CN103524408A - Method for preparing 7-chloroquinaldine by use of phase-transfer catalytic reaction - Google Patents
Method for preparing 7-chloroquinaldine by use of phase-transfer catalytic reaction Download PDFInfo
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- CN103524408A CN103524408A CN201310481907.XA CN201310481907A CN103524408A CN 103524408 A CN103524408 A CN 103524408A CN 201310481907 A CN201310481907 A CN 201310481907A CN 103524408 A CN103524408 A CN 103524408A
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- chloroquinaldine
- butanols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/18—Halogen atoms or nitro radicals
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Abstract
The invention discloses a method for preparing 7-chloroquinaldine by use of a phase-transfer catalytic reaction. M-chloroaniline and crotonaldehyde are used as raw materials, lauryl sodium sulfate (serving as a surface active agent) and phosphomolybdic acid (serving as a oxidizing agent) are added in a water and 2-butanol reaction system for reaction to obtain the 7-chloroquinaldine with high yield. Compared with the prior art, the method has the remarkable advantages that (1) the lauryl sodium sulfate is added to enhance emulsibility of reaction liquid, the generation of byproducts (5-isomer) is inhibited, and the reaction efficiency is greatly improved; (2) the phosphomolybdic acid is also added, as the oxidizing agent has common gender of acid, the traditional acid solvent is avoided, and the property of the oxidizing agent can be realized; (3) the reaction can be performed in water, the aftertreatment is simple, and the reaction yield (up to 89%) is greatly improved.
Description
Technical field
The invention belongs to medicine intermediate field, be specifically related to a kind of method of utilizing phase-transfer-catalyzed reactions to prepare 7-Chloroquinaldine.
Background technology
7-Chloroquinaldine is mainly used to prepare the important intermediate of antiasthmatics Mo Tesite, LTRA MK-0679 as a kind of important medicine intermediate.It is that main raw material reacts to prepare by classical Skraup reaction and DeobnerMiller that traditional method adopts m-chloro aniline, crotonic aldehyde, because reaction has 5 position isomers, generates, and need use ZnCl
2, tartrate or 4-nitrophthalic acid carry out separating-purifying with isomer mixing complex reaction, to obtain high purity 7-Chloroquinaldine, so yield is lower.(US, 5126456) disclosing a kind of is oxygenant with chloranil, back flow reaction in the aqueous isopropanol of hydrogenchloride, product 7-Chloroquinaldine yield is 67%, but because the separation of 5 position isomers need to be used a large amount of inflammable tetrahydrofuran (THF)s, and oxygenant chloranil price is higher, and processing condition are harsh, the time that drips crotonic aldehyde is oversize, in suitability for industrialized production, receives restriction.(CN 101638382) disclose a kind of method of utilizing phase transfer reaction to prepare 7-Chloroquinaldine, utilize m-chloro aniline and crotonic aldehyde to make raw material, adopt alkylphenol polyoxyethylene OP-10, OP-7 etc. as phase-transfer catalyst, chloranils etc. are as catalyzer reaction at 98 ~ 103 ℃ in the olefin(e) acid solution preparing, yield is 70%, but this post-reaction treatment is complicated, need continuous underpressure distillation to carry out mobile phone product, product is run off serious, be not suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to overcome above-mentioned defect, a kind of method of utilizing phase-transfer-catalyzed reactions to prepare 7-Chloroquinaldine is provided.The method adds Surfactant SDS and oxygenant phospho-molybdic acid, without reacting in acid solvent, in water, can react, and aftertreatment is simple, and reaction efficiency is improved greatly, and yield reaches 89%.
The technical solution that realizes the object of the invention is:
Utilize phase-transfer-catalyzed reactions to prepare a method for 7-Chloroquinaldine, comprise the following steps:
Step 1, is first dissolved in m-chloro aniline in organic solvent 2-butanols, adds wherein Surfactant SDS and oxygenant phospho-molybdic acid, stirring reaction in the aqueous solution and 2-butanols mixed solvent;
Step 2 drips crotonic aldehyde in the mixed solution in step 1, continues reaction;
Step 3, after reaction finishes, mixed solution layering, organic phase reclaims, and water underpressure distillation disacidify, through NaHCO
3solution washing, recrystallization obtain highly purified 7-Chloroquinaldine.
Wherein, in step 1, m-chloro aniline and sodium lauryl sulphate mol ratio are 1:0.5 ~ 1; M-chloro aniline and phospho-molybdic acid mol ratio are 10:0.1 ~ 0.5.
In step 2, the mol ratio of crotonic aldehyde and m-chloro aniline is 1:1; Temperature of reaction is 80 ~ 95 ℃, reaction times 3 ~ 4h.
NaHCO in step 3
3mass concentration is 5 ~ 10%.
Compared with prior art, its remarkable advantage is in the present invention: (1) the method for the invention adds Surfactant SDS, has increased the emulsifying property of reaction solution, has suppressed the generation of by product 5-position isomer, has greatly improved reaction efficiency; (2) reaction also adds oxygenant phospho-molybdic acid, and this oxygenant has the sour general character, has avoided the use of classical acid solvent, and can have the character of oxygenant simultaneously; (3) this reaction can be reacted in water, and aftertreatment is simple, and reaction yield rate is improved greatly, and yield reaches 89%.
Below in conjunction with accompanying drawing, the present invention is described in further detail.
Accompanying drawing explanation
Fig. 1 the present invention prepares the process flow sheet of the method for 7-Chloroquinaldine.
Embodiment
The following examples can make the present invention of those skilled in the art comprehend.
Utilize phase-transfer-catalyzed reactions to prepare a method for 7-Chloroquinaldine, comprise the following steps:
Step 1, is first dissolved in m-chloro aniline in organic solvent 2-butanols, adds wherein Surfactant SDS and oxygenant phospho-molybdic acid, stirring reaction in the aqueous solution and 2-butanols mixed solvent;
Step 2 drips crotonic aldehyde in the mixed solution in step 1, continues reaction;
Step 3, after reaction finishes, mixed solution layering, organic phase reclaims, and water underpressure distillation disacidify, through NaHCO
3solution washing, recrystallization obtain highly purified 7-Chloroquinaldine.
Reaction equation is as follows:
Embodiment 1
First 12.7g m-chloro aniline is dissolved in 50mL organic solvent 2-butanols, add in there-necked flask and stir, add wherein 14.4g Surfactant SDS and 18.25g oxygenant phospho-molybdic acid, add the 100mL aqueous solution and 2-butanols mixed solvent, stirring reaction 1h at 80 ℃; In mixed solution, drip 7g crotonic aldehyde afterwards, keep continuation reaction 4h at 80 ℃; After reaction finishes, mixed solution layering, organic phase reclaims 2-butanols, and water underpressure distillation disacidify, through 5wt%100mLNaHCO
3solution washing, ethyl alcohol recrystallization obtain highly purified 7-Chloroquinaldine, yield 85%.
Embodiment 2
First 12.7g m-chloro aniline is dissolved in 50mL organic solvent 2-butanols, add in there-necked flask and stir, add wherein 28.8g Surfactant SDS and 36.5g oxygenant phospho-molybdic acid, add the 100mL aqueous solution and 2-butanols mixed solvent, stirring reaction 2h at 85 ℃; In mixed solution, drip 7g crotonic aldehyde afterwards, keep continuation reaction 3h at 85 ℃; After reaction finishes, mixed solution layering, organic phase reclaims 2-butanols, and water underpressure distillation disacidify, through 8wt%100mLNaHCO
3solution washing, ethyl alcohol recrystallization obtain highly purified 7-Chloroquinaldine, yield 83%.
Embodiment 3
First 12.7g m-chloro aniline is dissolved in 50mL organic solvent 2-butanols, add in there-necked flask and stir, add wherein 20.4g Surfactant SDS and 30.5g oxygenant phospho-molybdic acid, add the 100mL aqueous solution and 2-butanols mixed solvent, stirring reaction 2h at 90 ℃; In mixed solution, drip 7g crotonic aldehyde afterwards, keep continuation reaction 4h at 90 ℃; After reaction finishes, mixed solution layering, organic phase reclaims 2-butanols, and water underpressure distillation disacidify, through 8wt%100mLNaHCO
3solution washing, ethyl alcohol recrystallization obtain highly purified 7-Chloroquinaldine, yield 89%.
Embodiment 4
First 38.1g m-chloro aniline is dissolved in 100mL organic solvent 2-butanols, add in there-necked flask and stir, add wherein 43.2g Surfactant SDS and 54.75g oxygenant phospho-molybdic acid, add the 200mL aqueous solution and 2-butanols mixed solvent, stirring reaction 2h at 80 ℃; In mixed solution, drip 21g crotonic aldehyde afterwards, keep continuation reaction 4h at 80 ℃; After reaction finishes, mixed solution layering, organic phase reclaims 2-butanols, and water underpressure distillation disacidify, through 5wt%100mLNaHCO
3solution washing, ethyl alcohol recrystallization obtain highly purified 7-Chloroquinaldine, yield 80%.
Claims (6)
1. utilize phase-transfer-catalyzed reactions to prepare a method for 7-Chloroquinaldine, it is characterized in that comprising the following steps:
Step 1, is first dissolved in m-chloro aniline in organic solvent 2-butanols, adds wherein Surfactant SDS and oxygenant phospho-molybdic acid, stirring reaction in the aqueous solution and 2-butanols mixed solvent;
Step 2 drips crotonic aldehyde in the mixed solution in step 1, continues reaction;
Step 3, after reaction finishes, mixed solution layering, organic phase reclaims, and water underpressure distillation disacidify, through NaHCO
3solution washing, recrystallization obtain highly purified 7-Chloroquinaldine.
2. method according to claim 1, is characterized in that: in step 1, m-chloro aniline and sodium lauryl sulphate mol ratio are 1:0.5 ~ 1; M-chloro aniline and phospho-molybdic acid mol ratio are 10:0.1 ~ 0.5.
3. method according to claim 1, is characterized in that: in step 1, temperature of reaction is 80 ~ 95 ℃, reaction times 1 ~ 2h.
4. method according to claim 1, is characterized in that: in step 2, the mol ratio of crotonic aldehyde and m-chloro aniline is 1:1.
5. method according to claim 1, is characterized in that: in step 2, temperature of reaction is 80 ~ 95 ℃, reaction times 3 ~ 4h.
6. method according to claim 1, is characterized in that: NaHCO in step 3
3mass concentration is 5 ~ 10%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727261A (en) * | 2018-06-21 | 2018-11-02 | 济南大学 | A kind of preparation method of that pyridine of nitro substitution quinoline |
| CN108822033A (en) * | 2018-06-10 | 2018-11-16 | 徐州诺克非医药科技有限公司 | A kind of synthetic method of 7-Chloroquinaldine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101638382A (en) * | 2009-08-26 | 2010-02-03 | 上海益民化工有限公司 | Method for preparing 7-chloroquinaldine by utilizing phase-transfer reaction |
| CN102464613A (en) * | 2010-11-10 | 2012-05-23 | 中国石油大学(北京) | Synthetic method of quinoline derivative |
-
2013
- 2013-10-16 CN CN201310481907.XA patent/CN103524408A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101638382A (en) * | 2009-08-26 | 2010-02-03 | 上海益民化工有限公司 | Method for preparing 7-chloroquinaldine by utilizing phase-transfer reaction |
| CN102464613A (en) * | 2010-11-10 | 2012-05-23 | 中国石油大学(北京) | Synthetic method of quinoline derivative |
Non-Patent Citations (5)
| Title |
|---|
| GANESABASKARAN SIVAPRASAD，ET AL.: "Synthesis of quinaldines and lepidines by a Doebner–Miller reaction under thermal and microwave irradiation conditions using phosphotungstic acid", 《TETRAHEDRON LETTERS》 * |
| 刘艳飞等: "兰索拉唑的合成工艺改进", 《精细化工中间体》 * |
| 李威渊等: "杂多酸（盐）的分子结构及催化有机合成研究进展", 《化工进展》 * |
| 李树安等: "用Skraup反应合成7-氯喹哪啶", 《淮海工学院学报（自然科学版）》 * |
| 邵栋等: "抗哮喘药中间体7-氯喹哪啶合成技术进展", 《化工时刊》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108822033A (en) * | 2018-06-10 | 2018-11-16 | 徐州诺克非医药科技有限公司 | A kind of synthetic method of 7-Chloroquinaldine |
| CN108822033B (en) * | 2018-06-10 | 2021-08-10 | 马海红 | Synthesis method of 7-chloroquinaldine |
| CN108727261A (en) * | 2018-06-21 | 2018-11-02 | 济南大学 | A kind of preparation method of that pyridine of nitro substitution quinoline |
| CN108727261B (en) * | 2018-06-21 | 2021-09-24 | 济南大学 | Preparation method of nitro-substituted quinaldine |
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