CN106687431A - Method for producing geminal difluoro compound - Google Patents
Method for producing geminal difluoro compound Download PDFInfo
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- CN106687431A CN106687431A CN201580052499.3A CN201580052499A CN106687431A CN 106687431 A CN106687431 A CN 106687431A CN 201580052499 A CN201580052499 A CN 201580052499A CN 106687431 A CN106687431 A CN 106687431A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/38—Separation; Purification; Stabilisation; Use of additives
- C07C17/42—Use of additives, e.g. for stabilisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/02—Monocyclic aromatic halogenated hydrocarbons
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/02—Monocyclic aromatic halogenated hydrocarbons
- C07C25/13—Monocyclic aromatic halogenated hydrocarbons containing fluorine
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Abstract
Provided is a novel method for producing a geminal difluoro compound. A novel production method for obtaining a geminal difluoro compound represented by formula (2) at a high yield by reacting a compound represented by formula (1) with a fluorinating agent in the presence of an N-chloroimide compound. (In the formula, R1 indicates a C1-4 alkyl, X indicates a halogen atom.)
Description
Technical field
The present invention relates to using oxime compound as the new manufacturing method of the gem difluorinated compound of initiation material.
Background technology
With gem difluorinated compound of the group as part-structure that two fluorine atoms are instead of on a carbon atom
(germinal difluoro compound) is, as the useful compound (patent document 1) of agriculture medicine or its intermediate, to make
For the manufacture method of these compounds, various reactions have been had been developed for.As representative reaction, oximate conjunction can be enumerated
Bifluoride reaction (non-patent literature 1～3) of thing.
React as the bifluoride that oxime compound is used as initiation material, it has been reported that the method using a fluorine iodine is (non-special
Sharp document 2).However, the fluorine iodine for being used can only be present at low temperature, and in the reaction, in order to generate one in system
Fluorine iodine, needs that chippy iodine is added the operation that fluorine/nitrogen is passed through in reaction solution, at -78 DEG C.Therefore, a fluorination
Using for iodine there is a problem of needing using special reaction condition and reaction unit (non-patent literature 2,4).
Additionally, there has been reported the method (non-patent literature using tetrafluoro boric acid nitrosyl ester and hydrogen fluoride-pyridine complex compound
3).However, for synthesizing 1- phenyl -1, in the example of 1- Difluoroethane derivatives, being merely able to obtain targeted with low yield
Compound (patent document 2).Because tetrafluoro boric acid nitrosyl ester has strong hygroscopicity, therefore when bifluoride reaction is carried out, must
Must be processed in dry inert gas, but also there are problems that price (non-patent literature 5,6).
Then, a kind of these reagents, also useful gem difluorinated as industrial process in high yield of not using are needed
The new manufacturing method of compound.
Prior art literature
Patent document
Patent document 1：International Publication No. 2011/154298
Patent document 2：International Publication No. 2012/139775
Non-patent literature
Non-patent literature 1：Synthesis science (Science of Synthesis), 2007, volume 29, page 13～61
Non-patent literature 2：Organic chemistry periodical (Journal of Organic Chemistry), 1991, volume 56, the
Page 4695～4700
Non-patent literature 3：Synthesising communication (Synlett), 1994, page 425～426
Non-patent literature 4：German chemical journal (Chemische Berichte), 1970, volume 103, page 590～593,
Page 880～884
Non-patent literature 5：Inorganic synthese (Inorganic Synthesis), 2004, volume 33, page 75～82
Non-patent literature 6：Organic synthesis reagent encyclopedia (Encyclopedia of Reagents for Organic
Synthesis), nineteen ninety-five, volume 6, page 3768～3770
The content of the invention
The technical problem to be solved
It is an object of the invention to provide a kind of without the need for special reaction device or the height of the gem difluorinated compound of reaction condition
Yield manufacture method.
