CN100432086C - Method of fluorination - Google Patents
Method of fluorination Download PDFInfo
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- CN100432086C CN100432086C CNB2003801046799A CN200380104679A CN100432086C CN 100432086 C CN100432086 C CN 100432086C CN B2003801046799 A CNB2003801046799 A CN B2003801046799A CN 200380104679 A CN200380104679 A CN 200380104679A CN 100432086 C CN100432086 C CN 100432086C
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The present invention provides a method in which a glucide, examples of which include a monosaccharide, an oligosaccharide, a polysaccharide, a composite saccharide comprising any of these saccharides and a protein or lipid bonded thereto, a polyalcohol, an aldehyde, ketone, or acid of a polyalcohol, a derivative or condensate of any of these, is reacted with a fluorinating agent represented by the general formula (I) either thermally or by irradiation with microwave or an electromagnetic wave with a wavelength around the microwave region. By the method, fluorination reaction can be safely conducted position-selectively even in a temperature range of 150 to 200 DEG C, in which fluorination has conventionally been difficult. The method in which the reactants are irradiated with microwave or an electromagnetic wave with a wavelength around the microwave region is applicable to substrates other than glucides. When a complex compound comprising HF and a base, for example, is reacted with a substrate by irradiation with microwave, fluorination in a specific position which has been difficult in conventional techniques proceeds highly selectively in a short time efficiently and safely.
Description
Technical field
The present invention relates to fluorination process.At length relate to optionally fluorizated method of the carbohydrate that will use as functional chemical substance such as medical material, makeup and protective foods, and near the hertzian wave various matrix (base) and fluorizating agent irradiating microwaves and the microwave made its reaction, thereby fluoridize the method for this matrix effectively.
Background technology
Because fluorochemicals can show the relevant useful function of specific physique that produces with fluorine atom, so gazed at by the various fields of representative with medicine, field of electronic materials, its examples of applications is too numerous to enumerate.Therefore, the method for effectively fluorine atom being introduced matrix is carried out various researchs.Can enumerate as known fluorination technology: the spy opens the direct fluorination method of fluorine gas that clear 53-1827 communique is put down in writing; As 258 pages of halogen exchange processes that (1999) are put down in writing of organic synthetic chemistry 47 volumes, this method uses an alkali metal salt of fluorine such as HF or KF that the compound with halogen atom is carried out halogen-fluorine exchange; Use the method for hydrogen fluoride and bases such as pyridine and triethylamine; Use the iodine of high price, for example IF
5Deng method; Use SF
4, specific fluorizating agent such as various fluoro-alkyl amine such as DAST or Yarovenko reagent method; And the electrofluorination method etc. (Chemistry of Organic Fluorine Compounds II, Monograph, American Chem.Society, 1995, p.187).
Yet, the use fluorine gas or the SF of prior art
4Or the fluorination process of DAST etc. has very big problem aspect reaction safety, can be simply and introduce the nucleophilicity fluorizating agent of fluorine atom safely, HF-bases for example, can change and alkali coordinate HF molecule number and distilling, can not produce corrosion, can use Glass Containers etc., so can use in the initial stage of research and development, for its use also have document describe in detail (Journal fur practische ChemieChemiker-Zeitung, 338 (1996), p.99-113; G.A.Olah, SyntheticFluorine Chemistry chapter 8,1992, John Wiley.).
Comprise following reaction as the method for using this nucleophilicity fluorizating agent: to containing halogen-fluorine exchange of being undertaken by the compound of α position carbonyl activatory halogen; The halogen of three chloro miazines-fluorine exchange; And fluoridizing of causing of halogen-fluorine permutoid reaction of sugared ト リ Off レ one ト; fluoridizing synthesizing of ethanol class of (fluoro alcoholization (Off Le オ ロ ヒ De リ Applicationization)) formation fluoridized in the open loop of oxirane compound; the halogenation fluoro of unsaturated compound or fluoridize sulfenylation, take off diazonium fluoride and be combined to fluorobenzene; 1, the gem-bifluoride of 3-two tetramethylene sulfides and hydrazone class or the deprotection reaction of silyl ethers etc.
