CN106279108B - A kind of method of industrialized production Rabeprazole and dextral-rabeprazole intermediate - Google Patents
A kind of method of industrialized production Rabeprazole and dextral-rabeprazole intermediate Download PDFInfo
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- CN106279108B CN106279108B CN201610666587.9A CN201610666587A CN106279108B CN 106279108 B CN106279108 B CN 106279108B CN 201610666587 A CN201610666587 A CN 201610666587A CN 106279108 B CN106279108 B CN 106279108B
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- ACQRSPBXNFSYMT-UHFFFAOYSA-O CC1[NH2+]C=CC([N+]([O-])=O)=C(C)C1O Chemical compound CC1[NH2+]C=CC([N+]([O-])=O)=C(C)C1O ACQRSPBXNFSYMT-UHFFFAOYSA-O 0.000 description 1
- KKSUAWXQEROLSX-UHFFFAOYSA-N Cc(c(CCl)[n+](cc1)O)c1OCCCOC Chemical compound Cc(c(CCl)[n+](cc1)O)c1OCCCOC KKSUAWXQEROLSX-UHFFFAOYSA-N 0.000 description 1
- BSXAHDOWMOSVAP-UHFFFAOYSA-N Cc(c(CSc1nc(cccc2)c2[nH]1)ncc1)c1OCCCOC Chemical compound Cc(c(CSc1nc(cccc2)c2[nH]1)ncc1)c1OCCCOC BSXAHDOWMOSVAP-UHFFFAOYSA-N 0.000 description 1
- DYWWLPRXOJUMST-UHFFFAOYSA-N Cc1nc(C=CC=CC2)c2[nH]1 Chemical compound Cc1nc(C=CC=CC2)c2[nH]1 DYWWLPRXOJUMST-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention provides a kind of method of industrialized production Rabeprazole and dextral-rabeprazole intermediate, the intermediate is thunder shellfish condensation product, is made under alkaline condition through condensation reaction by 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt with 2-mercaptobenzimidazole.The reaction dissolvent is water, and thunder shellfish condensation product is added in the reaction solution as crystal seed, can prevent the clustering phenomena that agglomerates in reaction solution.This method is easy to operate, environmentally friendly, and product yield is high, high-quality, can be used at least 7.5kg/ batches of amplification productions, is especially suitable for industrial applications.
Description
Technical field
The present invention relates to field of medicinal chemistry more particularly to a kind of preparation of industrialization Rabeprazole and dextral-rabeprazole to close
Key intermediate-thunder shellfish condensation product method.
Background technique
RABEPRAZOLE SODIUM, chemical name 2- [[[4- (3- methoxy propoxy) -3- methyl -2- pyridyl group] methyl] sulfenyl
Base] -1H- benzimidazole sodium salt, be by Japanese Wei Cai company develop proton pump inhibitor, in the end of the year 1997 Japan for the first time
Listing.Dextral-rabeprazole sodium is the dextrorotation optical isomer of RABEPRAZOLE SODIUM, stronger to H+/K+-ATP enzyme effect, and is inhibited
It can restore, plasma gastrin levels be influenced less；With selective strong inhibition helicobacter pylori (HP) effect, pharmacology is living
Property be significantly stronger than laevoisomer and its raceme, by EMCUER pharmaceuticals of India first exploitation, printed in September, 2007
Degree listing.RABEPRAZOLE SODIUM and dextral-rabeprazole sodium gastric ulcer, duodenal ulcer, kiss clinically mainly used for treating
It heals up ulcer, reflux esophagitis, Zhuo-Chinese mugwort (Zollinger-Ellison) syndrome etc..
Thunder shellfish condensation product, also known as Rabeprazole thioether, chemical name 2- { [4- (3- methoxy propoxy) -3- picoline -
2- yl] methyl mercapto } -1H- benzimidazole is the key intermediate for synthesizing RABEPRAZOLE SODIUM and its dextrorotation optical isomer, warp
Peroxidating or asymmetric oxidation, salt-forming reaction can prepare RABEPRAZOLE SODIUM and dextral-rabeprazole sodium.Thunder shellfish is condensed amount of substance
Quality and production cost height, directly influence the quality and production cost of finished product.
