CN108467355A - (R) preparation method of-Esomeprazole - Google Patents

(R) preparation method of-Esomeprazole Download PDF

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Publication number
CN108467355A
CN108467355A CN201810606694.1A CN201810606694A CN108467355A CN 108467355 A CN108467355 A CN 108467355A CN 201810606694 A CN201810606694 A CN 201810606694A CN 108467355 A CN108467355 A CN 108467355A
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esomeprazole
preparation
intermediate compound
reaction
solvent
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谢玲玲
袁华杰
代丽萍
叶雷
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Chongqing Runze Pharmaceutical Co Ltd
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Chongqing Runze Pharmaceutical Co Ltd
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Abstract

A kind of preparation method of 2 oxo of (R) 4 hydroxyl, 1 pyrrolidine acetamide, includes the following steps:(1) using 4 chlorine of R, 3 butyric ester as starting material, azido reaction is carried out with Azide reagenl, obtains intermediate compound I;(2) intermediate compound I is subjected to reduction reaction, obtains intermediate II;(2) intermediate II and halogenated acetic acids ester are subjected to condensation reaction, obtain intermediate III;(3) the progress ring closure reaction of intermediate III is obtained into intermediate compound IV;(4) intermediate compound IV is subjected to ammonolysis reaction, obtains 2 oxo of target product (R) 4 hydroxyl, 1 pyrrolidine acetamide.The present invention at least can get 2 oxo of (R) 4 hydroxyl, the 1 pyrrolidine acetamide product of 38% or more more satisfactory yield, open new 2 oxo of (R) 4 hydroxyl, a 1 pyrrolidine acetamide synthetic route.

Description

(R) preparation method of-Esomeprazole
The application is that application No. is " 201410386909.5 ", entitled " (R) -4- hydroxyl -2- oxo -1- pyrroles The divisional application of the application for a patent for invention of the preparation method of alkyl acetamide ".
Technical field
The present invention relates to (R)-Esomeprazoles, more particularly to a kind of (R) -4- hydroxyls -2- The preparation method of oxo-1-pyrrolidine ethanamide.
Background technology
Oxiracetam is the cereboactive drug synthesized for the first time in 1974 by Italian SmithKline ratio Qie Mu companies, is a kind of hydroxyl ammonia Base butyric acid (GABOB) derivative can promote study, enhance memory, protect the medicine for central nervous system of damaged nerve cell. (R)-Esomeprazole is the d-isomer of Oxiracetam, has been reported that and shows Oxiracetam levo form Activity is higher than d-isomer, but d-isomer remains unchanged to exist and promotes very much study, enhancing memory, the maincenter for protecting damaged nerve cell by force The effect of in terms of nervous system, and there is important market in the application of the reference substance of levo-oxiracetam.
It is essentially all using column chromatography or ion exchange resin in current dextrorotation Oxiracetam synthetic route Mode obtains high-purity target compound, this is unfavorable for industrialized production.Moreover, strong alkali environment is needed in building-up process, this appearance It is easier that dextrorotation Oxiracetam is destroyed, impurity content increases;Inventor has found under study for action, is closed using presently disclosed document At dextrorotation Oxiracetam, the content of enantiomter is higher in final product, does not meet needs that are clinical and examining.
Invention content
The purpose of the present invention is to provide a kind of synthetic methods of (R)-Esomeprazole, should Method is suitble to industrialized production.
The goal of the invention of the present invention is achieved by the following technical solution:
A kind of synthetic method of (R)-Esomeprazole, which is characterized in that including walking as follows Suddenly:
(1) using R-4- chloro-3-hydroxybutanoic acid esters as starting material, azido reaction is carried out, intermediate compound I is obtained;
(2) intermediate compound I is subjected to reduction reaction and obtains intermediate II;
(3) intermediate II and halogenated acetic acids ester are subjected to condensation reaction, obtain intermediate III;
(4) the progress ring closure reaction of intermediate III is obtained into intermediate compound IV;
(5) intermediate compound IV is subjected to ammonolysis reaction, obtains target product (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetyl Amine.
Reaction formula is as follows:
Above-mentioned R1 is alkyl, phenyl or the benzyl of C1-C6.R2 is alkyl, phenyl or the benzyl of C1-C6.
The preferred methyl of alkyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, the ring penta of the C1-C6 Base or cyclohexyl.
The Azide reagenl that above-mentioned steps (1) azido reaction uses is sodium azide, Lithium Azide, potassium azide, folds One or more of CaCl2, barium azide mix.
Above-mentioned steps (2) reduction reaction selection borohydride reduction or hydrogen reducing in any one.
Above-mentioned boron hydride can be the combination of one or more of sodium borohydride, potassium borohydride.
The catalyst of above-mentioned hydrogen reducing is metallic catalyst, one or more combinations in palladium, rhodium, platinum.
Above-mentioned halogenated acetic acids ester is chloracetic acid ester or monobromo-acetic acid ester.
In order to enable impurity is more easily separated, operating procedure is simple, to the work for obtaining high-purity product, promoting pharmaceutical production Industry, while also ensureing reaction yield, the chloracetic acid ester in above-mentioned steps (3) uses ethyl chloroacetate, monobromo-acetic acid ester to adopt With bromoacetate, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide.
Condensation reaction can use alkaline condition in above-mentioned above-mentioned steps (3), such as pyridine, triethylamine, lutidines, carbon One or more of sour potassium or sodium bicarbonate combine.
In order to further increase reactivity, to further increase reaction yield, the solvent of above-mentioned (1) step may be selected Methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, ethyl acetate, cyclohexanol, cyclopentanol, DMF, DMSO, it is preferred to use DMF, DMSO, ethyl alcohol or cyclopentanol.
Intermediate compound I general formula is as follows:
R1 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta or cyclohexyl etc..
In order to further improve reactivity, improve reaction yield, above-mentioned Azide reagenl and R-4- chloro-3-hydroxyl fourths The molar ratio of acid esters is:R-4- chloro-3-hydroxybutanoic acid esters:Azide reagenl or catalyst=1:1~2.5.
More specifically, above-mentioned (1) step is:
R-4- chloro-3-hydroxybutanoic acid esters are mixed with the above-mentioned solvent of 5~20 times of weight first, above-mentioned Azide is then added Reagent reacts 1~5 hour at 0~160 DEG C, and R-4- chloro-3-hydroxybutanoic acid esters are 1 with Azide reagenl molar ratio:1~2.5; The solution containing intermediate compound I is obtained, intermediate compound I is then collected from the solution containing intermediate compound I.
Above-mentioned R-4- chloros -3-hydroxybutyrate ester, solvent and Azide reagenl is commercial product.
Above-mentioned (2) step is urged in a solvent and in metal specifically, being the intermediate compound I that will be obtained from step (1) Reduction reaction is carried out with hydrogen 5~10 hours, reaction temperature is 0~60 DEG C, then collects and obtains intermediate II in the presence of agent; The solvent preferentially selects methanol, ethyl alcohol, isopropanol, tetrahydrofuran, one kind in DMF, DMSO, EA or more without particular/special requirement Kind combination;Described metallic catalyst is preferably one or more combinations in palladium, rhodium, platinum.
