CN108623446A - A kind of method of synthesis 3,3- difluoro cyclobutane formates - Google Patents
A kind of method of synthesis 3,3- difluoro cyclobutane formates Download PDFInfo
- Publication number
- CN108623446A CN108623446A CN201710180659.3A CN201710180659A CN108623446A CN 108623446 A CN108623446 A CN 108623446A CN 201710180659 A CN201710180659 A CN 201710180659A CN 108623446 A CN108623446 A CN 108623446A
- Authority
- CN
- China
- Prior art keywords
- cyclobutane
- oxygroup
- difluoro
- formates
- esters
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
The present invention provides a kind of methods of 3,3 difluoro cyclobutane formates of synthesis.Specifically using 3 oxygroup cyclobutane formate esters as starting material, by the way that double fluoro-reactions occur with fluorination reagent BAST, 3,3 difluoro cyclobutane formate esters are obtained, then saponification occurs with alkali, acidification obtains 3,3 difluoro cyclobutane formates.This reaction route is shorter, and raw material property stablizes safety, and reaction condition is mild, is suitble to industrialized production.
Description
Technical field
The invention belongs to chemical fields, are related to medicine intermediate 3, a kind of new synthesis side of 3- difluoro cyclobutane formates
Method.
Background technology
3,3- difluoro cyclobutane formates are an important medicine intermediates, and in exploitation kinase inhibitor, fibrin ferment inhibits
There is application in agent and some antitumor drugs.
The synthetic method of current 3,3- difluoros cyclobutane formate is mainly the following：
(1) Dolbier 1987 with 1,1-, bis- chloro- 2,2- difluoroethylenes and acrylonitrile for starting material, it is anti-by cycloaddition
2,2-, bis- chloro- 3,3- difluoros cyclobutyronitriles should be obtained, then hydrolysis obtains 2,2-, bis- chloro- 3,3- difluoros ring butyric acid and 2- bis- chloro- 3,
The mixture of bis- fluoro- 1- alkene ring butyric acid of 3-, most back end hydrogenation obtain 3,3- difluoro cyclobutane formates（J. Org. Chem, 52,
1872,1987）.Wu Ming is distant et al. to improve this route, is that starting is former with 1,1-, bis- chloro- 2,2- difluoroethylenes and methyl acrylate
Material, has carried out reaction condition optimization（CN105418406,2016.03.23）.But the first step reaction temperature of both routes
It is all very high, reach 150-160 degree, when final step dechlorination wants catalytic hydrogenation, pressure to reach 30-40atm, these are all unfavorable for
Industrialized production.
(2) 2005 years, Elend passed through sodium metaperiodate and catalyst tri-chlorination using 3- methylene cyclobutyronitrile as starting material
Ruthenium obtains 3,3- difluoro cyclobutyronitriles to aoxidize to obtain 3- oxo cyclobutyronitriles, then with two fluorine on DAST fluorination reagents, finally hydrolyzes
Cyano obtains 3,3- difluoro cyclobutane formates（Synthetic Communications, 35(5), 657-662; 2005）.This
Route raw material cost is higher, and uses the fluoro reagent DAST that explosion is easy when improper operation and post-processing, therefore uncomfortable
Close industrialization large-scale production.
(3) 2008 years, 3- oxo cyclobutane first was obtained by the reaction with 3- oxos cyclobutane formate and bromobenzyl in Balkovec et al.
Then acid benzyl ester obtains 3,3- difluoro cyclobutane formate benzyl esters with DAST fluoro-reactions, finally catalytic hydrogenation removes benzyl again, obtains
To 3,3- difluoro cyclobutane formates（US20080262051, 2008.10.23）.Raw material bromobenzyl has strong tear-gas in this route
Property, the DAST for being easy explosion is also used, also there is unsafe factor in when final step catalytic hydrogenation, therefore is also not suitable for industrializing
Production.
The above several routes, reaction condition is all harsher, and raw material is not readily available, and be easy to cause work safety accident.It is many
Well known, fluorination reaction has danger, and specifically include fluorination reagent has reaction violent with danger, fluorination reaction is fired
And strongly exothermic property, fluoride have strong corrosive and hypertoxicity.Therefore it is shorter to develop a route, raw material property, which is stablized, pacifies
Entirely, and reaction condition is mild, is suitble to the synthetic method of industrialized production necessary.
