aqueous solution cancellation that drips 38.1g S-WAT (0.304mol) is reacted.Separatory, methylene dichloride with 1L ammoniacal liquor extraction three times, merge the ammoniacal liquor phase mutually, and the ammoniacal liquor that merges is used the 1L ethyl acetate extraction three times mutually again, and extract reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter.
In gained yellowish brown oily matter, add 13.2g magnesium methylate (0.152mol), add the 200ml methanol solvate, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved (the decompression rotary evaporation is removed) methyl alcohol through decompression, gets 92.7g light yellow solid (esomeprazole magnesium crude product), two-step reaction total recovery 85.5%.
Above-mentioned Omeprazole magnesium crude product 100g is dissolved in the 100ml methyl alcohol, drips the 1000ml ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get 80g canescence esomeprazole magnesium pressed powder, and the ee value is 99.7%, recrystallization yield 80%, overall yield of reaction 66%; The ee value is 99.9% (acetonitrile-sodium dihydrogen phosphate moving phase is seen accompanying drawing 2 for HPLC detection, chirality AGP post).IR (KBr), v/cm
-1: 3185,2993,2951,1613,1570,1477,1410,1200,1154,1003,834,806,632(sees accompanying drawing 3).
1H-NMR (400MHz, CDCl
3), δ: 2.13[s, 3H], 2.25[s, 3H], 3.69[s, 3H] and, 3.82[s, 3H], 4.62[d, 2H] and, 6.83[d, 1H], 7.09[s, 1H] and, 7.45[d, 1H], 8.17[s, 1H] (seeing accompanying drawing 4).
Embodiment 2
The 2-sulfydryl of 1kg-5-methoxyl group benzo imidazoles (5.56mol) adds the 12L dissolve with methanol, drip 478g sodium hydroxide (12mol) aqueous solution, drip to clear liquor, stop dropping sodium, add the 2-chloromethyl-3 of 1.08kg in batches, 5-dimethyl-4-methoxypyridine hydrochloride (5.84mol), and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution 3L dichloromethane extraction three times, the reclaim under reduced pressure methylene dichloride carries out reflux after the interpolation 1.1L ethyl acetate in the gained resistates, cooling, the stirring at room crystallization.Suction filtration, ethyl acetate washing gets 1.74kg omeprazole thioether white solid, yield 95%, purity 99.5%, m.p.121～122 ℃.
Get reaction flask, add 100g omeprazole thioether (0.304mol) under the normal temperature, with the dissolving of 500ml methylene dichloride, add (2R)-2-amino-1 of 87.8g, 1,2-triphenyl-ethanol (0.304mol) and 43.2g tetraisopropoxy titanium (0.152mol) continue reaction 2h, dropping oxidizing agent 46.9g hydrogen phosphide cumene (0.304mol) under this temperature, drip and finish, thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, and the 100ml aqueous solution cancellation that drips 38.1g S-WAT (0.304mol) is reacted.Separatory, methylene dichloride with 1L ammoniacal liquor extraction three times, merge the ammoniacal liquor phase mutually, and the ammoniacal liquor that merges is used the 1L ethyl acetate extraction three times mutually again, and the reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter.In yellowish brown oily matter, add 13.2g magnesium methylate (0.152mol), add the 200ml methanol solvate, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved methyl alcohol through decompression, gets 65.8g light yellow solid (esomeprazole magnesium crude product), two-step reaction total recovery 60%.
Above-mentioned Omeprazole magnesium crude product 100g is dissolved in the 100ml methyl alcohol, drips the 1000ml ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get 82g canescence esomeprazole magnesium pressed powder, and the ee value is 99.6%, recrystallization yield 82%, overall yield of reaction 51.4%.
