For preparing intermediate of esomeprazole or its sodium salt and preparation method thereof
Technical field
The invention belongs to pharmaceutical synthesis field, in particular to a kind of new for preparation angstrom
Intermediate V of Suo Meila azoles or its sodium salt and preparation method thereof, be used for preparing esomeprazole or
Intermediate VI of its sodium salt and preparation method thereof, the preparation method of esomeprazole and angstrom
The preparation method of Suo Meila azoles sodium.
Background technology
Chemistry entitled the 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine of omeprazole
Base) methyl] sulfinyl]-1H-benzimidazole, Astrazeneca AB of Sweden develop, be first
The proton pump inhibitor of individual listing.
Esomeprazole is the S-isomer of omeprazole, chemical entitled 5-methoxyl group
-2-[(S)-[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzo miaow
Azoles, molecular formula is: C17H19N3O3S, molecular weight: 345.42, CAS numbering: 119141-88-7.
Shown in the following Formula VII of chemical structural formula:
Esomeprazole can reduce the secretion of gastric acid by specific targeting mechanism, for
The specific inhibitor of proton pump in parietal cell, simultaneously the liver first-pass effect ratio of esomeprazole
The omeprazole of the mixture of R type and two kinds of optical isomers of S type is low, active drug in blood plasma
Substrate concentration is high and lasting.
Esomeprazole listed in the U.S. through FDA approval first in 1999, within 2000, obtained
Accurate in European Union's listing, 2002 granted in China, within 2003, lists in the whole nation.Its injection
For the sodium-salt form of esomeprazole, it is used for treating short-term by FDA approval in March, 2005
The prescription drugs of gastroesophageal reflux disease.
Esomeprazole sodium chemistry is entitled: 5-methoxyl group-2-[(S)-[(4-methoxyl group-3,5-dimethyl
-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole sodium, molecular formula is:
C17H18N3NaO3S, molecular weight: 367.40, CAS numbering: 161796-78-7.Chemistry knot
Structure formula is as shown in following formula I:
At present the preparation method of esomeprazole and Esomeprazole sodium mainly has following a few class:
1. catalyzed by biological enzyme, representing document is WO9617076, is characterized in by single-minded
The catalysed oxidn of enzyme prepares esomeprazole.The method selectivity is high, but the purification of product
More difficult, yield is low, is not suitable for industrialized production.
2. Split Method, representing document has WO9427988, WO2010072759 etc..Its side
Method is to utilize chromatographic column to carry out resolution of omeprazole in order to prepare esomeprazole, this type of method cost
Height, yield is low, is only used for laboratory small lot and prepares.
3. asymmetric oxidation method, represent document have WO9208716, US5714504,
CN95194956 etc..The method is present stage more commonly used technology, and its principle is to utilize
After chiral ligand and metal complex, thioether is carried out asymmetry catalysis oxidation, obtain chirality single
Esomeprazole product, there is heavy metal pollution in the method, to bad environmental.
Therefore, develop that a kind of new pollution is little, low cost, yield high, it is big to be applicable to industrialization
The esomeprazole and the Esomeprazole sodium preparation method that produce are very important.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of new for
Prepare intermediate of esomeprazole or its sodium salt and preparation method thereof.
Specifically, the present invention provides:
(1) a kind of intermediate for preparing esomeprazole or its sodium salt, wherein, described
Intermediate be the compound shown in Formula V:
(2) one prepares the method according to the intermediate described in (1), and described method includes:
In organic solvent, make the compound 5-methoxyl group-1H-benzimidazolyl-2 radicals shown in formula IV-
The reaction as shown in reaction equation A is there is in mercaptan and dichloride sulfone in the presence of organic acid, thus
Obtain the compound shown in Formula V:
(3) according to the method described in (2), wherein, used by the reaction shown in reaction equation A
Organic solvent be chloroform or dichloromethane;More preferably dichloromethane.
(4) according to the method described in (2), wherein, the reaction shown in reaction equation A is anti-
Answering temperature is-40 DEG C to 50 DEG C, is preferably-30 DEG C to 30 DEG C.
(5) according to the method described in (2), wherein, the reaction shown in reaction equation A is anti-
Between Ying Shi 5-12 hour, preferably 7-9 hour.
(6) according to the method described in (2), wherein, the compound shown in formula IV is with described
The mol ratio of dichloride sulfone be 1:(1-3), preferably 1:2.
(7) according to the method described in (2), wherein, the compound shown in formula IV is with described
The mol ratio of organic acid be 1:(1-2), preferably 1:(1.0-1.2).
(8) according to the method described in (2), wherein, described organic acid is acetic acid.
The present invention compared with prior art has the advantages that:
1. present invention firstly provides a kind of new intermediate 5-methoxyl group-1H-benzimidazolyl-2 radicals-
Sulphinyl chlorine (Formula V) and preparation method thereof.
Wherein, described intermediate 5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V) is
The present invention obtains first, and described preparation method is that one makes 5-methoxyl group-1H-benzo
Imidazoles-2-mercaptan (formula IV) and dichloride sulfone react and obtain the compound shown in Formula V
New method.Described preparation method is easy and simple to handle, and products therefrom purity is good, and yield
Height, may be up to about 90% respectively, and particularly the purity of the preferred technical scheme of the present invention can
Up to more than 96%;Therefore industrialized great production it is suitable for.
2. secondly the present invention provides a kind of new intermediate (S)-5-methoxyl group-1H-benzimidazole
-2-sulfinic acid-(S)-1-phenyl chlorocarbonate (Formula IV) and preparation method thereof.
