CN108467384A - The synthetic method of 4- bromothiophene -2- formaldehyde - Google Patents
The synthetic method of 4- bromothiophene -2- formaldehyde Download PDFInfo
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- CN108467384A CN108467384A CN201810442819.1A CN201810442819A CN108467384A CN 108467384 A CN108467384 A CN 108467384A CN 201810442819 A CN201810442819 A CN 201810442819A CN 108467384 A CN108467384 A CN 108467384A
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
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Abstract
The present invention relates to 4 bromothiophene, 2 formaldehyde preparation methods.Mainly solve 2 formaldehyde technique of existing 4 bromothiophene be confined to laboratory preparation, can not large-scale production the technical issues of.Technical scheme of the present invention：A kind of synthetic method of 4 bromothiophene, 2 formaldehyde, includes the following steps：The first step, 2,4 dibromo thiophenes occur grignard under the effect of isopropylmagnesium chloride lithium chloride and exchange to form intermediate A；Second step, intermediate A is in N, the lower reaction of N dimethylformamides effect, post-treated to obtain 2 bromo thiazole of target product, 3 formaldehyde, and 4 bromothiophene, 2 formaldehyde that the present invention obtains is common intermediate important in pharmaceutical chemistry.
Description
Technical field
The present invention relates to 4- bromothiophene -2- formaldehyde preparation methods.
Background technology
Through retrieval, existing 4- bromothiophenes -2- formaldehyde prepares main following two process routes：
Method one：It is anti-at 0 DEG C with bromine dichloromethane solution under alchlor effect using thiophene -2-formaldehyde as starting material
It answers, reaction solution pours into 6N aqueous hydrochloric acid solutions, and crude product 4- bromothiophene -2- formaldehyde is obtained after organic layer concentration（Ref: Organic Preparations and Procedures International, 1997, vol. 29, # 4, p. 488 - 494）.As follows：
Document synthetic route 1：
This synthetic route is unsuitable for commercial scale batch production, the reason is as follows that：Raw materials used thiophene -2-formaldehyde is somewhat expensive, at
This height.Used bromine toxicity is big, preparation solution bromodichloromethane solution, needs closed to be transferred to thiophene -2-formaldehyde/tri-chlorination
In aluminium/dichloromethane reaction solution, operation is relative complex.Crude product by purifying, is not used directly in the following step.
Method two：It is anti-with n,N-Dimethylformamide under the conditions of n-BuLi with 2,4- dibromo thiophenes for starting material
It answers, through being quenched, concentrates, cross column and obtain product 4- bromothiophene -2- formaldehyde（Ref: Arkiv foer Kemi, 1961, vol. 17, p. 165,169）.As follows：
Document synthetic route 2：
This synthetic route is unsuitable for commercial scale batch production, the reason is as follows that：Yield is low, and crude product is not by purifying, directly
It connects and is used for next step.
The major defect of both above techniques is of high cost, and post-processing is not easy to amplify, and product does not purify, and is not suitable for rule
Modelling produces.Therefore, a kind of synthetic method and the effective purification process of high yield and low cost are found, keeps the technique big
Sizable application above just becomes the critical issue that present invention needs solve to production.
Invention content
Present invention aims at a kind of effective method for preparing 4- bromothiophene -2- formaldehyde is provided, solves existing 4- bromines thiophene
Pheno -2- formaldehyde techniques be confined to laboratory preparation, can not large-scale production the problem of；This method of the present invention has technique letter
The features such as list, high income, product purity is high；And the method can be realized in industrialization, provide that a kind of whole yield is higher, system
Standby 4- bromothiophene -2- formaldehyde industrialized process for preparing at low cost.
