CN101665407A - Preparation method of 2,4,5-trifluorobenzyl chloride - Google Patents
Preparation method of 2,4,5-trifluorobenzyl chloride Download PDFInfo
- Publication number
- CN101665407A CN101665407A CN200910152769A CN200910152769A CN101665407A CN 101665407 A CN101665407 A CN 101665407A CN 200910152769 A CN200910152769 A CN 200910152769A CN 200910152769 A CN200910152769 A CN 200910152769A CN 101665407 A CN101665407 A CN 101665407A
- Authority
- CN
- China
- Prior art keywords
- preparation
- benzyl chlorine
- acid
- trifluoro
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention relates to the field of the preparation method of the pharmaceutical intermediate, in particular to the field of the preparation method of 2,4,5-trifluorobenzyl chloride. The method adopts 1,2,4-trifluorobenzene and paraformaldehyde to react in the presence of chlorinating agent and obtain 2,4,5-trifluorobenzyl chloride. The content of 2,4,5-trifluorobenzyl chloride obtained by purification is above 99.8%. The preparation method of 2,4,5-trifluorobenzyl chloride has cheap and accessible raw material and mild reaction conditions, is economic and environmentally friendly and is easy to realize industrialization; in addition, the product purity and yield are high and the product fully meets the operating requirements of the pharmaceutical intermediate.
Description
Technical field
The present invention relates to the preparation method field of medicine intermediate, particularly relate to preparation 2,4, the preparation method field of 5-trifluoro benzyl chlorine.
Background technology
2,4,5-trifluoro benzyl chlorine is the key intermediate of synthetic treatment Glucovance.Chinese patent 200510030162.0 has reported 1,2, and the 4-trifluoro-benzene reacts through Blanc as chlorizating agent and Paraformaldehyde 96 with chlorsulfonic acid and zinc chloride, prepares 2,4,5-trifluoro benzyl chlorine, and this method yield is lower, and economy is not high, and environment is unfriendly.Chinese patent 200710039502.5 reports prepare 2,4 with chloromethyl ethers and Lewis acid as chlorizating agent, 5-trifluoro benzyl chlorine, and used chloromethyl ethers price is higher, causes the industrial production cost height, is difficult for industrialization.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, adopting the mixture of sodium-chlor or Repone K and acid is chlorizating agent.The characteristics of this technology provide simple, the economic environmental protection of a kind of technical process, reaction conditions gentleness, aftertreatment is easy and product purity good, yield increases substantially 2,4, the preparation method of 5-trifluoro benzyl chlorine.
2,4, the preparation method of 5-trifluoro benzyl chlorine is characterized in that it is realized by following reaction:
Be specially 1,2, add chlorizating agent in 4-trifluoro-benzene and the Paraformaldehyde 96 and carry out chloromethylation, reaction product hydrolysis in frozen water obtains 2,4,5-trifluoro benzyl chlorine.Used chlorizating agent is a kind of mixture of forming with a kind of acid that is selected from sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid in sodium-chlor or the Repone K in the reaction.
As embodiment preferred of the present invention, used chlorizating agent is sodium-chlor and a kind of sour mixture of forming that is selected from sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid in the reaction.
As embodiment preferred of the present invention, used chlorizating agent is the mixture of sodium-chlor and hydrochloric acid in the reaction.
As embodiment preferred of the present invention, used chlorizating agent is sodium-chlor and vitriolic mixture in the reaction.
As embodiment preferred of the present invention, used chlorizating agent is the mixture of sodium-chlor and acetic acid in the reaction.
As embodiment preferred of the present invention, used chlorizating agent is Repone K and a kind of sour mixture of forming that is selected from sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid in the reaction, preferred Repone K and vitriolic mixture, the perhaps mixture of Repone K and acetic acid, the perhaps mixture of Repone K and hydrochloric acid.
