CN105218510B - A kind of preparation method of the chloromethyl piperonyl cyclonene of 2,2 difluoro 5 - Google Patents
A kind of preparation method of the chloromethyl piperonyl cyclonene of 2,2 difluoro 5 Download PDFInfo
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- CN105218510B CN105218510B CN201510692102.9A CN201510692102A CN105218510B CN 105218510 B CN105218510 B CN 105218510B CN 201510692102 A CN201510692102 A CN 201510692102A CN 105218510 B CN105218510 B CN 105218510B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
Abstract
The present invention relates to organic synthesis field, more particularly to a kind of preparation method of the chloromethyl piperonyl cyclonene of 2,2 difluoro 5 comprises the following steps：2,2 difluoro piperonyl cyclonenes（Ⅰ）Occur chloromethylation under lewis acidic catalytic action with chloro methyl ether, obtain the chloromethyl piperonyl cyclonene of 2,2 difluoro 5（II), its reaction equation is as follows：
Description
Technical field
The present invention relates to the preparation side of organic synthesis field, the more particularly to fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis-
Method.
Background technology
2,2- bis- fluoro- 5- chloromethyls piperonyl cyclonenes are a kind of important intermediates, are mainly used as medicine intermediate, organic synthesis
In terms of intermediate.
Existing synthetic method（WO2011127241）, its reaction equation is as follows：
The route uses the fluoro- 5- carboxyls piperonyl cyclonenes of 2,2- bis- as raw material, is synthesized by 2 steps, initiation material does not have market
Change supply and expensive, be unfavorable for market-oriented a large amount of productions.And to use LAH to reduce in course of reaction, operational risk is big, right
Equipment requirement is high, and second step does chloro using thionyl chloride, produces substantial amounts of hydrogen chloride gas, sour water, tail gas, contaminated wastewater are tight
Weight, equipment corrosion is serious.
The content of the invention
It is an object of the invention to overcome above-mentioned preparation method in reaction cost present on industrialization high, operating difficulties,
The problems such as reacting seriously polluted is easy to industrialized production there is provided one kind, and high income reacts the easy fluoro- 5- chloromethyls of 2,2- bis-
The preparation method of piperonyl cyclonene.
To achieve these goals, the present invention uses following technical scheme：
The preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis-, comprises the following steps：
2,2- difluoro piperonyl cyclonenes（Ⅰ）（English name：2,2-difluorobenzo[d][1,3]dioxole）With chloro methyl ether
Chloromethyl reaction occurs under lewis acidic catalytic action, the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis- are obtained（II), its reaction side
Formula is as follows：
Preferably, the lewis acid is selected from anhydrous zinc dichloride, aluminum trichloride (anhydrous), anhydrous ferric trichloride, four chlorinations
Tin, titanium tetrachloride or boron trifluoride etherate.
Preferably, lewis acid and 2,2- the difluoro piperonyl cyclonene（Ⅰ）Mol ratio is 1-3：1.
Preferably, the chloro methyl ether is selected from chloromethyl methyl ether or dichlormethyl ether.
Preferably, chloro methyl ether and 2,2- the difluoro piperonyl cyclonene（Ⅰ）Mol ratio is 5-50:1.
Preferably, the reaction temperature is -10-50 DEG C.
Preferably, the step is also included 2,2- difluoro piperonyl cyclonenes（Ⅰ）It is placed in organic solvent and carries out with chloro methyl ether
Chloromethylation.
Preferably, the organic solvent is selected from dichloromethane, 1,2- dichloroethanes, carbon disulfide, nitrobenzene, nitromethane
In one kind.
Preferably, the step also includes the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-（II) purification procedures：Reaction knot
Shu Hou, reaction mixture is added water mixing, extracted with dichloromethane, and separation acquisition is dissolved with the fluoro- 5- chloromethyls of 2,2- bis- recklessly
Green pepper ring（II) organic phase, is dried to organic phase, filters, filtrate obtains light yellow oil through distillation and concentration, will be above-mentioned
Grease carries out vacuum distillation, obtains product 2, the fluoro- 5- chloromethyls piperonyl cyclonenes of 2- bis-（II) sterling.
The present invention uses difluoro piperonyl cyclonene cheap and easy to get for raw material, and the fluoro- 5- chloromethyls of 2,2- bis- are made through single step reaction
Piperonyl cyclonene；Reaction condition is gentle, high income, reduce that exhaust emission, post processing be simple, reaction cost is low, is appropriate for industrialization
Production.
Embodiment
Inventor, for raw material, the fluoro- 5- chloromethyls of 2,2- bis- is obtained by single step reaction with 2,2- difluoros piperonyl cyclonene
Piperonyl cyclonene, so that there is provided a kind of simple to operate, reaction condition is gentle, product yield is high suitable industrially mass produces
The preparation method of 2,2- bis- fluoro- 5- chloromethyls piperonyl cyclonenes, completes the present invention on this basis.