Invention content
It is an object of the invention to provide a kind of methods of synthesis 3,3- difluoro cyclobutane formates.This reaction route is shorter,
And the safer fluorination reagent BAST of performance, reaction condition is mild, is suitble to industrialized production.Specific reaction route is shown in
Formula（One）：
For said synthesis route, comprise the concrete steps that：
（1）Using 3- oxygroup cyclobutane formate esters as starting material, by the way that double fluoro-reactions occur with fluorination reagent BAST, 3 are obtained,
3- difluoro cyclobutane formate esters.
（2）Saponification occurs with alkali, then is acidified to obtain 3,3- difluoro cyclobutane formates.
In above-mentioned steps, step（1）In：Can be 3- oxygroup ring fourths using 3- oxygroup cyclobutane formate esters as starting material
Alkane methyl formate, 3- oxygroup cyclobutane formates ethyl ester, 3- oxygroup cyclobutane formates propyl ester, 3- oxygroup cyclobutane formate isopropyl esters
Deng.It is preferred that 3- oxygroup cyclobutane formate methyl esters.Fluorination reagent can be bis- (2- methoxy ethyls) amino sulfur trifluorides (BAST)
, Fluolead, XtalFluor-E, XtalFluor-M, preferably BAST.Reaction reagent can be dichloromethane, chloroform,
The anhydrous solvents such as benzene, toluene, preferably toluene solvant.Reaction temperature -50-90 degree, preferably 75-80 degree.
Step（2）In：Saponification can use sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide etc., best
It is sodium hydroxide.Its dosage and the molar ratio of 3,3- difluoro cyclobutane formate esters are 1-3：1, preferably 1.5：1.
The present invention generates 3,3- difluoro cyclobutane formates and is tested, come using 3- oxygroup cyclobutane formate methyl esters as starting material
Verify the reliability of synthetic method.The protection content of the present invention is not limited to following case study on implementation.
Case is embodied：
The synthesis of 1.3,3- difluoro cyclobutane formate methyl esters：
51.2 grams of 3- oxygroup cyclobutane formate methyl esters, 150ml dry toluenes, three drop first are added into tetra- mouthfuls of reaction bulbs of 1000ml
Alcohol, and connect tail gas absorbing by liquid caustic soda device starts stirring, is added dropwise 442 grams of BAST, 20 degree or so of temperature control, after being added dropwise, slowly
It is warming up to 75-80 degree, after reaction, room temperature is cooled to, reaction solution is poured slowly into the ice water solution of saturated sodium bicarbonate,
After liquid separation, again with toluene extracts a water phase, merges organic phase, and saturated salt solution washed once, and after anhydrous sodium sulfate drying, subtracts
Pressure distillation, obtains 51.6 grams of products, yield 86%.
The synthesis of 2.3,3- difluoro cyclobutane formates：
30 grams of 3,3- difluoro cyclobutane formate methyl esters are added into tetra- mouthfuls of reaction bulbs of 500ml, add 90ml toluene, 40 gram 30%
The aqueous solution of sodium hydroxide, 60 degree are reacted 2 hours down, are cooled to 20 degree, are acidified with concentrated hydrochloric acid, make PH=1-2, liquid separation, water phase is again
It is primary with the extraction of 45ml toluene, merge organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate drying, vacuum distillation obtains
28.5 grams of white solids, yield 95%.
Claims (6)
1. a kind of method of synthesis 3,3- difluoro cyclobutane formates, feature includes following steps：
(1) it using 3- oxygroup cyclobutane formate esters as starting material, by the way that double fluoro-reactions occur with fluorination reagent BAST, obtains
3,3- difluoro cyclobutane formate esters；
(2) saponification occurs with alkali, then is acidified to obtain 3,3- difluoro cyclobutane formates；
Specific reaction route is shown in formula（One）：
R represents the groups such as methyl, ethyl in formula.
2. according to claim 1, step（1）In：Can be 3- oxygroups using 3- oxygroup cyclobutane formate esters as starting material
Cyclobutane formate methyl esters, 3- oxygroup cyclobutane formates ethyl ester, 3- oxygroup cyclobutane formates propyl ester, 3- oxygroup cyclobutane formate isopropyls
Ester etc., preferably 3- oxygroups cyclobutane formate methyl esters.
3. according to claim 1, step（1）In：Fluorination reagent can be bis- (2- methoxy ethyls) amino sulfur trifluorides
(BAST), Fluolead, XtalFluor-E, XtalFluor-M, preferably BAST.
4. according to claim 1, step（1）In：Reaction reagent can be the nothings such as dichloromethane, chloroform, benzene, toluene
Aqueous solvent, preferably toluene solvant.
5. according to claim 1, step（1）In：Reaction temperature -50-90 degree, preferably 75-80 degree.