As embodiment preferred of the present invention, in the reaction 1,2, the mol ratio of 4-trifluoro-benzene and chlorizating agent (mole number with sodium-chlor or Repone K is represented), Paraformaldehyde 96 (mole number with monomer formaldehyde is represented) is 1: (1～5): (1～3), preferred 1: (1.5～3): (1.5～2.5).
As embodiment preferred of the present invention, temperature of reaction is-10～100 ℃, preferred 10～50 ℃.
As embodiment preferred of the present invention, the hydrolysis in frozen water of chloromethylation product.
Beneficial effect of the present invention: the present invention 2,4, the preparation method of 5-trifluoro benzyl chlorine, raw material is cheap and easy to get, reaction conditions is gentle, economic environmental protection, be easy to realize industrialization and good product purity, yield height, meet service requirements as pharmaceutical intermediate fully.
Description of drawings
Fig. 1 is among the present invention 2,4, the hydrogen spectrum spectrogram of 5-trifluoro benzyl chlorine.
Embodiment
Following type reaction is used for illustrating the present invention.Within the technical scheme that those skilled in that art all belong to the present invention to the simple replacement done of invention or improvement etc. and protected.
The raw material that uses: 1,2, the 4-trifluoro-benzene: our company has product by oneself; Paraformaldehyde 96: available from the big bright medication chemistry in Taizhou city company limited; Sodium-chlor: available from Linhai City Salt Company; Repone K: available from Guangdong siron chemical industry company limited; 98% sulfuric acid: available from Taizhou city triumphant human relations chemical industry of Jiangjiang company limited; 30% hydrochloric acid: available from Taizhou city new chemical industry of Huangyan power company limited; 98% acetic acid: available from Linhai City Salt Company; 85% phosphoric acid: available from Taizhou city harbour doctorization company limited.
The instrument model and the analysis condition of nucleus magnetic resonance: adopt Bruker Avance DMX500 type NMR spectrometer with superconducting magnet; Resonant frequency: 500MHZ; With CDCl
3Be solvent, TMS is interior mark.
Embodiment 1
In the four-hole reaction flask of 250ml, add 98% sulfuric acid 100ml, cool to 20 ℃, add Paraformaldehyde 96 21.3g (being equivalent to monomer formaldehyde 0.71mol), sodium-chlor 44.8g (0.766mol), add 1,2 at last, 4-trifluoro-benzene 50.8g (0.385mol), after finishing, 40 ℃ of insulation reaction 10 hours.Reaction solution is poured in the frozen water, finished the back and stir 30min, tell organic layer, be washed till neutrality, dry back underpressure distillation rectifying again obtains 2,4,5-trifluoro benzyl chlorine 58.8g, content 99.8%, yield 84.7%.Fig. 1 is 2,4 in the Figure of description, the hydrogen spectrum spectrogram of 5-trifluoro benzyl chlorine:.
Nuclear magnetic resonance data is analyzed::
1H-NMR(CDCl3，500Hz)δ：4.56(s，2H)，6.95(m，1H)，7.26(m，1H)。
Embodiment 2
Press embodiment 1, replace sodium-chlor with 57.1g (0.766mol) Repone K, reaction obtains 2,4,5-trifluoro benzyl chlorine 55.1g, content 98.2%, yield 79.3%.
Embodiment 3
Press embodiment 1, with 100ml 30% salt acid substitution sulfuric acid, reaction obtains 2,4,5-trifluoro benzyl chlorine 47.6g, content 98.6%, yield 68.5%.
Embodiment 4
Press embodiment 1, replace sulfuric acid with 100ml 98% acetic acid, reaction obtains 2,4,5-trifluoro benzyl chlorine 51.4g, content 98.0%, yield 73.9%.
Embodiment 5
Press embodiment 1, replace hydrochloric acid with 100ml 85% phosphoric acid, reaction obtains 2,4,5-trifluoro benzyl chlorine 48.9g, content 98.1%, yield 70.3%.
Press embodiment 1, the amount of sodium-chlor reduces to 22.5g (0.385mol), and reaction obtains 2,4,5-trifluoro benzyl chlorine 50.7g, content 99.1%, yield 73%.