The synthetic route for the thunder shellfish condensation product that document is recorded is mainly the following：
Route one (Cheng Maosheng etc., CN1045773C)：It is with 2- chloromethyl -3- methyl -4- [(3- methoxyl group) propoxyl group]
Raw material through thiocarbamide substitution, sodium hydroxide hydrolysis, chloro-formate replace after again with o-phenylenediamine cyclization and obtain.This route technique compared with
Complexity, yield is lower, and economic feasibility is not high.Its synthetic route is as follows：
Route two (Shandong Asia etc., the synthesis of proton pump inhibitor RABEPRAZOLE SODIUM, Chemical IN.Dustry
Times, 2011,25 (8)：46-48)：It is using 2,3- dimethyl -4- [(3- methoxyl group) propoxyl group]-pyridine-N-oxides
Raw material through acetylation, hydrolysis, chloro synthesize 2- chloromethyl -3- methyl -4- [(3- methoxyl group) propoxyl group]-pyridine, then with 2- mercapto
The condensation of base benzimidazole is made, and production technology is more mature.Specific route is as follows：
Due to 2- chloromethyl -3- methyl -4- (3- methoxy propoxy) pyridine (being stored in the form of hydrochloride) and 2- mercapto
Base benzimidazole is easier to buy on the market, technical maturity, and quality is stablized, and the synthetic method of route two can also be referred to, with 2-
Chloromethyl -3- methyl -4- (3- methoxy propoxy) pyridine hydrochloride and 2-mercaptobenzimidazole are starting material, prepare thunder
Shellfish condensation product (referring to CN103232437A).
Route three (brings up biography equality, CN103664886A)：With 2,3- dimethyl 4- nitropyridin-/ V-oxide and 3- methoxy
Base -1- propyl alcohol be raw material through condensation reaction, chlorination, again with 2-mercaptobenzimidazole occur condensation reaction, then with activated zinc
Powder, formic acid are made by reaction.This route technique is more complex, and industrialized production is immature.Specific route is as follows：
The above method all carries out in organic solvent substantially, needs to dispose waste liquid and recycle organic solvent etc., keeps technique numerous
Trivial, increased production cost.
CN102675285A discloses a kind of method that thunder shellfish condensation product is prepared in pure water phase, however the present inventor practices
It was found that the above method is only limitted to prepare several grams of bench scales to several hundred gram-grade samples under laboratory environment, carried out in workshop public
When jin grade amplification production, thunder shellfish condensation product is largely precipitated in reaction solution, and aggregation is blocking, hinders reaction to be normally carried out, to product
Quality and yield cause to seriously affect, and easily cause work safety accident, are not used to industrialized production.
Summary of the invention
It is an object of the invention to solve above-mentioned technical problem, the thunder shellfish for preparing for providing a kind of especially suitable industrial application contracts
The method for closing object, this method can be gone on smoothly in pure water phase, and reaction do not use with last handling process organic molten
Agent, it is environmentally friendly, it is easy to operate, it is at low cost.
To achieve the goals above, the present invention provides following technical scheme：
A kind of method of industrialized production thunder shellfish condensation product, by 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or
Its salt and 2-mercaptobenzimidazole are made through condensation reaction under alkaline condition, which is characterized in that and the reaction dissolvent is water,
Thunder shellfish condensation product is added in the reaction solution as crystal seed.
The reaction route is as follows：
In process of production, it is easy to happen aggregation and agglomeration since the thunder shellfish condensation product product in reaction solution is largely precipitated,
Stirring is caused to be obstructed, production process can not be successfully operation.The present inventor has been surprisingly found that after attempting various methods, and the contracting of thunder shellfish is added
Object is closed as crystal seed and induces crystallization, above-mentioned aggregation and the generation of caking phenomenon can be effectively prevented, guarantees product quality and production
Safety.Industrialized production of the present invention refers to 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or the amount of its salt
Not less than 2kg, preferably 3kg.
Thunder shellfish condensation product crystal seed can be before caking phenomenon occurs before condensation reaction starts or in reaction process
Any time is added.For example, adding before reaction solution becomes turbid and (solid is precipitated) or when reaction solution starts to become turbid
Enter thunder shellfish condensation product crystal seed.More easily, thunder shellfish condensation product crystal seed can be added before starting the reaction.Thunder shellfish condensation product crystal seed
It can be prepared according to any means known in the art, preferably content >=98.5% (area normalization method).