Solve the technical scheme that technical problem is adopted
As a result the present inventor is had found by making fluorization agent and oxime in the presence of N- chlorimide compounds through further investigation
Compound reacts to manufacture the new manufacturing method of gem difluorinated compound in high yield, so as to complete the present invention.That is, the present invention is
With herein below as feature invention.
[1] a kind of manufacture method of gem difluorinated compound, it is characterised in that make in the presence of N- chlorimide compounds with
The oxime compound that formula (1) is represented reacts with fluorization agent, manufactures the gem difluorinated compound represented with formula (2),
[in formula, R1Represent C1～4Alkyl, X represents halogen atom.]
[in formula, R1Implication same as described above is represented with X.]
[2] as described above the manufacture method of the gem difluorinated compound described in [1], wherein, N- chlorimides compound is N- chlorine
For succinimide, N- chlorophthalimides, 1,3 dichloro 5,5 dimethyl hydantoin, DCCNa
Or TCCA.
[3] as described above the manufacture method of the gem difluorinated compound described in [2], wherein, N- chlorimides compound is N- chlorine
For succinimide, 1,3 dichloro 5,5 dimethyl hydantoin or TCCA.
[4] as described above the manufacture method of the gem difluorinated compound any one of [1]～[3], wherein, N- chlorimides
The amount of compound is 0.1 equivalent～100 equivalent relative to the equivalent of oxime compound 1 of formula (1).
[5] as described above the manufacture method of the gem difluorinated compound any one of [1]～[4], wherein, the use of fluorization agent
Amount is 2～1000 equivalents relative to the equivalent of oxime compound 1 of formula (1).
[6] as described above the manufacture method of the gem difluorinated compound any one of [1]～[5], wherein, fluorization agent is fluorine
Change hydrogen-pyridine complex or poly- [4-vinylpridine poly- (hydrogen fluoride)].
[7] as described above the manufacture method of the gem difluorinated compound described in [6], wherein, fluorization agent is hydrogen fluoride-pyridine network
Compound.
[8] as described above the manufacture method of the gem difluorinated compound described in [7], wherein, in hydrogen fluoride-pyridine complex compound
Hydrogen fluoride is 70 with the weight ratio of pyridine:30～20:80.
[9] as described above the manufacture method of the gem difluorinated compound any one of [1]～[5], wherein, fluorization agent is fluorine
Change hydrogen.
[10] as described above the manufacture method of the gem difluorinated compound any one of [1]～[9], wherein, R1For methyl.
[11] as described above the manufacture method of the gem difluorinated compound any one of [1]～[10], wherein, X is that chlorine is former
Son or bromine atoms.
[12] as described above the manufacture method of the gem difluorinated compound described in [11], wherein, X is bromine atoms.
[13] as described above the manufacture method of the gem difluorinated compound any one of [1]～[12], wherein, in solvent
In the presence of reacted.
[14] as described above the manufacture method of the gem difluorinated compound described in [13], wherein, solvent is halogenated hydrocarbons.
The effect of invention
By means of the invention it is possible to provide a kind of to obtain in high yield as the useful gem difluorinated conjunction such as agriculture medicine intermediate
The new manufacturing method of thing.
Specific embodiment
Below, the present invention is described in detail.
In this specification, " n- " expression " just ", " s- " expression " secondary ", " t- " expression " uncle ".
Additionally, " (E) " used in the record of chemical constitution represents E type bodies, " (Z) " represents Z-type body.
“C1～4Alkyl " refers to the alkyl of the straight chain that carbon number is 1～4 or branch chain.Specifically, methyl, second are represented
Base, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or the tert-butyl group.
" halogen atom " refers to fluorine atom, chlorine atom, bromine atoms or atomic iodine.
(manufacture method of gem difluorinated compound)
By the oxime compound (compound (1)) that makes to represent with formula (1) in the presence of N- chlorimide compounds and fluorination
Agent is reacted, and can manufacture the gem difluorinated compound (compound 2) represented with formula (2).