Yet the security that improves the HF-bases does not make it easily emit HF, has to be difficult to discharge the fluorine anion with nucleophilicity the reactive shortcoming that yet reduces but then concurrently.Therefore, in order to improve reaction effect, need too strict condition, desired response is difficult to carry out mostly.In addition,, also have in lower temperature, finish reaction in the short period of time, improve the space of energy consumption from the viewpoint of industry.
Present situation is that other fluorizating agent is also quite expensive, can not use simply.Wherein, use specific fluorochemicals can introduce fluorine atom, so can use in the primary stage of the research and development of medicine or functional materials etc. as the method for fluorizating agent fairly simplely.But, from highly selective, effectively and carry out the viewpoint of desirable fluoridation safely, can't say abundant as described above.
In addition, in recent years,, various trials have been carried out in order to improve the selectivity and the activity of reaction simultaneously.For example, use microwave to promote that reaction also is one of them.Past is not because microwave causes the energy of the degree of chemical reaction, so microwave is not to almost there being this method in the application of chemical reaction.Recently, begin to report irradiating microwaves gradually and improve Activity of Chemical Reaction and example optionally, gazed at be not only the explanation heating promote reaction etc. (Journal ofPhysical Organic Chemistry, 2000, (13), 579-586).But, only be to attempt in fluoridizing, using microwave, for example, almost do not find western graceful reaction application (the flat 12-59384 communique of special table) in addition.
On the other hand, carbohydrate as the energy, sugar chain albumen not only vital movement such as interchange between pair cell and immune mechanism play important effect, and have tissue such as skin or bone and form functions, use so wish to carry out widely.For example, with the glycosamine structure is to repeat the chitosan of unitary high-order condenses, can be by crustaceans or glucose hydrolysis or fermentation in raw material be made, at field of food, as uses such as additive, sanitas, feed for pet, at medical field as uses such as artificial skin, suture, hemodialysis's film, slow-releasing films, perhaps as anticarcinogen, immunoactivator, inhibition blood sugar increasing, suppress the drug use of cholesterol absorption; Use as soil improvement agent, antiviral agent, sterilant at agriculture field, at industrial circle as uses such as soap, hair agent, makeup, tooth powder, at environmental area as uses such as waste collection agent and heavy metal-polluted water treatment purposes.
Just; by making specific monose form the high order combination; perhaps in carbohydrate, introduce amino, ethanoyl or fluorine atom etc., can develop as the purposes of carbohydrate and can be used for the goods that field of food, medical medical field, agricultural, various industrial circle and environmental area etc. have function.
Wherein, carried out widely to fluoridize to form and fluoridized the research that sugar uses as carcinostatic agent and immunosuppressor etc. human body adaptability higher carbohydrate.In order to realize this purpose, can enumerate as employed fluorination technology: the direct fluorination method of aforementioned fluorine gas, halogen-fluorine exchange process, the method for use hydrogen fluoride and bases such as pyridine or triethylamine is used IF
5, SF
4, various fluorizating agents such as DAST or Yarovenko reagent method etc.
Yet, because carbohydrate has a plurality of activity hydroxies etc., so be difficult to mostly optionally introduce fluorine at privileged site.For example, if known use DAST is with methyl 2,3-O-isopropylidene-β-D-ribofuranoside is fluoridized, then can only obtain as 2 of rearrangement product, 3-O-isopropylidene-5-O-methyl-β-D-ribofuranosyl fluorochemical (ribofuranosyl fluoride) can't be fluoridized the target hydroxyl.In addition, the method for HF-bases such as the HF-pyridine of the simple fluorizating agent of use conduct or HF-triethylamine also can't be carried out goal response.In addition, in order to react,, can produce side reactions such as protecting group cracking if use the bigger material of acidity.
In addition, reactive high fluorine gas can't optionally be introduced fluorine, in order to obtain target compound, must use other reactive low halogen halogenation after, carry out methods such as halogen-fluoridize again.