Press embodiment 1, the amount of sodium-chlor is increased to 58.6g (1.0mol), and reaction obtains 2,4,5-trifluoro benzyl chlorine 57g, content 99.2%, yield 82%.
Embodiment 8
By implementing 1, the amount of Paraformaldehyde 96 reduces to 15g (being equivalent to monomer formaldehyde 0.5mol), and reaction obtains 2,4,5-trifluoro benzyl chlorine 55.4g, content 99.6%, yield 79.8%.
Embodiment 9
Press embodiment 1, temperature of reaction drops to 5 ℃, and reaction obtains 2,4,5-trifluoro benzyl chlorine 35g, content 96.1%, yield 50.3%.
Press embodiment 1, temperature of reaction is elevated to 60 ℃, and reaction obtains 2,4,5-trifluoro benzyl chlorine 52g, content 97.1%, yield 74.8%.
Claims (10)
1.2,4, the preparation method of 5-trifluoro benzyl chlorine is characterized in that it is realized by following reaction:
Be specially 1,2, add chlorizating agent in 4-trifluoro-benzene and the Paraformaldehyde 96 and carry out chloromethylation, reaction product hydrolysis in frozen water obtains 2,4,5-trifluoro benzyl chlorine.
2. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine, used chlorizating agent is a kind of mixture of forming with a kind of acid that is selected from sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid in sodium-chlor or the Repone K in it is characterized in that reacting.
3. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine, the used chlorizating agent mixture that to be sodium-chlor form with a kind of acid that is selected from sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid in it is characterized in that reacting.
4. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine, used chlorizating agent is the mixture of sodium-chlor and hydrochloric acid in it is characterized in that reacting.
5. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine, used chlorizating agent is sodium-chlor and vitriolic mixture in it is characterized in that reacting.
6. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine, used chlorizating agent is the mixture of sodium-chlor and acetic acid in it is characterized in that reacting.
7. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine, used chlorizating agent is Repone K and a kind of sour mixture of forming that is selected from sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid in it is characterized in that reacting, preferred Repone K and vitriolic mixture, the perhaps mixture of Repone K and acetic acid, the perhaps mixture of Repone K and hydrochloric acid.
8. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine, it is characterized in that the reaction in 1,2, the mol ratio of 4-trifluoro-benzene and chlorizating agent (mole number with sodium-chlor or Repone K is represented), Paraformaldehyde 96 (mole number with monomer formaldehyde is represented) is 1: (1～5): (1～3), preferred 1: (1.5～3): (1.5～2.5).
9. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine is characterized in that temperature of reaction is-10～100 ℃, preferred 10～50 ℃.
10. as claimed in claim 12,4, the preparation method of 5-trifluoro benzyl chlorine is characterized in that the hydrolysis in frozen water of chloromethylation product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101527694A CN101665407B (en) | 2009-09-28 | 2009-09-28 | Preparation method of 2,4,5-trifluorobenzyl chloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101527694A CN101665407B (en) | 2009-09-28 | 2009-09-28 | Preparation method of 2,4,5-trifluorobenzyl chloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101665407A true CN101665407A (en) | 2010-03-10 |
| CN101665407B CN101665407B (en) | 2011-04-20 |
Family
ID=41802215
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101527694A Active CN101665407B (en) | 2009-09-28 | 2009-09-28 | Preparation method of 2,4,5-trifluorobenzyl chloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101665407B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114591141A (en) * | 2022-04-08 | 2022-06-07 | 浙江永太科技股份有限公司 | Preparation method of 2,4, 5-trifluorobenzyl bromide |