The 2-sulfydryl of 1kg-5-methoxyl group benzo imidazoles (5.56mol) adds the 12L dissolve with methanol, drip 478g sodium hydroxide (12mol) aqueous solution, drip to clear liquor, stop dropping sodium, add the 2-chloromethyl-3 of 1.08kg in batches, 5-dimethyl-4-methoxypyridine hydrochloride (5.84mol), and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution 3L dichloromethane extraction three times, and the reclaim under reduced pressure methylene dichloride carries out reflux, cooling, stirring at room crystallization after the interpolation 1.1L ethyl acetate in resistates.Suction filtration, ethyl acetate washing gets 1.78kg omeprazole thioether white solid, yield 97%, purity 99.5%, m.p.121～122 ℃.
Get reaction flask, add 100g omeprazole thioether (0.304mol) under the normal temperature, with the dissolving of 500ml methylene dichloride, add (2R)-2-amino-1 of 22.0g, 1,2-triphenyl-ethanol (0.076mol) and 43.2g tetraisopropoxy titanium (0.152mol) continue reaction 2h, dropping oxidizing agent 46.9g hydrogen phosphide cumene (0.304mol) under this temperature, drip and finish, thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, and the 100ml aqueous solution cancellation that drips 38.1g S-WAT (0.304mol) is reacted.Separatory, methylene dichloride with 1L ammoniacal liquor extraction three times, merge the ammoniacal liquor phase mutually, and the ammoniacal liquor that merges is used the 1L ethyl acetate extraction three times mutually again, and extract reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter.
In the yellowish brown oily matter of gained, add 13.2g magnesium methylate (0.152mol), add the 200ml methanol solvate, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved methyl alcohol through decompression, gets 35.8g light yellow solid (esomeprazole magnesium crude product), two-step reaction total recovery 33%.
Above-mentioned Omeprazole magnesium crude product 100g is dissolved in the 100ml methyl alcohol, drips the 1000ml ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get 85g canescence esomeprazole magnesium pressed powder, and the ee value is 99.3%, recrystallization yield 85%, overall yield of reaction 27.2%.
Embodiment 4
The 2-sulfydryl of 1kg-5-methoxyl group benzo imidazoles (5.56mol) adds the 12L dissolve with methanol, drip 478g sodium hydroxide (12mol) aqueous solution, drip to clear liquor, stop dropping sodium, add the 2-chloromethyl-3 of 1.08kg in batches, 5-dimethyl-4-methoxypyridine hydrochloride (5.84mol), and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution 3L dichloromethane extraction three times, and the reclaim under reduced pressure methylene dichloride carries out reflux, cooling, stirring at room crystallization after the interpolation 1.1L ethyl acetate in resistates.Suction filtration, ethyl acetate washing gets 1.69kg omeprazole thioether white solid, yield 92%, purity 99.8%, m.p.121～122 ℃.
Get reaction flask, add 100g omeprazole thioether (0.304mol) under the normal temperature, dissolve with the 500ml methylene dichloride, (the 2R)-2-amino-1 that adds 46.1g, 1,3-triphenyl-1-propyl alcohol (0.152mol) and 43.2g tetraisopropoxy titanium (0.152mol), under this temperature, continue reaction 2h, dropping oxidizing agent 46.9g hydrogen phosphide cumene (0.304mol), drip and finish, thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, and the 100ml aqueous solution cancellation that drips 38.1g S-WAT (0.304mol) is reacted.Separatory, methylene dichloride with 1L ammoniacal liquor extraction three times, merge the ammoniacal liquor phase mutually, and the ammoniacal liquor that merges is used the 1L ethyl acetate extraction three times mutually again, and extract reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter.In the yellowish brown oily matter of gained, add 13.2g magnesium methylate (0.152mol), add the 200ml methanol solvate, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved methyl alcohol through decompression, gets 89.0g light yellow solid (esomeprazole magnesium crude product), two-step reaction total recovery 82.1%.
Above-mentioned Omeprazole magnesium crude product 100g is dissolved in the 100ml methyl alcohol, drips the 1000ml ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get 83g canescence esomeprazole magnesium pressed powder, and the ee value is 97%, recrystallization yield 83%, overall yield of reaction 62.6%.