So, according to prior art, do not influence under the situation of protecting group, it is very difficult that the privileged site of carbohydrate is fluoridized simply.
The purpose of this invention is to provide and solve above-mentioned prior art problems; highly selective, effectively and carry out the method for the fluoridation of desirable matrix safely; particularly provide the privileged site selectivity of carbohydrate or do not influence protecting group, safety and fluorizated method simply in wide temperature range.
Summary of the invention
The inventor studies repeatedly in earnest in order to solve above-mentioned problem, found that: use specific fluorizating agent, heat or microwave or microwave near electromagnetic irradiation under, for example make monose, oligose, polyose and these carbohydrates and protein, the compound carbohydrate of fatty bonded etc. or contain the carbohydrate reaction of aldehyde, ketone, acid and their derivative or the condenses etc. of polyvalent alcohol, polyvalent alcohol, can regioselectivity ground and in 150～200 ℃ scope as existing difficult point, carry out fluoridation safely.
In addition, the inventor also finds: make near the method for the electromagnetic wave irradiation of above-mentioned microwave or microwave can also be applicable to carbohydrate matrix in addition, by use other fluorizating agent under microwave irradiation with substrate reaction, also can be high selectively, at short notice effectively and safely to fluoridizing for the specific position of difficult point in the prior art.
Just, the invention provides following fluorination process.
1. a fluorination process is characterized in that: use the fluorizating agent shown in the general formula (I) to fluoridize carbohydrate.
(in the formula, Y represents nitrogen or phosphorus atom, R
0, R
1And R
2Represent hydrogen atom or the alkyl or aryl with substituent situation is arranged.R
0, R
1And R
2Can be identical, also can be different.In addition, R
0, R
1And R
2In also can connect into ring more than 2.)
2. according to above-mentioned 1 fluorination process, the Y in its formula of (I) is a nitrogen-atoms, R
0Be 3-aminomethyl phenyl or 2-p-methoxy-phenyl, R
1And R
2It is ethyl.
3. according to above-mentioned 1 or 2 fluorination process, wherein be carbohydrate to be fluoridized by thermal response.
4. a fluorination process is characterized in that: matrix and fluorizating agent are reacted under near the electromagnetic irradiation microwave and/or the microwave, thereby aforementioned matrix is fluoridized.
5. according to aforementioned 4 described fluorination process, wherein fluorizating agent is the compound shown in the following general formula (II).
(in the formula, X represents hydrogen atom or halogen atom, and Y represents nitrogen-atoms or phosphorus atom, R
0, R
1And R
2Represent hydrogen atom or the alkyl or aryl with substituent situation is arranged.R
0, R
1And R
2Can be identical, also can be different.In addition, R
0, R
1And R
2In also can connect into ring more than 2.)
6. according to aforementioned 5 described fluorination process, wherein fluorizating agent is the compound shown in the following general formula (III).
(in the formula, R
3, R
4And R
5Expression independently of one another has the alkyl or aryl with substituent situation.X represents hydrogen atom or halogen atom.In addition, substituent R
3, R
4And R
5In also can connect into ring more than 2.)
7. according to the fluorination process of record in above-mentioned 5 or 6, its mesostroma is to contain at least a kind the compound that is selected from oxygen, nitrogen and the sulphur atom.
8. according to above-mentioned 4 fluorination process, wherein fluorizating agent is the complex compound that is formed by HF and alkali.
9. according to above-mentioned 8 fluorination process, its mesostroma is compound, the silyl ether compound that has by α position, β position or γ bit substituent labilized hydrogen atom, perhaps contain unsaturated group, hydroxyl, halogen, amino, diazo, triazenyl or isocyano-compound, or have the above ring compound of heteroatomic 3 yuan of rings as the functional group.