N- chlorimide compounds in this specification refer to the group with imine moiety that nitrogen-atoms has been chlorinated.As in the present invention
The N- chlorimide compounds for being used, can enumerate such as N-chlorosuccinimide, N- chlorophthalimides, 1,3- bis-
Chloro- 5,5- dimethyl hydantoins, DCCNa, TCCA etc..Preferred N- chlorimides compound is N-
Chloro- 5, the 5- dimethyl hydantoins of chlorosuccinimide, 1,3- bis- or TCCA, preferred N- chlorimides chemical combination
Thing is TCCA.
These N- chlorimide compounds both can be used alone, it is also possible to which two or more is used in mixed way.
In N- chlorimide compounds used in the present invention, it is known that TCCA has swimming pool bactericide, deodorant
The purposes such as agent.It is also known that TCCA is that the high cheap reagent of stability (research and develop by organic process
(Organic Process Research and Development), 2002, volume 6, page 384～393).
The consumption of N- chlorimide compounds is preferably 0.1 equivalent～100 equivalent relative to compound (1), and more preferably 0.5
Equivalent～30 equivalent, more preferably 1 equivalent～15 equivalent.
Fluorization agent used in the present invention can enumerate such as hydrogen fluoride-pyridine complex compound, poly- [4-vinylpridine gathers
(hydrogen fluoride)] etc..Preferred fluorization agent is hydrogen fluoride-pyridine complex compound.
As fluorization agent, hydrogen fluoride is it is also possible to use.
The weight ratio of hydrogen fluoride-pyridine complex compound is hydrogen fluoride:Pyridine=70:30 material is known as Olah reagents (to be had
Machine synthetic agent encyclopedia, nineteen ninety-five, volume 6, page 4373～4375).Known Olah reagents can be waved as stable
The little hydrogen fluoride of the property sent out plays a role, and is adapted to industrially use.
Poly- [4-vinylpridine poly- (hydrogen fluoride)] refers to the change being made up of the polymer and hydrogen fluoride of pyridine derivate
Compound (synthesising communication, nineteen ninety, page 267～269).
With regard to the hydrogen fluoride-pyridine complex compound used in the present invention, its weight ratio is hydrogen fluoride:Pyridine=70:30
Olah reagents can be purchased for example, by aldrich company (ア Le De リ ッ チ societies), fluorine chemistry company (Off Le オ ロ ケ system society) etc.
Enter.Additionally, having its weight ratio to be hydrogen fluoride:Pyridine=60:40、50:50、40:60 and 20:The material of 80 composition can lead to
Cross such as Manchester organic matter company (マ Application チ ェ ス タ ー オ ー ガ ニ ッ Network ス societies) to buy, with hydrogen fluoride:Pyridine=
55:The material of 45 composition can be bought for example, by Apollo scientific company (ア Port ロ サ イ エ Application テ ィ フィック societies).
The weight of the hydrogen fluoride-pyridine complex compound used in the present invention is than preferably hydrogen fluoride:Pyridine=70:30～
20:80.Preferred weight ratio is hydrogen fluoride:Pyridine=70:30～50:50, further preferred weight ratio is hydrogen fluoride:Pyrrole
Pyridine=68:32～63:37.
The consumption of the fluorization agent used in the present invention can work as relative to the equivalent of oxime compound 1 represented with formula (1) using 2
～1000 equivalents of amount, preferred consumption is 2 equivalent～500 equivalents, and preferred consumption is 5 equivalent～200 equivalents.
Compound (1) used in the present invention refers to arbitrary in the oxime compound represented with formula (1a) or formula (1b)
Kind, or the mixture for referring to formula (1a) and formula (1b).
According to sequence rule (Japanese：Cis Wei Fa The), tied as (E) type spatial chemistry with the oxime compound that formula (1a) is represented
Structure, and the oxime compound represented with formula (1b) is as (Z) type stereochemical structure.
