CN107857724A - A kind of pyridine hydrochloride B3 workshop sections chlorination reaction method - Google Patents
A kind of pyridine hydrochloride B3 workshop sections chlorination reaction method Download PDFInfo
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- CN107857724A CN107857724A CN201711110056.2A CN201711110056A CN107857724A CN 107857724 A CN107857724 A CN 107857724A CN 201711110056 A CN201711110056 A CN 201711110056A CN 107857724 A CN107857724 A CN 107857724A
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- kettle
- pocl3
- concentrate
- under reduced
- reduced pressure
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
Abstract
The present invention relates to a kind of pyridine hydrochloride B3 workshop sections chlorination reaction method, comprise the following steps：A. B2 dry products are added to above fixed bed and form accumulation bed material, b. POCl3 is uniformly added drop-wise to above B2 dry products and reacted, c. the liquid product for reacting generation is the picoline of 4 chlorine, 3 methoxyl group 2, and reactor bottom is flowed to by fixed bed, and flow to and following kettle is recovered under reduced pressure；D. the whole products for reacting production are moved to kettle is recovered under reduced pressure to vacuumize and POCl3 is recovered under reduced pressure, concentrate is put into hydrolysis kettle in kettle；E. after concentrate hydrolysis, ammoniacal liquor regulation pH value 8 is added dropwise, after the liquid sufficient standing layering after f. hydrolysis, layer oily matter is the picoline of B3 workshop sections 4 chlorine of product, 3 methoxyl group 2, is put to B3 intermediate storage tanks.The advantage of the invention is that：1st, the conversion ratio of reaction is improved.2nd, direct solid-liquid reaction has saved the use of a large amount of dichloromethane, reduces operating process, reduces employee labour, reduces cost of material.3rd, the security risk of reaction is originally reduced.
Description
Technical field：
The present invention relates to a kind of preparation method of bulk drug, B3 chlorination reactions workshop section is anti-in more particularly to a kind of pyridine hydrochloride
Induction method.
Background technology：
Pyridiniujm is the important medicine intermediate of Pantoprazole, and pyridiniujm, wherein B3 are produced by the use of methyl maltol as raw material
Chlorination reaction workshop section utilizes former chlorination reaction mechanism：
Former process conditions are still reaction, and chlorination reaction is participated in using POCl3 as chlorinating agent, is first fully dissolved with chloromethanes
B2 dry products（3- methoxyl group -2- methyl -4- pyridones）, reacted after the POCl3 of quintuple has all been added, because of three
Chlorethoxyfos amount is bigger, larger potential safety hazard be present and yield is not high.
The content of the invention
The purpose of the present invention is exactly to solve the shortcomings that yield low-security difference existing for existing still reaction, there is provided
A kind of pyridine hydrochloride B3 workshop sections chlorination reaction method.
The technical solution adopted by the present invention is as follows：
A kind of pyridine hydrochloride B3 workshop sections chlorination reaction method, it is characterised in that comprise the following steps：
A. by B2 workshop sections above obtained by B2 dry products, be added to above the fixed bed in fixed bed reactors formed accumulation bed
Material, the temperature in bed is controlled to be no more than 35 DEG C by heat transferring medium；
B. POCl3 is pumped into head tank, directly POCl3 is uniformly added drop-wise to above B2 dry products and occurred instead with B2 dry products
Should, it is 500kg/h to control POCl3 that flow is added dropwise, and controlling reaction temperature is at 80-85 DEG C；
C. the liquid product for reacting generation is the chloro- 3- methoxyl groups -2- picolines of 4-, and liquid product flows to reaction by fixed bed
Device bottom, and flow to and following kettle is recovered under reduced pressure；
D. after POCl3 completion of dropwise addition, the whole products for reacting production are moved to kettle is recovered under reduced pressure, kettle is recovered under reduced pressure and vacuumizes
POCl3 is recovered under reduced pressure, has reclaimed and remaining concentrate temperature is down to 70 DEG C after POCl3, by concentrate in kettle while hot
It is put into lower floor's hydrolysis kettle；
E. running water should be put into hydrolysis kettle in advance and is cooled to less than 5 DEG C, the concentrate after decompression is put into hydrolysis kettle, is controlled
Dispensing speed processed, hydrolysis kettle kettle temperature are controlled below 35 degree, and concentrate continues after discharging after stirring concentrate two hours of hydrolysis,
Ammoniacal liquor regulation pH value 8 is added dropwise, keeps material temperature to be no more than 40 DEG C；
F. after the liquid sufficient standing layering after hydrolyzing, layer oily matter is the chloro- 3- methoxyl groups -2- methyl pyrroles of B3 workshop sections product 4-
Pyridine, it will be put after the product filtering of B3 workshop sections to B3 intermediate storage tanks.