The dosage of the thunder shellfish condensation product crystal seed can be based on 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine
The 3~20% of weight, preferably 5~15%, more preferable 6~12%.
The temperature of the condensation reaction is 10~50 DEG C, preferably 20~40 DEG C, more preferably 25~35 DEG C.
The salt of 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine can be known in the art in the condensation reaction
The organic salt or inorganic salts, such as hydrochloride, bromate, sulfate, phosphate of any suitable etc..
The alkaline condition of the condensation reaction can be the alkali that any suitable known in the art is added, such as hydroxide
Sodium, potassium hydroxide, potassium carbonate, sodium carbonate etc..
2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt, 2-mercaptobenzimidazole, alkali in the reaction
The dosage of equal substances, is that those skilled in the art can be obtained by conventional technical means.In general, 2- chloromethyl -3- first
Base -4- methoxy propoxy pyridine or its salt, 2-mercaptobenzimidazole, alkali molar ratio be 1:(0.7~1.5):(1~4).
Preferably, 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt, 2-mercaptobenzimidazole, alkali molar ratio be
1:(1~1.1):(2~2.5).
In a kind of specific embodiment, the method for above-mentioned industrialized production thunder shellfish condensation product, including step：
1) alkali, 2-mercaptobenzimidazole, thunder shellfish condensation product crystal seed are mixed in water, obtains mixed liquor 1；
2) 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt are added to the water, obtain mixed liquor 2；
3) mixed liquor 2 is added drop-wise in mixed liquor 1, is stirred to react, obtain thunder shellfish condensation product.
In another specific embodiment, the method for above-mentioned industrialized production thunder shellfish condensation product, including step：
1) alkali, 2-mercaptobenzimidazole are mixed in water, obtains mixed liquor 1；
2) 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt are added to the water, obtain mixed liquor 2；
3) mixed liquor 2 is added drop-wise to mixed liquor 1, while thunder shellfish condensation product crystal seed is added, be stirred to react, obtain the condensation of thunder shellfish
Object.
The present invention also provides a kind of methods for preparing Rabeprazole or its sodium salt, including step：
1) by 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt and 2-mercaptobenzimidazole in alkaline item
Through condensation reaction under part, thunder shellfish condensation product is obtained；
2) thunder shellfish condensation product obtains Rabeprazole through oxidation reaction；
3) optionally, Rabeprazole is reacted with sodium salt, obtains RABEPRAZOLE SODIUM；
It is characterized in that, the reaction dissolvent of the step 1) is water, thunder shellfish condensation product is added in the reaction solution as brilliant
Kind.
The present invention also provides a kind of methods for preparing dextral-rabeprazole or its sodium salt, including step：
1) by 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt and 2-mercaptobenzimidazole in alkaline item
Through condensation reaction under part, thunder shellfish condensation product is obtained；
2) the chosen property oxidation reaction of thunder shellfish condensation product, obtains dextral-rabeprazole；
3) optionally, dextral-rabeprazole is reacted with sodium salt, obtains dextral-rabeprazole sodium；
It is characterized in that, the reaction dissolvent of the step 1) is water, thunder shellfish condensation product is added in the reaction solution as brilliant
Kind.
Similarly, in the preparation method of above-mentioned Rabeprazole or sodium salt, dextral-rabeprazole or sodium salt：
The condensation reaction has following one or more features：
A) dosage of the thunder shellfish condensation product crystal seed can be based on 2- chloromethyl -3- methyl -4- methoxy propoxy pyrrole
The 3~20% of pyridine weight, preferably 5~15%, more preferable 6~12%；
B) temperature of the condensation reaction is 10~50 DEG C, preferably 20~40 DEG C, more preferably 25~35 DEG C；
C) in the condensation reaction, 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt, 2- sulfydryl benzo
Imidazoles, alkali molar ratio be 1：(0.7~1.5)：(1~4), preferably 1：(1~1.1)：(2~2.5)；
D) the thunder shellfish condensation product crystal seed is that product agglomeration does not occur before condensation reaction starts or in reaction process now
As the addition of any time before；
E) salt of 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine can be this field in the condensation reaction
Organic salt or inorganic salts, such as hydrochloride, bromate, sulfate, phosphate of any suitable known etc..
F) alkaline condition of the condensation reaction can be the alkali that any suitable known in the art is added, such as hydroxide
Sodium, potassium hydroxide, potassium carbonate, sodium carbonate etc..
The oxidation reaction, sodium salt salt-forming reaction can be carried out according to methods known in the art.
Technical solution of the present invention has the advantages that：
1) reaction carries out in water phase, and reaction process and post-processing do not use any organic solvent, and waste liquid is easy to handle, to ring
Border is friendly, reduces production cost；
2) by the way that thunder shellfish condensation product crystal seed is added, a large amount of thunder shellfish condensation product products being precipitated in water phase agglomeration is effectively prevented
The progress being stirred to react with obstruction, ensure that product quality and production safety；
3) easy to operate, process stabilizing, high income at least can be used for workshop 7.5kg/ batches of amplification productions, be very suitable for work
Industry production application；
4) product purity made from is high, high-quality, be further used for preparing Rabeprazole and dextral-rabeprazole or they
Salt, ensure that going on smoothly and excellent product quality for subsequent reactions.
Specific embodiment
Following embodiment for further describe technical solution of the present invention the characteristics of and advantage, below will to the present invention into
One step it is described in detail.
Embodiment 1：The synthesis of thunder shellfish condensation product
In 50L glass reaction kettle be added purified water (9.0Kg), be added with stirring sodium hydroxide (1.08Kg,
27.00mol), 2-mercaptobenzimidazole (1.80Kg, 11.98mol) then is added and purified water (3.0Kg) stirs evenly, then
Thunder shellfish condensation product (0.30Kg) is added and is used as crystal seed, stirs evenly.
Purified water (12.0Kg) is added in 20L glass reaction kettle, 2- chloromethyl -3- methyl -4- methoxy propoxy pyrrole
Thiamine hydrochloride (3.00Kg, 11.27mol), stirs evenly, and is then added dropwise in the solution of above-mentioned 2-mercaptobenzimidazole.It is added dropwise
In the process, the temperature of reaction solution is controlled at 30 ± 5 DEG C.Drop finishes, and 30 ± 5 DEG C of temperature control are stirred to react 12h.Reaction solution centrifugation, filter cake
It is eluted with 4% sodium hydroxide solution (6.0Kg, W/W), centrifugation.Filter cake is added to 4% sodium hydroxide solution (30.0Kg, W/W)
In, 2h, centrifugation are stirred, filter cake is eluted with 4% sodium hydroxide solution (6.0Kg, W/W), is drenched after centrifugation with purified water (30.0Kg)
Filtrate pH7.0~8.0 are washed till, are centrifuged, dry get Lei Bei condensation product (deducting added crystal seed).
Above-mentioned production process repeats three batches, as a result as follows：
| Batch | Product | Yield | Largest single impurity | Purity |
| First | 3.685kg | 95.20% | 0.52% | 99.26% |
| Second batch | 3.647kg | 94.22% | 0.39% | 99.30% |
| Third batch | 3.677kg | 95.00% | 0.47% | 99.21% |
Embodiment 2：The synthesis of thunder shellfish condensation product
In 100L glass reaction kettle be added purified water (18Kg), be added with stirring sodium hydroxide (2.16Kg,
54.00mol), 2-mercaptobenzimidazole (3.6Kg, 23.96mol) then is added and purified water (6.0Kg) stirs evenly, then plus
Enter thunder shellfish condensation product (0.60Kg) as crystal seed, stirs evenly.
