CN110229075A - A kind of preparation process of Indobufen intermediate - Google Patents
A kind of preparation process of Indobufen intermediate Download PDFInfo
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- CN110229075A CN110229075A CN201910456611.XA CN201910456611A CN110229075A CN 110229075 A CN110229075 A CN 110229075A CN 201910456611 A CN201910456611 A CN 201910456611A CN 110229075 A CN110229075 A CN 110229075A
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- nitrobenzophenone
- butyric acid
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
Abstract
The invention belongs to pharmaceutical synthesis fields, specifically disclose a kind of preparation process of Indobufen intermediate, this method is using hydrazine hydrate and FeOOH reductase 12-(4- nitrobenzophenone) butyric acid, and obtained product purity reaches 99.5% or more, and yield reaches 99.0% or more.Reaction dissolvent of the invention has only used water, and synthesis technology, post-processing operation are simple, and safety and environmental protection is at low cost, improves the yield and product purity of reaction, is suitble to industrialized production.
Description
Technical field
The invention belongs to compound synthesis fields, and in particular to a kind of preparation process of Indobufen intermediate.
Background technique
Indobufen is a kind of raceme mixture researched and developed by Pfizer Inc., by Italian Farmfalia
Carlo Erba, S.P.A is succeeded in developing first, and is listed first in August, 1984 in Italian (ICH member state).Indoles cloth
Sweet smell assembles drug as powerful anti-platelet of new generation, and what it can be selected acts on the blood platelet of circulation, blocks thrombosis, suppression
Platelet factor processed discharges and plays antiplatelet aggregative activity, and this inhibition is reversible, and does not change plasma parameters, lossless blood
Platelet function, and the platelet function for making a variation normal is made to restore normal.It can be such that peripheral blood vessel lesion patient and intermittent claudication suffers from
The microcirculation parameter and travel distance of person is obviously improved.Compared with similar drugs, Indobufen inhibits platelet factor, and anti-blood is small
Plate congregational rate is salicylic 2~5 times, compared with there is shorter bleeding time light continuous time.
Gao Xuemin etc. is in " synthesis of anticoagulation Indobufen " (Chinese Journal of Pharmaceuticals, 1989,20 (11)), Zheng Gengxiu
Deng in " preparation process of Indobufen " (Chinese Journal of Pharmaceuticals, 1991,22 (7)), 106631974 B of patent of invention CN
Disclosed in Indobufen preparation route can be summarized as
From above-mentioned route: 2- (4- aminophenyl) butyric acid is the important intermediate of synthesis of indole cloth sweet smell, at present industry
Upper use mainly has iron reduction, catalytic hydrogenation etc., wherein iron chip filter technical maturity, production process be easy to control, product matter
It measures, but it generates a large amount of waste residues；Catalytic hydrogenation method is cleaned with its technique, reduction efficiency is high and replace iron chip filter, but it sets
It is standby to invest big, high production cost, it is typically only used for being mass produced.More commonly used reducing agent is hydrogen, and hydrogen is as a kind of
Inflammable, explosive gas has risk at high temperature under high pressure.Liquid reducer hydrazine hydrate is cheap and easy to get, has reaction condition
It is easily controllable, it is easy to industrialized feature, so hydrazine hydrate causes the extensive research of chemist as reducing agent.
Patent of invention CN 102558085A discloses the preparation method of Linezolid, and wherein the fluoro- 4- morpholinyl phenylamine of 3- is
As the fluoro- 4- morpholinyl nitrobenzene of 3- through made from reduction reaction, reduction reaction is with the mixture of FeOOH and hydrazine hydrate
Reducing agent；The fluoro- 4- morpholinyl nitrobenzene of 3- need to be dissolved in tetrahydrofuran in the patent, and evaporation of solvent, obtains after reaction
The fluoro- purified step of 4- morpholinyl phenylamine crude product of 3- obtain the fluoro- 4- morpholinyl phenylamine of 3-.Using organic molten in reaction process
Agent, post-processing are evaporated off again, and operational sequence is cumbersome, while can generate a large amount of organic liquid wastes, all unfavorable to operator and environment, and increase
The cost for adding liquid waste processing does not meet the objective of Green Chemistry.