Technical scheme of the present invention：A kind of synthetic method of 4- bromothiophenes -2- formaldehyde, includes the following steps：The first step, 2,
4- dibromo thiophenes occur grignard under the effect of isopropylmagnesium chloride lithium chloride and exchange to form intermediate A；Second step, intermediate A exist
The lower reaction of n,N-Dimethylformamide effect, post-treated to obtain target product 2- bromo thiazole -3- formaldehyde, two step total recoverys are about
70-80% obtains purity and is more than 98% final product.Reaction route is as follows：
The specific synthesis route of the present invention is as follows：
The first step：By raw material 2,4- dibromo thiophenes and anhydrous THF are added in reaction bulb, and to dissolving, nitrogen replaces 2 for stirring
Secondary, solution cools to -50 ~ -40 DEG C, and isopropylmagnesium chloride lithium chloride is slowly added dropwise（It is dissolved in 1.3M tetrahydrofuran solutions）, control
Dropping temperature is no more than -40 DEG C, and 7 ~ 8h is reacted at -50 ~ -40 DEG C.The dosage of isopropylmagnesium chloride lithium chloride is 1.7 in reaction
Equivalent.
The second step：It is slowly added dropwise in n,N-Dimethylformamide to reaction bulb, control dropping temperature is no more than -40
DEG C, temperature is adjusted to 16 ~ 18h of reaction at -15 ~ -5 DEG C, -15 ~ -5 DEG C.The dosage of N,N-dimethylformamide is 1.5 equivalents.Instead
After answering, reaction solution is added dropwise in the aqueous citric acid solution that mass percentage concentration is 16%, control dropping temperature is no more than
10 DEG C, organic layer is detached, organic layer is replaced as toluene solution, and washing is primary, and organic layer is concentrated into ~ 2V, and solution is heated to 50-60
DEG C, it stirs to being completely dissolved, is cooled to 20 ~ 30 DEG C, stir 1 ~ 2h, methyl ring methane is added dropwise, control dropping temperature is no more than 30
DEG C, it is cooled to 0 ~ 10 DEG C, 5-10h is stirred at 0 ~ 10 DEG C.Filtering, it is dry, obtain target product 4- bromothiophene -2- formaldehyde B.
Beneficial effects of the present invention：The sharpest edges of the present invention are to have done larger improvement to technique, develop new grignard
Exchange reagent（Isopropylmagnesium chloride lithium chloride）, and use toluene and hexahydrotoluene crystallization mode obtains high-purity and finally produces
Object.The synthetic method of multistep in original process is avoided, product is used to be directly thickened to solvent dry or cross column purification, to nothing
Method realizes the shortcomings that industrialized production.The technological process raw material is cheap, easily operated, and the required production time is shorter, reduces life
Produce cost；Not only it was suitble to laboratory small lot to prepare, but also is appropriate for large-scale industrial production.
Description of the drawings
Fig. 1 is product purity figure of the present invention.
Fig. 2 is product nuclear magnetic spectrum of the present invention.
Specific implementation mode
The content of present invention is better described in following embodiments, but the present invention is not limited to following examples.Synthesis technology road
Line is as follows：
。
Embodiment 1
The synthesis of 4- bromothiophene -2- formaldehyde：
Under mechanical stirring, will（0.42mol, 100g) SM and the anhydrous THF of 200mL be added in there-necked flask, stirring to being completely dissolved,
Nitrogen is replaced twice, and solution cools to -50 ~ -40 DEG C, and (0.71mol, 545mL) isopropylmagnesium chloride lithium chloride is slowly added dropwise
（1.3M tetrahydrofuran solution）, control dropping temperature and be no more than -40 DEG C, the reaction 7-8h at -50 DEG C is added dropwise, to reaction solution
In (0.63 mol, 45.7g is slowly added dropwise）N,N-Dimethylformamide, control dropping temperature are no more than -40 DEG C, temperature adjustment
To -15 DEG C, continue to react 16-18h at -15 DEG C.Reaction solution is added dropwise to（812g）Mass percentage concentration is 16% citric acid water
In solution, control dropping temperature is no more than 10 DEG C, and adjustment temperature to 15-25 DEG C, 15-25 DEG C is stirred to 15-30min, standing point
Layer.Organic layer is concentrated into 100mL, 500mL toluene is added, toluene layer is washed once with 200mL, organic layer is concentrated into
200mL, is heated to 50-60 DEG C, and 50-60 DEG C of stirring 0.5-1h is cooled to 20 ~ 30 DEG C to being completely dissolved, and 20 ~ 30 DEG C of stirrings 1 ~
2h is added dropwise 400mL methyl ring methane, continues to be cooled to 0 DEG C, 10h is stirred at 0 DEG C, filters, and is rinsed with 100mL methyl ring methane
Filter cake is primary, be dried to obtain white solid intermediate B (62g,>98% GC purity, yield 78%).Product purity is shown in Fig. 1, core
Magnetic is shown in Fig. 2.
