CN107011316A - A kind of preparation method of 2 [(aminomethyl phenyl of 5 bromine 2) methyl] 5 (4 fluorophenyl) thiophene - Google Patents
A kind of preparation method of 2 [(aminomethyl phenyl of 5 bromine 2) methyl] 5 (4 fluorophenyl) thiophene Download PDFInfo
- Publication number
- CN107011316A CN107011316A CN201710421543.4A CN201710421543A CN107011316A CN 107011316 A CN107011316 A CN 107011316A CN 201710421543 A CN201710421543 A CN 201710421543A CN 107011316 A CN107011316 A CN 107011316A
- Authority
- CN
- China
- Prior art keywords
- methyl
- thiophene
- fluorophenyls
- bromo
- preparation
- 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.)
- Pending
Links
- 0 CCC(C*)C(C)F Chemical compound CCC(C*)C(C)F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of preparation method of 2 [(aminomethyl phenyl of 5 bromine 2) methyl] 5 (4 fluorophenyl) thiophene.The present invention is by using 4 toluene bromides as initiation material, reacted by 4 toluene bromides and paraformaldehyde with concentrated hydrochloric acid, the bromine benzyl chloride of 2 methyl 5 is prepared under zinc chloride catalysis, then the bromine benzyl chloride of 2 methyl 5 and 2 p-fluorophenyl thiophene are dissolved in ethyl acetate, it is catalyzed by zinc chloride, 80 DEG C of reaction 2 [(aminomethyl phenyl of 5 bromine 2) methyl] 5 (4 fluorophenyl) thiophene of synthesis, cost of material of the present invention is cheap and easily-available, raw material selection variation, production technology is easily realized, easy management and control, gained final products purity is high, without dangerous technique, equipment is simple, synthetic route is novel, synthetic route is short, lift production capacity, reduction production and processing cost.
Description
Technical field
The present invention relates to a kind of preparation method for treating diabetes B medicine canagliflozin intermediate, i.e., a kind of 2- [(bromo- 2- of 5-
Aminomethyl phenyl) methyl] -5- (4- fluorophenyls) thiophene preparation method.
Background technology
Canagliflozin (canagliflozin, 1), chemistry entitled (1S) -1,5- dehydrogenations -1-C- [3- [[5- (4- fluorobenzene
Base) -2- thienyls] methyl] -4- aminomethyl phenyls] -D- glucitol hydrate (2: 1), is by Mitsubishi
One kind that Tanabe Pharma companies original is ground is oralCThe type of-glycoside sodium dependent glucose 2 cotransports body inhibitor.Can
By blocking proximal convoluted tubule the glucose of filtration is discharged from urine the re-absorption of glucose, so as to reach hypoglycemic purpose.
Ratify in March, 2013 to list through U.S. FDA first, be clinically used for treating diabetes B, trade name Invokana.
2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene is the key intermediate for preparing canagliflozin,
Its synthetic method mainly has following several, a kind of scheme be using the bromo- 2- methyl benzoic acids of 5- as initiation material, through chloride, with
2- p-fluorophenyls thiophene pays a gram acylation, then reduces and is made.Program route is shorter, but initiation material synthesis difficulty is big,
Cost is high, expensive.Such as document：PCT Int. Appl., 2016098016; PCT Int. Appl.,
2016016852；Another synthetic schemes is equally using 5- nitro -2- methyl benzoyl chlorides as initiation material, with the bromo- 5- thiophenes of 2-
Fen boric acid coupled reaction, then pays a gram acylation with 2- p-fluorophenyls thiophene, and nitro reduction, diazotising bromo is made.The synthesis
Scheme route is long, and yield is low.Such as patent：CN104311532.The third scheme be equally using 2- methyl -5- bromobenzaldehydes as rise
Beginning raw material, is reacted with 2- p-fluorophenyl thiophene by butyl lithium, is then reduced and is made, the raw materials technology is expensive, uses butyl lithium, work
Skill is dangerous high.Such as patent：CN104987320.4th kind of scheme be using 2 thiophene carboxaldehyde as initiation material, it is anti-with 4- bromofluorobenzenes
Should, then aoxidize, chloride, reacted with 4- toluene bromides, then reduce and be made, the reaction scheme is longer, and yield is relatively low.As specially
Profit：Eur. Pat. Appl., 20152918579.5th kind of synthetic schemes is using o-toluic acid as initiation material, through bromine
In generation, then occur friedel-crafts reaction with 2- p-fluorophenyls thiophene, then reduce and be made.The process route uses bromine, and environmental pollution is tight
Weight.Such as patent：CN103980263.