Purified water (24.0Kg) is added in 50L glass reaction kettle, 2- chloromethyl -3- methyl -4- methoxy propoxy pyrrole
Thiamine hydrochloride (6.00Kg, 22.54mol), stirs evenly, and is then added dropwise in above-mentioned solution.During dropwise addition, control reaction
The temperature of liquid is at 30 ± 5 DEG C.Drop finishes, and 30 ± 5 DEG C of temperature control are stirred to react 12h.Solid is uniformly precipitated in reaction solution, substantially without agglomeration
Phenomenon.Reaction solution centrifugation, filter cake are eluted with 4% sodium hydroxide solution (12.0Kg, W/W), centrifugation.Filter cake is added to 4% hydrogen-oxygen
To change in sodium solution (60.0Kg, W/W), stirs 2h, centrifugation, filter cake is eluted with 4% sodium hydroxide solution (12.0Kg, W/W), from
With purified water (60.0Kg) elution to filtrate pH7.0~8.0, centrifugation, dry get Lei Bei condensation product (the added crystalline substance of deduction after the heart
Kind).
Above-mentioned production process repeats three batches, as a result as follows：
Embodiment 3：The synthesis of thunder shellfish condensation product
In 100L glass reaction kettle be added purified water (18Kg), be added with stirring sodium hydroxide (2.16Kg,
54.00mol), 2-mercaptobenzimidazole (3.6Kg, 23.96mol) then is added and purified water (6.0Kg) stirs evenly, then plus
Enter thunder shellfish condensation product (0.30Kg) as crystal seed, stirs evenly.
Purified water (24.0Kg) is added in 50L glass reaction kettle, 2- chloromethyl -3- methyl -4- methoxy propoxy pyrrole
Thiamine hydrochloride (6.00Kg, 22.54mol), stirs evenly, and is then added dropwise in above-mentioned solution.During dropwise addition, control reaction
The temperature of liquid is at 30 ± 5 DEG C.Drop finishes, and 30 ± 5 DEG C of temperature control are stirred to react 12h.Reaction solution caking phenomenon is greatly improved, and reacts energy
Enough go on smoothly.Reaction solution centrifugation, filter cake are eluted with 4% sodium hydroxide solution (12.0Kg, W/W), centrifugation.Filter cake be added to
In 4% sodium hydroxide solution (60.0Kg, W/W), 2h is stirred, centrifugation, filter cake is with 4% sodium hydroxide solution (12.0Kg, W/W)
Elution, with purified water (60.0Kg) elution to filtrate pH7.0~8.0, centrifugation, dry get Lei Bei condensation product after centrifugation.
Embodiment 4：The synthesis of thunder shellfish condensation product
In 100L glass reaction kettle be added purified water (18Kg), be added with stirring sodium hydroxide (2.16Kg,
54.00mol), 2-mercaptobenzimidazole (3.6Kg, 23.96mol) then is added and purified water (6.0Kg) stirs evenly.
Purified water (24.0Kg) is added in 50L glass reaction kettle, 2- chloromethyl -3- methyl -4- methoxy propoxy pyrrole
Thiamine hydrochloride (6.00Kg, 22.54mol), stirs evenly, and is then added dropwise in above-mentioned solution.During dropwise addition, solution is observed
Thunder shellfish condensation product crystal seed (0.30Kg) is added when starting muddy and continues to stir.Drop finishes, and 30 ± 5 DEG C of temperature control are stirred to react 12h.
Caking phenomenon is greatly improved, and reaction can be gone on smoothly.Reaction solution centrifugation, 4% sodium hydroxide solution (12.0Kg, W/ of filter cake
W it) elutes, centrifugation.Filter cake is added into 4% sodium hydroxide solution (60.0Kg, W/W), stirs 2h, centrifugation, 4% hydrogen of filter cake
Sodium hydroxide solution (12.0Kg, W/W) elution is centrifuged with purified water (60.0Kg) elution to filtrate pH7.0~8.0 after centrifugation,
Dry get Lei Bei condensation product.
Comparative example 1：The synthesis of thunder shellfish condensation product
In 5L glass reaction kettle be added purified water (1.00Kg), be added with stirring sodium hydroxide (0.18Kg), then plus
Enter 2-mercaptobenzimidazole (0.30Kg) and purified water (1.0Kg) stirs evenly.By 2- chloromethyl -3- methyl -4- methoxy propyl
Oxygroup pyridine hydrochloride (0.50Kg) and purified water (2.0Kg) mixing, stir evenly, are then added dropwise in above-mentioned solution.It is added dropwise
In the process, 30 ± 5 DEG C of temperature of reaction solution are controlled.Drop finishes, 30 ± 5 DEG C of stirring 12h of reaction solution temperature control.After the reaction was completed, it reacts
Liquid filtering, filter cake are eluted with 4% sodium hydrate aqueous solution (1.0Kg, W/W), then 4% sodium hydrate aqueous solution of filter cake
(5.0Kg, W/W) agitator treating 2h, filtering, filter cake are eluted with 4% sodium hydrate aqueous solution (1.0Kg, W/W), filtering, filter cake
It with purified water (3.3Kg) elution to filtrate pH7~8, filters, dry solid about 0.6Kg.Yield：93.02%.