(E) compound of the compound of type stereochemical structure and (Z) type stereochemical structure geometric isomer each other,
In most cases, they can be separately separated.In order to obtain one of which isomers, it is also possible to using recrystallization, salt respectively
Acid treatment etc. is thermodynamically stably transformed into the isomerization of isomers.In the present invention, oxime compound both can have only been used
A kind of isomers, it is also possible to use the mixture of (E) type and (Z) type oxime compound.
As the conventional method of manufacture oxime compound, the condensation reaction of such as carbonyls and azanol can be enumerated, can be pressed
Oxime compound (conversion (the Comprehensive of comprehensive organo-functional group is manufactured according to method described in known document
Organic Functional Group Transformations) II, 2005, volume 3, page 451～467).
As long as the solvent without prejudice to reaction used in the present invention is then not particularly limited, can enumerate as its example following molten
Agent.Alcoholic solvent (such as methyl alcohol, ethanol, 2- propyl alcohol), halogenated hydrocarbon solvent (such as dichloromethane, chloroform, carbon tetrachloride, 1,2- bis-
Chloroethanes, 1,1,1- trichloroethanes, trichloro ethylene, tetrachloro-ethylene), halogenated aromatic hydro carbons solvent (such as chlorobenzene, dichloro-benzenes), virtue
Race's varsol (such as benzene,toluene,xylene), aliphatic hydrocarbon solvent (such as hexane, heptane), amine solvent (such as triethylamine,
N, N- dibutyl 1- butylamine, 2- methyl-N, N- bis- (2- methyl butyls) -1- butylamine, N, accelerine), pyridine-type solvents
(such as pyridine, picoline), ether solvents (such as dimethyl ether, diethyl ether, 1,2- dimethoxy-ethanes, tetrahydrofuran, 1,4- bis-
Oxane, cyclopentyl methyl ether, 1- methoxyl group -2- (2- methoxy ethoxies) ethane) etc..
Preferably halogenated hydrocarbon solvent, amine solvent, pyridine-type solvents or ether solvents, more preferably halogenated hydrocarbon solvent, enter one
Step is preferably dichloromethane, chloroform.
These solvents both can be used alone, it is also possible to which two or more is used in mixed way.
The consumption that can be used for the solvent of the manufacture method of the present invention is preferably 0 relative to the oxime compound represented with formula (1)
Times of weight～1000 times of weight, more preferably 1 times of weight～100 times of weight, more preferably 5 times of weight～50 times of weight.
Reaction temperature is not particularly limited, preferably -78 DEG C to reactant mixture of reflux temperature, more preferably -60 DEG C
～50 DEG C, more preferably -40 DEG C～30 DEG C.Additionally, being to about after reaction starts as other forms of preferred reaction
Interior reaction temperature is 0 DEG C within 7 hours, is reacted 3～21 hours at 20 DEG C～30 DEG C afterwards.
Total reaction time within about 28 hours, preferably 3～21 hours.Additionally, work as using hydrogen fluoride as fluorization agent
When, total reaction time within about 20 hours, preferably 1～5 hour.
[embodiment]
It is given below with reference to synthesis example, synthesis example, the present invention will be described in more detail, but the invention is not restricted to these
Embodiment.
Proton magnetic resonance (PMR) in embodiment (synthesis example) (1H NMR) use Jeol Ltd. (Japanese Electricity
(JEOL) society) manufacture JNM-ECP300 or NEC (JEOL) Co., Ltd. manufacture JNM-ECX300 in deuterated chlorine
Determine in imitative solvent, chemical shift is so that 4-methyl furan to be represented as the δ values (ppm) when internal standard (0.0ppm).
Embodiment fluorine nmr (19F NMR) JNM-ECX300 of Jeol Ltd.'s manufacture is used deuterated
Determine in chloroform solvent, chemical shift is so that phenyl-hexafluoride to be represented as the δ values (ppm) when internal standard (- 162.2ppm).