Wherein, described intermediate (S)-5-methoxyl group-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-benzene
Base ethyl ester (Formula IV) is that the present invention obtains first, and described preparation method be a kind of by
Mesosome 5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V) luring at derivant lithium bromide
Lead under effect, utilize the benzimidazole ring in Formula V and chiral raw material (S)-1-phenylethanol simultaneously
Phenyl ring between space steric effect carry out spatiall induction placing reaction prepare (S)-5-methoxyl group
The new method of-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-phenyl chlorocarbonate (Formula IV).Described preparation
Method is easy and simple to handle, and products therefrom purity is good, and yield is high, may be up to 90% respectively
The purity of the preferred technical scheme of left and right, the particularly present invention may be up to more than 98%;Therefore
It is suitable for industrialized great production.
3. present invention also offers a kind of new method preparing esomeprazole.
Wherein, described method is through intermediate (S)-5-methoxyl group-1H-benzimidazolyl-2 radicals-Asia sulphur
Acid-(S)-1-phenyl chlorocarbonate (Formula IV) prepares esomeprazole.The Esso that described method prepares
U.S.A draws the purity of azoles good, and yield is high, may be up to about 90% respectively, the particularly present invention
The purity of preferred technical scheme may be up to more than 95%;And the method operation of the present invention
Simplicity, raw material is easy to get, and is suitably applied industrialized great production.
4. the present invention finally provides a kind of new method preparing Esomeprazole sodium.
Based on the inventive method, the purity of the final Esomeprazole sodium prepared is good, and yield
Height, may be up to about 90% respectively, and particularly the purity of the preferred technical scheme of the present invention can
Up to more than 99.5%, ee value (i.e. enantiomeric excess value) may be up to more than 99%;And
The method of the present invention is easy and simple to handle, and raw material is easy to get, and is suitably applied industrialized great production.
5. whole preparation process of the present invention are all not related to asymmetric oxidation step, therefore
Do not result in heavy metal pollution, and easy and simple to handle, and raw material is easy to get and with low cost, and being suitable for should
For industrialized great production.
6. to prepare Esomeprazole sodium yield high for whole preparation process of the present invention, from
Beginning material (formula IV) may be up to about 70% to a mole total recovery for end product (Formulas I).
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is not
Being limitation of the present invention, those skilled in the art, according to the basic thought of the present invention, can do
Go out various amendment or improvement, but without departing from the basic thought of the present invention, all in the present invention
Within the scope of.
It is an object of the invention to provide one pollute little, low cost, yield height and be applicable to industry
Change the big esomeprazole produced and Esomeprazole sodium preparation method.
To achieve these goals, present invention firstly provides one for preparing esomeprazole
Intermediate V with Esomeprazole sodium and preparation method thereof.Secondly the present invention provides a kind of use
In intermediate VI preparing esomeprazole and Esomeprazole sodium and preparation method thereof.The present invention
Additionally provide the preparation method of a kind of new esomeprazole.Finally the invention provides a kind of new
The preparation method of Esomeprazole sodium.
A. for intermediate V preparing esomeprazole and Esomeprazole sodium and preparation method thereof
Present invention firstly provides a kind of new for preparing esomeprazole and esomeprazole
The intermediate V of sodium, wherein, the chemical name of described intermediate V is 5-methoxyl group-1H-
Benzimidazolyl-2 radicals-sulphinyl chlorine, chemical formula is shown below:
Present invention also offers shown in a kind of formula V for prepare esomeprazole and angstrom
The method of the intermediate of Suo Meila azoles sodium, said method comprising the steps of:
In organic solvent, make the compound 5-methoxyl group-1H-benzimidazolyl-2 radicals shown in formula IV-
The reaction as shown in reaction equation A is there is in mercaptan and dichloride sulfone in the presence of organic acid, thus
Obtain the compound shown in Formula V:
Preferably, described organic solvent can be chloroform or dichloromethane;More preferably
For dichloromethane.
Preferably, intermediate compound IV and the mass/volume of organic solvent are than being (0.8-4.0): 1;
More preferably (1.5-3.0): 1(unit is: g/ml).The too high meeting of this ratio causes intermediate compound IV
Dissolve not exclusively, be unfavorable for that reaction is carried out;The too low cost of material that can increase of ratio, and can prolong
The long response time.
Preferably, the reaction temperature of the reaction shown in reaction equation A be-40 DEG C to 50 DEG C, excellent
Elect-30 DEG C to 30 DEG C as.The too high meeting of reaction temperature causes impurity to increase, and too low meeting causes reaction
Not exclusively.
Preferably, in the 5-12 hour response time of the reaction shown in reaction equation A, it is preferably
7-9 hour.Response time, long meeting caused impurity to increase, and too short meeting causes reaction not exclusively.
Preferably, the compound shown in formula IV is 1 with the mol ratio of described dichloride sulfone:
(1-3), preferably 1:2.The too high meeting of mol ratio cause raw material 5-methoxyl group-1H-benzimidazolyl-2 radicals-
Thiol reactant is incomplete, too low can reduce product 5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine
Purity.
Preferably, described organic acid is acetic acid.It is further preferred that the 5-shown in formula IV
Methoxyl group-1H-benzimidazolyl-2 radicals-mercaptan is 1:(1-2 with the mol ratio of described acetic acid), preferably
For 1:(1.0-1.2).The too high meeting of mol ratio causes raw material 5-methoxyl group-1H-benzimidazolyl-2 radicals-mercaptan
Reaction not exclusively, too low can increase cost of material.