Comparative example 2：The synthesis of thunder shellfish condensation product
In 5L glass reaction kettle be added purified water (2.2Kg), be added with stirring sodium hydroxide (0.40Kg), then plus
Enter 2-mercaptobenzimidazole (0.66Kg) and purified water (2.2Kg), stirs evenly.By 2- chloromethyl -3- methyl -4- methoxyl group
Propoxyl group pyridine hydrochloride (1.10Kg) and purified water (2.0Kg) mixing, stir evenly, are then added dropwise in above-mentioned solution.Drop
During adding, 30 ± 5 DEG C of temperature of reaction solution are controlled.Drop finishes, 30 ± 5 DEG C of stirring 12h of reaction solution temperature control.During the reaction,
There is a caking phenomenon, but relatively slight, agglomeration is easily broken up when stirring, does not influence the operation of production process.After the reaction was completed, reaction solution
Filtering, filter cake with 4% sodium hydrate aqueous solution (2.2Kg, W/W) elution, then filter cake with 4% sodium hydrate aqueous solution (11Kg,
W/W) agitator treating 2h, filtering, filter cake are eluted with 4% sodium hydrate aqueous solution (2.2Kg, W/W), filtering, filter cake purified water
(7.26Kg) elution is filtered to filtrate pH7~8, dry solid about 1.329Kg.Yield：93.63%, largest single impurity：
0.53%, HPLC purity：99.19%.
Comparative example 3：The synthesis of thunder shellfish condensation product
In 50L glass reaction kettle be added purified water (9.0Kg), be added with stirring sodium hydroxide (1.08Kg), then plus
Enter 2-mercaptobenzimidazole (1.80Kg) and purified water (3.0Kg), stirs evenly.2- chloromethane is added in 20L glass reaction kettle
Base -3- methyl -4- methoxy propoxy pyridine hydrochloride (3.00Kg) and purified water (12.0Kg), stir evenly, then instill
Into above-mentioned solution.During dropwise addition, the temperature of reaction solution is controlled at 30 ± 5 DEG C.When about half volume is added dropwise, in reaction solution
There is harder agglomeration, can not break up.It is stirred to react and is obstructed, production process smooth can not be run, and influence product quality and production
Safety.
Comparative example 4：The synthesis of thunder shellfish condensation product
In 100L glass reaction kettle be added purified water (18Kg), be added with stirring sodium hydroxide (2.16Kg), then plus
Enter 2-mercaptobenzimidazole (3.6Kg) and purified water (6.0Kg), dehydrated alcohol (7.0L) stirs evenly.
2- chloromethyl -3- methyl -4- methoxy propoxy pyridine hydrochloride (6.00Kg) is added in 50L glass reaction kettle
It with purified water (24.0Kg), stirs evenly, is then added dropwise in above-mentioned solution.During dropwise addition, the temperature for controlling reaction solution exists
30±5℃.Drop finishes, and 30 ± 5 DEG C of temperature control are stirred to react 12h.Reaction solution has caking phenomenon, but can break up, reaction can smoothly into
Row.Reaction solution centrifugation, filter cake are eluted with 4% sodium hydroxide solution (12.0Kg, W/W), centrifugation.Filter cake is added to 4% hydroxide
In sodium solution (60.0Kg, W/W), in 25 ± 5 DEG C of stirring 2h, centrifugation, filter cake is drenched with 4% sodium hydroxide solution (12.0Kg, W/W)
It washes, with purified water (60.0Kg) elution to filtrate pH7.0~8.0, centrifugation, dry get Lei Bei condensation product 5.365Kg after centrifugation.