Cai Keying etc. " research of Reduction of Nitro Aromatic Compounds with Hydrazine Hydrate in water " [J] (chemistry world, 2007,4,
It 232-235) discloses and obtains corresponding virtue with FeOOH Compounds with Hydrazine Hydrate Catalyzed 9 kinds of aromatic nitro compounds of reduction in water
Amine, yield 96%~99%；Post-reaction treatment process is not disclosed in document and obtains the purity of product.
In the prior art, it is lower to directly obtain aromatic amine compound purity for Reduction of Nitro Aromatic Compounds with Hydrazine Hydrate, needs pure
Changing rear can be used for subsequent production, so that the production cycle extends, and the production cost increases；The waste liquid of generation is also increase accordingly,
To personnel and environmental pollution.Inventor passes through repeatedly research in this patent, and exploration is easy to operate to one kind, environmentally protective
The preparation process of Indobufen intermediate.The technological reaction and after it is easy to operate, catalyst amount is few, post-process acid adding tune pH
99.5% or more obtained compound purity, 99.0% or more yield, waste liquid are the waste water that pH is 5~6, substantially close to neutrality,
Waste residue, the processing of waste liquid and the pollution to environment are reduced, industrialized production is suitble to.
Summary of the invention:
In view of the deficiencies of the prior art, the present invention provides a kind of preparation processes of Indobufen intermediate, specific to walk
Suddenly 2- (4- nitrobenzophenone) butyric acid, purified water, catalyst is added in a kettle are as follows: A), stirring is warming up to 60~90 DEG C；B it) protects
Hydrazine hydrate is added dropwise in temperature, drips 70~100 DEG C of 1~4h of reaction of Bi Baowen；C) after reaction, temperature is down to room temperature, filtering, to filtrate
Organic acid is added in middle addition purified water, begins with crystal precipitation, after pH is adjusted to faintly acid, continuation insulated and stirred crystallization 0.5~
2h is filtered, dry, obtains product.
Wherein step A) in 2- (4- nitrobenzophenone) butyric acid: mass ratio=1:2~4 of purified water, preferably 1:2.5~3.5；
The catalyst is FeOOH, and dosage is 2- (4- nitrobenzophenone) butyric acid: FeOOH (mass ratio)=1:0.03
~0.08, preferably 1:0.05~0.06.
Step B) in 2- (4- nitrobenzophenone) butyric acid: hydrazine hydrate (mass ratio)=1:0.8~1.5, preferably 1:0.9~1.2.
The step C) in purified water amount be 2- (4- nitrobenzophenone) butyric acid: purified water (mass ratio)=1:3~8, it is excellent
Select 1:4~6；Wherein organic acid is any one of formic acid, acetic acid, propionic acid, preferably acetic acid；The faintly acid be pH be 4~
6, preferably 4~5；The stirring and crystallizing temperature is 5~30 DEG C.
The utility model has the advantages that
1, the application hydrazine hydrate reduction 2- (4- nitrobenzophenone) butyric acid, the high conversion rate of reduction, 2- (4- nitrobenzophenone)
Butyric acid is reduced sufficiently, and obtained product purity is up to 99.5% or more, 99% or more yield.
2, cool down filtering after this technological reaction, directly adds water, acid adding tune pH in filtrate, is dissolved in impurity acid water-soluble
It is not precipitated in liquid, and product is gradually precipitated during adjusting pH, pH only need to stir 0.5~2h growing the grain after adjusting, and obtain
2- (4- aminophenyl) butyric acid be not required to carry out the subsequent operations such as additional purifying, can be directly used for the next centre of Indobufen
The synthesis of body.
3, the application technical process is easy to operate, and catalyst usage amount is few, and the solid waste of subsequent generation is few, and waste liquid is that pH is 5
~6 waste water reduces the processing of waste liquid and the pollution to environment, has on the one hand saved production cost, separately substantially close to neutrality
On the one hand reduce the pollution to environment.Meet Modern Green Chemistry theory.
Specific embodiment:
Below in conjunction with specific embodiment, the invention will be further described, and the following description is only intended to explain the invention,
Protection scope of the present invention is not limited to these examples, it should be understood by those skilled in the art that made by the content of present invention
Equivalent replacement, or be correspondingly improved, it still falls within protection scope of the present invention.
Embodiment 1
Purified water 2.5kg is added in reaction kettle, opens stirring, 1kg 2- (4- nitrobenzophenone) butyric acid, 0.03kg hydroxyl is added
Base iron oxide, stirs evenly, and is heated to 60~70 DEG C.Hydrazine hydrate 0.9kg is added dropwise in heat preservation, is added dropwise, heat preservation 70~85
It DEG C is stirred to react 4h, stops heating, starts to cool down.15~20 DEG C are cooled to, purified water 4kg is added into filtrate for centrifugation, opens
Acetic acid tune pH to 4.5~5.2 is added dropwise in stirring.5~15 DEG C of stirring and crystallizing 0.5h of temperature control.Centrifugation, wet product are dried under reduced pressure, and it is white to obtain class
Color solid 2- (4- aminophenyl) butyric acid 0.853kg, yield 99.57%, purity 99.70%.
Embodiment 2
Purified water 2kg is added in reaction kettle, opens stirring, 1kg 2- (4- nitrobenzophenone) butyric acid, 0.05kg hydroxyl is added
Iron oxide stirs evenly, and is heated to 65~80 DEG C.Hydrazine hydrate 1.5kg is added dropwise in heat preservation, is added dropwise, and keeps the temperature 75~90 DEG C
It is stirred to react 2h, stops heating, starts to cool down.20~25 DEG C are cooled to, purified water 3kg is added into filtrate for centrifugation, and unlatching is stirred
It mixes, formic acid tune pH to 4.0~4.8 is added dropwise.10~20 DEG C of stirring and crystallizing 1h of temperature control.Centrifugation, wet product are dried under reduced pressure, and it is solid to obtain off-white color
Body 2- (4- aminophenyl) butyric acid 0.850kg, yield 99.22%, purity 99.73%.
Embodiment 3
Purified water 4kg is added in reaction kettle, opens stirring, 1kg 2- (4- nitrobenzophenone) butyric acid, 0.06kg hydroxyl is added
Iron oxide stirs evenly, and is heated to 70~85 DEG C.Hydrazine hydrate 0.8kg is added dropwise in heat preservation, is added dropwise, and keeps the temperature 80~95 DEG C
It is stirred to react 1h, stops heating, starts to cool down.10~15 DEG C are cooled to, purified water 6kg is added into filtrate for centrifugation, and unlatching is stirred
It mixes, propionic acid tune pH to 5.0~6.0 is added dropwise.15~25 DEG C of stirring and crystallizing 2h of temperature control.Centrifugation, wet product are dried under reduced pressure, and it is solid to obtain off-white color
Body 2- (4- aminophenyl) butyric acid 0.851kg, yield 99.33%, purity 99.74%.
Embodiment 4
Purified water 3.5kg is added in reaction kettle, opens stirring, 1kg 2- (4- nitrobenzophenone) butyric acid, 0.08kg hydroxyl is added
Base iron oxide, stirs evenly, and is heated to 75~90 DEG C.Hydrazine hydrate 1.2kg is added dropwise in heat preservation, is added dropwise, heat preservation 85~100
It DEG C is stirred to react 3h, stops heating, starts to cool down.10~20 DEG C are cooled to, purified water 8kg is added into filtrate for centrifugation, opens
Acetic acid tune pH to 4.7~5.6 is added dropwise in stirring.20~30 DEG C of stirring and crystallizing 1.5h of temperature control.Centrifugation, wet product are dried under reduced pressure, and it is white to obtain class
Color solid 2- (4- aminophenyl) butyric acid 0.851kg, yield 99.33%, purity 99.73%.
Claims (9)
1. a kind of preparation process of Indobufen intermediate, which comprises the following steps:
A purified water, catalyst, 2- (4- nitrobenzophenone) butyric acid) are added in a kettle, stirring is warming up to 60~90 DEG C；
B) hydrazine hydrate is added dropwise in heat preservation, and drop finishes, and keeps the temperature 70~100 DEG C of 1~4h of reaction；
C) after reaction, temperature is down to room temperature, and purified water is added into filtrate for filtering, and organic acid is added, and adjusts pH to 4~6
Afterwards, continue 0.5~2h of insulated and stirred crystallization, filter, it is dry, obtain product.
2. technique according to claim 1, which is characterized in that the catalyst is FeOOH；The organic acid is
Any one of formic acid, acetic acid, propionic acid.
3. technique according to claim 2, which is characterized in that the organic acid is acetic acid.
4. technique according to claim 1, which is characterized in that step A) in, 2- (4- nitrobenzophenone) butyric acid with it is pure
The mass ratio for changing water is 1:2~4；The mass ratio of 2- (4- nitrobenzophenone) butyric acid and FeOOH is 1:0.03~0.08.
5. technique according to claim 1, which is characterized in that step B) in 2- (4- nitrobenzophenone) butyric acid and hydrazine hydrate
Mass ratio is 1:0.8~1.5.
6. technique according to claim 1, which is characterized in that step C) in 2- (4- nitrobenzophenone) butyric acid and purified water
Mass ratio is 1:3~8；The pH is 4~5；Stirring and crystallizing temperature is 5~30 DEG C.
7. technique according to claim 3, which is characterized in that step A) in, 2- (4- nitrobenzophenone) butyric acid with it is pure
The mass ratio for changing water is 1:2.5~3.5；The mass ratio of 2- (4- nitrobenzophenone) butyric acid and FeOOH be 1:0.05~
0.06。
8. technique according to claim 4, which is characterized in that step B) in 2- (4- nitrobenzophenone) butyric acid and hydrazine hydrate
Mass ratio is 1:0.9~1.2.
9. technique according to claim 5, which is characterized in that step C) in 2- (4- nitrobenzophenone) butyric acid and purified water
Mass ratio is 1:4~6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201910456611.XA CN110229075A (en) | 2019-05-29 | 2019-05-29 | A kind of preparation process of Indobufen intermediate |
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| CN201910456611.XA CN110229075A (en) | 2019-05-29 | 2019-05-29 | A kind of preparation process of Indobufen intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114380694A (en) * | 2021-12-31 | 2022-04-22 | 拓信达(启东)医药生物科技有限公司 | Synthetic method for preparing indobufen intermediate by continuous flow |
| CN114624339A (en) * | 2020-12-10 | 2022-06-14 | 杭州中美华东制药有限公司 | Analysis method for determining indobufen impurities |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106631974A (en) * | 2017-02-17 | 2017-05-10 | 杭州中美华东制药有限公司 | Method for preparing indobufen |
| WO2017205451A1 (en) * | 2016-05-24 | 2017-11-30 | Temple University-Of The Commonwealth System Of Higher Education | Novel functionalized n,n-dialkylamino phenyl ethers and their method of use |
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2019
- 2019-05-29 CN CN201910456611.XA patent/CN110229075A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017205451A1 (en) * | 2016-05-24 | 2017-11-30 | Temple University-Of The Commonwealth System Of Higher Education | Novel functionalized n,n-dialkylamino phenyl ethers and their method of use |
| CN106631974A (en) * | 2017-02-17 | 2017-05-10 | 杭州中美华东制药有限公司 | Method for preparing indobufen |
Non-Patent Citations (3)
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| 田雪 等: "吲哚布芬中间体2-(4-氨基苯基)丁酸的合成", 《广东化工》 * |
| 蔡可迎 等: "水中氢氧化氧铁催化水合肼还原芳香族硝基化合物", 《河北师范大学学报(自然科学版)》 * |
| 蔡可迎 等: "水中水合肼还原芳香族硝基化合物的研究", 《化学世界》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114624339A (en) * | 2020-12-10 | 2022-06-14 | 杭州中美华东制药有限公司 | Analysis method for determining indobufen impurities |
| CN114380694A (en) * | 2021-12-31 | 2022-04-22 | 拓信达(启东)医药生物科技有限公司 | Synthetic method for preparing indobufen intermediate by continuous flow |
| CN114380694B (en) * | 2021-12-31 | 2024-02-09 | 拓信达(启东)医药生物科技有限公司 | Synthesis method for preparing indobufen intermediate by continuous flow |
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