The present invention provides the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis-, comprises the following steps：
2,2- difluoro piperonyl cyclonenes（Ⅰ）（English name：2,2-difluorobenzo[d][1,3]dioxole）With chloro methyl ether
Occur chloromethylation under lewis acidic catalytic action, obtain the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-（Ⅱ) （English
Name, 5- (chloromethyl) -2,2-difluorobenzo [d] [1,3] dioxole）, its reaction equation is as follows：
The specific method of the reaction is：2,2- difluoros piperonyl cyclonene, chloro methyl ether and lewis acid are added into reaction vessel
It is middle to be reacted.
The catalyst lewis acid can disposably be added to reaction vessel, can also be added portionwise.Workable road
Lewis acid include but is not limited to anhydrous zinc dichloride, aluminum trichloride (anhydrous), anhydrous ferric trichloride, butter of tin, titanium tetrachloride or
The one or more combination of boron trifluoride etherate, in a preferred embodiment, lewis acid are anhydrous dichloro
Change zinc, lewis acidic consumption is lewis acid and 2,2- difluoro piperonyl cyclonene mol ratio 1-3：1, in one embodiment of the present invention
In, lewis acid and 2,2- difluoro piperonyl cyclonene mol ratio are 2:1.
The chloro methyl ether is selected from chloromethyl methyl ether or dichlormethyl ether, in a preferred embodiment, chloro methyl ether
For chloromethyl methyl ether, the mol ratio of chloro methyl ether and 2,2- difluoro piperonyl cyclonene is 5-50:1, preferred molar ratio is 22:1.
Workable solvent includes but is not limited to benzene, chlorobenzene, toluene, nitrobenzene, nitromethane, dichloromethane, two chloroethenes
One or more combinations in alkane, chloroform, carbon tetrachloride, carbon disulfide, tetrahydrofuran, dioxane, for reaction dissolvent
Consumption be not particularly limited, as long as not to the present invention goal of the invention produce limitation, the present invention preferably without using solvent.
Preferably -10-50 DEG C, more preferably 0-30 DEG C, further preferred 0-10 DEG C of the reaction temperature.At this temperature can be with
Obtain faster reaction speed and accessory substance is few.Those skilled in the art can be according to the reaction process (consumption of raw material in reaction system
Situation) the control reaction time, in a preferred embodiment, the reaction time is 3h.
It is preferred that, the step also includes the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-（II) purification procedures：React
Reaction solution is added to the water after, extracted with organic solvent, separation obtain organic phase, precipitation, after purification i.e. prepare 2,
The fluoro- 5- chloromethyls piperonyl cyclonenes of 2- bis-.The preferred frozen water of water, those skilled in the art can select according to actual conditions suitably to be had
Machine solvent is extracted, and available organic solvent includes but is not limited to：Chloroform, dichloromethane, dichloroethanes, ethyl acetate,
One or more combinations in isopropyl acetate, methyl tertiary butyl ether(MTBE) etc..The purifying can select the various purifying sides in this area
Method, is preferably distilled, in a preferred embodiment, and the cut that boiling point is 70-74 DEG C/0.5mmHg is collected during distillation.
Reaction raw materials 2,2- difluoros piperonyl cyclonene, other reaction raw materials, catalyst and solvent are purchase.
Illustrate embodiments of the present invention below by way of specific instantiation, those skilled in the art can be by this specification
Disclosed content understands other advantages and effect of the present invention easily.The present invention can also pass through specific realities different in addition
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints with application, without departing from
Various modifications or alterations are carried out under the spirit of the present invention.
It should be clear that the process equipment or device that are not indicated specifically in the following example use conventional equipment in the art
Or device.
Embodiment 1
The fluoro- 5- chloromethyls piperonyl cyclonenes (10g, 0.063mol) of 2,2- bis-, chloromethyl methyl ether are separately added into reaction bulb
(105ml, 1.386mol), 100ml dichloromethane, anhydrous zinc dichloride (17.2g, 0.126mol), are reacted at room temperature 3 hours,
TLC monitoring reactions are complete.Reaction solution is poured into 500ml frozen water, stirred 10 minutes, dichloromethane extraction 100ml × 3 time are closed
And organic phase, washed with water 200ml × 3, saturated aqueous common salt 350ml is washed, dry, be spin-dried for, obtain the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-
15 grams of light yellow oil.70-74 DEG C of cut, obtains 11.7g products, separation yield under vacuum distillation, reception 0.5mmHg
90%.Purity when product does not distill：TLC detects purity more than 90%, and lcms detections purity is：90.41%（Agilent 1200）.
1H NMR (400MHz, DMSO) δ 7.42 (s, 1H), 7.32 (d, 1H), 7.24 (d, 1H), 4.71 (s, 2H).
19F-NMR (DMSO) δ -49.228, -49.329.
Embodiment 2：The preparation of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-
Be the same as Example 1, simply catalyst is aluminum trichloride (anhydrous), and the separation yield of product is 70%.
Embodiment 3：The preparation of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-
Be the same as Example 1, simply catalyst is titanium tetrachloride, and the separation yield of product is 80%.
Embodiment 4：The preparation of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-
Be the same as Example 1, simply catalyst is butter of tin, and the separation yield of product is 85%.
Embodiment 5：The preparation of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-
Be the same as Example 1, simply the mol ratio of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis- and chloromethyl methyl ether is 1:10, product
Separation yield be 88%.
Embodiment 6：The preparation of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-
Be the same as Example 1, simply the mol ratio of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis- and chloromethyl methyl ether is 1:50, product
Separation yield be 90%.
Embodiment 7：The preparation of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis-
Be the same as Example 1, simply the mol ratio of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2,2- bis- and chloromethyl methyl ether is 1:5, product
Separation yield is 87%.
In summary, the present invention effectively overcomes defect of the prior art and has high industrial utilization.
The above-described embodiments merely illustrate the principles and effects of the present invention, not for the limitation present invention.It is any ripe
Know the personage of this technology all can carry out modifications and changes under the spirit and scope without prejudice to the present invention to above-described embodiment.Cause
This, those of ordinary skill in the art is complete without departing from disclosed spirit and institute under technological thought such as
Into all equivalent modifications or change, should by the present invention claim be covered.
Claims (8)
1. one kind 2, the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of 2- bis-, comprises the following steps：
Under lewis acidic catalytic action chloromethylation occurs for 2,2- difluoro piperonyl cyclonenes (I) and chloro methyl ether, obtains 2,
The fluoro- 5- chloromethyls piperonyl cyclonenes (II) of 2- bis-, its reaction equation is as follows：
The lewis acid is selected from anhydrous zinc dichloride, aluminum trichloride (anhydrous), anhydrous ferric trichloride, butter of tin, titanium tetrachloride
Or boron trifluoride etherate.
2. the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis- as claimed in claim 1, it is characterised in that described
Lewis acid and 2,2- difluoros piperonyl cyclonene (I) mol ratio are 1-3：1.
3. the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis- as claimed in claim 1, it is characterised in that described
Chloro methyl ether is selected from chloromethyl methyl ether or dichlormethyl ether.
4. the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis- as described in claim 1 or 3, it is characterised in that institute
It is 5-50 to state chloro methyl ether and 2,2- difluoros piperonyl cyclonene (I) mol ratio:1.
5. the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis- as claimed in claim 1, it is characterised in that described
Reaction temperature is -10-50 DEG C.
6. the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis- as claimed in claim 1, it is characterised in that described
Step also includes 2,2- difluoros piperonyl cyclonene (I) and chloro methyl ether being placed in organic solvent carrying out chloromethylation.
7. the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis- as claimed in claim 6, it is characterised in that described
The one kind of organic solvent in dichloromethane, 1,2- dichloroethanes, carbon disulfide, nitrobenzene, nitromethane.
8. the preparation method of the fluoro- 5- chloromethyls piperonyl cyclonenes of one kind 2,2- bis- as claimed in claim 1, it is characterised in that described
Step also includes the purification procedures of the fluoro- 5- chloromethyls piperonyl cyclonenes (II) of 2,2- bis-：After reaction terminates, by reaction mixture
Add water mixing, is extracted with dichloromethane, and separation acquisition is dissolved with the organic phase of the fluoro- 5- chloromethyls piperonyl cyclonenes (II) of 2,2- bis-, right
Organic phase is dried, filtered, and the rotated evaporation of filtrate obtains light yellow oil, and above-mentioned grease is carried out into vacuum distillation,
Obtain the fluoro- 5- chloromethyls piperonyl cyclonenes (II) of product 2,2- bis-.
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| CN102917692A (en) * | 2010-04-07 | 2013-02-06 | 弗特克斯药品有限公司 | Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyriodin-2-yl)benzoic acid and administration thereof |
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| CN102917692A (en) * | 2010-04-07 | 2013-02-06 | 弗特克斯药品有限公司 | Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyriodin-2-yl)benzoic acid and administration thereof |
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| Photochemistry of the phthalimide system. 40. Photoreaction of phthalimides possessing an ortho-methylphenyl group in their N-side chain. Synthesis of tetracyclic nitrogen heterocycles;Machida, Minoru等;《Heterocycles》;19871231;第26卷(第10期);第2683-2690页 * |
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