B. for intermediate VI preparing esomeprazole and Esomeprazole sodium and preparation method thereof
Secondly the present invention provides a kind of new for preparing esomeprazole and esomeprazole
The intermediate VI of sodium, wherein, wherein, the chemical name of described intermediate VI is (S)-5-
Methoxyl group-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-phenyl chlorocarbonate, chemical formula is as shown in Formula IV:
Present invention also offers a kind of prepare shown in Formula IV for prepare esomeprazole and angstrom
The method of the intermediate of Suo Meila azoles sodium, said method comprising the steps of:
In organic solvent, make the compound 5-methoxyl group-1H-benzimidazolyl-2 radicals shown in Formula V-
Sulphinyl chlorine is under the effect of derivant lithium bromide and acid binding agent, with chipal compounds (S)-1-
There is following spatiall induction placing reaction in phenylethanol, thus obtains the chirality shown in Formula IV
Compound:
Furthermore, above-mentioned reaction is by intermediate 5-methoxyl group-1H-benzimidazolyl-2 radicals-Asia
Sulfonic acid chloride (Formula V), under the inducing action of derivant lithium bromide, utilizes the benzene in Formula V simultaneously
And the space steric effect between the phenyl ring of imidazole ring and chiral raw material (S)-1-phenylethanol is carried out
Spatiall induction placing reaction prepares (S)-5-methoxyl group-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-benzene
Base ethyl ester (Formula IV).Its reaction mechanism is as follows:
Preferably, described intermediate 5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (formula
V) mol ratio with chiral raw material (S)-1-phenylethanol is 1:(1-1.5);More preferably 1:
(1.1-1.2).If the too high meeting of mol ratio causes intermediate V reaction not exclusively, too low meeting causes
Reaction has (S)-1-phenylethanol of too many excess after terminating, add the difficulty of post processing.
Preferably, described intermediate 5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (formula
V) mol ratio with derivant is 1:(1-3);More preferably 1:(1.2-1.5).If mol ratio
Too high meeting causes inductive effect inconspicuous, if too low increase cost of material.
Preferably, described acid binding agent can be pyridine, triethylamine or trimethylamine;More preferably
For triethylamine.
Preferably, described intermediate 5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (formula
V) mol ratio with acid binding agent is 1:(1-2);More preferably 1:(1.0-1.1).If mol ratio
Too high reaction rate and the efficiency of reducing, the too low cost of material that can increase, increase post processing simultaneously
The difficulty of purification.
Preferably, described organic solvent is oxolane, acetone or dichloromethane;More excellent
Elect oxolane as.
Preferably, intermediate V and the mass/volume of organic solvent are than being (1.0-3.0): 1;More
It is preferably (1.0-2.0): 1(unit is: g:ml);The too high meeting of ratio causes reaction impurities to increase,
The too low meeting of ratio causes reaction to be difficult to carry out completely.
Preferably, the reaction temperature of described spatiall induction placing reaction is-70 DEG C to-10 DEG C;
It is preferably-40 DEG C to-20 DEG C.The too high reaction rate of accelerating of temperature, but spatiall induction is positioned
Effect is bad, and the too low meeting of temperature causes reacting the slowest.
Preferably, the response time of described spatiall induction placing reaction is 3-24 hour;Excellent
Elect 6-10 hour as.Response time is too short can react incomplete, and overlong time can produce more
Impurity.
C. the preparation method of esomeprazole
Present invention also offers a kind of method preparing esomeprazole, wherein, described Esso
U.S.A draws azoles as shown in Formula VII:
Described method includes:
Make the chipal compounds shown in Formula IV, with the Grignard reagent shown in formula III, following grignard occur
Reaction, thus obtain described esomeprazole:
Wherein, M is magnesium or zinc, preferably magnesium;X is halogen, preferably chlorine, bromine or iodine,
More preferably chlorine.
Preferably, the intermediate VI of described grignard reaction and intermediate III Grignard reagent
Mol ratio is 1:(1-1.2);More preferably 1:(1-1.1).Mol ratio too high too low all can cause former
The surplus of material.
Preferably, described grignard reaction is carried out in non-protonic solvent, described
Non-protonic solvent is preferably oxolane, methyl tertiary butyl ether(MTBE), toluene or dimethylbenzene, preferably
For oxolane.Described non-protonic solvent is preferably anhydrous non-protonic solvent.
Preferably, described grignard reaction temperature is between-15 DEG C to 15 DEG C;More preferably
-5 DEG C to 0 DEG C.If reaction temperature is too high can produce more impurity;Too low meeting causes reaction
Not exclusively.
Preferably, the described grignard reaction time is 1-6 hour;More preferably 1-3 hour.
More impurity can be produced if the response time is long;Too short meeting causes reaction not exclusively.
Preferably, the mass/volume ratio of the non-protonic solvent that intermediate VI adds with this step
For (1.0-5.0): 1;More preferably (1.0-2.0): 1(unit is: g/ml).Wherein, if
Intermediate VI makes quantity of solvent on the low side with the mass/volume of non-protonic solvent than too high meeting, product
Impurity increases;The too low consumption that can increase solvent, and in reactant liquor, concentration of substrate is thinning, instead
Should carry out not exclusively.