Embodiment
As the carbohydrate that uses among the present invention except can using polyvalent alcohol etc.; can also use for example glucose; Fucose; the N-acetyl glucosamine; N-ethanoyl GalN; the N-acetyl neuraminic acid; erythrose; threose; ribose; pectinose; wood sugar; allose; lyxose; altrose; seminose; gulose; idose; semi-lactosi; talose; psicose; fructose; sorbose; tagatose; unsaturated sugar such as hexaenose with unsaturated link(age); side chain sugar such as apiose; desoxy sugar; aminosugar; thiosugar or condensation sugar; monose acid anhydride etc. is the monose of various derivatives; perhaps contain the maltose that forms glycosidic link with other sugar unit; sucrose; disaccharides such as lactose with 2 oligosaccharides to several monose bondings; starch; glycogen; polyoses such as Mierocrystalline cellulose; the nucleosides of these carbohydrates and compound carbohydrate of bonded such as protein or lipid and nucleic acid base bonding and oligomeric nucleosides; Yeast Nucleic Acid or deoxidation thymus nucleic acid etc.
The fluorizating agent of fluoridizing middle use of above-mentioned carbohydrate is the compound shown in the following general formula (I).
The R of general formula (I)
0, R
1And R
2Represent hydrogen atom or alkyl or the aryl with substituent situation arranged, they can be identical, also can be different, also can connect into ring more than 2.
Saturated, unsaturated, the aliphatics of the preferred carbonatoms 1～32 of abovementioned alkyl or alicyclic alkyl, comprise methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl, octyl group, 2-ethylhexyl, nonyl, decyl, cyclohexyl, ring octyl group, naphthane, norcamphyl, dicyclohexyl, adamantyl and their isomer as concrete example, in addition, can also enumerate methylol, hydroxyethyl, hydroxypropyl and hydroxyl butyl etc.
In addition, can enumerate phenyl, o-tolyl, a tolyl, p-methylphenyl, o-Xylol base, m-xylene base, p-Xylol base, 3,5-dimethylphenyl and positional isomers, cumyl, Lai Ji, trimethylphenyl, hydroxy phenyl, p-methoxy-phenyl and positional isomers thereof as aryl, aromatic series aryl such as naphthyl, methyl naphthyl, dimethyl naphthyl, hydroxyl naphthyl, xenyl, tetralyl, terphenyl (terphenyl), anthryl, benzothienyl, chromenyl, indyl, pyridyl, quinolyl perhaps contain the heterocyclic group.
In these alkyl and aryl, can also contain other functional group, for example, functional groups such as hydroxyl, halogen, nitro, sulfydryl, amino, amide group, cyano group, carbonyl, carboxyl, ethanoyl, acyl group, alkoxyl group and sulfuryl.
In the fluorizating agent shown in the general formula (I), preferably Y is a nitrogen-atoms, R
0Be 3-aminomethyl phenyl or 2-p-methoxy-phenyl, R
1And R
2Material for ethyl; Aspect also can stablizing under, the high temperature more than 150 ℃ higher in thermostability, preferred especially R
0Be 3-aminomethyl phenyl or 2-p-methoxy-phenyl, R
1And R
2Be the N of ethyl, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine.And N, N-diethyl-α, α-two fluoro-(2-methoxyl group) benzylamine.
With respect to 1 mole as the functional group in the matrix of object, the consumption of the fluorizating agent shown in the general formula (I) is preferably more than 1 mole, but also can be excessive or not enough stoichiometry ground react.
This fluoridation can batch-type, semi-batch or continous way ground carry out, and can react by common reacting by heating or under near the electromagnetic irradiation microwave and/or the microwave.
If temperature of reaction just can be carried out below so-called thermal runaway temperature (the beginning heating temp of ARC test) safely.Fluoridation is preferably being carried out below 200 ℃, is preferably the temperature range of room temperature～150 ℃ especially.When thermal response was fluoridized, fluoridation was carried out under the scope that is lower than the thermal runaway temperature.