Tank reactor is replaced as reaction carriers to occur using new fixed bed reactors in above-mentioned technical proposal
Chlorination reaction, using liquid-solid phase fixed bed reactors, B2 dry products are in granular form, 2~15mm of particle diameter or so, are piled into certain
The bed of height, bed transfixion, POCl3 are reacted by bed.POCl3 reacts when being added dropwise, and simultaneously will
Product is removed, and promotes reaction positive direction to carry out.
The advantage of the invention is that：
1st, can make to remove production in time in the more abundant and course of reaction of solid-liquid reaction by the use of fixed bed reactors
Thing, reaction positive direction is carried out, improve the conversion ratio of reaction.
2nd, the principle first reacted again with dichloromethane dissolving before reaction changes, direct solid-liquid reaction have been saved greatly
The use of dichloromethane is measured, reduces operating process, reduces employee labour, reduces cost of material.
3rd, the present apparatus changes the mode that POCl3 participates in reaction, is disposably added and is participated in again instead by original POCl3
The mode answered is changed to the border ring when being added dropwise and removes product, because the amount in fixed bed with respect to POCl3 greatly reduces, reduces
The security risk of reaction（Because chuck medium is that water POCl3 chance water can explode）.
Brief description of the drawings：
Fig. 1 is the process chart of the present invention；
Fig. 2 is the structural representation of fixed bed reactors in Fig. 1.
Embodiment：
First, as shown in Fig. 2 fixed bed reactors of the present invention, including the tank body with chuck, heat transferring medium pass through chuck
Exchanged heat to tank body；Reactant feeding mouth is provided with above tank body, product discharge mouth is arranged below；The position in tank interior portion on the lower side
Provided with fixed bed, to support reaction mass above, the uniform aperture of fixed bed, flow down reaction liquid.
2nd, as shown in figure 1, a kind of pyridine hydrochloride B3 workshop sections chlorination reaction method provided by the invention, i.e. chlorination workshop section
Chlorination reaction method, comprise the following steps：
1. by 700 kilograms of B2 dry products（Dry product obtained by B2 workshop sections）3- methoxyl group -2- methyl -4- pyridones, above tank body
Feeding mouth, which is added to above fixed bed, forms accumulation bed material, controls the temperature in bed to be no more than 35 by heat transferring medium
Spend, carried out under normal pressure；
2. the 3.5 tons of suction head tanks of POCl3 that will be measured, are then even added in fixed bed reactors and B2 dry products
React, directly POCl3 is added drop-wise to above B2 dry products by the way that Valve controlling is added dropwise, control and dripped in or so 7 hours
Complete, flow 500kg/h, controlling reaction temperature should open return valve in 80-85 degree, dropwise addition, and condenser is emptied into exhaust valve
Door is opened, and tail gas is introduced into absorption tower and absorbed；
After 3. POCl3 adds from the top of fixed bed reactors, the liquid product for now reacting generation is the chloro- 3- methoxies of 4-
Base -2- picolines, liquid product flow to reactor bottom by fixed bed, then pass to and following kettle are recovered under reduced pressure；
4. after POCl3 completion of dropwise addition, the whole products for reacting production move to kettle are recovered under reduced pressure, and take vacuum decompression recovery three
Chlorethoxyfos, just start and evaporate bigger, and control vacuum does not have to logical about 1 hour of thermal source, decompression one now within 0.08Mpa
After the section time is stable, leads to heat source temperature control and go out to evaporate in 0.095Mpa or so stabilizations, entirely subtract in 80-85 degree, vacuum degree control
Process control is pressed through in or so nine hours, to not going out to evaporate substantially as terminal is depressurized, slightly logical cooling water is by the concentrate after decompression
Temperature is down to 70 DEG C or so, by concentrate in kettle（The chloro- 3- methoxyl groups -2- picolines of predominantly 4- and a small amount of POCl3）
It is put into while hot in lower floor's hydrolysis kettle.
5. 2800kg running water should be put in hydrolysis kettle well in advance and be cooled to less than 5 DEG C, the concentrate after decompression put to
In hydrolysis kettle, dispensing speed is controlled, hydrolysis kettle kettle temperature is controlled below 35 degree, and about four small time shifts are complete, continue to stir after having moved
After concentrate hydrolyzes two hours, ammoniacal liquor regulation pH value 8 or so is added dropwise（Note：It should control and ammoniacal liquor speed is added dropwise, keep material temperature not surpass
40 DEG C are crossed, ammonia volume is about 2200kg）.
6. it is the product of B3 workshop sections by layer oily matter after sufficient standing（The chloro- 3- methoxyl groups -2- picolines of 4-）, pass through
By B3 products after filter（The chloro- 3- methoxyl groups -2- picolines of 4-）Put to B3 intermediate storage tanks.