Preferably, it is protic reagent that described grignard reaction terminates rear cancellation reagent used,
Can be such as 1%-5% dilute hydrochloric acid, 1% dilute sulfuric acid, the aqueous ammonium chloride solution of 10%, preferably
It it is the aqueous ammonium chloride solution of 10%;The most each concentration is mass percent concentration.Because during cancellation
Reaction relatively acutely and also can heat release, be conducive to reaction so adding protic reagent under low temperature
The control of temperature, between therefore protic reagent own temperature is preferably-10 DEG C to 30 DEG C, more
It is preferably 0 DEG C to 5 DEG C.
Preferably, intermediate VI and the mass/volume of protonic solvent are than being (1.5-4.5): 1;
More preferably (2-3): 1(unit is: g/ml).Wherein, if intermediate VI and protic
The mass/volume of solvent causes cancellation incomplete than too high meeting, too low can increase protonic solvent
Consumption, add cost of material.
Preferably, described Grignard reagent intermediate III is by raw material 2-(halogenated methyl)-4-
Methoxyl group-3,5-lutidines (Formula II) and active metal M there is reaction as follows and
Prepare:
Preferably, described active metal M is magnesium or zinc, preferably magnesium.X is halogen,
It is preferably chlorine, bromine or iodine, more preferably chlorine.
Preferably, 2-(halogenated methyl)-4-methoxyl group-3 shown in Formula II, 5-lutidines with
The mol ratio of active metal M is 1:(1.0-1.4), more preferably: 1:(1.0-1.2).Wherein,
If the 2-shown in Formula II (halogenated methyl)-4-methoxyl group-3,5-lutidines and active metal M
Mol ratio too high can increase cost of material;Too low meeting makes reaction incomplete.
Preferably, 2-(halogenated methyl)-4-methoxyl group-3 shown in Formula II, 5-lutidines with
The reaction temperature of active metal M is 0-50 DEG C, more preferably 10-30 DEG C;If reaction temperature
The too high unstability that can increase reaction;Temperature is too low can extend the response time, even results in anti-
Should be incomplete.
Preferably, 2-(halogenated methyl)-4-methoxyl group-3 shown in Formula II, 5-lutidines with
The response time of active metal M is 1-10 hour, more preferably 5-8 hour.Wherein, as
Really the response time long can increase unstable factor, is easily generated more impurity;Too short meeting causes
Reaction is not exclusively.
Preferably, 2-(halogenated methyl)-4-methoxyl group-3 shown in Formula II, 5-lutidines with
The reaction of active metal M is carried out in non-protonic solvent, and described aprotic is molten
Oxolane, methyl tertiary butyl ether(MTBE), more preferably oxolane are preferably selected in agent.
Preferably, 2-(halogenated methyl)-4-methoxyl group-3 shown in Formula II, 5-lutidines with
The mass/volume of non-protonic solvent is than being (1.0-3.0): 1;More preferably (1.0-2.0): 1(is mono-
Position is: g/ml).If the 2-shown in Formula II (halogenated methyl)-4-methoxyl group-3,5-dimethyl pyrazole
Pyridine makes reaction system uneven with the mass/volume of non-protonic solvent than too high meeting, and impact is anti-
Should be normally carried out;Too low meeting makes substrate concentration in reaction system too low, and reaction is difficult to carry out
Entirely.
Preferably, 2-(halogenated methyl)-4-methoxyl group-3 shown in Formula II, 5-lutidines with
The reaction of active metal M is to carry out under the effect of initiator, and described initiator is preferred
For iodine, glycol dibromide or iodomethane, more preferably iodine.
Preferably, 2-(halogenated methyl)-4-methoxyl group-3 shown in Formula II, 5-lutidines with
The mol ratio of initiator is (20-80): 1, more preferably (40-60): 1.If shown in Formula II
Too high meeting causes 2-(halogenated methyl)-4-methoxyl group-3,5-lutidines with the mol ratio of initiator
Cause not exclusively;The too low meeting of molar ratio makes initiator excess, brings tired to follow-up removing impurity
Difficulty, too increases cost of material simultaneously.
Preferably, the Grignard reagent shown in formula III is to protect at noble gas (such as nitrogen)
Protect lower preparation.
Such as, in one embodiment of the invention, the Grignard reagent shown in formula III is logical
Cross what following methods was prepared: by 2-(the halogenated methyl)-4-methoxyl group-3,5-shown in Formula II
Lutidines is in non-protonic solvent, under noble gas (such as nitrogen) is protected, and profit
With initiator, make 2-(halogenated methyl)-4-methoxyl group-3 shown in Formula II, 5-lutidines and work
Property metal reaction, thus prepare the Grignard reagent shown in formula III.
D. the preparation method of Esomeprazole sodium
Present invention also offers a kind of method preparing Esomeprazole sodium, wherein, described angstrom
Suo Meila azoles sodium is shown in formula I:
Described method includes:
1) esomeprazole shown in Formula VII is prepared according to the method described in C;And
2) make the esomeprazole shown in Formula VII that following salt-forming reaction occurs, thus obtain institute
The Esomeprazole sodium stated:
Preferably, in step 2) in, make the esomeprazole shown in Formula VII and organic sodium
Salt (such as sodium alkoxide) in corresponding organic solvent (such as alcohol) occur described in salt-forming reaction,
Thus obtain described Esomeprazole sodium.
Preferably, the esomeprazole shown in Formula VII is 1 with the mol ratio of Organic Sodium Salt:
(1.0-1.5), more preferably 1:(1.0-1.2).Mol ratio too low increase cost of material, and
Bringing too much Organic Sodium Salt in later crystallization into causes content defective;Too high meeting makes into salt and does not fills
Point, affect yield.
Preferably, the matter of the solvent corresponding with Organic Sodium Salt of the esomeprazole shown in Formula VII
Amount/volume ratio is 1:(1.0-3.0), more preferably 1:(1.5-2.0) (unit is: g/ml);Ratio
It is worth the difficulty of the follow-up crystallize of too low increase, reduces yield;Too high meeting causes too early crystallize, reduces
The purity of product.
Preferably, in step 2) in, make the esomeprazole shown in Formula VII and Feldalat NM
Methanol solution occur described in salt-forming reaction, thus obtain described Esomeprazole sodium.
Preferably, in step 2) in, the solution after described salt-forming reaction adds first
Base tertbutyl ether, crystallize, filters, thus obtains described Esomeprazole sodium.Preferred
It is, the esomeprazole shown in Formula VII and the mass volume ratio of described methyl tertiary butyl ether(MTBE)
(g/ml) it is 1:(3-10), more preferably 1:(4-6).If the too high meeting of ratio makes crystallize the completeest
Entirely, ratio is too low can increase unnecessary cost of material.
In one embodiment of the invention, first pass through 5-methoxyl group-1H-benzo miaow
Azoles-2-mercaptan (formula IV) makes 5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V),
Then chiral intermediate (S)-5-methoxyl group-1H-benzimidazole is prepared with (S)-1-phenylethanol reaction
-2-sulfinic acid-(S)-1-phenyl chlorocarbonate (Formula IV).Separately, by raw material 2-(chloromethyl)-4-methoxyl group-3,5-
Lutidines (Formula II) and active metal M react and make Grignard reagent (formula III).In
Mesosome VI and intermediate III generation grignard reaction obtain esomeprazole (Formula VII), finally
Salt is become to prepare target product Esomeprazole sodium (Formulas I) again.Its course of reaction can be for following institute
The course of reaction shown:
According to above reaction equation, the method for the present invention may particularly include following steps:
1. raw material II is in non-protonic solvent, under noble gas (such as nitrogen) protection, adds
Enter a small amount of initiator, react with active metal and prepare Grignard reagent (III):
Above-mentioned reactivity metal can be magnesium and zinc, preferably magnesium;Reaction temperature can be at 0 DEG C
To 50 DEG C, preferably 10 DEG C to 30 DEG C;Response time can be at 1-10 hour, preferably 5-8
Hour;Non-protonic solvent is selected from methyl tertiary butyl ether(MTBE), oxolane, preferably tetrahydrochysene furan
Mutter;Initiator is selected from iodine, glycol dibromide, iodomethane, preferably iodine.
2. prepare 5-methoxyl group-1H-with 5-methoxyl group-1H-benzimidazolyl-2 radicals-mercaptan (formula IV)
Benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V):
Above-mentioned reaction solvent for use can be chloroform, dichloromethane, preferably dichloromethane;
Reaction temperature is between-40 DEG C to 50 DEG C, is preferably-30 DEG C to 30 DEG C;Response time is at 5-12
Within hour, preferably 7-9 hour;5-methoxyl group-1H-benzimidazolyl-2 radicals shown in formula IV-
Mercaptan is 1:(1-3 with the mol ratio of dichloride sulfone), preferably 1:2;5-first shown in formula IV
Oxy-1 H-benzimidazolyl-2 radicals-mercaptan is 1:(1-2 with the mol ratio of glacial acetic acid), preferably 1:
(1.0-1.2)。
3.5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V) is at derivant lithium bromide
Under inducing action, utilize the benzimidazole ring in Formula V and chiral raw material (S)-1-phenyl second simultaneously
Space steric effect between the phenyl ring of alcohol carries out spatiall induction placing reaction and prepares (S)-5-methoxy
Base-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-phenyl chlorocarbonate (Formula IV):
Above-mentioned reaction 5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V) is former with chirality
The mol ratio of material (S)-1-phenylethanol is 1:(1-1.5), preferably 1:(1.1-1.2);5-methoxy
Base-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V) is 1:(1-3 with the mol ratio of derivant),
It is preferably 1:(1.2-1.5);Acid binding agent used can be pyridine, triethylamine, trimethylamine, preferably
For triethylamine;5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V) rubs with acid binding agent
That ratio is 1:(1-2), preferably 1:(1.0-1.1);Solvent for use can be oxolane, acetone,
Dichloromethane, preferably oxolane;Reaction temperature can be-70 DEG C to-10 DEG C, is preferably
-40 DEG C to-20 DEG C;The response time of described reaction is 3-24 hour, preferably 6-10 hour.
4. the chiral intermediate compounds shown in Formula IV is carried out with the Grignard reagent shown in formula III
Grignard reaction, makes sodium salt the most again, obtains Esomeprazole sodium:
Above-mentioned grignard reaction intermediate VI is 1:(1-1.2 with the mol ratio of intermediate III), excellent
Elect 1:(1-1.1 as);Solvent for use can be oxolane, methyl tertiary butyl ether(MTBE), toluene, two
Toluene, preferably oxolane;Reaction temperature is between-15 DEG C to 15 DEG C, is preferably-5 DEG C
To 0 DEG C;Response time is 1-6 hour, preferably 1-3 hour;Grignard reaction terminates rear institute
Can be 1%-5% dilute hydrochloric acid, 1% dilute sulfuric acid, the aqueous ammonium chloride solution of 10% with cancellation reagent,
It is preferably the aqueous ammonium chloride solution of 10%;The most each concentration is mass percent concentration.
Products obtained therefrom HPLC purity is more than 99.5%, and ee value is more than 99%.
Mode by the following examples further explains and describes present invention, but these
Embodiment is not to be construed as limiting the scope of the invention.
In the examples below, HPLC detection instrument can be (such as) Japan Shimadzu
The Shimadzu LC-20A that company produces.The computational methods of purity use area normalization
Method;It is attached that the assay method of purity and ee value can be found in Chinese Pharmacopoeia (2010 editions) second
Record VD;The computing formula of molar yield is: (product molar number/main material mole
Number) × 100%.Mass Spectrometer Method instrument is the API being available from American AB SCIES company
5500 type liquid chromatography mass combined instruments.NMR detection instrument is for being available from BRUKER
The AM 400MHZ type nuclear magnetic resonance analyser of company.
In the examples below, 2-(chloromethyl)-4-methoxyl group-3,5-lutidines is available from Li
Sun city Rui Pu chemical technology research and development centre;5-methoxyl group-1H-benzimidazolyl-2 radicals-mercaptan is available from Hubei Province
Heng Tong great achievement Chemical Co., Ltd. of state city;Lithium bromide is available from Jinghui Chemical Inst., Hefei;
(S)-1-phenylethanol is available from Dalian Rong Yu development in science and technology company limited;Dichloride sulfone is available from
Chinese and Western, Beijing tech Science and Technology Ltd.;Glacial acetic acid is available from Suzhou Le Cheng Chemical Co., Ltd..
Embodiment 1: the preparation of the Grignard reagent shown in formula III:
It is incubated at about 20 DEG C, nitrogen displacement reaction system, adds in 1000ml reaction bulb
150ml oxolane (hereinafter referred to as THF) and magnesium chips (after pretreatment) 68.0g(2.80mol),
Iodine 12.7g(0.05mol), stir 1 hour, be warmed up to 30 DEG C, be slowly added dropwise simultaneously and be dissolved in
2-(chloromethyl)-4-methoxyl group-3,5-lutidines 464.3g (2.50mol) of 150ml THF and
12.7g(0.05mol) the mixture of iodine, drips and finishes, and is incubated and reacts 5 hours at 30 DEG C, cooling
To 20 DEG C to 25 DEG C, stand-by.
Wherein, magnesium chips preprocess method is as follows: the hydrochloric acid agitator treating with 5% 30 minutes, soon
Speed sucking filtration with acetone drip washing (minimizing and time of air contact as far as possible), horse after vacuum drying
Upper use.
Embodiment 2: the preparation of the Grignard reagent shown in formula III:
It is incubated at about 20 DEG C, nitrogen displacement reaction system, adds in 1000ml reaction bulb
150ml oxolane (hereinafter referred to as THF) and zinc bits (after pretreatment) 183.1g
(2.80mol), iodine 12.7g(0.05mol), stir 1 hour, be warmed up to 30 DEG C, with
Time be slowly added dropwise 2-(the chloromethyl)-4-methoxyl group-3,5-lutidines being dissolved in 150ml THF
The mixture of 464.3g (2.50mol) and 12.7g(0.05mol) iodine, drips and finishes, and insulation is at 30 DEG C
React 8 hours, be cooled to 20 DEG C to 25 DEG C, stand-by.
Wherein, zinc bits preprocess method is as follows: the hydrochloric acid agitator treating with 5% 30 minutes, soon
Speed sucking filtration with acetone drip washing (minimizing and time of air contact as far as possible), horse after vacuum drying
Upper use.
The preparation of embodiment 3:5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V):
630.8g(3.50mol is added under 3L tri-mouthfuls of reaction bulbs, mechanical agitation) 5-methoxyl group-1H-
Benzimidazolyl-2 radicals-mercaptan, 300ml dichloromethane and 210.2g(3.50mol) glacial acetic acid, cold
But to about-30 DEG C, 945g(7.00mol is dripped) dichloride sulfone, dropping in about 2 hours is complete.
It is incubated-30 DEG C of stirring reactions 0.5 hour, rises to 30 DEG C and react 9 hours, TLC is controlled (stone
Oil ether: ethyl acetate=2:1) raw material disappearance, stopped reaction removes solvent and by-product under reduced pressure,
Obtain pale yellow oil 777.5g, molar yield 96.3%, HPLC purity 96.1%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI):
C8H7ClN2O2S molecular weight: 230.7, [M+H]+Measured value: 231.6.
The preparation of embodiment 4:5-methoxyl group-1H-benzimidazolyl-2 radicals-sulphinyl chlorine (Formula V):
630.8g(3.50mol is added under 3L tri-mouthfuls of reaction bulbs, mechanical agitation) 5-methoxyl group-1H-
Benzimidazolyl-2 radicals-mercaptan, 300ml chloroform and 420.3g(7.00mol) glacial acetic acid, cold
But to about-40 DEG C, 1417.5g(10.5mol is dripped) dichloride sulfone, within about 2 hours, drip
Finish.It is incubated-40 DEG C of stirring reactions 0.5 hour, rises to 50 DEG C and react 5 hours, in TLC
Control (petroleum ether: ethyl acetate=2:1) raw material disappear, stopped reaction remove under reduced pressure solvent and
By-product, obtains pale yellow oil 767.1g, molar yield 95.0%, HPLC purity 95.8%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI):
C8H7ClN2O2S molecular weight: 230.7, [M+H]+Measured value: 231.3.
Embodiment 5:(S)-5-methoxyl group-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-phenyl chlorocarbonate
The preparation of (Formula IV):
In reaction bulb add 353.2g(2.89mol) (S)-1-phenylethanol, 274.3g
(3.16mol) lithium bromide, 292.8g(2.89mol) triethylamine and 500ml THF, stirring
Uniformly, it is cooled to-40 DEG C, is slowly added dropwise the intermediate V660.7g that embodiment 3 is produced
(2.86mol), dropping process temperature controls at-40 DEG C to-30 DEG C, drips and finishes, and continues insulation and exists
-40 DEG C to-30 DEG C are reacted 8 hours.Controlling in HPLC, raw material disappears substantially, removes THF under reduced pressure,
Adding 400ml dichloromethane and about the 10 DEG C pure water of 300ml, agitator treating removes bromination
The by-product triethylamine hydrochloride of lithium and acid binding agent, extracts target product.Separatory, organic facies is used
30g anhydrous sodium sulfate is dried, sucking filtration, and organic solvent is evaporated off, and adds 550ml isopropanol and heats up
To dissolving, it is cooled to 0 DEG C to 5 DEG C, crystallize 3 hours.Obtain light yellow product 857.8g, rub
That yield 94.8%, HPLC purity 98.8%, ee value 98.61%.
The detection data of the title product obtained by nuclear magnetic resonance, NMR and mass spectral analysis are as follows:1H
NMR (400MHz, CD3OD): δ=7.48 (d, 1H), 7.38(d, 5H), 7.14 (s, 1H),
6.92 (t, 1H), 6.26 (m, 1H), 5.10 (s, 1H), 3.83 (s, 3H), 1.49 (d, 3H);13C NMR (75MHz, CD3OD): δ=156.1,141.5,140.6,139.8,131.2,128.9,
128.9,127.6,127.1,127.1,116.3,111.6,100.9,76.1,56.0,19.8;
HR-MS (ESI): C16H16N2O3S molecular weight: 316.4, [M+H]+Measured value: 317.5.
Embodiment 6:(S)-5-methoxyl group-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-phenyl chlorocarbonate
The preparation of (Formula IV):
In reaction bulb add 523.8g(4.29mol) (S)-1-phenylethanol, 372.4g
(4.29mol) lithium bromide, 292.8g(2.89mol) triethylamine and 500ml THF, stirring
Uniformly, it is cooled to-70 DEG C, is slowly added dropwise the intermediate V660.7g that embodiment 4 is produced
(2.86mol), dropping process temperature controls at-30 DEG C to-20 DEG C, drips and finishes, and continues insulation and exists
-30 DEG C to-20 DEG C are reacted 10 hours.Controlling in HPLC, raw material disappears substantially, removes under reduced pressure
THF, adds 400ml dichloromethane and about the 10 DEG C pure water of 300ml, and agitator treating removes
The by-product triethylamine hydrochloride of lithium bromide and acid binding agent, extracts target product.Separatory, organic
It is dried with 30g anhydrous sodium sulfate, sucking filtration, organic solvent is evaporated off, add 550ml isopropanol
It is warming up to dissolve, is cooled to 0 DEG C to 5 DEG C, crystallize 3 hours.Obtain light yellow product 890.4g,
Molar yield 95.3%, HPLC purity 98.4%, ee value 98.53%.
The detection data of the title product obtained by nuclear magnetic resonance, NMR and mass spectral analysis are as follows:1H
NMR (400MHz, CD3OD): δ=7.47 (d, 1H), 7.36(d, 5H), 7.15 (s, 1H),
6.93 (t, 1H), 6.26 (m, 1H), 5.10 (s, 1H), 3.85 (s, 3H), 1.48 (d, 3H);13C NMR (75MHz, CD3OD): δ=156.1,141.5,140.5,139.6,131.1,128.9,
128.8,127.5,127.1,127.1,116.2,111.6,100.9,76.0,55.9,19.7;
HR-MS (ESI): C16H16N2O3S molecular weight: 316.4, [M+H]+Measured value: 317.7.
Embodiment 7: preparation 5-methoxyl group-2-[(S)-[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)
Methyl] sulfinyl]-1H-benzimidazole (VII):
Three mouthfuls of reaction bulbs add the 727.7g(2.30mol of embodiment 5 preparation) (S)-5-methoxy
Base-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-phenyl chlorocarbonate (Formula IV) and 450ml oxolane,
It is cooled to about-5 DEG C, under mechanical agitation, the about 630ml that dropping is produced according to embodiment 1 method
Grignard reagent (III), dropping temperature controls at-5 DEG C to 0 DEG C, drips complete follow-up continuation of insurance temperature
Reacting 3 hours at about-5 DEG C, control (chloroform: methanol=5:1) in TLC, raw material disappears.
Removing THF under reduced pressure, add 400ml dichloromethane extraction target product, reaction bulb is placed in frozen water
10% ammonium chloride solution (0 DEG C to 5 DEG C) 300ml is added under bath (about 0 DEG C) mechanical agitation
Carry out cancellation.Separatory, organic facies 30g anhydrous sodium sulfate is dried, sucking filtration, is evaporated off organic molten
Agent, obtains purple grease 733.2g, molar yield 92.3%, HPLC purity 96.9%, ee
Value 98.84%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI):
C17H19N3O3S, molecular weight: 345.4, [M+H]+Measured value: 346.6.
Embodiment 8: preparation 5-methoxyl group-2-[(S)-[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)
Methyl] sulfinyl]-1H-benzimidazole (VII):
Three mouthfuls of reaction bulbs add the 829.0g(2.40mol of embodiment 6 preparation) (S)-5-methoxy
Base-1H-benzimidazolyl-2 radicals-sulfinic acid-(S)-1-phenyl chlorocarbonate (Formula IV) and 450ml oxolane,
It is cooled to about-15 DEG C, under mechanical agitation, the pact that dropping is produced according to embodiment 2 method
630ml Grignard reagent (III), dropping temperature controls, at-15 DEG C to 0 DEG C, to drip complete follow-up
Continuation of insurance temperature is reacted 1 hour at about-15 DEG C, controls (chloroform: methanol=5:1) in TLC, former
Material is basic to disappear.Remove THF under reduced pressure, add 400ml dichloromethane extraction target product, instead
Answer bottle to be placed under ice-water bath (about 0 DEG C) mechanical agitation and add 10% ammonium chloride solution (0
DEG C to 5 DEG C) 300ml carries out cancellation.Separatory, organic facies 30g anhydrous sodium sulfate is dried,
Sucking filtration, is evaporated off organic solvent, obtains purple grease 747.7g, molar yield 90.2%, HPLC
Purity 96.5%, ee value 98.81%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI):
C17H19N3O3S molecular weight: 345.4, [M+H]+Measured value: 346.3.
Embodiment 9: prepare Esomeprazole sodium crude product (I):
The purple grease 700g(2.03mol of Example 7 gained), addition 500ml
Absolute ethyl alcohol and stirring is dissolved, and adds 700ml dehydrated alcohol and 90g(2.25mol) hydroxide
The mixed solution of sodium, 25 DEG C stirring 1 hour after add 4000ml methyl tertiary butyl ether(MTBE) (angstrom
Suo Meila azoles sodium indissoluble solvent, can promote crystallize), about 10 DEG C are stirred 12 hours, have solid
Body separates out, and filters, decompression drying, obtains Esomeprazole sodium crude product 654.8g, molar yield
87.8%, HPLC purity 98.4%, ee value 99.92%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI):
C17H18N3NaO3S molecular weight: 367.4, [M+H]+Measured value: 368.1.
Embodiment 10: prepare Esomeprazole sodium crude product (I):
The purple grease 700g(2.03mol of Example 8 gained), addition 500ml
Absolute methanol stirring and dissolving, adds 700ml absolute methanol and 90g(2.25mol) hydroxide
The mixed solution of sodium, 25 DEG C of stirrings added the methyl tertiary butyl ether(MTBE) of 4500ml after 1 hour,
About 10 DEG C are stirred 12 hours, have solid to separate out, and filter, decompression drying, obtain Esso beautiful
Draw azoles sodium crude product 657.1g, molar yield 88.1%, HPLC purity 98.2%, ee value 99.94%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI):
C17H18N3NaO3S molecular weight: 367.4, [M+H]+Measured value: 368.4.
Embodiment 11: refining of Esomeprazole sodium (I):
Reaction bulb adds the Esomeprazole sodium crude product 500g(1.36mol of embodiment 9),
The dichloromethane of 1000ml and 1000ml pure water, stirring is cooled to about 0 DEG C;It is slowly added to
Glacial acetic acid, is adjusted to pH value 6.5-6.8(and about needs 100ml), finish, stir extraction 0.5
Hour, separatory, aqueous phase dichloromethane extracts twice 500ml/ time * 2 again.Merge all organic
Phase, is dried 2 hours with 40g anhydrous sodium sulfate, removes solvent under reduced pressure, again obtain after filtration
Purple grease.Add 350ml absolute methanol stirring and dissolving, add 500ml subsequently anhydrous
Methanol and 60.0g(1.50mol) mixed solution of sodium hydroxide, add after stirring 1 hour
2700ml methyl tertiary butyl ether(MTBE), about 10 DEG C are stirred 12 hours, have a large amount of solid to separate out, mistake
Filter, decompression drying, obtain Esomeprazole sodium finished product 476.0g, molar yield 95.2%, HPLC
Purity 99.7%, ee value 99.97%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI):
C17H18N3NaO3S molecular weight: 367.4, [M+H]+Measured value: 368.7.
Embodiment 12: refining of Esomeprazole sodium (I):
Reaction bulb adds the Esomeprazole sodium crude product 500g(1.36mol of embodiment 10),
The dichloromethane of 1000ml and 1000ml pure water, stirring is cooled to about 0 DEG C;It is slowly added to
Glacial acetic acid, is adjusted to pH value 6.5-6.8(and about needs 100ml), finish, stir extraction 0.5
Hour, separatory, aqueous phase dichloromethane extracts twice 500ml/ time * 2 again.Merge all organic
Phase, is dried 2 hours with 40g anhydrous sodium sulfate, removes solvent under reduced pressure, again obtain after filtration
Purple grease.Add 350ml absolute methanol stirring and dissolving, add 500ml subsequently anhydrous
Methanol and 60.0g(1.50mol) mixed solution of sodium hydroxide, add after stirring 1 hour
2700ml methyl tertiary butyl ether(MTBE), about 10 DEG C are stirred 12 hours, have a large amount of solid to separate out, mistake
Filter, decompression drying, obtain Esomeprazole sodium finished product 474.0g, molar yield 94.8%, HPLC
Purity 99.8%, ee value 99.99%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI):
C17H18N3NaO3S molecular weight: 367.4, [M+H]+Measured value: 368.5.