Embodiment 5
The 2-sulfydryl of 1kg-5-methoxyl group benzo imidazoles (5.56mol) adds the 12L dissolve with methanol, drip 478g sodium hydroxide (12mol) aqueous solution, drip to clear liquor, stop dropping sodium, add the 2-chloromethyl-3 of 1.08kg in batches, 5-dimethyl-4-methoxypyridine hydrochloride (5.84mol), and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution 3L dichloromethane extraction three times, and the reclaim under reduced pressure methylene dichloride adds 1.1L ethyl acetate post-heating and refluxes cooling, stirring at room crystallization in resistates.Suction filtration, ethyl acetate washing gets 1.72kg omeprazole thioether white solid, yield 94%, purity 99.6%, m.p.121～122 ℃.
Get reaction flask, add 100g omeprazole thioether (0.304mol) under the normal temperature, dissolve with the 500ml methylene dichloride, (the 2R)-2-amino-4-methyl isophthalic acid that adds 40.9g, 1-phenylbenzene-1-amylalcohol (0.152mol) and 43.2g tetraisopropoxy titanium (0.152mol), under this temperature, continue reaction 2h, dropping oxidizing agent 46.9g hydrogen phosphide cumene (0.304mol), drip and finish, thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, the 100ml aqueous solution cancellation that drips 38.1g S-WAT (0.304mol) is reacted.Separatory, methylene dichloride with 1L ammoniacal liquor extraction three times, merge the ammoniacal liquor phase mutually, and the ammoniacal liquor that merges is used the 1L ethyl acetate extraction three times mutually again, and extract reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter.In yellowish brown oily matter, add 13.2g magnesium methylate (0.152mol), add the 200ml methanol solvate, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved methyl alcohol through decompression, gets 85.6g light yellow solid (esomeprazole magnesium crude product), two-step reaction total recovery 79%.
Above-mentioned Omeprazole magnesium crude product 100g is dissolved in the 100ml methyl alcohol, drips the 1000ml ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get 81g canescence esomeprazole magnesium pressed powder, and the ee value is 91%, recrystallization yield 81%, overall yield of reaction 60%.
Embodiment 6
The 2-sulfydryl of 1kg-5-methoxyl group benzo imidazoles (5.56mol) adds the 12L dissolve with methanol, drip 478g sodium hydroxide (12mol) aqueous solution, drip to clear liquor, stop dropping sodium, add the 2-chloromethyl-3 of 1.08kg in batches, 5-dimethyl-4-methoxypyridine hydrochloride (5.84mol), and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution 3L dichloromethane extraction three times, and the reclaim under reduced pressure methylene dichloride carries out reflux, cooling, stirring at room crystallization after the interpolation 1.1L ethyl acetate in resistates.Suction filtration, ethyl acetate washing gets 1.76kg omeprazole thioether white solid, yield 96%, purity 99.5%, m.p.121～122 ℃.
Get reaction flask, add 100g omeprazole thioether (0.304mol) under the normal temperature, dissolve with the 500m methylene dichloride, (the 2R)-2-amino-3-(1H-indol-3-yl)-1 that adds 52.0g, 1-phenylbenzene-1-propyl alcohol (0.152mol) and 43.2g tetraisopropoxy titanium (0.152mol), under this temperature, continue reaction 2h, dropping oxidizing agent 46.9g hydrogen phosphide cumene (0.304mol), drip and finish, thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, the 100ml aqueous solution cancellation that drips 38.1g S-WAT (0.304mol) is reacted.Separatory, methylene dichloride with 1L ammoniacal liquor extraction three times, merge the ammoniacal liquor phase mutually, and the ammoniacal liquor that merges is used the 1L ethyl acetate extraction three times mutually again, and extract reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter.In the yellowish brown oily matter of gained, add 13.2g magnesium methylate (0.152mol), add the 200ml methanol solvate, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved methyl alcohol through decompression, gets 81.8g light yellow solid (esomeprazole magnesium crude product), two-step reaction total recovery 75.4%.