Purity and yield are reacted in order to further improve, the weight ratio of intermediate compound I and solvent is:1:10~15, it is intermediate Body I and the weight ratio of the metallic catalyst are:1:0.1~0.5.
It most specifically says, above-mentioned (2) step is the intermediate compound I that will be obtained from step (1), in R-4- chloro-3-hydroxyl butyric acid It is reacted with hydrogen 5~10 hours in the presence of metallic catalyst in the solvent of the 10-15 times of weight of ester, reaction temperature is 0~60 DEG C, it then collects and obtains intermediate II;The solvent without particular/special requirement, preferentially select methanol, ethyl alcohol, isopropanol, tetrahydrofuran, One or more combinations in DMF, DMSO;Described metallic catalyst is preferably one or more combinations in palladium, rhodium, platinum; Intermediate compound I and the weight ratio of solvent are:1:10~15, intermediate compound I and the weight ratio of the metallic catalyst are:1:0.1~ 0.5。
Intermediate II general formula is as follows:
R1 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta or cyclohexyl etc..
Above-mentioned (3) step, specifically, be the intermediate II that will be obtained from step (2), in a solvent with halogenated acetic acids ester It is reacted 5~10 hours in the presence of base catalyst, reaction temperature is 0~60 DEG C, then collects and obtains intermediate III;The solvent Without particular/special requirement, one or more combinations in methanol, ethyl alcohol, isopropanol, tetrahydrofuran, DMF, DMSO are preferentially selected;It is described Base catalyst be preferably pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate.
It is to further improve reaction purity and yield, intermediate II and the molar ratio of halogenated acetic acids ester:1:1~3, Intermediate II and the molar ratio of the base catalyst are:1:2~3.
It most specifically says, above-mentioned (3) step is the intermediate II that will be obtained from step (2), in R-4- chloro -3- hydroxyls It is reacted in the presence of base catalyst 5~10 hours with halogenated acetic acids ester in the solvent of the 10-15 times of weight of butyrate, reaction temperature It is 0~60 DEG C, then collects and obtain intermediate III;The solvent preferentially selects methanol, ethyl alcohol, isopropanol, four without particular/special requirement One or more combinations in hydrogen furans, DMF, DMSO;The base catalyst be preferably pyridine, triethylamine, lutidines, One kind in potassium carbonate or sodium bicarbonate;Intermediate II and the molar ratio of halogenated acetic acids ester are:1:1~3, intermediate II with it is described The molar ratio of base catalyst is:1:2~3.
III general formula of intermediate is as follows:
R1 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta or cyclohexyl etc.; R2 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, benzyl or cyclopenta etc..
Above-mentioned steps (4), specifically, the intermediate III that step (3) is obtained, in a solvent under the conditions of 50~130 DEG C Ring closure reaction is carried out, the time is 3~8 hours, the solution containing intermediate compound IV is obtained, then from the solution containing intermediate compound IV Collection obtains intermediate compound IV;The solvent may be selected:Ethyl alcohol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, acetic acid fourth Ester or ethyl butyrate, it is preferred to use ethyl alcohol, toluene or dimethylbenzene.
Intermediate compound IV general formula is as follows:
R2 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, benzyl or methoxybenzyl etc..
Purity and yield are reacted in order to further improve, the molar ratio of intermediate III and solvent is 1:10~30.
Above-mentioned steps (5), specifically, the intermediate compound IV that step (4) is obtained, reacts at 20~30 DEG C with concentrated ammonia liquor 4~16 hours, target product (R)-Esomeprazole is then collected from reaction product.
In order to further increase reactivity to improve overall yield of reaction, above-mentioned intermediate compound IV:During the molar ratio of ammonia is Mesosome IV:Ammonia=1:12~15, in terms of the ammonia in ammonia methanol solution;What the concentrated ammonia liquor was known in the art, solution Concentrations by weight be 25~28% or so.
Target product (R)-Esomeprazole is collected from the reaction product of above-mentioned steps (5) Method, preferably as follows:Reaction product is dissolved in the water, is dissolved by heating, activated carbon decolorizing is filtered to remove activity Water removal is concentrated under reduced pressure in charcoal, stops concentration when surplus water is that 2~3 times of products weight is added, 0~5 DEG C of sub-cooled crystallization, Obtain to obtain product (R)-Esomeprazole.
More specifically, a kind of method preparing (R)-Esomeprazole, using following step Suddenly:
(1), first R-4- chloro-3-hydroxybutanoic acid esters are mixed with the solvent of 5~20 times of weight, Azide reagenl is then added It is reacted 1~5 hour at 0~60 DEG C, R-4- chloro-3-hydroxybutanoic acid esters are 1 with Azide reagenl molar ratio:1.5~2.5, it obtains The solution containing intermediate compound I is obtained, intermediate compound I is then collected from the solution containing intermediate compound I;The solvent is ethyl alcohol, ring penta One kind in alcohol, DMF, DMSO;
(2), the intermediate compound I that will be obtained from step (1) is carried out with hydrogen in a solvent and in the presence of metallic catalyst Reduction reaction 7~9 hours, reaction temperature are 30~50 DEG C, then collect and obtain intermediate II;The solvent is selected from methanol, second One or more combinations in alcohol, isopropanol, tetrahydrofuran, DMF, DMSO, EA;Described metallic catalyst is in palladium, rhodium, platinum One or more combinations;
(3), will from step (2) obtain intermediate II, R-4- chloro-3-hydroxybutanoic acid esters 10-15 times of weight it is molten It is reacted in the presence of base catalyst 5~10 hours with halogenated acetic acids ester in agent, reaction temperature is 0~60 DEG C, then collects and obtains Intermediate III;One or more combinations of the solvent in methanol, ethyl alcohol, isopropanol, tetrahydrofuran, DMF, DMSO, institute The base catalyst stated is selected from pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate, and the halogenated acetic acids ester is bromine One in ethyl acetate, ethyl chloroacetate, bromoacetic acid N-butyl, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide Kind;The intermediate II and the molar ratio of halogenated acetic acids ester are:1:1~3, the molar ratio of intermediate II and the base catalyst For:1:2~3;
(4), it is the intermediate III for obtaining step (3), carries out ring closure reaction under the conditions of 50~130 DEG C in a solvent, when Between be 3~8 hours, obtain the solution containing intermediate compound IV, then from the solution containing intermediate compound IV collect obtain intermediate IV;The molar ratio of the one kind of the solvent in ethyl alcohol, toluene, dimethylbenzene, the intermediate II and solvent is 1:10~ 30;
(5), the intermediate compound IV for obtaining step (4), reacts 4~16 hours at 20~30 DEG C with concentrated ammonia liquor, obtains anti- Answer product (R)-Esomeprazole crude product;The intermediate compound IV:The molar ratio of ammonia is intermediate compound IV: Ammonia=1:12~15, in terms of the ammonia in ammonia methanol solution;
(6), reaction product obtained by (5) step is dissolved in the water, is dissolved by heating, activated carbon decolorizing is filtered to remove activity Water removal is concentrated under reduced pressure in charcoal, stops concentration when surplus water is that 2~3 times of products weight is added, 0~5 DEG C of sub-cooled crystallization, Obtain product (R)-Esomeprazole.