Yield 69.3%, largest single impurity 0.78%, HPLC purity 99.11%.
Comparative example 5：The synthesis of thunder shellfish condensation product
The step of the present embodiment, is identical as comparative example 4, and difference is that the dehydrated alcohol amount being added is 3L.Resulting thunder
Shellfish condensation product about 5.955Kg.Yield 76.9%, largest single impurity 0.74%, HPLC purity 98.48%.
In the reaction process of the present embodiment, compared than comparative example 4, caking phenomenon is more serious, but with ethyl alcohol is not added
Comparative example 3 is compared, and is still improved significantly, and reaction can continue to carry out substantially.Ethyl alcohol is added in reaction system to be changed
Caking phenomenon in kind reaction solution, but products therefrom yield is substantially reduced, and impurity content increases, and product quality decline is not suitable for
Industrialized production and application.
Above embodiments are only purposes of explanation, are effectively reached in order to more fully understand the present invention by the way that crystal seed is added
To the purpose of industrialized production thunder shellfish condensation product.Those of ordinary skill in the art can change on the basis of this specification
Into adjustment response parameter, charge ratio, operating procedure are added other and are conducive to the substance that reaction carries out, such as catalyst etc.
Deng.As long as the change made under the premise of without prejudice to spirit of the invention, belongs to design of the invention, institute of the present invention is fallen into
The range for disclosing and protecting.
Claims (24)
1. a kind of method of industrialized production thunder shellfish condensation product, by 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its
Salt and 2-mercaptobenzimidazole are made through condensation reaction under alkaline condition, which is characterized in that the reaction dissolvent is water, described
Thunder shellfish condensation product is added in reaction solution as crystal seed.
2. the method as described in claim 1, which is characterized in that the dosage of the crystal seed of the thunder shellfish condensation product is 2- chloromethyl-
The 3~20% of 3- methyl -4- methoxy propoxy pyridine weight.
3. method according to claim 2, which is characterized in that the dosage of the crystal seed of the thunder shellfish condensation product is 2- chloromethyl-
The 5~15% of 3- methyl -4- methoxy propoxy pyridine weight.
4. method as claimed in claim 3, which is characterized in that the dosage of the crystal seed of the thunder shellfish condensation product is 2- chloromethyl-
The 6~12% of 3- methyl -4- methoxy propoxy pyridine weight.
5. the method as described in claim 1, which is characterized in that the temperature of the condensation reaction is 10~50 DEG C.
6. method as claimed in claim 5, which is characterized in that the temperature of the condensation reaction is 20~40 DEG C.
7. method as claimed in claim 6, which is characterized in that the temperature of the condensation reaction is 25~35 DEG C.
8. the method as described in claim 1, which is characterized in that in the condensation reaction, 2- chloromethyl -3- methyl -4- methoxy
Base propoxyl group pyridine or its salt, 2-mercaptobenzimidazole, alkali molar ratio be 1：(0.7~1.5)：(1~4).
9. method according to claim 8, which is characterized in that in the condensation reaction, 2- chloromethyl -3- methyl -4- methoxy
Base propoxyl group pyridine or its salt, 2-mercaptobenzimidazole, alkali molar ratio be 1：(1~1.1)：(2~2.5).
10. method as described in any one of claims 1 to 9, which is characterized in that the crystal seed of the thunder shellfish condensation product is to be condensed
Any time before caking phenomenon occurs before reaction starts or in reaction process is added.
11. method as described in any one of claims 1 to 9, which is characterized in that 2- chloromethyl -3- first in the condensation reaction
The salt of base -4- methoxy propoxy pyridine is its organic salt or inorganic salts.
12. method as claimed in claim 11, which is characterized in that 2- chloromethyl -3- methyl -4- methoxy in the condensation reaction
The salt of base propoxyl group pyridine is hydrochloride, bromate, sulfate or phosphate.
13. method as described in any one of claims 1 to 9, which is characterized in that the alkaline condition of the condensation reaction is to pass through
Alkali is added to realize.
14. method as claimed in claim 13, which is characterized in that the alkali be sodium hydroxide, potassium hydroxide, potassium carbonate or
Sodium carbonate.