Above-mentioned Omeprazole magnesium crude product 100g is dissolved in the 100ml methyl alcohol, drips the 1000ml ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get 84.5g canescence esomeprazole magnesium pressed powder, and the ee value is 94%, recrystallization yield 84.5%, overall yield of reaction 61.2%.
Embodiment 7
The 2-sulfydryl of 1kg-5-methoxyl group benzo imidazoles (5.56mol) adds the 12L dissolve with methanol, drip 478g sodium hydroxide (12mol) aqueous solution, drip to clear liquor, stop dropping sodium, add the 2-chloromethyl-3 of 1.08kg in batches, 5-dimethyl-4-methoxypyridine hydrochloride (5.84mol), and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution 3L dichloromethane extraction three times, and the reclaim under reduced pressure methylene dichloride carries out reflux, cooling, stirring at room crystallization after the interpolation 1.1L ethyl acetate in resistates.Suction filtration, ethyl acetate washing gets 1.69kg omeprazole thioether white solid, yield 93%, purity 99.8%, m.p.121～122 ℃.
Get reaction flask, add 100g omeprazole thioether (0.304mol) under the normal temperature, with the dissolving of 500ml methylene dichloride, add (2R)-2-amino-1 of 32.4g, 1-phenylbenzene-ethanol (0.152mol) and 43.2g tetraisopropoxy titanium (0.152mol), under this temperature, continue reaction 2h, dropping oxidizing agent 46.9g hydrogen phosphide cumene (0.304mol) drips and finishes, and thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, the 100ml aqueous solution cancellation that drips 38.1g S-WAT (0.304mol) is reacted.Separatory, methylene dichloride with 1L ammoniacal liquor extraction three times, merge the ammoniacal liquor phase mutually, and water is used the 1L ethyl acetate extraction three times again, and extract reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter.In gained yellowish brown oily matter, add 13.2g magnesium methylate (0.152mol), add the 200ml methanol solvate, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved methyl alcohol through decompression, gets 85.6g light yellow solid (esomeprazole magnesium crude product), two-step reaction total recovery 79.0%.
Above-mentioned Omeprazole magnesium crude product 100g is dissolved in the 100ml methyl alcohol, drips the 1000ml ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get 80.1g canescence esomeprazole magnesium pressed powder, and the ee value is 82%, recrystallization yield 80.1%, overall yield of reaction 58.9%.
The 2-sulfydryl of 1kg-5-methoxyl group benzo imidazoles (5.56mol) adds the 12L dissolve with methanol, drip 478g sodium hydroxide (12mol) aqueous solution, drip to clear liquor, stop dropping sodium, add the 2-chloromethyl-3 of 1.08kg in batches, 5-dimethyl-4-methoxypyridine hydrochloride (5.84mol), and then continuation drips the residual hydrogen sodium oxide, drip off, be warming up to 85 ℃, stirring and refluxing 5h.After reaction finished, reclaim under reduced pressure methyl alcohol, remaining aqueous solution used acetic acid acid adjustment degree to pH=8, aqueous solution 3L dichloromethane extraction three times, and the reclaim under reduced pressure methylene dichloride carries out reflux, cooling, stirring at room crystallization after the interpolation 1.1L ethyl acetate in resistates.Suction filtration, ethyl acetate washing gets 1.71kg omeprazole thioether white solid, yield 93.3%, purity 99.6%, m.p.121～122 ℃.