When carrying out fluoridation under near the electromagnetic irradiation microwave and/or microwave, the microwave of preferred 1～30GHz is higher than the following millimeter wave of 30GHz, 300GHz but also can use usually, and perhaps 0.3GHz is to the interior hertzian wave in zone that is lower than 1GHz.Can when reacting, the continuously or intermittently controlled temperature shine this hertzian wave.For example, common batch-type reactor etc. shielded to prevent that microwave from revealing produce fault, thereby only irradiating microwaves just can.Based on this purpose, suitable is microwave oven, can use commercially available chemosynthesis microwave oven.Output and exposure intensity that the microwave that uses in the reaction produces with magnetron have no particular limits (except legal restriction), the preferred output of using the 200W～6000W that obtains easily.During bigger if desired output, can be used in combination a plurality of.The exposure intensity of microwave is preferably 20W/cm usually
2More than, be preferably 100W/cm especially
2More than.
The reaction times of thermal response is preferably 10 minutes～and 360 minutes.The reaction times of under near the electromagnetic wave irradiation microwave and/or the microwave, reacting, compare with the situation of reacting by heating, usually short getting final product, irradiation time is according to matrix and different, preferably carried out 0.1 minute～200 minutes, and more preferably carried out reaction in 0.1 minute～60 minutes.Particularly preferred irradiation time is 1 minute～30 minutes.But,, also can shine the microwave more than 3 hours as required for the pre-treatment or the fluoridation of drying etc.Temperature of reaction can be carried out in making the stable scope of matrix, fluorizating agent and reaction product, is preferably usually from about 25 ℃ room temperature to 200 ℃, also can carry out below the room temperature or more than 200 ℃.
Though this fluoridation does not need solvent, in order to stir fully and to prevent that temperature from rising, and also can use solvent.Preferred solvent is that relative matrix, fluorizating agent and product are inert aliphatic hydrocarbon, aromatic hydrocarbons, halohydrocarbon, aromatic series halohydrocarbon, nitrile, ethers etc., also can suitably be used in combination after the selection in them.
Microwave irradiation can carry out the aftertreatment identical with common thermal response, extraction, distillation, filtration etc., with reaction product isolated after finishing.
Use the fluorizating agent shown in the general formula (I) of above excellent heat stability; can react by reacting by heating or under near the electromagnetic irradiation microwave and/or the microwave; under wide temperature range, the privileged site of carbohydrate optionally, is not influenced protecting group and fluoridizes simply as the difficult point of prior art.
The above-mentioned fluorizated method of reacting under near the electromagnetic irradiation microwave and/or the microwave, carry out is used the fluorizating agent in addition of the fluorizating agent shown in the general formula (I), also goes for fluoridizing of carbohydrate matrix in addition.
For example, carry out in the fluorizated method under near the electromagnetic irradiation microwave and/or microwave, can use the fluorizating agent shown in the general formula (II).
In general formula (II), X represents hydrogen atom or halogen atom, R
0, R
1, R
2Identical with Y with aforementioned formula (I).
Further, can use the fluorizating agent shown in the general formula (III) as preferred fluorizating agent.
In general formula (III), R
3, R
4And R
5Expression independently of one another has the alkyl or aryl with substituent situation, substituent R in addition
3, R
4And R
5In also can connect into ring more than 2.This R
3, R
4And R
5Alkyl and the aryl R that can enumerate aforementioned formula (I)
0, R
1, R
2Explanation in illustrated group.
X in the general formula (III) represents hydrogen atom or halogen atom, just fluorine, chlorine, bromine or iodine atom.
Fluorizating agent shown in the general formula (III) is preferably as follows material: R
3For have substituent aryl, X is fluorine atom, R
4And R
5It is the alkyl or aryl that the carbonatoms 1～32 with substituent situation is arranged.
As the compound shown in the general formula (III) alkyl fluoroamine and aryl fluoride amine are arranged, in substituent R
4, R
5During for ethyl, can enumerate N, N-diethyl-α, α-two fluoro-benzylamine, N, N-diethyl-α, α-two fluoro-(2-methyl) benzylamine, N, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine, N, N-diethyl-α, α-two fluoro-(4-methyl) benzylamine, N, N-diethyl-α, α-two fluoro-(2-methoxyl group) benzylamine, N, N-diethyl-α, α-two fluoro-(4-phenyl) benzylamine, N, N-diethyl-α, α-two fluoro-cyclohexyl methyl amine, N, N-diethyl-α, α-two fluoro-pyridylmethyl amine, N, N-diethyl-α, α-two fluoro-cyclohexyl methyl amine etc.