15. a kind of method for preparing Rabeprazole or its sodium salt, including step：
1) under alkaline condition by 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt and 2-mercaptobenzimidazole
Through condensation reaction, thunder shellfish condensation product is obtained；
2) thunder shellfish condensation product obtains Rabeprazole through oxidation reaction；
3) optionally, Rabeprazole is reacted with sodium salt, obtains RABEPRAZOLE SODIUM；
It is characterized in that, the reaction dissolvent of the step 1) is water, thunder shellfish condensation product is added in the reaction solution as crystal seed.
16. a kind of method for preparing dextral-rabeprazole or its sodium salt, including step：
1) under alkaline condition by 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt and 2-mercaptobenzimidazole
Through condensation reaction, thunder shellfish condensation product is obtained；
2) the chosen property oxidation reaction of thunder shellfish condensation product, obtains dextral-rabeprazole；
3) optionally, dextral-rabeprazole is reacted with sodium salt, obtains dextral-rabeprazole sodium；
It is characterized in that, the reaction dissolvent of the step 1) is water, thunder shellfish condensation product is added in the reaction solution as crystal seed.
17. the method as described in claim 15 or 16, which is characterized in that have following one or more features：
A) dosage of the thunder shellfish condensation product crystal seed be 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine weight 3~
20%；
B) temperature of the condensation reaction is 10~50 DEG C；
C) in the condensation reaction, 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine or its salt, 2-mercaptobenzimidazole,
The molar ratio of alkali is 1：(0.7~1.5)：(1~4)；
D) crystal seed of the thunder shellfish condensation product is before caking phenomenon occurs before condensation reaction starts or in reaction process
Any time is added；
E) salt of 2- chloromethyl -3- methyl -4- methoxy propoxy pyridine can be its organic salt or nothing in the condensation reaction
Machine salt；
F) alkaline condition of the condensation reaction is realized by the way that alkali is added.
18. method as claimed in claim 17, it is characterised in that a) dosage of the thunder shellfish condensation product crystal seed is 2- chloromethyl-
The 5~15% of 3- methyl -4- methoxy propoxy pyridine weight.
19. method as claimed in claim 18, it is characterised in that a) dosage of the thunder shellfish condensation product crystal seed is 2- chloromethyl-
The 5~10% of 3- methyl -4- methoxy propoxy pyridine weight.
20. method as claimed in claim 17, it is characterised in that b) temperature of the condensation reaction is 20~40 DEG C.
21. method as claimed in claim 20, it is characterised in that b) temperature of the condensation reaction is 25~35 DEG C.
22. method as claimed in claim 17, it is characterised in that c) in the condensation reaction, 2- chloromethyl -3- methyl -4- first
Oxygroup propoxyl group pyridine or its salt, 2-mercaptobenzimidazole, alkali molar ratio be 1：(1~1.1)：(2~2.5).
23. method as claimed in claim 17, it is characterised in that e) 2- chloromethyl -3- methyl -4- first in the condensation reaction
The salt of oxygroup propoxyl group pyridine is hydrochloride, bromate, sulfate or phosphate.
24. method as claimed in claim 17, it is characterised in that the alkali described in f) is sodium hydroxide, potassium hydroxide, potassium carbonate
Or sodium carbonate.
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| CN101805327A (en) * | 2010-04-29 | 2010-08-18 | 郝志艳 | Rabeprazole sodium compound and novel preparation method thereof |
| CN102675285A (en) * | 2012-06-02 | 2012-09-19 | 大连理工大学 | Method for pure water phase preparation of rabeprazole sodium |
| CN102702173A (en) * | 2012-06-26 | 2012-10-03 | 滕州市悟通香料有限责任公司 | Method for preparing sulfur ether intermediates of proton pump inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101805327A (en) * | 2010-04-29 | 2010-08-18 | 郝志艳 | Rabeprazole sodium compound and novel preparation method thereof |
| CN102675285A (en) * | 2012-06-02 | 2012-09-19 | 大连理工大学 | Method for pure water phase preparation of rabeprazole sodium |
| CN102702173A (en) * | 2012-06-26 | 2012-10-03 | 滕州市悟通香料有限责任公司 | Method for preparing sulfur ether intermediates of proton pump inhibitor |
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