Get reaction flask, add 100g omeprazole thioether (0.304mol) under the normal temperature, dissolve with the 500ml methylene dichloride, (the 2R)-2-amino-1 that adds 39.1g, 1-phenylbenzene-1,4-pentanediol (0.152mol) and 43.2g tetraisopropoxy titanium (0.152mol), under this temperature, continue reaction 2h, dropping oxidizing agent 46.9g hydrogen phosphide cumene (0.304mol), drip and finish, thin-layer chromatography is followed the tracks of reaction, stirring at normal temperature reaction 12h, and the 100ml aqueous solution cancellation that drips 38.1g S-WAT (0.304mol) is reacted.Separatory, methylene dichloride with 1L ammoniacal liquor extraction three times, merge the ammoniacal liquor phase mutually, and the ammoniacal liquor that merges is used the 1L ethyl acetate extraction three times mutually again, and extract reclaim under reduced pressure ethyl acetate obtains yellowish brown oily matter.In the yellowish brown oily matter of gained, add 13.2g magnesium methylate (0.152mol), add the 200ml methanol solvate, stirring at normal temperature reaction 2h.Reaction solution is through membrane filtration, and filtrate is revolved methyl alcohol through decompression, gets 90.5g light yellow solid (esomeprazole magnesium crude product), two-step reaction total recovery 83.5%.
Above-mentioned Omeprazole magnesium crude product 100g is dissolved in the 100ml methyl alcohol, drips the 1000ml ethyl acetate under the stirring at normal temperature, drip and finish stirring at normal temperature 2h.Suction filtration, the ethyl acetate washing, 50 ℃ of vacuum-dryings of solid get 83.2g canescence esomeprazole magnesium pressed powder, and the ee value is 98.9%, recrystallization yield 83.2%, overall yield of reaction 64.8%.
Claims (12)
1. the preparation method of an esomeprazole, it is characterized in that: in organic solvent, in the presence of the bidentate chiral amino alcohol that contains phenyl and titan-alkoxide, adopt oxygenant with 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline oxidation obtains esomeprazole.
2. preparation method according to claim 1, it is characterized in that: the structure of described bidentate chiral amino alcohol is:
Wherein, R
1Can be in hydrogen, phenyl, benzyl, C1～4 alkyl, 1H-indoles-3-alkyl, C1～4 alkyl any one;
Preferably, described bidentate chiral amino alcohol is (2R)-2-amino-1,1,2-triphenyl-ethanol, (2R)-2-amino-1,1,3-triphenyl-1-propyl alcohol, (2R)-2-amino-4-methyl isophthalic acid, 1-phenylbenzene-1-amylalcohol, (2R)-and 2-amino-3-(1H-indol-3-yl)-1,1-phenylbenzene-1-propyl alcohol, (2R)-2-amino-1,1-phenylbenzene-ethanol, or (2R)-2-amino-1,1-phenylbenzene-1, any one in the 4-pentanediol;
Preferably, the consumption mol ratio of bidentate chiral amino alcohol and 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline is 0.02:1.0～1.2:1.0, further preferred 0.05:1.0～1.0:1.0.
3. preparation method according to claim 1 and 2, it is characterized in that: described titan-alkoxide is four (C1-C10) titan-alkoxide, be more preferably the tetramethoxy titanium, purity titanium tetraethoxide, four titanium propanolates, four titanium butoxide, tetraisopropoxy titanium, four isobutoxy titaniums, any one in the four tert.-butoxy titaniums;
Preferably, the consumption mol ratio of titan-alkoxide and 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline is 0.1:1.0～1.5:1.0, more preferably 0.15:1.0～1.2:1.0.
4. according to any described preparation method of claim 1-3, it is characterized in that: described organic solvent be in esters solvent, ether solvent, halogenated hydrocarbon solvent, aromatic solvent, ketones solvent, the nitrile solvents any one or two or more, preferred methylene dichloride.
5. according to any described preparation method of claim 1-4, it is characterized in that: the required oxygenant of described oxidation is inorganic peroxide type oxygenant or organo-peroxide type oxygenant, is more preferably hydrogen peroxide, Potassium Persulphate or Sodium Persulfate or C1-C20 organic radical peroxide type oxygenant; Further preferred hydrogen phosphide cumene;
Preferably the consumption mol ratio of described oxygenant and 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline is 0.6:1.0～3.5:1.0, more preferably 0.7:1.0～3.0:1.0.