Embodiment 2
The synthesis of 4- bromothiophene -2- formaldehyde：
Under mechanical stirring, will（0.42mol, 100g) SM and the anhydrous THF of 200mL be added in there-necked flask, stirring to being completely dissolved,
Nitrogen is replaced twice, and solution cools to -50 ~ -40 DEG C, and (0.71mol, 545mL) isopropylmagnesium chloride lithium chloride is slowly added dropwise
（1.3M tetrahydrofuran solution）, control dropping temperature and be no more than -40 DEG C, the reaction 7-8h at -40 DEG C is added dropwise, to reaction solution
In (0.63 mol, 45.7g is slowly added dropwise）N,N-Dimethylformamide, control dropping temperature are no more than -40 DEG C, temperature adjustment
To -10 DEG C, continue to react 16-18h at -10 DEG C.Reaction solution is added dropwise to（812g）Mass percentage concentration is 16% citric acid water
In solution, control dropping temperature is no more than 10 DEG C, and adjustment temperature to 15-25 DEG C, 15-25 DEG C is stirred to 15-30min, standing point
Layer.Organic layer is concentrated into 100mL, 500mL toluene is added, toluene layer is washed once with 200mL, organic layer is concentrated into
200mL, is heated to 50-60 DEG C, and 50-60 DEG C of stirring 0.5-1h is cooled to 20 ~ 30 DEG C to being completely dissolved, and 20 ~ 30 DEG C of stirrings 1 ~
2h is added dropwise 400mL methyl ring methane, continues to be cooled to 5 DEG C, 7h is stirred at 5 DEG C, filters, and is rinsed with 100mL methyl ring methane
Filter cake is primary, be dried to obtain white solid intermediate B (63g,>98% GC purity, yield 79%).Product purity referring to Fig. 1,
Nuclear-magnetism is referring to Fig. 2.
Embodiment 3
The synthesis of 4- bromothiophene -2- formaldehyde：
Under mechanical stirring, will（0.42mol, 100g) SM and the anhydrous THF of 200mL be added in there-necked flask, stirring to being completely dissolved,
Nitrogen is replaced twice, and solution cools to -50 ~ -40 DEG C, and (0.71mol, 545mL) isopropylmagnesium chloride lithium chloride is slowly added dropwise
（1.3M tetrahydrofuran solution）, control dropping temperature and be no more than -40 DEG C, the reaction 7-8h at -50 DEG C is added dropwise, to reaction solution
In (0.63 mol, 45.7g is slowly added dropwise）N,N-Dimethylformamide, control dropping temperature are no more than -40 DEG C, temperature adjustment
To -5 DEG C, continue to react 16-18h at -5 DEG C.Reaction solution is added dropwise to（812g）Mass percentage concentration is that 16% citric acid is water-soluble
In liquid, control dropping temperature is no more than 10 DEG C, and adjustment temperature to 15-25 DEG C, 15-25 DEG C is stirred to 15-30min, stratification.
Organic layer is concentrated into 100mL, 500mL toluene is added, toluene layer is washed once with 200mL, and organic layer is concentrated into 200mL,
It is heated to 50-60 DEG C, 50-60 DEG C of stirring 0.5-1h is cooled to 20 ~ 30 DEG C to being completely dissolved, and 20 ~ 30 DEG C of 1 ~ 2h of stirring are added dropwise
400mL methyl ring methane continues to be cooled to 10 DEG C, 5h is stirred at 10 DEG C, filtering, and filter cake one is rinsed with 100mL methyl ring methane
It is secondary, be dried to obtain white solid intermediate B (61g,>98% GC purity, yield 77%).Product purity is referring to Fig. 1, nuclear-magnetism ginseng
See Fig. 2.
Embodiment 4
The synthesis of 4- bromothiophene -2- formaldehyde：
Under mechanical stirring, will（0.42mol, 100g) SM and the anhydrous THF of 200mL be added in there-necked flask, stirring to being completely dissolved,
Nitrogen is replaced twice, and solution cools to -50 ~ -40 DEG C, and (0.71mol, 545mL) isopropylmagnesium chloride lithium chloride is slowly added dropwise
（1.3M tetrahydrofuran solution）, control dropping temperature and be no more than -40 DEG C, the reaction 7-8h at -40 DEG C is added dropwise, to reaction solution
In (0.63 mol, 45.7g is slowly added dropwise）N,N-Dimethylformamide, control dropping temperature are no more than -40 DEG C, temperature adjustment
To -5 DEG C, continue to react 16-18h at -5 DEG C.Reaction solution is added dropwise to（812g）Mass percentage concentration is that 16% citric acid is water-soluble
In liquid, control dropping temperature is no more than 10 DEG C, and adjustment temperature to 15-25 DEG C, 15-25 DEG C is stirred to 15-30min, stratification.
Organic layer is concentrated into 100mL, 500mL toluene is added, toluene layer is washed once with 200mL, and organic layer is concentrated into 200mL,
It is heated to 50-60 DEG C, 50-60 DEG C of stirring 0.5-1h is cooled to 20 ~ 30 DEG C to being completely dissolved, and 20 ~ 30 DEG C of 1 ~ 2h of stirring are added dropwise
400mL methyl ring methane continues to be cooled to 0 DEG C, 10h is stirred at 0 DEG C, filtering, and filter cake one is rinsed with 100mL methyl ring methane
It is secondary, be dried to obtain white solid intermediate B (62g,>98% GC purity, yield 78%).Product purity is referring to Fig. 1, nuclear-magnetism ginseng
See Fig. 2.
Embodiment 5
The synthesis of 4- bromothiophene -2- formaldehyde：
Under mechanical stirring, will（0.42mol, 100g) SM and the anhydrous THF of 200mL be added in there-necked flask, stirring to being completely dissolved,
Nitrogen is replaced twice, and solution cools to -50 ~ -40 DEG C, and (0.71mol, 545mL) isopropylmagnesium chloride lithium chloride is slowly added dropwise
（1.3M tetrahydrofuran solution）, control dropping temperature and be no more than -40 DEG C, the reaction 7-8h at -50 DEG C is added dropwise, to reaction solution
In (0.63 mol, 45.7g is slowly added dropwise）N,N-Dimethylformamide, control dropping temperature are no more than -40 DEG C, temperature adjustment
To -15 DEG C, continue to react 16-18h at -15 DEG C.Reaction solution is added dropwise to（812g）Mass percentage concentration is 16% citric acid water
In solution, control dropping temperature is no more than 10 DEG C, and adjustment temperature to 15-25 DEG C, 15-25 DEG C is stirred to 15-30min, standing point
Layer.Organic layer is concentrated into 100mL, 500mL toluene is added, toluene layer is washed once with 200mL, organic layer is concentrated into
200mL, is heated to 50-60 DEG C, and 50-60 DEG C of stirring 0.5-1h is cooled to 20 ~ 30 DEG C to being completely dissolved, and 20 ~ 30 DEG C of stirrings 1 ~
2h is added dropwise 400mL methyl ring methane, continues to be cooled to 10 DEG C, 5h is stirred at 10 DEG C, filters, and is floated with 100mL methyl ring methane
Filter wash cake is primary, be dried to obtain white solid intermediate B (60g,>98% GC purity, yield 75%).Product purity is referring to figure
1, nuclear-magnetism is referring to Fig. 2.
Claims (7)
1. a kind of synthetic method of 4- bromothiophenes -2- formaldehyde, it is characterized in that：Include the following steps：The first step, 2,4- dibromo thiophenes
Grignard occurs under the effect of isopropylmagnesium chloride lithium chloride to exchange to form intermediate A；Second step, intermediate A is in N, N- dimethyl
The lower reaction of formamide effect, post-treated to obtain target product 2- bromo thiazole -3- formaldehyde, reaction route is as follows：
。
2. the synthetic method of 4- bromothiophenes -2- formaldehyde aldehyde according to claim 1, it is characterized in that：Isopropyl chloride in reaction
The dosage for changing magnesium lithium chloride is 1.7 equivalents.
3. the synthetic method of 4- bromothiophenes -2- formaldehyde according to claim 1, it is characterized in that：Grignard exchanges anti-in reaction
It is -50 ~ -40 DEG C to answer temperature.
4. the synthetic method of 4- bromothiophenes -2- formaldehyde according to claim 1, it is characterized in that：N in reaction, N- dimethyl
The dosage of formamide is 1.5 equivalents.
5. the synthetic method of 4- bromothiophenes -2- formaldehyde according to claim 1, it is characterized in that：N, N- bis- are added dropwise in reaction
Methylformamide temperature is -50 ~ -40 DEG C.
6. the synthetic method of 4- bromothiophenes -2- formaldehyde according to claim 1, it is characterized in that：N, N- dimethyl methyls is added dropwise
After amide, reaction temperature is -15--5 DEG C.
7. the synthetic method of 4- bromothiophenes -2- formaldehyde according to claim 1, it is characterized in that:The post-processing is：Reaction
Liquid needs to be added dropwise in the aqueous citric acid solution that mass percentage concentration is 16%, and control dropping temperature is no more than 10 DEG C, and separation is organic
Layer, organic layer are replaced as toluene solution, and washing organic layer is primary, and solution is heated to 50-60 DEG C, and stirring cools down to being completely dissolved
To 20 ~ 30 DEG C, 1 ~ 2h is stirred, methyl ring methane is added dropwise, control dropping temperature is no more than 30 DEG C, is cooled to 0 ~ 10 DEG C, 0 ~ 10 DEG C
Lower stirring 5-10h is filtered, dry, obtains target product 4- bromothiophene -2- formaldehyde B.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002092564A2 (en) * | 2001-05-15 | 2002-11-21 | Basell Polyolefine Gmbh | Synthesis of cyclopentadiene derivatives |
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2018
- 2018-05-10 CN CN201810442819.1A patent/CN108467384A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002092564A2 (en) * | 2001-05-15 | 2002-11-21 | Basell Polyolefine Gmbh | Synthesis of cyclopentadiene derivatives |
Non-Patent Citations (4)
| Title |
|---|
| ERICA L. LANNI等: "Mechanistic Studies on Ni(dppe)Cl2-Catalyzed Chain-Growth Polymerizations: Evidence for Rate-Determining Reductive Elimination", 《J.AM.CHEM.SOC.》 * |
| G.J.MARTIN等: "NMR study of heterocyclic organomagnesium in the furan，thiophene，selenophene，and pyridine series", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》 * |
| KEISUKE FUJITA等: "Synthesis of Poly(3-substituted thiophene)s of Remarkably High Solubility in Hydrocarbon via Nickel-Catalyzed Deprotonative Cross-Coupling Polycondensation", 《MACROMOLECULES》 * |
| SANG GIL YOUM等: "Polythiophene Thin Films by Surface-Initiated Polymerization:Mechanistic and Structural Studies", 《CHEMISTRY OF MATERIALS》 * |
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