In the record of NMR spectra, " s " represents that unimodal, " d " represents that doublet, " t " represent that triplet, " q " represent quadruple
Peak, " m " represent that multiplet, " br " represent that broad peak, " J " represent that coupling constant, " Hz " represent hertz, " CDCl3" represent deuterated chlorine
It is imitative.
Synthesis example 1
The manufacture of 1- (fluoro ethyls of 1,1- bis-) -4- bromobenzenes
Reacted by made by tetrafluoroethene perfluoroalkyl vinyl ether copolymer (referred to as PFA) resin with nitrogen displacement
After the inside of container, hydrogen fluoride-pyridine complex compound is added in reaction vessel, and (10.0g, weight ratio is [63.8% (fluorination
Hydrogen):36.2% (pyridine)], it is 318.8 mMs as hydrogen fluoride, the manufacture of aldrich company), it is cooled to 0 DEG C.Then, to
Sequentially add in reaction vessel TCCA (2.70g, 11.62 mMs) and 1- (4- bromophenyls) acetophenone oxime (1.00g,
4.67 mMs) dichloromethane (30.0g) solution, the stirring of 7 hours is carried out to reactant mixture at 0 DEG C.Further, anti-
Answer temperature to rise to after 20 DEG C, stir 3 hours at the same temperature.Then, reaction is made by adding water in reactant mixture
Stop.Subsequently, chloroform is added in reactant mixture, organic layer is separated.With saturated sodium bicarbonate aqueous solution and water to resulting
Organic layer cleaned after, solvent is distilled off under reduced pressure.With silica gel chromatography (eluent：N-hexane) to resulting
Crude product purified, obtain the target compound (0.93g, yield 90%) of colourless liquid.
1H NMR(CDCl3):δ 7.56 (d, J=8.6Hz, 1H), 7.37 (d, J=8.6Hz, 1H), 1.90 (t, J=
18.3Hz,3H).
19F NMR(CDCl3):δ -88.3 (2F, q, J=18.3Hz).
Synthesis example 2
The manufacture of 1- (fluoro ethyls of 1,1- bis-) -4- bromobenzenes
After with nitrogen displacement inside of reaction vessel by made by PFA resins, hydrogen fluoride-pyrrole is added in reaction vessel
(10.0g, weight ratio is [63.8% (hydrogen fluoride) to pyridine complex compound:36.2% (pyridine)], it is 318.8 mMs as hydrogen fluoride,
Aldrich company manufactures), it is cooled to 0 DEG C.Then, sequentially add in reaction vessel N-chlorosuccinimide (5.01g,
37.52 mMs) and 1- (4- bromophenyls) acetophenone oxime (1.00g, 4.67 mMs) dichloromethane (30.0g) solution, at 0 DEG C
Under the stirring of 3 hours is carried out to reactant mixture.Further, rise to after 25 DEG C～30 DEG C, at the same temperature in reaction temperature
Stirring 21 hours.Then, stop reaction by adding water in reactant mixture.Subsequently, chlorine is added in reactant mixture
It is imitative, separate organic layer.After being cleaned to resulting organic layer with saturated sodium bicarbonate aqueous solution and water, steam under reduced pressure
Solvent is removed in distillation.With silica gel chromatography (eluent：N-hexane) resulting crude product is purified, obtain colourless liquid
Target compound (0.94g, yield 88%).1H NMR(CDCl3):δ 7.55 (d, J=8.7Hz, 1H), 7.37 (d, J=8.7Hz,
1H), 1.90 (t, J=18.2Hz, 3H).