6. according to claim 1, step（2）In：Saponification can use sodium hydroxide, potassium hydroxide, lithium hydroxide,
Calcium hydroxide etc., preferably sodium hydroxide, dosage and the molar ratio of 3,3- difluoro cyclobutane formate esters are 1-3：1, preferably
1.5：1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710180659.3A CN108623446A (en) | 2017-03-24 | 2017-03-24 | A kind of method of synthesis 3,3- difluoro cyclobutane formates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710180659.3A CN108623446A (en) | 2017-03-24 | 2017-03-24 | A kind of method of synthesis 3,3- difluoro cyclobutane formates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108623446A true CN108623446A (en) | 2018-10-09 |
Family
ID=63706694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710180659.3A Withdrawn CN108623446A (en) | 2017-03-24 | 2017-03-24 | A kind of method of synthesis 3,3- difluoro cyclobutane formates |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108623446A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101663033A (en) * | 2007-04-18 | 2010-03-03 | 默克公司 | Triazole derivatives which are smo antagonists |
| CN101855209A (en) * | 2007-09-11 | 2010-10-06 | 第一三共株式会社 | Alkylsulfone derivative |
| CN102159548A (en) * | 2008-09-18 | 2011-08-17 | 辉瑞有限公司 | Amide compounds useful in therapy |
-
2017
- 2017-03-24 CN CN201710180659.3A patent/CN108623446A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101663033A (en) * | 2007-04-18 | 2010-03-03 | 默克公司 | Triazole derivatives which are smo antagonists |
| CN101855209A (en) * | 2007-09-11 | 2010-10-06 | 第一三共株式会社 | Alkylsulfone derivative |
| CN102159548A (en) * | 2008-09-18 | 2011-08-17 | 辉瑞有限公司 | Amide compounds useful in therapy |
Non-Patent Citations (3)
| Title |
|---|
| 李学敏等: "有机化合物的氟化反应研究进展", 《精细与专用化学品》 * |
| 杨燕等: "氟化剂的研究进展", 《中国科技信息》 * |
| 胡宏纹: "《有机化学》", 31 May 2006, 北京：高等教育出版社 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103288718B (en) | Preparation method of 2-chloro-5-tirfluoromethylpyridine | |
| CN105967986B (en) | The synthetic method of 3- hydroxy acetophenone | |
| CN105541819A (en) | Preparation method and intermediate of brexpiprazole and preparation method of intermediate | |
| CN103508942B (en) | A kind of synthetic method of 2,3-bis-chloro-5-methypyridine | |
| CN109232259B (en) | Preparation method of nitroacetophenone | |
| Li et al. | Transition metal free decarboxylative fluorination of cinnamic acids with selectfluor® | |
| CN105418494B (en) | A kind of preparation method of clodinafop-propargyl | |
| CN103224451A (en) | Method for synthesizing 3,5-dichlorobenzoic acid | |
| FI3765440T3 (en) | Process for the preparation of n-alkyl-nitratoethylnitramines | |
| CN107056590B (en) | Industrial method for preparing and purifying 4, 4' -dimethoxy triphenylchloromethane | |
| CN108623446A (en) | A kind of method of synthesis 3,3- difluoro cyclobutane formates | |
| CN107473948A (en) | A kind of synthetic method that the pentanone of 3,5 dichloro 2 is prepared by ethyl acetoacetate | |
| CN100494146C (en) | Process for preparing cyclopropyl methyl ketone | |
| CN105061209A (en) | Synthetic method of 2-diester methylmalonate compounds | |
| CN110204452B (en) | Preparation method of diacetone acrylamide with low acrylamide content | |
| CN107417643B (en) | Synthesis process of dyclonine hydrochloride | |
| CN103965047B (en) | The preparation method of 3,3,3-trifluoroacetic acid and ester thereof | |
| CN103467268B (en) | Preparation method of 2,2'- dyhydroxyl-4,4'-dimethoxybenzophenone | |
| CN106117060A (en) | A kind of purification process of 7 chlorine 2 oxoheptanoates | |
| CN113493386B (en) | Novel high-selectivity asymmetric synthesis process of 2-fluorocyclopropylamine | |
| CN103787936A (en) | Simple synthetic method of trans-p-methylthiocinnamyl alcohol used for industrial production | |
| CN104478715B (en) | The preparation method of compound | |
| CN104311456A (en) | Preparation method of guaiacol potassium sulfoacid | |
| CN103772151A (en) | Preparation method of 2-methyl-3-phenyl benzyl alcohol | |
| CN105859531A (en) | Method for obtaining ketone through methylene oxidation |
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 | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20181009 |