In the compound shown in the general formula (III), aspect excellent heat stability, preferably as the N of aromatic series fluoroamine, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine, N, N-di-isopropyl-α, α-two fluoro-(3-methyl) benzylamine, N, N-diethyl-α, α-two fluoro-(2-methoxyl group) benzylamine, N, N-di-isopropyl-α, α-two fluoro-(2-methoxyl group) benzylamine and N, N-di-n-butyl-α, α-two fluoro-(2-methoxyl group) benzylamine etc.
Can be organic compound, polymkeric substance, mineral compound etc. by the fluorizating agent fluorizated matrix shown in the general formula (III),,, normally contain the organic compound of aerobic, nitrogen or sulphur atom so all illustration is come out because this quantity is very big.As these organic compound can enumerate have independent hydroxyl as functional group primary, the second month in a season and tertiary alcohols; Or have 1 of a plurality of oxy-compound adjacency, 2-glycol or 1,3-glycol and other polyalcohols; Perhaps compound, cyanalcohol, sulfonic acid, sulphonate, thiocarboxylic acid, carbothioic acid ester class and the dinitrobenzene etc. that contain carbonyl or carboxyl such as thio-alcohol, aldehydes, ketone, carboxylic-acid, hydroxycarboxylic acid, carboxylicesters, lactone have electron withdrawing group and cage shape hydro carbons such as carbohydrate such as aromatics class that nucleophilicity improves or aromatic series diazonium salt, heterogeneous ring compound, monose, glucosides, monose acid anhydride, oligose or polyose or soccerballene etc., can also enumerate epoxide such as oxyethane and epoxy chloropropane.The concrete example of these matrix can be enumerated ethanol, propyl alcohol, butanols, enanthol, octanol, phenylcarbinol, phenylethyl alcohol, nitrophenols, hexalin, adamantanol, cholesterol, epiandrosterone, ethylene glycol, cyclohexanediol, glycerol, propylene oxide, alkyl hydroxy silane, phenyl aldehyde, alkylbenzene formaldehyde, methyl phenyl ketone, benzophenone, cyclopentanone, pimelinketone, indone, mandelonitrile, gamma-butyrolactone, acid (mevanolactone) in the first hydroxyl penta, Phenylsulfonic acid, naphthene sulfonic acid, thiobenzoic acid, the thiobenzoic acid methyl esters, dinitrochlorobenzene, α-D-Glucopyranose, beta-D-fructofuranose, α-D-wood-own pyranose-4-alcohol (ウ ロ-ス), β-D-glucobinalranicacid, soccerballene alcohol etc.If enumerate the high specific compound of value added, comprise 2-hydroxymethyl asccharin as the raw material of the useful 2-glycosyl methyl aryl carboxylicesters of protein decomposition enzyme supressor, as 2 of the pyridyl thiophene intermediate of cytokine mediated diseases treatment usefulness, 3-two (4-pyridyl)-4-thiotolene-3-formaldehyde, form the dinucleotides or the oligonucleotide class of treatment of viral infections medicines such as influenza or bleb, as the 7 β-carboxymethyl-4-azepine-5 α-cholestanone of 5 inhibitor raw material etc.
Can be not limited to these concrete examples certainly with the fluorizating agent fluorizated matrix shown in the general formula (III).In these matrix, preferably have the compound of hydroxyl, particularly have glycol, the carbohydrate of the hydroxyl of adjacency, compound and epoxide with carbonyl or carboxyl.
Can under near the electromagnetic irradiation microwave and/or the microwave, use the fluorizating agent shown in the general formula (III) to carry out the fluorizated working method, with to use the compound shown in the general formula (I) to carry out the fluorizated situation under near the electromagnetic irradiation microwave and/or the microwave roughly the same.Temperature of reaction can be the scope that makes matrix, fluorizating agent and reaction product stable, is preferably the room temperature to 200 ℃ about 25 ℃ usually, but also can carrying out below the room temperature or more than 200 ℃.
Y in the fluorizating agent shown in the general formula (I) is under the situation of nitrogen-atoms, and use under the situation of the fluorizating agent shown in the general formula (III), after fluoridation finished, fluorizating agent can be used as corresponding amide and reclaims, thus can easily obtain can cycling and reutilization flaorination process.
Under near the electromagnetic irradiation microwave and/or the microwave, use the method for the fluorizating agent shown in the general formula (III), can be at short notice effectively, safety and highly selective fluoridize above-mentioned matrix.
In addition, the above-mentioned fluorizated method of carrying out under near the electromagnetic irradiation microwave and/or the microwave is applicable to that also use fluoridized as fluorizating agent by the complex compound that HF and alkali form.
The complex compound that is formed by HF and alkali is during as fluorizating agent, and fluorizating agent can be enumerated alkylamine-HF complex compound, trimeric cyanamide-HF complex compound, pyridine-HF complex compound etc.Wherein, preferred triethylamine-nHF complex compound (n is generally integer) particularly because triethylamine-3HF can distill, not have corrodibility, can use Glass Containers etc., and is simple to operate, so preferred especially.
The complex compound that use is formed by HF and alkali is during as fluorizating agent, and the purpose based on promoting reaction except fluorizating agent, can also have reagent.For example, use NBS (n-bromo-succinimide), DBH (1,3-two bromo-5,5-T10) or sulfur subchloride etc., to 1,3-dithiane etc. carries out the gem-bifluoride; HF-alkali and sulfonyl compound used simultaneously with the halo that carries out alkene and alkynes fluoridize or fluoridize sulfenylation.
So, the complex compound that use is formed by HF and alkali is as fluorizating agent, under near the electromagnetic irradiation microwave and/or the microwave, fluoridize, can enumerate the compound that has by α position, β position or γ bit substituent labilized hydrogen atom as the example of the matrix in this method, the silyl ether compound, perhaps have unsaturated group, hydroxyl, halogen radical, amino, diazo, triazenyl or isocyano-as substituent compound, perhaps have the above multicomponent heterocycle compound of heteroatomic 3 yuan of rings.
These matrix for example are the compounds that can produce following reaction: the halogen of halogenide class-fluorine exchange; the halo of unsaturated group such as alkene or alkynes is fluoridized or the fluoro sulfenylation; nitro is fluoridized; fluoridizing of the hydroxyl of pure and mild carbohydrate; will be with amino; diazo; the diazonium of taking off of triazenyl and isocyano-is fluoridized etc. to this functional group of representative and is converted to fluorine; the open loop of ring compound is fluoridized; 1; the gem-bifluoride of 3-dithiolane or hydrazone etc.; the gem-three of former monothioester class fluoridizes, and oxidation is fluoridized; the deprotection reaction of reduction fluoridation and silyl ethers etc.
Can enumerate cyclopropane particularly as these matrix, tetramethylene, pentamethylene, cyclobutene, cyclopentenes, tetrahydrobenzene, suberene, cyclooctene, cyclodecene, cyclododecane alkene, butylene, 2, the 3-neohexene, the methylene radical tetrahydrobenzene, 5-α-courage steroid-2-alkene, oxyethane, propylene oxide, trimethylene oxide, tetrahydrofuran, cyclohexene oxide, the oxidation cyclooctene, the oxidation cyclodecene, oxidation cyclododecane alkene, alkyl epoxy ethane, Styrene oxide 98min., the oxidation norbornylene, ethylenimine, nitrogen heterocyclic third is because of (ア ジ リ Application), cured ethylene, azetidine, aza-cyclopentane, thiazolidine, 1,3-dithiane etc. has the ring compound class with heteroatomic situation, perhaps has electron withdrawing group and higher aromatics class and the aromatic series diazonium salt of nucleophilicity, heterocycles, for example indone, cyclopentanone, gamma-butyrolactone, acid in the first hydroxyl penta, bromo acetone, Phenylsulfonic acid, naphthene sulfonic acid, thiobenzoic acid, the thiobenzoic acid methyl esters, vinylformic acid, methyl acrylate, methacrylic acid, methyl methacrylate and three chloro pyrimidines etc.In addition, also comprise and contain alcohol or the carbohydrates such as monose, glucosides, monose acid anhydride, oligose and polyose of hydroxyl as functional group, for example, can enumerate allyl alcohol, allylveratrol, geranial, α-D-Glucopyranose, beta-D-fructofuranose, the α-own pyranose of D-wood-4-alcohol, β-D-glucobinalronic acid etc.In addition, also comprise cage shape hydro carbons such as propylene, butylene, tolane, acetylene or soccerballene with unsaturated double-bond etc., they can also contain a plurality of other functional groups in addition.