Synthesis example 3
The manufacture of 1- (fluoro ethyls of 1,1- bis-) -4- bromobenzenes
After with nitrogen displacement inside of reaction vessel by made by PFA resins, hydrogen fluoride-pyrrole is added in reaction vessel
(10.0g, weight ratio is [63.8% (hydrogen fluoride) to pyridine complex compound:36.2% (pyridine)], it is 318.8 mMs as hydrogen fluoride,
Aldrich company manufactures), it is cooled to 0 DEG C.Then, sequentially add in reaction vessel in chloro- 5, the 5- dimethyl second of 1,3- bis-
The dichloromethane of uride (4.60g, 23.35 mMs) and 1- (4- bromophenyls) acetophenone oxime (1.00g, 4.67 mMs)
(30.0g) solution, carries out to reactant mixture the stirring of 7 hours at 0 DEG C.Further, rise to after 20 DEG C in reaction temperature,
Stir 3 hours at identical temperature.Then, stop reaction by adding water in reactant mixture.Subsequently, to reactant mixture
Middle addition chloroform, separates organic layer.After being cleaned to resulting organic layer with saturated sodium bicarbonate aqueous solution and water,
Solvent is distilled off under decompression.With silica gel chromatography (eluent：N-hexane) resulting crude product is purified, obtain nothing
The target compound (0.96g, yield 93%) of color liquid.1H NMR(CDCl3):δ 7.55 (d, J=8.6Hz, 1H), 7.37 (d, J
=8.6Hz, 1H), 1.90 (t, J=18.1Hz, 3H).
In following synthesis example 4 to synthesis example 6, to be separately separated 1- (1,1- bis- the fluoro ethyl) -4- bromines that purifying is obtained
Benzene as standard substance, with 4-HBA methyl esters as internal standard material, by determining using ultrahigh speed liquid chromatograph
Measure analytic approach to calculate reaction yield.
Ultrahigh speed liquid chromatograph：The ACQUITY UPLC H-Class of water generation company (Waters societies) manufacture
Chromatographic column：Waters Acquity UPLC BEH C18 (1.7 μm, 2.1x50mm) chromatographic columns
Column oven temperature：40℃
Eluent：Acetonitrile：10mM ammonium acetate solutions/acetonitrile=100/5 (v/v), 30:70 (0～1 minutes), 30:70～
95:5 (1～3 minutes), 95:5 (3～5 minutes), (v/v)
Eluant velocity：0.5 ml/min
Detection wavelength：230nm
Synthesis example 4
The manufacture of 1- (fluoro ethyls of 1,1- bis-) -4- bromobenzenes
After with nitrogen displacement inside of reaction vessel by made by PFA resins, hydrogen fluoride-pyrrole is added in reaction vessel
(1.00g, weight ratio is [63.8% (hydrogen fluoride) to pyridine complex compound:36.2% (pyridine)], it is 31.9 mMs as hydrogen fluoride,
Aldrich company manufactures), it is cooled to 0 DEG C.Then, TCCA (0.24g, 1.03 mmoles are added in reaction vessel
You), dichloromethane (2.01g) solution of 1- (4- bromophenyls) acetophenone oxime (103.5g, 0.484 mM) is added, at 0 DEG C
The stirring of 3 hours is carried out to reactant mixture.Then, stop reaction by adding chloroform and water in reactant mixture,
After dividing liquid, organic layer is cleaned with saturated sodium bicarbonate aqueous solution.Resulting organic layer is carried out quantitatively, 1- (1,1-
Two fluoro ethyls) -4- bromobenzenes (target compound) quantitative yield be 97%.
Synthesis example 5
The manufacture of 1- (fluoro ethyls of 1,1- bis-) -4- bromobenzenes
After with nitrogen displacement inside of reaction vessel by made by PFA resins, hydrogen fluoride-pyrrole is added in reaction vessel
(1.00g, weight ratio is [63.8% (hydrogen fluoride) to pyridine complex compound:36.2% (pyridine)], it is 31.9 mMs as hydrogen fluoride,
Aldrich company manufactures), it is cooled to 0 DEG C.Then, TCCA (0.23g, 0.99 mmoles are added in reaction vessel
You), 1- (4- bromophenyls) acetophenone oxime (104.3g, 0.487 mM) is added, 3 hours are carried out to reactant mixture at 0 DEG C
The stirring of 30 minutes.Then, stop reaction by adding chloroform and water in reactant mixture, after point liquid, use saturated carbon
Sour hydrogen sodium water solution is cleaned to organic layer.Resulting organic layer is carried out quantitatively, 1- (1,1- bis- fluoro ethyl) -4- bromobenzenes
The quantitative yield of (target compound) is 94%.