6. according to any described preparation method of claim 1-5, it is characterized in that: described 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline is by 2-sulfydryl-5-methoxyl group benzo imidazoles and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride is in solvent, reaction obtains under dropping inorganic alkali solution condition, wherein: described solvent be in organic alcohols solvent, nitrile solvents or the esters solvent any one or two or more, particular methanol; And/or
Described mineral alkali is any one or a few in sodium hydroxide, potassium hydroxide, sodium bicarbonate, the yellow soda ash, preferred sodium hydroxide.
7. preparation method according to claim 6, it is characterized in that: described 2-sulfydryl-5-methoxyl group benzo imidazoles, 2-chloromethyl-3, the reaction mol ratio of 5-dimethyl-4-methoxypyridine hydrochloride and mineral alkali is (0.7～2.0): (0.7～3.5): (1.4～7), preferred (0.8～1.8): (0.9～3.0): (1.6～5); Preferably, temperature of reaction is 40～100 ℃, preferred 60～80 ℃; Preferably, the reaction times is 3～10h, preferred 4～8h.
8. the preparation method of an esomeprazole magnesium, this method comprise the esomeprazole according to each acquisition of claim 1-7 joined in the alcoholic solution that is formed in organic alcohol solvent by magnesium alkoxide and react.
9. preparation method according to claim 8, wherein the consumption mol ratio of magnesium alkoxide and omeprazole thioether is preferably 0.3:1.0～2.5:1.0, preferred 0.4:1.0～2.0:1.0; Preferably, this magnesium alkoxide is the C1-C6 magnesium alkoxide, is more preferably magnesium methylate or magnesium ethylate.
10. the preparation method of an esomeprazole magnesium, this method may further comprise the steps:
(1) with 2-sulfydryl-5-methoxyl group benzo imidazoles and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride adds in the solvent, dripping alkaline solution reacts, obtain 5-methoxyl group-2-(4-methoxyl group-3 through aftertreatment, 5-dimethyl-2-pyridyl) methyl sulfo--1H-benzoglyoxaline, i.e. omeprazole thioether;
(2) the omeprazole thioether that obtains in the step (1) is dissolved in obtains reaction system in the organic solvent.
(3) adding the bidentate chiral amino alcohol and the titan-alkoxide that contain phenyl in the reaction system of step (2) reacts;
(4) dropping oxidizing agent in the reaction system of step (3) continues reaction;
(5) after step (4) reaction finishes, drip reductive agent cancellation reaction;
(6) solution that obtains in the step (5) is carried out separatory, wherein organic phase extracts with ammoniacal liquor, and gained ammoniacal liquor is used organic solvent extraction mutually again, obtains the extract organic phase;
(7) solvent in the extract organic phase that obtains in the step (6) is removed, in the residue of gained, added the alcoholic solution that in organic alcohol solvent, is formed by magnesium alkoxide and react;
(8) after step (7) reaction finishes, with reacting liquid filtering, remove the alcoholic solvent of filtrate, get the esomeprazole magnesium crude product;
(9) with the esomeprazole magnesium crude product organic solvent recrystallization that obtains in the step (8), purifying obtains esomeprazole magnesium.
11. preparation method according to claim 9 is characterized in that: the reductive agent that adopts in the described method steps (5) is sulphite; Preferably, the consumption mol ratio of sulphite and omeprazole thioether is 0.6:1.0～1.8:1.0, preferred 0.8:1.0～1.6:1.0; And/or
The magnesium alkoxide that adopts in the described method steps (6) is the C1-C6 magnesium alkoxide; Preferably, the consumption mol ratio of described magnesium alkoxide and omeprazole thioether is 0.3:1.0～2.5:1.0, preferred 0.4:1.0～2.0:1.0.
12. according to claim 10 or 11 described preparation methods, it is characterized in that: recrystallization solvent is ethyl acetate in the described method steps (8), N, dinethylformamide, N,N-dimethylacetamide, any one or a few in the acetone, ethyl acetate.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936714A (en) * | 2014-04-15 | 2014-07-23 | 北京华禧联合科技发展有限公司 | Preparation method of esomeprazole magnesium |
| CN104803978A (en) * | 2015-03-19 | 2015-07-29 | 山东鲁抗立科药业有限公司 | Preparation method of esomeprazole magnesium |
| CN105669649A (en) * | 2015-12-24 | 2016-06-15 | 寿光富康制药有限公司 | Preparation method of esomeprazole and salt thereof |
| CN106632256A (en) * | 2016-11-24 | 2017-05-10 | 河南师范大学 | Synthesis method of proton pump inhibitors |
| CN109705092A (en) * | 2018-12-24 | 2019-05-03 | 湖南千金湘江药业股份有限公司 | A kind of preparation method of esomeprazole magnesium solid |
| CN109705091A (en) * | 2018-12-24 | 2019-05-03 | 湖南千金湘江药业股份有限公司 | A kind of preparation method and application of esomeprazole |
| CN110407809A (en) * | 2019-08-29 | 2019-11-05 | 湖州安屹诺生物医药科技有限公司 | A kind of synthetic method of proton pump inhibitor esomeprazole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1934078A (en) * | 2004-03-18 | 2007-03-21 | 利奥制药有限公司 | Stereoselective synthesis of vitamin D analogues |
| CN102408412A (en) * | 2011-10-25 | 2012-04-11 | 广东华南药业集团有限公司 | (S)-omeprazole preparation method with high antipode selectivity |
| CN102584792A (en) * | 2012-01-06 | 2012-07-18 | 南京优科生物医药研究有限公司 | Method for preparing high-purity esomeprazole |
-
2013
- 2013-05-10 CN CN201310172173.7A patent/CN103265528B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1934078A (en) * | 2004-03-18 | 2007-03-21 | 利奥制药有限公司 | Stereoselective synthesis of vitamin D analogues |
| CN102408412A (en) * | 2011-10-25 | 2012-04-11 | 广东华南药业集团有限公司 | (S)-omeprazole preparation method with high antipode selectivity |
| CN102584792A (en) * | 2012-01-06 | 2012-07-18 | 南京优科生物医药研究有限公司 | Method for preparing high-purity esomeprazole |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936714A (en) * | 2014-04-15 | 2014-07-23 | 北京华禧联合科技发展有限公司 | Preparation method of esomeprazole magnesium |
| CN104803978A (en) * | 2015-03-19 | 2015-07-29 | 山东鲁抗立科药业有限公司 | Preparation method of esomeprazole magnesium |
| CN104803978B (en) * | 2015-03-19 | 2019-06-18 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of esomeprazole magnesium |
| CN105669649A (en) * | 2015-12-24 | 2016-06-15 | 寿光富康制药有限公司 | Preparation method of esomeprazole and salt thereof |
| CN105669649B (en) * | 2015-12-24 | 2018-06-01 | 寿光富康制药有限公司 | A kind of preparation method of esomeprazole and its salt |
| CN106632256A (en) * | 2016-11-24 | 2017-05-10 | 河南师范大学 | Synthesis method of proton pump inhibitors |
| CN109705092A (en) * | 2018-12-24 | 2019-05-03 | 湖南千金湘江药业股份有限公司 | A kind of preparation method of esomeprazole magnesium solid |
| CN109705091A (en) * | 2018-12-24 | 2019-05-03 | 湖南千金湘江药业股份有限公司 | A kind of preparation method and application of esomeprazole |
| CN110407809A (en) * | 2019-08-29 | 2019-11-05 | 湖州安屹诺生物医药科技有限公司 | A kind of synthetic method of proton pump inhibitor esomeprazole |
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