The present invention has the advantages that:
1, the present invention uses R-4- chloro-3-hydroxybutanoic acid esters and Azide reagenl for starting material, raw material a large amount of works Industry metaplasia produce, be easy to purchase and it is cheap;Circuit is simple, and intermediate and product do not need column chromatography, at low cost, operation letter Just, it is suitble to industrialized production.
2, during cyclization of the present invention, strong alkali environment is not needed, reduces the generation of impurity in reaction.
3, the present invention is not in the case where needing column chromatography, (R)-Esomeprazole obtained Product purity reaches 99.9% or more through efficient liquid phase detection, and total recovery reaches as high as 43%, and isomery 38% or more Body ratio is less than 0.1%, 99.9% or more optical purity.
The present invention opens a new dextrorotation Oxiracetam synthetic route.
Specific implementation mode
The present invention is specifically described below by embodiment, it is necessary to which indicated herein to be, following embodiment is only used It is further detailed in the present invention, should not be understood as limiting the scope of the invention, which is skilled in technique Personnel can make some nonessential modifications and adaptations according to foregoing invention content to the present invention.Agents useful for same of the present invention is Commercial product.
Embodiment 1
A kind of synthetic method of (R)-Esomeprazole, it is carried out as follows,
(l) preparation of intermediate compound I:
Raw material R-4- chloro-3-hydroxyl methyl butyrate 50g are taken, is added in a single neck bottle, DMF50ml, stirring, ice-water bath is added It is cooling, sodium azide 50g is added, keeps temperature to be no more than 40 DEG C, 60 DEG C is warming up to after adding.Reaction 2 hours, stopping are reacted Yellow solution.Water 100ml is added, is extracted with ethyl acetate 100ml, concentration removes ethyl acetate, obtains among yellow oil Body I.It is detected through nuclear-magnetism, intermediate compound I is:1H-NMR(300MHz,CDCl3):δ1.42-1.73(m,2H)2.76-2.67(AB system,m,2H,),3.31-3.23(AB system,m,2H),3.75(s,3H),4.40(m,1H),3.70(s,1H).
Intermediate compound I is:R1 is methyl.
(2) preparation of intermediate II
The intermediate compound I that step (2) obtains is dissolved in the methanol of 500ml, 0 DEG C of outer temperature is cooled to, 10% palladium carbon is added Catalyst 10g is passed through stirring under hydrogen 5 hours, and contact plate is shown in raw material, and the reaction was complete, stops reaction, and concentration removing solvent obtains light Yellow oil intermediate II.It is detected through nuclear-magnetism, intermediate II:1H-NMR(300MHz,D2O):δ2.76-2.67 (ABsystem,m,2H,),3.31-3.23(AB system,m,2H),3.75(s,3H),4.40(m,1H),4.70(bs,3H) .13C-NMR(50MHz,D2O):δ43.7(C-2),48.4(C-4),57.0(OCH,),68.9(C-3),177.5(C-I).
Intermediate II isR1 is methyl.
(3) preparation of intermediate III
The intermediate II that step (2) obtains is dissolved in the methanol of 500ml, 0 DEG C of outer temperature is cooled to, potassium carbonate is added 173g (3eq) has a large amount of solids to generate, and stirs five minutes, starts that bromoacetate 90ml (2eq) is added dropwise, dropwise addition process is put Thermal phenomenon continues stirring 2 hours after being added dropwise, contact plate is shown in raw material, and the reaction was complete, stops reaction, and EA (ethyl acetate) is added 500ml, water 300ml, solid are completely dissolved, and water layer is saturated with solid sodium chloride, separate organic layer, and water layer is extracted with EA 200ml Take twice, merge organic layer, organic layer is washed three times with the hydrochloric acid 200ml of 2M, merges hydrochloric acid water phase, and organic phase discards, water phase after Continuous to adjust pH to 8, solid sodium chloride saturation with sodium bicarbonate, EA 300ml extractions three times, merge organic phase, and anhydrous magnesium sulfate is dry Dry, concentration removes solvent and obtains pale yellow oil, and curing at low temperatures obtains intermediate III.It is detected through nuclear-magnetism, intermediate III: 1H-NMR(300MHz,D2O):δ1.3(t,3H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),3.67 (s,3H),4.09-4.12(m,3H).
Intermediate III isR1 is methyl, and R2 is ethyl.
(4) preparation of intermediate compound IV
The intermediate III that step (2) is obtained 500ml ethyl alcohol dissolves, and is warming up to 75 DEG C, flows back 8 hours, it is red to obtain one Brown solution, contact plate is shown in raw material, and the reaction was complete.Stop reaction, concentration removes ethyl alcohol, and EA (ethyl acetate) is added and dissolves, crosses and filters out Desalt, activated carbon decolorizing, concentration remove yellow oil obtains intermediate compound IV.It is detected through nuclear-magnetism, intermediate compound IV is:1H-NMR (300MHz,CDCl3)δ1.280(t,3H),2.38(dd,1H),2.69(dd,1H),3.34(dd,1H),3.77(dd,lH), 3.93(d,lH),4.18(d,1H),4.19(q,2H),4.30(bs,1H),4.50(m,1H).
Intermediate compound IV:
R2 is ethyl.
(5) preparation of (R)-Esomeprazole
Concentrated ammonia liquor 200ml is added in the intermediate compound IV that step (4) is obtained, and is stirred at room temperature 18 hours, and contact plate is shown in that raw material reacts Completely, stop reaction, water removal and ammonia are removed in concentration, obtain yellow oil, and acetone solution grease is added, a small amount of crystal seed is added Solid is precipitated in stirring, and a small amount of acetone rinsing bottle wall, -10 DEG C crystallize 5 hours, and off-white color crude product 24g is obtained by filtration.Purity 99.3%, isomer proportion 0.2%.The crude product is dissolved in the water of 100ml, heating makes it dissolve, and activated carbon decolorizing half is small When, it is filtered to remove activated carbon, crystallisation by cooling, 5 DEG C stand overnight, and next day filters to obtain white solid 22g, purity 99.9%, isomery Body ratio 0.1%.It is detected through nuclear-magnetism, dextrorotation Oxiracetam:1H-NMR(300MHz,DMSO-d6)δ2.10(d,1H),2.57 (dd,1H),3.69(d,1H),3.88(d,1H),4.10(d,1H),4.31(m,1H),5.25(s,1H),7.13(s,1H), 7.33 (s, 1H) optical values:-37.3.