Claims (1)
- A kind of 1. pyridine hydrochloride B3 workshop sections chlorination reaction method, it is characterised in that comprise the following steps：A. by leading portion B2 workshop sections obtained by B2 dry products, be added to above the fixed bed in fixed bed reactors formed accumulation bed Material, the temperature in bed is controlled to be no more than 35 DEG C by heat transferring medium；B. POCl3 is pumped into head tank, directly POCl3 is uniformly added drop-wise to above B2 dry products and occurred instead with B2 dry products Should, it is 500kg/h to control POCl3 that flow is added dropwise, and controlling reaction temperature is at 80-85 DEG C；C. the liquid product for reacting generation is the chloro- 3- methoxyl groups -2- picolines of 4-, and liquid product flows to reaction by fixed bed Device bottom, and flow to and following kettle is recovered under reduced pressure；D. after POCl3 completion of dropwise addition, the whole products for reacting production are moved to kettle is recovered under reduced pressure, kettle is recovered under reduced pressure and vacuumizes POCl3 is recovered under reduced pressure, has reclaimed and remaining concentrate temperature is down to 70 DEG C after POCl3, by concentrate in kettle while hot It is put into lower floor's hydrolysis kettle；E. running water should be put into hydrolysis kettle in advance and is cooled to less than 5 DEG C, the concentrate after decompression is put into hydrolysis kettle, is controlled Dispensing speed processed, hydrolysis kettle kettle temperature are controlled below 35 degree, and concentrate continues after discharging after stirring concentrate two hours of hydrolysis, Ammoniacal liquor regulation pH value 8 is added dropwise, keeps material temperature to be no more than 40 DEG C；F. after the liquid sufficient standing layering after hydrolyzing, layer oily matter is the chloro- 3- methoxyl groups -2- methyl pyrroles of B3 workshop sections product 4- Pyridine, it will be put after the product filtering of B3 workshop sections to B3 intermediate storage tanks.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711110056.2A CN107857724A (en) | 2017-11-12 | 2017-11-12 | A kind of pyridine hydrochloride B3 workshop sections chlorination reaction method |
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| CN201711110056.2A CN107857724A (en) | 2017-11-12 | 2017-11-12 | A kind of pyridine hydrochloride B3 workshop sections chlorination reaction method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109608391A (en) * | 2018-12-11 | 2019-04-12 | 安徽金禾实业股份有限公司 | The chlorination synthesis technology of chlorination workshop section in pyridiniujm production |
| CN110724090A (en) * | 2019-09-30 | 2020-01-24 | 安徽金禾实业股份有限公司 | Method for heating pyridinium B3 chlorination reaction |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101875629A (en) * | 2010-03-31 | 2010-11-03 | 南京元华科技咨询有限公司 | Industrial preparation method of pantoprazole intermediate pyridine hydrochloride |
| CN102304083A (en) * | 2011-06-24 | 2012-01-04 | 南通诚信氨基酸有限公司 | Preparation method of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride |
| CN103483248A (en) * | 2013-09-09 | 2014-01-01 | 江苏宇翔化工有限公司 | Synthesis method of 4-chloro-3-methoxy-2-methyl-4-pyridine |
| CN105153027A (en) * | 2015-07-21 | 2015-12-16 | 东华大学 | 3-cyano-4-hydroxy-2-pyridone compound and preparation method therefor and application thereof |
-
2017
- 2017-11-12 CN CN201711110056.2A patent/CN107857724A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101875629A (en) * | 2010-03-31 | 2010-11-03 | 南京元华科技咨询有限公司 | Industrial preparation method of pantoprazole intermediate pyridine hydrochloride |
| CN102304083A (en) * | 2011-06-24 | 2012-01-04 | 南通诚信氨基酸有限公司 | Preparation method of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride |
| CN103483248A (en) * | 2013-09-09 | 2014-01-01 | 江苏宇翔化工有限公司 | Synthesis method of 4-chloro-3-methoxy-2-methyl-4-pyridine |
| CN105153027A (en) * | 2015-07-21 | 2015-12-16 | 东华大学 | 3-cyano-4-hydroxy-2-pyridone compound and preparation method therefor and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王济昌主编: "《现代科学技术知识词典》", 31 October 2011, 中国科学技术出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109608391A (en) * | 2018-12-11 | 2019-04-12 | 安徽金禾实业股份有限公司 | The chlorination synthesis technology of chlorination workshop section in pyridiniujm production |
| CN110724090A (en) * | 2019-09-30 | 2020-01-24 | 安徽金禾实业股份有限公司 | Method for heating pyridinium B3 chlorination reaction |
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Application publication date: 20180330 |