| CN114605223A (en) * | 2022-04-08 | 2022-06-10 | 浙江永太科技股份有限公司 | Method for preparing 2,4, 5-trifluorobenzyl bromide by using 2,4, 5-trifluorobenzyl chloride |
| CN114773147A (en) * | 2022-05-10 | 2022-07-22 | 浙江永太科技股份有限公司 | Preparation method of 2,4, 5-trifluorobenzyl bromide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100347142C (en) * | 2005-09-29 | 2007-11-07 | 上海康鹏化学有限公司 | Process for preparing 2,4,5-triflorophenylacetic acid |
| CN100516014C (en) * | 2007-04-04 | 2009-07-22 | 浙江永太科技股份有限公司 | Method for preparing 2,4,5 trifluorobenzene acetic acid |
| CN101033169A (en) * | 2007-04-16 | 2007-09-12 | 上海展昱生化科技有限公司 | Method for preparing 1-chloromethyl-2,4,5-trifluoro-benzene |
-
2009
- 2009-09-28 CN CN2009101527694A patent/CN101665407B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114591141A (en) * | 2022-04-08 | 2022-06-07 | 浙江永太科技股份有限公司 | Preparation method of 2,4, 5-trifluorobenzyl bromide |
| CN114605223A (en) * | 2022-04-08 | 2022-06-10 | 浙江永太科技股份有限公司 | Method for preparing 2,4, 5-trifluorobenzyl bromide by using 2,4, 5-trifluorobenzyl chloride |
| CN114605223B (en) * | 2022-04-08 | 2024-03-15 | 浙江永太科技股份有限公司 | Method for preparing 2,4, 5-trifluoro-benzyl bromide by using 2,4, 5-trifluoro-benzyl chloride |
| CN114773147A (en) * | 2022-05-10 | 2022-07-22 | 浙江永太科技股份有限公司 | Preparation method of 2,4, 5-trifluorobenzyl bromide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101665407B (en) | 2011-04-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101665407B (en) | Preparation method of 2,4,5-trifluorobenzyl chloride | |
| CN110862310B (en) | Synthesis method of cyclopropyl methyl ketone | |
| CN101659611B (en) | Method for preparing 2, 4, 5-trifluoro-phenylacetic-acid | |
| CN101265269B (en) | Method for preparing pentafluorophenyl boric acid | |
| CN110452089A (en) | The synthetic method of p-chloromethyl styrene | |
| CN108047019A (en) | 2,2,2- trifluoroacetophenones clean the preparation method of high conversion | |
| CN104910091A (en) | Preparation method of anhydrous and non-solvation A crystallization parecoxib sodium | |
| CN111116336A (en) | Synthetic method of 2, 4-dichloroacetophenone | |
| CN101012148A (en) | Method of reducing polyfluorobenzoic acid to polyfluorobenzyl alcohol by sodium borohydride | |
| CN105198753B (en) | 2,2 ' is double（Trifluoromethoxy）The preparation method of 4,4 ' benzidines | |
| CN109970793A (en) | A kind of process synthesizing 15 triphenylphosphine salt of carbon | |
| CN103044230B (en) | Preparation method of 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone | |
| CN102531854A (en) | Synthesis method for 4-bromo-2, 6-difluoro-trifluoromethoxybenzene | |
| CN102134190A (en) | Polycarboxylic acid for electrolyte as well as preparation method and application thereof | |
| CN104628575A (en) | Preparation method of 2-aminoindan | |
| CN102557993B (en) | Preparation method of oxidant as well as doping agent for synthesizing conductive high polymer | |
| CN108530301A (en) | A kind of synthetic method of tri- fluorin benzyl amines of 2,4,6- | |
| CN101220006B (en) | Buflomedil production method | |
| CN107459443A (en) | A kind of preparation method of 2,6 di-t-butyl phenates | |
| CN101575301B (en) | Preparation method of 2-amino-5-chlorobenzamide | |
| CN101274949B (en) | Preparation for sucrose-6-ester | |
| CN101659630B (en) | Method for preparing 2, 4, 5-trifluoro-phenylacetonitrile | |
| CN101723889B (en) | Method for synthesizing 6-chloropyridine-3-carbonyl chloride | |
| CN104774166A (en) | Synthetic method for disulfide diisopropyl xanthate | |
| CN104892534A (en) | Technology for synthesizing intermediate of cycleanine of gadolinium contrast agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |