CN101538186A - Method for preparing compounds containing difluoromethylene - Google Patents

Method for preparing compounds containing difluoromethylene Download PDF

Info

Publication number
CN101538186A
CN101538186A CN200910049927A CN200910049927A CN101538186A CN 101538186 A CN101538186 A CN 101538186A CN 200910049927 A CN200910049927 A CN 200910049927A CN 200910049927 A CN200910049927 A CN 200910049927A CN 101538186 A CN101538186 A CN 101538186A
Authority
CN
China
Prior art keywords
halogen
initiator
alkyl
aryl
difluoromethyl
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
Application number
CN200910049927A
Other languages
Chinese (zh)
Other versions
CN101538186B (en
Inventor
胡金波
王飞
张伟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CN2009100499273A priority Critical patent/CN101538186B/en
Publication of CN101538186A publication Critical patent/CN101538186A/en
Application granted granted Critical
Publication of CN101538186B publication Critical patent/CN101538186B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention relates to a method for synthesizing compounds containing difluoromethylene group, more specifically a method for synthesizing difluoromethylene (in fact difluorocyclopropyl) compounds. Monohalogendifluoromethyl trialkylsilane(R<a>R<b>R<c>SiCF2X) used as difluorocarbene reagent is reacted with olefin compounds containing double bond of carbon in the presence of the initiator with catalytic amounts for 2-20 hours to obtain compounds containing difluorocyclopropyl. The monohalogendifluoromethyl trialkylsilane used in the invention can be prepared easily, which is a highly effective new difluorocarbene reagent with a good universal adaptation.

Description

A kind of preparation contains the method for difluoro methylene compound
Technical field
The present invention relates to the synthetic method of fluorine-containing medicines, pesticide intermediate, is to utilize a halogen difluoromethyl trialkyl silane (R first aR bR cSiCF 2X) come the synthetic method that contains the difluoro methylene compound.
Background technology
Introducing difluoromethyl or difluoro methylene often can effectively improve the physiologically active of organic molecule in the molecule, so at medicine, more and more come into one's own in the fields such as agricultural chemicals and material.((a) Kirsch, P.ModernFluoroorganic Chemistry:Synthesis, Reactivity, Applications; Wiley-VCH:Weinheim, 2004. (b) Organofluorine Compounds:chemistry and Applications; Hiyama, T., Ed.; Springer:New York, 2000.) be a kind of approach preferably that achieves the above object with the difluorocarbene as a kind of difluoromethyl or difluoro methylene building block.
The most cost-effective so far difluorocarbene's precursor is Freon22 gas (HCF 2Cl) ((a) Miller, T.G.; Thanassi, J.W.J.Org.Chem.1960,25,2009. (b) Shen, T.Y.; Lucas, S.; Sarett, L.H.Tetrahedron Lett.1961,2,43. (c) Langlois, B.J.Fluorine Chem.1988,41,247. (d) Morimota, K.; Makino, K.; Sakata, G.J.Fluorine Chem.1992,59,417.), but Freon gas has destruction to atmospheric ozone layer.And its reactive behavior is general, and needed amount is bigger.In addition ClF 2CCOONa and ClF 2CCOOMe relatively effectively uses wider method ((a) Christensen, S.B., IV; Dabbs, H.E.; Karpinski, J.M.PCT International Application, WO 96/23754,1996. (b) Ho, J.Z.; Elmore, C.S.; Wallace, M.A.; Yao, D.; Braun, M.P.; Dean, D.C.; Melillo, D.G.; Chen, C.-Y.Helvetica Chim.Acta 2005,88,1040. (c) O ' shea, P.D.; Chen, C.-Y.; Chen, W.; Dagneau, P.; Frey, L.F.; Grabowski, E.J.J.; Marcantonio, K.M.; Reamer, R.A.; Tan, L.; Tillyer, R.D.; Roy, A.; Wang, X.; Zhao, D.J.Org.Chem.2005,70,3021.).The metallic compound of trifluoromethyl such as Me 3SnCF 3, PhHgCF 3, BrZnCF 3, BrCdCF 3Also can be as Cabbeen reagent, but its synthetic relative complex, the toxicity height, thus limited its application ((a) Seyferth, D. greatly; Hoppe, S.P., J.Organomet.Chem., 1971,26,64. (b) Seyferth, D.; Hoppe, S.P; Darragh.K.V., J.Am.Chem.Soc.1969,91,6536.).Other is as CF 2Br 2((a) Dolbier, W.R.; Burkholder, Jr.C R, J.Org.Chem., 1990,55; 589; (b) Dolbier, W.R.; Wojtowicz, J.H.; Burkholder, C.R., J.Org.Chem., 1990; 55,5420; (c) Crabbe, P.; Cervantes, A.; Cruz A.; Galeazzi, E.; Iriarte, J.; Velarde, E., J.Am.Chem.Soc, 1973,95,6655), FSO 2CF 2COOH (Chen, Q.-Y.; Wu, S.-W.J.Fluorine Chem.1989,44,433.), FSO 2CF 2COOSiMe 3(Tian, F.; Virginie, B.; Duan, J.X., Dolbier, W.R.Jr.; Chen, Q.Y., Org Lett., 2000,2,563.) etc. certain application is also arranged, but generally do not possess higher universality and selectivity.
People such as Prakash had reported a halogen difluoromethyl trimethyl silane ((Me) in 1997 3SiCF 2X) synthetic method, and reported nucleophilic reaction (Yudin, the A.K. of this reagent; Prakash, G.K.S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G.A., J.Am.Chem.Soc, 1997,119,1572.).
Utilize a halogen difluoromethyl trialkyl silane ((R in this patent aR bR cSiCF 2X) as a kind of highly effective difluorocarbene's reagent, can be with the difluoro methylene reaction of its utilization to carbon-carbon double bond.
Summary of the invention
The purpose of this invention is to provide the synthetic method that contains the difluoro methylene group compound, is exactly the synthetic compound that contains difluoro methylene (actual is the difluoro cyclopropyl) type specifically.It is a kind of method of the efficient and compound that universality is good inserts carbon-carbon double bond the alkenes compounds difluoro methylene.
Method of the present invention adopts a halogen difluoromethyl trialkyl silane (R aR bR cSiCF 2X, wherein R a, R b, R cBe the alkyl of C1-C6, perhaps phenyl, X is a halogen) as difluorocarbene's reagent, it can be introduced difluoro methylene in the organic molecule, is a kind of mild condition, productive rate height, reagent that universality is high.
The synthetic method of reaction of the present invention is as follows:
In organic solvent, under 60～150 ℃, the alkenes compounds that contains carbon-carbon double bond is a raw material, under the condition of the initiator that adds catalytic amount, reacts 2～20 hours with a halogen difluoromethyl trialkyl silane, makes to contain difluoro cyclopropyl compounds;
Described olefin(e) compound is R 1, R 2, R 3Or the alkene of R4 replacement; Wherein, R 1Be the alkyl of H, C1-C12, trimethyl silicon based, aryl, R 5Or/and R 6Alkyl or the R of the C1-C4 that the aryl that replaces, aryl replace 5Or/and R 6The alkyl of the C1-C4 that the aryl that replaces replaces; Described R 5Or R 6Be the alkyl of H, C1-C4, alkoxyl group or the difluoro-methoxy of C1-C4; Make and contain difluoro cyclopropyl compounds.Wherein a part of product can further change into β-fluorine α, beta unsaturated ketone again.
Aryl described in the synthetic method is a phenyl or naphthyl;
Described solvent can be ether, tetrahydrofuran (THF), glycol dimethyl ether, toluene, N,N-dimethylacetamide etc.
Catalytic amount of initiator described in the synthetic method generally is tetrabutyl ammonium fluoride, tetrabutylammonium chloride, Methanaminium, N,N,N-trimethyl-, fluoride, tetrabutyl ammonium acetate etc.
The mol ratio of the alkenes compounds described in the synthetic method, a halogen difluoromethyl trialkyl silane and initiator is 1: 1～4: 0.01～0.1, and recommending mol ratio is 1: 2～3: 0.02～0.04.
Type reaction is as follows:
Figure A20091004992700051
Traditional method is generally used has destructive Freon gas to ozone, and the general yield of additive method is lower, and universality is poor.And above method adopts same class difluorocarbene's reagent, and such reagent can not make by Freon gas, reaction conditions gentleness, productive rate height, advantage such as it is good to have universality, and selectivity is strong.
Embodiment
Utilize following embodiment will help to understand the present invention, but do not limit content of the present invention.
Embodiment 1
With vinylbenzene
Figure A20091004992700061
(104mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700062
126mg, productive rate 82%.
Embodiment 2
With vinylbenzene (132mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700064
104mg, productive rate 57%.
Embodiment 3
With vinylbenzene
Figure A20091004992700065
(84mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700066
Fluorine spectrum productive rate 80%.
Embodiment 4
With vinylbenzene
Figure A20091004992700067
(84mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product Fluorine spectrum productive rate 66%.
Embodiment 5
With vinylbenzene
Figure A20091004992700072
(112mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700073
Fluorine spectrum productive rate 71%.
Embodiment 6
With vinylbenzene (82mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4mlTHF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700075
Fluorine spectrum productive rate 82%.
Embodiment 7
With vinylbenzene
Figure A20091004992700076
(118mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700077
1126mg, productive rate 75%.
Embodiment 8
With vinylbenzene
Figure A20091004992700081
(118mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product 126mg, productive rate 75%.
Embodiment 9
With vinylbenzene
Figure A20091004992700083
(164mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700084
Productive rate 56%.
Embodiment 10
With vinylbenzene
Figure A20091004992700085
(178mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700086
Productive rate 70%.
Embodiment 11
With vinylbenzene
Figure A20091004992700087
(214mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg 0.02mmol) in reaction solution, screws tube sealing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure A20091004992700091
140mg, productive rate 53%.

Claims (5)

1. one kind is synthesized the method that also has the difluoro methylene compound, it is characterized in that in organic solvent, under 60～150 ℃, the alkenes compounds that contains carbon-carbon double bond is a raw material, under the condition of the initiator that adds catalytic amount, with halogen difluoromethyl trialkyl silane reaction 2～20 hours, make and contain difluoro cyclopropyl compounds;
Described olefin(e) compound is R 1, R 2, R 3Or R 4The alkene that replaces; Wherein, R 1Be the alkyl of H, C1-C12, trimethyl silicon based, aryl, R 5Or/and R 6Alkyl or the R of the C1-C4 that the aryl that replaces, aryl replace 5Or/and R 6The alkyl of the C1-C4 that the aryl that replaces replaces; Described R 5Or R 6Be the alkyl of H, C1-C4, alkoxyl group or the difluoro-methoxy of C1-C4;
Described aryl is a phenyl or naphthyl;
Described initiator is tetrabutyl ammonium fluoride, tetrabutylammonium chloride, Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium acetate;
The mol ratio of described alkenes compounds, a halogen difluoromethyl trialkyl silane and initiator is 1: 1～4: 0.01～0.1.
2. the method for claim 1 is characterized in that a described halogen difluoromethyl trialkyl silane is R aR bR cSiCF 2X, wherein R a, R b, R cBe the alkyl of C1-C6, perhaps phenyl, X is a halogen.
3. the method for claim 1 is characterized in that the mol ratio of described alkenes compounds, a halogen difluoromethyl trialkyl silane and initiator is 1: 2～3: 0.02～0.04.
4. described solvent is ether, tetrahydrofuran (THF), glycol dimethyl ether, toluene or N,N-dimethylacetamide.
5. the method for claim 1 is characterized in that described initiator is tetrabutyl ammonium fluoride, tetrabutylammonium chloride, Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium acetate.
CN2009100499273A 2009-04-24 2009-04-24 Method for preparing compounds containing difluoromethylene Active CN101538186B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2009100499273A CN101538186B (en) 2009-04-24 2009-04-24 Method for preparing compounds containing difluoromethylene

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2009100499273A CN101538186B (en) 2009-04-24 2009-04-24 Method for preparing compounds containing difluoromethylene

Publications (2)

Publication Number Publication Date
CN101538186A true CN101538186A (en) 2009-09-23
CN101538186B CN101538186B (en) 2012-07-04

Family

ID=41121614

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2009100499273A Active CN101538186B (en) 2009-04-24 2009-04-24 Method for preparing compounds containing difluoromethylene

Country Status (1)

Country Link
CN (1) CN101538186B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014117452A1 (en) * 2013-02-04 2014-08-07 中国科学院上海有机化学研究所 Synthesis and application of difluoro methylene phosphorus inner salt
CN111517954A (en) * 2020-06-08 2020-08-11 浙江师范大学 (Z) -5-fluoro-2-difluoromethylene olefin derivative and preparation method thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989845A (en) * 1974-12-26 1976-11-02 W. R. Grace & Co. Anesthetic chlorocyclopropanes

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014117452A1 (en) * 2013-02-04 2014-08-07 中国科学院上海有机化学研究所 Synthesis and application of difluoro methylene phosphorus inner salt
CN111517954A (en) * 2020-06-08 2020-08-11 浙江师范大学 (Z) -5-fluoro-2-difluoromethylene olefin derivative and preparation method thereof

Also Published As

Publication number Publication date
CN101538186B (en) 2012-07-04

Similar Documents

Publication Publication Date Title
CN1073096C (en) Process for preparation of 2 -chloro -5 -cholromethyl -1, 3 -thiazole
CN102617434B (en) Process for preparing Vildagliptin by one-pot method
CN101538186B (en) Method for preparing compounds containing difluoromethylene
CN101538193B (en) Method for preparing compounds containing difluoromethyl
CN110903264B (en) Method for preparing diazoxide
WO2011093439A1 (en) Method for producing n,n&#39;-diallyl-1,3-diaminopropane
JP5784336B2 (en) Compound, method for producing the same, and method for producing oseltamivir phosphate
CN109956871B (en) Preparation method of 3,4, 5-trifluoro-2&#39; -nitrobiphenyl
JP6028606B2 (en) Method for producing amine compound
CN1606557A (en) Deuterated pyrazolopyrimidinones and drugs containing said compounds
JP2012067030A (en) Improved method for producing fluoroalkyl chloroformate
CN104672180B (en) Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate
CN105254530B (en) A kind of synthetic method containing amphene base Schiff class compound
CN1226228A (en) Process for preparing preparing racemic phenethylamines
CN105017126B (en) Perfluoroalkyl azole derivatives and its synthetic method
JP5136987B2 (en) New production method of nitrile compounds
JP5219086B2 (en) Process for producing trifluoromethylarenes
JP4282146B2 (en) Method for producing silylated aniline derivative
CN1211356C (en) Method for preparing azoiminoethers and azocarboxylic acid esters and novel azocarboxylic acid mixed esters
JP4643566B2 (en) Method for allylation of N-acylhydrazone
CN101466662B (en) Method for producing fluoroamine
KR101754779B1 (en) Method for manufacturing dabigatran etexilate
CN1310870C (en) Enantiomerically enriched 1-phenylethylamines
JP2013129616A (en) Brominating agent and application of the same
CN106543010A (en) A kind of method of synthetic hydrochloric acid cinacalcet

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