Synthesis example 6
1- (4- bromophenyls) acetophenone oxime is sequentially added in the reaction vessel by made by chlorotrifluoroethylene resin
(1.00g, 4.67 mMs) and TCCA (2.40g, 10.33 mMs).Then, with dry ice-methanol bath to reaction
Container is cooled down, and hydrogen fluoride (11 milliliters, 551 mMs) is imported under reduced pressure.Subsequently, the outer temperature for making reaction vessel keeps
At -38～-35 DEG C, stir 3 hours.Then, reaction vessel is cooled down with dry ice-methanol bath, is distilled off under reduced pressure
Hydrogen fluoride.Subsequently, after chloroform and water and stirring are added in reaction vessel, a point liquid is carried out, it is molten with saturated sodium bicarbonate water
Liquid is cleaned to organic layer.Resulting organic layer is carried out quantitatively, 1- (1,1- bis- fluoro ethyl) -4- bromobenzenes (target chemical combination
Thing) quantitative yield be 51%.
With reference to synthesis example 1
The manufacture of 1- (4- bromophenyls) acetophenone oxime
After inside with nitrogen displacement glass reaction container, add in reaction vessel 4 '-bromoacetophenone (50.0g,
251.31 mMs), ethanol (100g) and hydroxylamine hydrochloride (19.6g, 282.05 mMs), reactant mixture is heated into 72
℃.Then, the stirring of 3 hours is carried out to reactant mixture at 72 DEG C～80 DEG C.Subsequently, by the way that reactant mixture is cooled to
5 DEG C stop making reaction.Then, water (100g) is added to separate out solid in reactant mixture, after filtration, with ethanol (50g)
Resulting solid is cleaned with the mixed solution of water (100g).Subsequently, resulting solid and ethanol (100g) are added
In entering reaction vessel, 65 DEG C are heated the mixture to afterwards, reactant mixture is cooled into 4 DEG C, mistake after again separating out solid
Filter.Resulting solid is cleaned with the ethanol (50g) for being cooled to 0 DEG C, the drying under reduced pressure of 3 hours is carried out at 50 DEG C, obtain white
The target compound (26.15g, yield 49%) of color solid.1H NMR(CDCl3):δ8.59(s,1H),7.50(s,4H),2.27
(s,3H).
Industrial practicality
The gem difluorinated compound obtained by the present invention can be widely used as the manufacture intermediate of agriculture medicine etc..
In addition, herein cited September in 2014 submits the explanation of the Japanese patent application 2014-199055 of application on the 29th
The full content of book, claims and summary, includes herein as the disclosure of description of the invention.
Claims (14)
1. a kind of manufacture method of gem difluorinated compound, it is characterised in that make in the presence of N- chlorimide compounds with formula (1)
The oxime compound of expression reacts to manufacture the gem difluorinated compound represented with formula (2) with fluorization agent,
In formula, R1Represent C1～4Alkyl, X represents halogen atom,
In formula, R1Implication same as described above is represented with X.
2. the manufacture method of gem difluorinated compound as claimed in claim 1, it is characterised in that N- chlorimides compound is N- chlorine
For succinimide, N- chlorophthalimides, 1,3 dichloro 5,5 dimethyl hydantoin, DCCNa
Or TCCA.
3. the manufacture method of gem difluorinated compound as claimed in claim 2, it is characterised in that N- chlorimides compound is N- chlorine
For succinimide, 1,3 dichloro 5,5 dimethyl hydantoin or TCCA.
4. the manufacture method of the gem difluorinated compound as any one of claims 1 to 3, it is characterised in that N- chlorimides
The amount of compound is 0.1 equivalent～100 equivalent relative to the equivalent of oxime compound 1 of formula (1).