Specific route is as follows：
The route of scheme one：
The route of scheme two：
The route of scheme three：
The route of scheme four：
The route of scheme five：
The content of the invention：
The present invention is in order to solve the problem of prior art in above-mentioned background technology is present there is provided with low cost, easily to operate
A kind of preparation method of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene, by using 4- toluene bromides as starting
Raw material, is reacted with concentrated hydrochloric acid by 4- toluene bromides and paraformaldehyde, prepares 2- methyl -5- bromine benzyl chlorides under zinc chloride catalysis, so
2- methyl -5- bromines benzyl chloride and 2- p-fluorophenyl thiophene are dissolved in ethyl acetate afterwards, are catalyzed by zinc chloride, 80 DEG C of reaction synthesis
2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene, cost of material of the present invention is cheap and easily-available, former
Material selection variation, production technology easily realizes that easy management and control, gained final products purity is high, without dangerous technique, and equipment is simple, closes
Novel into route, synthetic route is short, lifts production capacity, reduction production and processing cost.
The synthetic route of the present invention is as follows：
The preparation method of canagliflozin key intermediate of the present invention, its feature is as follows：
The first step：With 4- toluene bromides and paraformaldehyde in concentrated hydrochloric acid, 2- methyl -5- bromine benzyl chlorides are catalyzed and synthesized with zinc chloride.
I
Second step：2- methyl -5- bromine benzyl chlorides, 2- p-fluorophenyls thiophene and zinc chloride are dissolved in ethyl acetate, through paying a gram alkylation
Reaction prepares 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene.
II
Preferably, 2- methyl -5- bromines benzyl chloride is prepared from by ratio of weight and the number of copies by following components in the first step：4- toluene bromides
160-180, paraformaldehyde 170-190, concentrated hydrochloric acid 170-180, zinc chloride 25-30, ethyl acetate 280-320.
Preferably, 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene is by following components in second step
It is prepared from by ratio of weight and the number of copies：2- methyl -5- bromine benzyl chloride 100-120, ethyl acetate 240-260,2- p-fluorophenyl thiophene 75-
90, zinc chloride 60-80, water 600-700.
Preferably, the preparation process of 2- methyl -5- bromine benzyl chlorides is in the first step：Take 4- toluene bromide 160-180, poly
Formaldehyde 170-190,170-180 concentrated hydrochloric acid, zinc chloride 25-30 reacts 6h at 50 DEG C, after reaction terminates, is cooled to room temperature,
280-320 ethyl acetate is extracted, and organic layer is washed to neutrality, and anhydrous sodium sulfate drying, filtering, filtrate decompression distillation recovery is molten
Agent, residual night vacuum distillation obtains white liquid.
Preferably, in second step 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene preparation process
For：2- methyl -5- bromine benzyl chloride 100-120 are taken, are dissolved in 240-260 ethyl acetate, 2- p-fluorophenyl thiophene 75-90, chlorine is added
Change zinc 60-80, heating reflux reaction 6h, after reaction terminates, be cooled to room temperature, add water 400-450, extraction, 200-250 water
Wash, anhydrous sodium sulfate drying, filter, filtrate reclaims 100kg, crystallisation by cooling obtains Light yellow crystals.
The beneficial effects of the invention are as follows：
The present invention by 4- toluene bromides and paraformaldehyde with concentrated hydrochloric acid by using 4- toluene bromides as initiation material, being reacted, in chlorination
Zinc catalysis is lower to prepare 2- methyl -5- bromine benzyl chlorides, and 2- methyl -5- bromines benzyl chloride and 2- p-fluorophenyl thiophene then are dissolved in into ethyl acetate
In, it is catalyzed by zinc chloride, 80 DEG C of reaction synthesis 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene, this hair
Bright used cost of material is cheap and easily-available, and raw material selection variation, production technology is easily realized, easy management and control, gained final products
Purity is high, without dangerous technique, and equipment is simple, and synthetic route is novel, and synthetic route is short, lifts production capacity, reduction production and processing cost.
Embodiment
Embodiment 1
The first step：The preparation of 2- methyl -5- bromine benzyl chlorides
Take 4- toluene bromide 170kg, paraformaldehyde 180kg, 180kg concentrated hydrochloric acid, zinc chloride 27kg reacts 6h at 50 DEG C, reacted
After end, room temperature is cooled to, 300kg ethyl acetate extraction, organic layer is washed to neutrality, anhydrous sodium sulfate drying, filtering, filtrate
Vacuum distillation recovered solvent, residual night vacuum distillation obtains white liquid 162kg, yield 74%.
Second step：The preparation of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene
2- methyl -5- bromine benzyl chloride 110kg are taken, are dissolved in 250kg ethyl acetate, 2- p-fluorophenyl thiophene 80kg, zinc chloride is added
70kg, heating reflux reaction 6h, after reaction terminates, are cooled to room temperature, add water 400kg, extraction, 200kg washings, anhydrous sulphur
Sour sodium is dried, and filtering, filtrate reclaims 100kg, and crystallisation by cooling obtains Light yellow crystals 141kg, yield 78%.
Embodiment 2
The first step：The preparation of 2- methyl -5- bromine benzyl chlorides
Take 4- toluene bromide 160kg, paraformaldehyde 170kg, 170kg concentrated hydrochloric acid, zinc chloride 25kg reacts 6h at 50 DEG C, reacted
After end, room temperature is cooled to, 280kg ethyl acetate extraction, organic layer is washed to neutrality, anhydrous sodium sulfate drying, filtering, filtrate
Vacuum distillation recovered solvent, residual night vacuum distillation obtains white liquid 160kg, yield 73.8%.
Second step：The preparation of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene
2- methyl -5- bromine benzyl chloride 100kg are taken, are dissolved in 240kg ethyl acetate, 2- p-fluorophenyl thiophene 75kg, zinc chloride is added
60kg, heating reflux reaction 6h, after reaction terminates, are cooled to room temperature, add water 400kg, extraction, 200kg washings, anhydrous sulphur
Sour sodium is dried, and filtering, filtrate reclaims 98kg, and crystallisation by cooling obtains Light yellow crystals 135kg, yield 78%.
Claims (5)
1. a kind of preparation method of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene, it is characterised in that institute
Method is stated including as follows：
The first step：The preparation of 2- methyl -5- bromine benzyl chlorides（I）
Reacted with 4- toluene bromides and paraformaldehyde with concentrated hydrochloric acid, 2- methyl -5- bromines benzyl chlorides (I) are prepared under zinc chloride catalysis；Tool
Precursor reactant is as follows：
I
Second step：2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene（II）
2- methyl -5- bromines benzyl chloride is dissolved in ethyl acetate with 2- p-fluorophenyl thiophene, is catalyzed by zinc chloride, 80 DEG C of reaction synthesis
2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene（II）, it is specific to react as follows：
II。
2. a kind of preparation of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene according to claim 1
Method, it is characterised in that 2- methyl -5- bromines benzyl chloride is prepared from by ratio of weight and the number of copies by following components in the first step：4-
Toluene bromide 160-180, paraformaldehyde 170-190, concentrated hydrochloric acid 170-180, zinc chloride 25-30, ethyl acetate 280-320.
3. a kind of preparation of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene according to claim 1
Method, it is characterised in that 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene is by following in the second step
Component is prepared from by ratio of weight and the number of copies：2- methyl -5- bromine benzyl chloride 100-120, ethyl acetate 240-260,2- p-fluorophenyl thiophene
Fen 75-90, zinc chloride 60-80, water 600-700.
4. a kind of preparation of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene according to claim 1
Method, it is characterised in that the preparation process of 2- methyl -5- bromine benzyl chlorides is in the first step：4- toluene bromides 160-180 is taken, it is many
Polyformaldehyde 170-190,170-180 concentrated hydrochloric acid, zinc chloride 25-30 reacts 6h at 50 DEG C, after reaction terminates, is cooled to room temperature,
280-320 ethyl acetate is extracted, and organic layer is washed to neutrality, and anhydrous sodium sulfate drying, filtering, filtrate decompression distillation recovery is molten
Agent, residual night vacuum distillation obtains white liquid.
5. a kind of preparation of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene according to claim 1
Method, it is characterised in that the preparation of 2- [(the bromo- 2- aminomethyl phenyls of 5-) methyl] -5- (4- fluorophenyls) thiophene in the second step
Step is：2- methyl -5- bromine benzyl chloride 100-120 are taken, are dissolved in 240-260 ethyl acetate, 2- p-fluorophenyl thiophene 75- is added
90, zinc chloride 60-80, heating reflux reaction 6h, after reaction terminates, are cooled to room temperature, add water 400-450, extraction, 200-
250 washings, anhydrous sodium sulfate drying, filtering, filtrate reclaims 100kg, and crystallisation by cooling obtains Light yellow crystals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710421543.4A CN107011316A (en) | 2017-06-07 | 2017-06-07 | A kind of preparation method of 2 [(aminomethyl phenyl of 5 bromine 2) methyl] 5 (4 fluorophenyl) thiophene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710421543.4A CN107011316A (en) | 2017-06-07 | 2017-06-07 | A kind of preparation method of 2 [(aminomethyl phenyl of 5 bromine 2) methyl] 5 (4 fluorophenyl) thiophene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107011316A true CN107011316A (en) | 2017-08-04 |
Family
ID=59452318
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710421543.4A Pending CN107011316A (en) | 2017-06-07 | 2017-06-07 | A kind of preparation method of 2 [(aminomethyl phenyl of 5 bromine 2) methyl] 5 (4 fluorophenyl) thiophene |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107011316A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108033955A (en) * | 2017-12-15 | 2018-05-15 | 东南大学 | A kind of preparation method of antidiabetic drug canagliflozin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311532A (en) * | 2014-10-31 | 2015-01-28 | 山东大学 | Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl) methyl] thiophene |
| CN104892566A (en) * | 2015-05-29 | 2015-09-09 | 上海应用技术学院 | Preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene |
| EP2918579A1 (en) * | 2014-03-14 | 2015-09-16 | LEK Pharmaceuticals d.d. | Synthesis of 2-arylmethyl-5-aryl-thiophene |
-
2017
- 2017-06-07 CN CN201710421543.4A patent/CN107011316A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2918579A1 (en) * | 2014-03-14 | 2015-09-16 | LEK Pharmaceuticals d.d. | Synthesis of 2-arylmethyl-5-aryl-thiophene |
| CN104311532A (en) * | 2014-10-31 | 2015-01-28 | 山东大学 | Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl) methyl] thiophene |
| CN104892566A (en) * | 2015-05-29 | 2015-09-09 | 上海应用技术学院 | Preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene |
Non-Patent Citations (1)
| Title |
|---|
| LOUIS F等: "《The Synthesis of Methylcholanthrene》", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108033955A (en) * | 2017-12-15 | 2018-05-15 | 东南大学 | A kind of preparation method of antidiabetic drug canagliflozin |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107011316A (en) | A kind of preparation method of 2 [(aminomethyl phenyl of 5 bromine 2) methyl] 5 (4 fluorophenyl) thiophene | |
| JP4787759B2 (en) | Method for preparing 4,7-bis (5-halothien-2-yl) -2,1,3-benzothiadiazole and its precursor | |
| CN111646893A (en) | Preparation method of 2,4, 6-trimethylbenzoyl chloride | |
| CN104844593A (en) | Synthetic method for Apixaban drug intermediate | |
| CN108947870B (en) | Preparation method of bromosartanbiphenyl | |
| CN106831702A (en) | A kind of preparation method of the thiophenic acid of 5 substitution 2 | |
| CN110256451B (en) | Synthetic method of benzofuro [2,3-b ] quinoline derivative | |
| CN102070428B (en) | Method for synthesizing 3-hydroxyacetophenone | |
| CN108017612A (en) | A kind of preparation method of canagliflozin intermediate | |
| KR100297624B1 (en) | Process for producing organophosphorus compounds | |
| CN108033955A (en) | A kind of preparation method of antidiabetic drug canagliflozin | |
| CN106986762A (en) | A kind of technique for preparing DL mandelic acids | |
| CN106631937A (en) | Method for synthesizing 4,4'-thiodibenzenethiol | |
| CN103420785A (en) | Preparation method of 9, 9'-(4-halogen phenyl) fluorene derivative | |
| CN116239465B (en) | Preparation method of 4,4' -diphenyl ether diformyl chloride | |
| CN112159364B (en) | Synthetic method of isothiazole derivative | |
| CN113563234B (en) | Production process of acetamido benzene sulfonyl chloride | |
| CN111410600A (en) | Preparation method of p-phenylbutoxy benzoic acid | |
| CN1827612B (en) | New process for synthesizing daphnetin | |
| JP6046827B2 (en) | 4- (5-Amino-6-hydroxybenzoxazol-2-yl) ammonium benzoate and its production and use | |
| JPS58131925A (en) | Production of 2,2',4,4'-tetrachlorobenzophenone dichloride | |
| CN102101849B (en) | Preparation method of clausenamide intermediate | |
| CN110878057B (en) | Method for preparing Raxinader | |
| Walton et al. | Studies in the Quinoline Series. II. The Monoaminophenylquinaldylcarbinols | |
| CN106749280B (en) | 5H- quinazolines [3,2-b] cinnolines -7,13- cyclohexadione compounds and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170804 |
|
| WD01 | Invention patent application deemed withdrawn after publication |