(R)-Esomeprazole is that structural formula is as follows:
Embodiment 2
A kind of synthetic method of (R)-Esomeprazole, it is carried out as follows,
(l) preparation of intermediate compound I:
R-4- chloro-3-hydroxyl methyl butyrate 50kg are weighed, are added in the azido reaction kettle of 500L, DMF 50L are added, stir It mixes uniformly, chuck leads to ice-water bath and cools down, and sodium azide 50Kg is added, and temperature is kept to be no more than 40 DEG C, and pressure removes the ice water in chuck, Chuck, which leads to hot water, makes interior temperature be warming up to 60 DEG C.Yellow solution is reacted to obtain in reaction 2 hours, stopping.Water 100L is added in kettle, uses acetic acid Ethyl ester 100L extractions, liquid separation discard water phase, and organic phase concentration removes ethyl acetate, obtains yellow oil intermediate compound I.Through nuclear-magnetism Detection, intermediate compound I are:1H-NMR(300MHz,CDCl3):δ1.42-1.73(m,2H)2.76-2.67(AB system,m, 2H,),3.31-3.23(AB system,m,2H),3.75(s,3H),4.40(m,1H),3.70(s,1H).
Intermediate compound I is:R1 is methyl.
(2) preparation of intermediate II
The intermediate compound I that step (2) obtains is dissolved in the methanol of 500L, is transferred in the hydrogenation reaction cauldron of 1000L, is pressed from both sides Set leads to cryosel and is water-cooled to 0 DEG C of interior temperature, and 10% palladium-carbon catalyst 10kg is added, is passed through stirring under hydrogen 5 hours, takes in sample and control Raw material is shown in liquid phase detection, and the reaction was complete, stops reaction, and concentration removes solvent and obtains pale yellow oil intermediate II.It is examined through nuclear-magnetism It surveys, intermediate II:1H-NMR(300MHz,D2O):δ2.76-2.67(AB system,m,2H,),3.31-3.23(AB system,m,2H),3.75(s,3H),4.40(m,1H),4.70(bs,3H).13C-NMR(50MHz,D2O):δ43.7(C-2), 48.4(C-4),57.0(OCH,),68.9(C-3),177.5(C-I).
Intermediate II isR1 is methyl.
(3) preparation of intermediate III
The intermediate II that step (2) obtains is dissolved in the methanol of 500L, is transferred in the condensation reaction kettle of 1500L, Lead to ice water with 150L dropping tanks one, in chuck and be cooled to 0 DEG C of outer temperature, potassium carbonate 173kg (3eq) is added, there are a large amount of solids to give birth to At bromoacetate is pressed into dropping tank by stirring five minutes, starts that bromoacetate 90L (2eq) is added dropwise, dropwise addition process is put Thermal phenomenon continues stirring 2 hours after being added dropwise, take in sample draining mutually to detect and see raw material the reaction was complete, stop reaction, be added EA (ethyl acetate) 500L, water 300L, solid are completely dissolved, and water layer is saturated with solid sodium chloride, separate organic layer, and water layer turns Enter extractor, continue to be extracted twice with EA 200L, merge organic layer, organic layer is washed three times with the hydrochloric acid 200L of 2M, merges hydrochloric acid Water phase is transferred to extractor, and organic phase discards, and water phase continues to adjust pH to 8 with sodium bicarbonate in extractor, and solid sodium chloride is full With EA 300L extraction three times, merges organic phase, anhydrous magnesium sulfate drying, concentration removes solvent and obtains pale yellow oil, low The lower solidification of temperature obtains intermediate III.It is detected through nuclear-magnetism, intermediate III:1H-NMR(300MHz,D2O):δ1.3(t,3H),2.28- 2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),3.67(s,3H),4.09-4.12(m,3H).
Intermediate III isR1 is methyl, and R2 is ethyl.
(4) preparation of intermediate compound IV
The intermediate III that step (2) is obtained 500L ethyl alcohol dissolves, and is transferred to the cyclization kettle of 1000L, and chuck leads to hot water liter Temperature is flowed back 8 hours, obtains a red tan solution to 75 DEG C of interior temperature, is taken in sample draining mutually to detect and is seen raw material the reaction was complete.Stop Reaction, concentration remove ethyl alcohol, and EA (ethyl acetate) 200L dissolvings are added, and are filtered to remove salt, activated carbon decolorizing, concentration removes yellow Color grease obtains intermediate compound IV.It is detected through nuclear-magnetism, intermediate compound IV is:1H-NMR(300MHz,CDCl3)δ1.280(t,3H), 2.38(dd,1H),2.69(dd,1H),3.34(dd,1H),3.77(dd,lH),3.93(d,lH),4.18(d,1H),4.19(q, 2H),4.30(bs,1H),4.50(m,1H).
Intermediate compound IV:
R2 is ethyl.
(5) preparation of (R)-Esomeprazole
Concentrated ammonia liquor 200L is added in the intermediate compound IV that step (4) is obtained, and is transferred in the ammonolysis reaction kettle of 500L, is stirred at room temperature It 18 hours, takes in sample draining mutually to detect and sees raw material the reaction was complete, stop reaction, concentration removes water removal and ammonia, obtains yellow oil Shape object is added acetone 100L and dissolves grease, and a small amount of crystal seed stirring is added, and solid, 10L acetone rinsing kettle walls, -10 DEG C of knots are precipitated It is 5 hours brilliant, off-white color crude product 24kg is obtained by filtration.Purity 99.3%, isomer proportion 0.2%.The crude product is dissolved in 100L Water in, heating makes it dissolve, activated carbon decolorizing half an hour, is filtered to remove activated carbon, and crystallisation by cooling, 5 DEG C stand overnight, next day Filter to obtain white solid 22kg, purity 99.9%, isomer proportion 0.05%.It is detected through nuclear-magnetism, dextrorotation Oxiracetam:1H-NMR (300MHz,DMSO-d6)δ2.10(d,1H),2.57(dd,1H),3.69(d,1H),3.88(d,1H),4.10(d,1H),4.31 (m, 1H), 5.25 (s, 1H), 7.13 (s, 1H), 7.33 (s, 1H) optical values:-37.3.
(R)-Esomeprazole is that structural formula is as follows:
Embodiment 3
1, a kind of synthetic method of (R)-Esomeprazole, as follows:
(1) by R-4- chloro-3-hydroxyls ethyl butyrate and the DMSO for accounting for its 18 times of weight, the sodium azide of 1 times of weight is together Stirring, in 60 DEG C of azido reactions 5 hours or so, raw material fundamental reaction is complete, stops reaction, and directly concentration removes solvent, low The lower solidification of temperature obtains intermediate compound I;The above solvent additionally uses DMF, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, toluene simultaneously Or cyclopentanol etc. prepares intermediate compound I, is most detected afterwards through nuclear-magnetism, obtained intermediate compound I is:1H-NMR(300MHz, CDCl3):δ1.42-1.73(m,5H)2.76-2.67(AB system,m,2H,),3.31-3.23(AB system,m,2H), 4.40(m,1H),3.70(s,1H)。
(2) intermediate compound I that will be obtained from step (1), in the ethyl alcohol of 15 times of weight of R-4- chloro-3-hydroxyl ethyl butyrates In, 10% platinum carbon catalyst of 0.5 times of weight is added, stirring cooling is passed through 60 DEG C of hydrogen reduction reaction 10 hours, the centre The weight ratio of body II and solvent is 1:15, it then collects and obtains intermediate II, while the above solvent additionally uses methanol, isopropyl Alcohol, tetrahydrofuran, DMF or DMSO etc. prepare intermediate II, are most detected afterwards through nuclear-magnetism, obtained intermediate II is:1H- NMR(300MHz,D2O):δ 1.30 (m, 3H), 2.76-2.67 (AB system, m, 2H), 3.31-3.23 (AB system, m, 2H),4.12(m,2H),4.40(m,1H),4.70(bs,3H).。
(3) intermediate II that will be obtained from step (2), in the ethyl alcohol of 15 times of weight of R-4- chloro-3-hydroxyl ethyl butyrates In, bromoacetic acid 60 DEG C of N-butyl condensation reaction 10 hours, mole of the intermediate compound I and halogenated acetic acids ester is added dropwise in stirring cooling Than being 1:1.5, then collect obtain intermediate III, while the above solvent additionally use methanol, isopropanol, tetrahydrofuran, DMF or DMSO etc. prepares intermediate III, is most detected afterwards through nuclear-magnetism, obtained intermediate II is:1H-NMR(300MHz,D2O):δ 0.96(t,3H),1.30-1.33(m,5H),1.57(m,2H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s, 2H),4.08-4.12(m,5H).。
(4) intermediate III for obtaining step (3), is dissolved in ethyl acetate, the intermediate III and ethyl acetate Molar ratio is 1:12, be warming up at 85 DEG C and carry out ring closure reaction 6.5 hours, obtain the solution containing intermediate compound IV, then from containing Have to collect in the solution of intermediate compound IV and obtain intermediate compound IV, the solvent additionally uses as ethyl alcohol, the tert-butyl alcohol, toluene, diformazan Benzene, water, butyl acetate or ethyl butyrate, are most detected through nuclear-magnetism afterwards, and obtained intermediate compound IV is:1H-NMR(300MHz, CDCl3)δ0.96(t,3H)1.33(m,2H),1.57(m,2H)2.38(dd,1H),2.69(dd,1H),3.34(dd,1H), 3.77(dd,lH),3.93(d,lH),4.18(d,1H),4.19(q,2H),4.30(bs,1H),4.50(m,1H).。
(5) intermediate compound IV for obtaining step (4) is added in concentrated ammonia liquor, is stirred at room temperature and carries out ammonolysis reaction 15 hours, institute State intermediate compound IV:The molar ratio of ammonia is intermediate compound IV:Ammonia=1:13, in terms of the ammonia in ammonia methanol solution;Concentration that the reaction was complete Water removal and ammonia are removed, is purified using acetone, crystallization obtains product (R)-Esomeprazole crude product.It will be thick Product are dissolved in the water, and dissolve by heating, activated carbon decolorizing, are filtered to remove activated carbon, and water removal is concentrated under reduced pressure, when surplus water is to be added Stop concentration when 2~3 times of products weight, 0~5 DEG C of sub-cooled crystallization obtains product (R) -4- hydroxyl -2- oxo -1- pyrroles Alkyl acetamide.HPLC measure its purity be 99.9%, calculate yield be 38%, detected through nuclear-magnetism, gained dextrorotation Oxiracetam is: 1H-NMR(300MHz,DMSO-d6)δ2.10(d,1H),2.57(dd,1H),3.69(d,1H),3.88(d,1H),4.10(d, 1H), 4.31 (m, 1H), 5.25 (s, 1H), 7.13 (s, 1H), 7.33 (s, 1H) optical values:-37.2.
Embodiment 4-13:The step of according to the form below and parameter carry out, other same as Example 1.
Step 1 table 1
Step 2
Table 2
Step 3
Table 3
Step 4
Table 4
Step 5
Table 5
Conclusion:Acquisition target product dextrorotation Oxiracetam that can be relatively simple using the route of Patent design of the present invention, And entire route does not have cumbersome column chromatography separating purification process, is suitble to industrialized production, total recovery:38%-45%.It obtains Product examined through liquid chromatogram, purity reaches 99.9%, and isomer proportion is less than 0.1%.

Claims (63)

1. a kind of preparation method of (R)-Esomeprazole, it is characterised in that:Reaction formula is as follows,
(1) using (R) -4- chloro-3-hydroxybutanoic acid esters as starting material, azido reaction is carried out, intermediate compound I is obtained;
(2) intermediate compound I is subjected to reduction reaction and obtains intermediate II;
(3) intermediate II and halogenated acetic acids ester are subjected to condensation reaction, obtain intermediate III;
(4) the progress ring closure reaction of intermediate III is obtained into intermediate compound IV;
(5) intermediate compound IV is subjected to ammonolysis reaction, obtains target product (R)-Esomeprazole;Institute It is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl to state R1; The R2 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl Base;The Azide reagenl that step (1) azido reaction uses is sodium azide, Lithium Azide, potassium azide, Azide One or more of calcium, barium azide mix;The solvent used in the step (1) is selected from methanol, ethyl alcohol, normal propyl alcohol, different One or more of propyl alcohol, n-butanol, the tert-butyl alcohol, cyclohexanol, cyclopentanol, DMF, DMSO mix.
2. the preparation method of (R)-Esomeprazole as described in claim 1, it is characterised in that:Institute The molar ratio for stating Azide reagenl and 4- chloro-3-hydroxybutanoic acid esters is 4- chloro-3-hydroxybutanoic acid esters:Azide reagenl=1:1~ 2.5。
3. the preparation method of (R)-Esomeprazole as claimed in claim 1 or 2, feature exist In:A kind of several mixing of the solvent used in the step (1) in DMF, DMSO, ethyl alcohol or cyclopentanol.
4. the preparation method of (R)-Esomeprazole as described in claim any one of 1-3, special Sign is:The step (1) is first to mix R-4- chloro-3-hydroxybutanoic acid esters with the above-mentioned solvent of 5~20 times of weight, is then added Enter above-mentioned Azide reagenl to react 1~5 hour at 0~160 DEG C, R-4- chloro-3-hydroxybutanoic acid esters and Azide reagenl mole Than being 1:1~2.5;The solution containing intermediate compound I is obtained, intermediate compound I is then collected from the solution containing intermediate compound I.
5. the preparation method of (R)-Esomeprazole as described in claim any one of 1-4, special Sign is:The step (2) is the intermediate compound I that will be obtained from step (1), in a solvent and in the presence of metallic catalyst with Hydrogen carries out reduction reaction 5~10 hours, and reaction temperature is 0~60 DEG C, then collects and obtains intermediate II.
6. the preparation method of (R)-Esomeprazole as described in claim any one of 1-5, special Sign is:The reduction reaction of the step (2) is one kind in boron hydride or hydrogen reducing.
7. the preparation method of (R)-Esomeprazole as described in claim any one of 1-6, special Sign is:The catalyst of the hydrogen reducing is metallic catalyst;The metallic catalyst is palladium, rhodium, one kind in platinum or more Kind combination.
8. the preparation method of (R)-Esomeprazole as described in claim any one of 1-7, special Sign is:One or more groups in methanol, ethyl alcohol, isopropanol, tetrahydrofuran, DMF, DMSO, EA of the solvent of step (2) It closes.
9. the preparation method of (R)-Esomeprazole as claimed in claim 8, it is characterised in that:Institute The intermediate compound I and weight of solvent ratio for stating step (2) be:1:10~15.
10. the preparation method of (R)-Esomeprazole as claimed in claim 7, it is characterised in that: The intermediate compound I and the weight ratio of the metallic catalyst are:1:0.1~0.5.
11. the preparation method of (R)-Esomeprazole as described in claim any one of 1-10, It is characterized in that:(2) step is the intermediate compound I that will be obtained from step (1), in the 10-15 weights of R-4- chloro-3-hydroxybutanoic acid esters It is reacted with hydrogen 5~10 hours in the presence of metallic catalyst in the solvent of amount times, reaction temperature is 0~60 DEG C, is then collected Obtain intermediate II;One or more combinations of the solvent in methanol, ethyl alcohol, isopropanol, tetrahydrofuran, DMF, DMSO;Gold One or more combinations of the metal catalyst in palladium, rhodium, platinum;The intermediate compound I and the weight ratio of solvent are:1:10~15, Intermediate compound I and the weight ratio of metallic catalyst are:1:0.1~0.5.
12. the preparation method of (R)-Esomeprazole as described in claim any one of 1-11, It is characterized in that:The step (3) is the intermediate II that will be obtained from step (2), in a solvent with halogenated acetic acids ester in base catalysis It is reacted 5~10 hours in the presence of agent, reaction temperature is 0~60 DEG C, then collects and obtains intermediate III;The solvent is selected from first One or more combinations in alcohol, ethyl alcohol, isopropanol, tetrahydrofuran, DMF, DMSO.
13. the preparation method of (R)-Esomeprazole, feature exist as described in claim 1-12 In:The halogenated acetic acids ester is chloracetic acid ester or monobromo-acetic acid ester.
14. the preparation method of (R)-Esomeprazole as claimed in claim 13, it is characterised in that: The chloracetic acid ester is ethyl chloroacetate;The monobromo-acetic acid ester is bromoacetate, bromoacetic acid N-butyl, bromoacetic acid isobutyl Ester, bromo-acetic acid tert-butyl or benzyl acetate bromide.
15. the preparation method of (R)-Esomeprazole as described in claim any one of 1-14, It is characterized in that:The intermediate II and the molar ratio of halogenated acetic acids ester are:1:1~3.
16. the preparation method of (R)-Esomeprazole as described in claim any one of 12-15, It is characterized in that:The base catalyst is selected from pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate.
17. the preparation method of (R)-Esomeprazole as described in claim any one of 12-16, It is characterized in that:The intermediate II and the molar ratio of base catalyst are:1:2~3.
18. the preparation method of (R)-Esomeprazole as described in claim any one of 1-17, It is characterized in that:The step (4) is the intermediate III for obtaining step (3), carries out cyclization under the conditions of 50~130 DEG C in a solvent Reaction, time are 3~8 hours, obtain the solution containing intermediate compound IV, then collect and obtain from the solution containing intermediate compound IV Intermediate compound IV;The solvent that the step (4) uses is selected from ethyl alcohol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, acetic acid fourth Ester or ethyl butyrate.
19. the preparation method of (R)-Esomeprazole as described in claim any one of 1-18, It is characterized in that:The solvent that the step (4) uses is selected from ethyl alcohol, toluene or dimethylbenzene.
20. the preparation method of (R)-Esomeprazole as described in claim any one of 1-19, It is characterized in that:Intermediate III and solvent molar ratio in the step (4) are 1:10~30.
21. the preparation method of (R)-Esomeprazole as described in claim any one of 1-20, It is characterized in that:The step (5) is the intermediate compound IV for obtaining step (4), and it is small with concentrated ammonia liquor to react 4~16 at 20~30 DEG C When, target product (R)-Esomeprazole is then collected from reaction product.
22. the preparation method of (R)-Esomeprazole as described in claim any one of 1-21, It is characterized in that:The step (5) is the intermediate compound IV for obtaining step (4), and it is small with concentrated ammonia liquor to react 4~16 at 20~30 DEG C When, target product (R)-Esomeprazole, wherein intermediate compound IV is then collected from reaction product Molar ratio with ammonia is intermediate compound IV:Ammonia=1:12~15, in terms of the ammonia in ammonia methanol solution;The weight of the concentrated ammonia solution It is 25~28% to measure percentage concentration.
23. the preparation method of (R)-Esomeprazole as described in claim any one of 1-22, It is characterized in that:Target product (R)-Esomeprazole is collected from the reaction product of step (5) Method is that reaction product is dissolved in the water, and is dissolved by heating, activated carbon decolorizing, and activated carbon is filtered to remove, and water removal is concentrated under reduced pressure, when Surplus water is to stop concentration when 2~3 times of products weight is added, and 0~5 DEG C of sub-cooled crystallization obtains to obtain product (R) -4- hydroxyls Base -2- oxo-1-pyrrolidine ethanamides.
24. a kind of preparation method of (R)-Esomeprazole, it is characterised in that:Reaction formula is such as Under,
(1) using (R) -4- chloro-3-hydroxybutanoic acid esters as starting material, azido reaction is carried out, intermediate compound I is obtained;
(2) intermediate compound I is subjected to reduction reaction and obtains intermediate II;
(3) intermediate II and halogenated acetic acids ester are subjected to condensation reaction, obtain intermediate III;
(4) the progress ring closure reaction of intermediate III is obtained into intermediate compound IV;
(5) intermediate compound IV is subjected to ammonolysis reaction, obtains target product (R)-Esomeprazole;Institute It is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl to state R1; The R2 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl Base;The step (2) is the intermediate compound I that will be obtained from step (1), in a solvent and in the presence of metallic catalyst with hydrogen Carry out reduction reaction 5~10 hours, reaction temperature is 0~60 DEG C, then collects and obtains intermediate II.
25. the preparation method of (R)-Esomeprazole as claimed in claim 24, it is characterised in that: The reduction reaction of the step (2) is one kind in boron hydride or hydrogen reducing.
26. the preparation method of (R)-Esomeprazole as claimed in claim 25, it is characterised in that: The catalyst of the hydrogen reducing is metallic catalyst;The metallic catalyst is one or more combinations in palladium, rhodium, platinum.
27. the preparation method of (R)-Esomeprazole as described in claim any one of 24-26, It is characterized in that:The solvent of step (2) is one or more in methanol, ethyl alcohol, isopropanol, tetrahydrofuran, DMF, DMSO, EA Combination.
28. the preparation method of (R)-Esomeprazole as described in claim any one of 24-27, It is characterized in that:The intermediate compound I and the weight ratio of solvent are:1:10~15.
29. the preparation method of (R)-Esomeprazole as claimed in claim 26, it is characterised in that: The intermediate compound I and the weight ratio of the metallic catalyst are:1:0.1~0.5.
30. the preparation method of (R)-Esomeprazole as described in claim any one of 24-29, It is characterized in that:(2) step is the intermediate compound I that will be obtained from step (1), in the 10-15 weights of R-4- chloro-3-hydroxybutanoic acid esters It is reacted with hydrogen 5~10 hours in the presence of metallic catalyst in the solvent of amount times, reaction temperature is 0~60 DEG C, is then collected Obtain intermediate II;One or more groups in methanol, ethyl alcohol, isopropanol, tetrahydrofuran, DMF, DMSO of the solvent It closes;One or more combinations of the described metallic catalyst in palladium, rhodium, platinum;The weight ratio of the intermediate compound I and solvent For:1:10~15, the weight ratio of intermediate compound I and metallic catalyst is:1:0.1~0.5.
31. the preparation method of (R)-Esomeprazole as described in claim any one of 24-30, It is characterized in that:The step (3) is the intermediate II that will be obtained from step (2), in a solvent with halogenated acetic acids ester in base catalysis It is reacted 5~10 hours in the presence of agent, reaction temperature is 0~60 DEG C, then collects and obtains intermediate III;The solvent is selected from first One or more combinations in alcohol, ethyl alcohol, isopropanol, tetrahydrofuran, DMF, DMSO.
32. the preparation method of (R)-Esomeprazole as described in claim any one of 24-31, It is characterized in that:The halogenated acetic acids ester is chloracetic acid ester or monobromo-acetic acid ester.
33. the preparation method of (R)-Esomeprazole as claimed in claim 32, it is characterised in that: The chloracetic acid ester is ethyl chloroacetate;The monobromo-acetic acid ester is bromoacetate, bromoacetic acid N-butyl, bromoacetic acid isobutyl Ester, bromo-acetic acid tert-butyl or benzyl acetate bromide.
34. the preparation method of (R)-Esomeprazole as described in claim any one of 24-33, It is characterized in that:The intermediate II and the molar ratio of halogenated acetic acids ester are:1:1~3.
35. the preparation method of (R)-Esomeprazole as described in claim any one of 31-34, It is characterized in that:The base catalyst is selected from pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate.
36. the preparation method of (R)-Esomeprazole as described in claim any one of 31-35, It is characterized in that:The intermediate II and the molar ratio of base catalyst are:1:2~3.
37. the preparation method of (R)-Esomeprazole as described in claim any one of 24-36, It is characterized in that:The step (4) is the intermediate III for obtaining step (3), carries out cyclization under the conditions of 50~130 DEG C in a solvent Reaction, time are 3~8 hours, obtain the solution containing intermediate compound IV, then collect and obtain from the solution containing intermediate compound IV Intermediate compound IV;The solvent that the step (4) uses is selected from ethyl alcohol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, acetic acid fourth Ester or ethyl butyrate.
38. the preparation method of (R)-Esomeprazole as claimed in claim 37, it is characterised in that: The solvent that the step (4) uses is selected from ethyl alcohol, toluene or dimethylbenzene.
39. the preparation method of (R)-Esomeprazole as described in claim any one of 24-37, It is characterized in that:Intermediate III and solvent molar ratio in the step (4) are 1:10~30.
40. the preparation method of (R)-Esomeprazole as described in claim any one of 24-39, It is characterized in that:The step (5) is the intermediate compound IV for obtaining step (4), and it is small with concentrated ammonia liquor to react 4~16 at 20~30 DEG C When, target product (R)-Esomeprazole is then collected from reaction product.
41. the preparation method of (R)-Esomeprazole as described in claim any one of 24-40, It is characterized in that:The step (5) is the intermediate compound IV for obtaining step (4), and it is small with concentrated ammonia liquor to react 4~16 at 20~30 DEG C When, target product (R)-Esomeprazole, wherein intermediate compound IV is then collected from reaction product Molar ratio with ammonia is intermediate compound IV:Ammonia=1:12~15, in terms of the ammonia in ammonia methanol solution;The weight of the concentrated ammonia solution It is 25~28% to measure percentage concentration.
42. the preparation method of (R)-Esomeprazole as described in claim any one of 24-41, It is characterized in that:Target product (R)-Esomeprazole is collected from the reaction product of step (5) Method is that reaction product is dissolved in the water, and is dissolved by heating, activated carbon decolorizing, and activated carbon is filtered to remove, and water removal is concentrated under reduced pressure, when Surplus water is to stop concentration when 2~3 times of products weight is added, and 0~5 DEG C of sub-cooled crystallization obtains to obtain product (R) -4- hydroxyls Base -2- oxo-1-pyrrolidine ethanamides.
43. a kind of preparation method of (R)-Esomeprazole, it is characterised in that:Reaction formula is such as Under,
(1) using (R) -4- chloro-3-hydroxybutanoic acid esters as starting material, azido reaction is carried out, intermediate compound I is obtained;
(2) intermediate compound I is subjected to reduction reaction and obtains intermediate II;
(3) intermediate II and halogenated acetic acids ester are subjected to condensation reaction, obtain intermediate III;
(4) the progress ring closure reaction of intermediate III is obtained into intermediate compound IV;
(5) intermediate compound IV is subjected to ammonolysis reaction, obtains target product (R)-Esomeprazole;Institute It is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl to state R1; The R2 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl Base;The step (3) is the intermediate II that will be obtained from step (2), is existed in a solvent in base catalyst with halogenated acetic acids ester Lower reaction 5~10 hours, reaction temperature are 0~60 DEG C, then collect and obtain intermediate III;The solvent be selected from methanol, ethyl alcohol, One or more combinations in isopropanol, tetrahydrofuran, DMF, DMSO.
44. the preparation method of (R)-Esomeprazole as described in claim 43, it is characterised in that: The halogenated acetic acids ester is chloracetic acid ester or monobromo-acetic acid ester.
45. the preparation method of (R)-Esomeprazole, feature as described in claim 43 or 44 It is:The chloracetic acid ester is ethyl chloroacetate;The monobromo-acetic acid ester is bromoacetate, bromoacetic acid N-butyl, bromine second Sour isobutyl ester, bromo-acetic acid tert-butyl or benzyl acetate bromide.
46. the preparation method of (R)-Esomeprazole as described in claim any one of 43-45, It is characterized in that:The intermediate II and the molar ratio of halogenated acetic acids ester are:1:1~3.
47. the preparation method of (R)-Esomeprazole as described in claim any one of 43-46, It is characterized in that:The base catalyst is selected from pyridine, triethylamine, lutidines, potassium carbonate or sodium bicarbonate.
48. the preparation method of (R)-Esomeprazole as described in claim 47, it is characterised in that: The intermediate II and the molar ratio of base catalyst are:1:2~3.
49. the preparation method of (R)-Esomeprazole as described in claim any one of 43-48, It is characterized in that:The step (4) is the intermediate III for obtaining step (3), carries out cyclization under the conditions of 50~130 DEG C in a solvent Reaction, time are 3~8 hours, obtain the solution containing intermediate compound IV, then collect and obtain from the solution containing intermediate compound IV Intermediate compound IV;The solvent that the step (4) uses is selected from ethyl alcohol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, acetic acid fourth Ester or ethyl butyrate.
50. the preparation method of (R)-Esomeprazole as described in claim any one of 43-49, It is characterized in that:The solvent that the step (4) uses is selected from ethyl alcohol, toluene or dimethylbenzene.
51. the preparation method of (R)-Esomeprazole as described in claim any one of 43-50, It is characterized in that:Intermediate III and solvent molar ratio in the step (4) are 1:10~30.
52. the preparation method of (R)-Esomeprazole as described in claim any one of 43-51, It is characterized in that:The step (5) is the intermediate compound IV for obtaining step (4), and it is small with concentrated ammonia liquor to react 4~16 at 20~30 DEG C When, target product (R)-Esomeprazole is then collected from reaction product.
53. the preparation method of (R)-Esomeprazole as described in claim any one of 43-52, It is characterized in that:The step (5) is the intermediate compound IV for obtaining step (4), and it is small with concentrated ammonia liquor to react 4~16 at 20~30 DEG C When, target product (R)-Esomeprazole, wherein intermediate compound IV is then collected from reaction product Molar ratio with ammonia is intermediate compound IV:Ammonia=1:12~15, in terms of the ammonia in ammonia methanol solution;The weight of the concentrated ammonia solution It is 25~28% to measure percentage concentration.
54. the preparation method of (R)-Esomeprazole as described in claim any one of 43-53, It is characterized in that:Target product (R)-Esomeprazole is collected from the reaction product of step (5) Method is that reaction product is dissolved in the water, and is dissolved by heating, activated carbon decolorizing, and activated carbon is filtered to remove, and water removal is concentrated under reduced pressure, when Surplus water is to stop concentration when 2~3 times of products weight is added, and 0~5 DEG C of sub-cooled crystallization obtains to obtain product (R) -4- hydroxyls Base -2- oxo-1-pyrrolidine ethanamides.
55. a kind of preparation method of (R)-Esomeprazole, it is characterised in that:Reaction formula is such as Under,
(1) using (R) -4- chloro-3-hydroxybutanoic acid esters as starting material, azido reaction is carried out, intermediate compound I is obtained;
(2) intermediate compound I is subjected to reduction reaction and obtains intermediate II;
(3) intermediate II and halogenated acetic acids ester are subjected to condensation reaction, obtain intermediate III;
(4) the progress ring closure reaction of intermediate III is obtained into intermediate compound IV;
(5) intermediate compound IV is subjected to ammonolysis reaction, obtains target product (R)-Esomeprazole;Institute It is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl to state R1; The R2 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl Base;The step (4) is the intermediate III for obtaining step (3), carries out ring closure reaction under the conditions of 50~130 DEG C in a solvent, Time is 3~8 hours, obtains the solution containing intermediate compound IV, is then collected from the solution containing intermediate compound IV and obtains centre Body IV;The solvent that the step (4) uses be selected from ethyl alcohol, the tert-butyl alcohol, toluene, dimethylbenzene, water, ethyl acetate, butyl acetate or Ethyl butyrate.
56. the preparation method of (R)-Esomeprazole as described in claim 55, it is characterised in that: The solvent that the step (4) uses is selected from ethyl alcohol, toluene or dimethylbenzene.
57. the preparation method of (R)-Esomeprazole, feature as described in claim 55 or 56 It is:Intermediate III and solvent molar ratio in the step (4) are 1:10~30.
58. the preparation method of (R)-Esomeprazole as described in claim any one of 55-57, It is characterized in that:The step (5) is the intermediate compound IV for obtaining step (4), and it is small with concentrated ammonia liquor to react 4~16 at 20~30 DEG C When, target product (R)-Esomeprazole is then collected from reaction product.
59. the preparation method of (R)-Esomeprazole as described in claim 58, it is characterised in that: The step (5) is the intermediate compound IV for obtaining step (4), reacts 4~16 hours with concentrated ammonia liquor at 20~30 DEG C, then from Target product (R)-Esomeprazole, wherein mole of intermediate compound IV and ammonia is collected in reaction product Than for intermediate compound IV:Ammonia=1:12~15, in terms of the ammonia in ammonia methanol solution;The concentration expressed in percentage by weight of the concentrated ammonia solution It is 25~28%.
60. the preparation method of (R)-Esomeprazole as described in claim any one of 55-59, It is characterized in that:Target product (R)-Esomeprazole is collected from the reaction product of step (5) Method is that reaction product is dissolved in the water, and is dissolved by heating, activated carbon decolorizing, and activated carbon is filtered to remove, and water removal is concentrated under reduced pressure, when Surplus water is to stop concentration when 2~3 times of products weight is added, and 0~5 DEG C of sub-cooled crystallization obtains to obtain product (R) -4- hydroxyls Base -2- oxo-1-pyrrolidine ethanamides.
61. a kind of preparation method of (R)-Esomeprazole, it is characterised in that:Reaction formula is such as Under,
(1) using (R) -4- chloro-3-hydroxybutanoic acid esters as starting material, azido reaction is carried out, intermediate compound I is obtained;
(2) intermediate compound I is subjected to reduction reaction and obtains intermediate II;
(3) intermediate II and halogenated acetic acids ester are subjected to condensation reaction, obtain intermediate III;
(4) the progress ring closure reaction of intermediate III is obtained into intermediate compound IV;
(5) intermediate compound IV is subjected to ammonolysis reaction, obtains target product (R)-Esomeprazole;Institute It is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl to state R1; The R2 is methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, cyclopenta, cyclohexyl, phenyl or benzyl Base;The step (5) is the intermediate compound IV for obtaining step (4), reacts 4~16 hours with concentrated ammonia liquor at 20~30 DEG C, so Target product (R)-Esomeprazole is collected from reaction product afterwards.
62. the preparation method of (R)-Esomeprazole as described in claim 61, it is characterised in that: The step (5) is the intermediate compound IV for obtaining step (4), reacts 4~16 hours with concentrated ammonia liquor at 20~30 DEG C, then from Target product (R)-Esomeprazole, wherein mole of intermediate compound IV and ammonia is collected in reaction product Than for intermediate compound IV:Ammonia=1:12~15, in terms of the ammonia in ammonia methanol solution;The concentration expressed in percentage by weight of the concentrated ammonia solution It is 25~28%.
63. the preparation method of (R)-Esomeprazole, feature as described in claim 61 or 62 It is:The method that target product (R)-Esomeprazole is collected from the reaction product of step (5) For reaction product is dissolved in the water, dissolves by heating, activated carbon decolorizing, be filtered to remove activated carbon, water removal is concentrated under reduced pressure, works as residue Water is to stop concentration when 2~3 times of products weight is added, and 0~5 DEG C of sub-cooled crystallization obtains to obtain product (R) -4- hydroxyls -2- Oxo-1-pyrrolidine ethanamide.
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