5. the manufacture method of the gem difluorinated compound as any one of Claims 1 to 4, it is characterised in that fluorization agent
Consumption is 2～1000 equivalents relative to the equivalent of oxime compound 1 of formula (1).
6. the manufacture method of the gem difluorinated compound as any one of Claims 1 to 5, it is characterised in that fluorization agent is
Hydrogen fluoride-pyridine complex compound or poly- [4-vinylpridine poly- (hydrogen fluoride)].
7. the manufacture method of gem difluorinated compound as claimed in claim 6, it is characterised in that fluorization agent is hydrogen fluoride-pyridine
Complex compound.
8. the manufacture method of gem difluorinated compound as claimed in claim 7, it is characterised in that in hydrogen fluoride-pyridine complex compound
The weight ratio of hydrogen fluoride and pyridine be 70:30～20:80.
9. the manufacture method of the gem difluorinated compound as any one of Claims 1 to 5, it is characterised in that fluorization agent is
Hydrogen fluoride.
10. the manufacture method of the gem difluorinated compound as any one of claim 1～9, it is characterised in that R1For methyl.
The manufacture method of the 11. gem difluorinated compounds as any one of claim 1～10, it is characterised in that X is that chlorine is former
Son or bromine atoms.
The manufacture method of 12. gem difluorinated compounds as claimed in claim 11, it is characterised in that X is bromine atoms.
The manufacture method of the 13. gem difluorinated compounds as any one of claim 1～12, it is characterised in that in solvent
In the presence of reacted.
The manufacture method of 14. gem difluorinated compounds as claimed in claim 13, it is characterised in that solvent is halogenated hydrocarbons.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014199055 | 2014-09-29 | ||
| JP2014-199055 | 2014-09-29 | ||
| PCT/JP2015/077175 WO2016052353A1 (en) | 2014-09-29 | 2015-09-25 | Method for producing geminal difluoro compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106687431A true CN106687431A (en) | 2017-05-17 |
Family
ID=55630390
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580052499.3A Pending CN106687431A (en) | 2014-09-29 | 2015-09-25 | Method for producing geminal difluoro compound |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPWO2016052353A1 (en) |
| KR (1) | KR20170066310A (en) |
| CN (1) | CN106687431A (en) |
| WO (1) | WO2016052353A1 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4416272C2 (en) * | 1993-05-19 | 2003-09-11 | Merck Patent Gmbh | Partially fluorinated benzene derivatives |
| KR20130136504A (en) * | 2010-12-07 | 2013-12-12 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | Substituted 1-benzylcycloalkylcarboxlic acids and use thereof |
| EP2511263A1 (en) * | 2011-04-14 | 2012-10-17 | Phenex Pharmaceuticals AG | Pyrrolo sulfonamide compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-gamma (RORgamma, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
| JP5853771B2 (en) * | 2012-03-01 | 2016-02-09 | セントラル硝子株式会社 | Method for producing α, α-difluoroaromatic compound |
-
2015
- 2015-09-25 CN CN201580052499.3A patent/CN106687431A/en active Pending
- 2015-09-25 KR KR1020177002861A patent/KR20170066310A/en unknown
- 2015-09-25 JP JP2016551988A patent/JPWO2016052353A1/en active Pending
- 2015-09-25 WO PCT/JP2015/077175 patent/WO2016052353A1/en active Application Filing
Non-Patent Citations (1)
| Title |
|---|
| YORK,C.等: "Synthetic Methods and Reactions. Part 189. Novel Preparation of gem- Difluorides (II) from Ketoximes (I) with Nitrosonium Tetrafluoroborate and Pyridinium Polyhydrogen Fluoride", 《SYNLETT》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016052353A1 (en) | 2016-04-07 |
| KR20170066310A (en) | 2017-06-14 |
| JPWO2016052353A1 (en) | 2017-07-13 |
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