Described other functional group for example can be primary, independent or a plurality of hydroxyls of Zhong Heshu, thiol group, formyl radical, carbonyl, acyloxy, alkyl oxy carbonyl, cyano group, alkylsulfonyl, alkyl sulphonyl, sulfinyl, thiocarbonyl, nitro, amino, diazo etc.; but be not limited to organic compound, mineral compound or material or the same organic-inorganic hybrid material of introducing this functional group on the surface of polymkeric substance also are suitable for.
The complex compound that use is formed by HF and alkali is fluoridized under near the electromagnetic wave irradiation microwave and/or the microwave as fluorizating agent, and the matrix in this method obviously is not limited to these concrete examples.This method is suitable for the carbohydrate in these matrix or contains cyclopropane ring, oxyethane ring, ethylenimine ring, nitrogen heterocyclic third because of ring or 1, the ring compound of 3-dithiane ring very much.
Using under near microwave and/or the microwave the electromagnetic irradiation under the situation of complex compound as fluorizating agent that is formed by HF and alkali, its working method is roughly the same with the situation of using the compound shown in the general formula (I).Temperature of reaction is to make matrix, fluorizating agent and reaction product stable and in the scope that can react, the temperature of usually preferred about 25 ℃ room temperature to 300 ℃, it is following or be controlled at equally in the temperature range of room temperature to 200 ℃ with common thermal response and react to be controlled at room temperature as required.
Above using under near the electromagnetic irradiation microwave and/or the microwave under the situation of complex compound that forms by HF and alkali as fluorizating agent; use such stable of triethylamine-3HF; there is not corrosive HF-alkali complex compound in use; to various matrix or carry out various fluoridations; for example; has position by α; the compound of the substituting group labilized hydrogen atom of β position or γ position; silyl ether compound or have unsaturated group; hydroxyl; halogen radical; amino or diazo are as the compound of functional group; perhaps having the various matrix such as multicomponent heterocycle compound more than 3 yuan with heteroatomic situation to carry out open loop fluoridizes; the halo fluoro of unsaturated compound or fluoro sulfinylization; halogen-fluorine exchange; taking off diazonium fluoridizes; 1; the gem-bifluoride of 3-dithiolane and hydrazone class or the deprotection reaction of silyl ethers etc.; compare with the situation of thermal response, can in the following short period of time of condition stably, carry out effectively.
Below, by embodiment and comparative example the present invention is more specifically described.But these embodiment are not intended to limit the invention.
A. use the situation of the fluorizating agent shown in the general formula (I)
Synthesizing of＜fluorizating agent 〉
A) chlorination N, tolyl ammonium between N-diethyl-alpha-chloro
Under nitrogen atmosphere, in there-necked flask (300ml), add tetracol phenixin (125g) solution that contains oxalyl chloride (25g, 0.197 mole), the limit is flask cooling and stirring under frozen water, and the limit is with dripping N, N-n,N-diethyl meta-toluamide (45g in 20 minutes, 0.236 mole, below, abbreviate DEET as).After dripping end, under uniform temp, kept 10 minutes, after making the content temperature be 50 ℃, reacted 1 hour.When reaction, confirm to have gas to produce, afterwards, obtain white precipitate.The precipitate of filtering separation gained, after tetracol phenixin, normal hexane washing, drying obtains chlorination N, tolyl ammonium between N-diethyl-alpha-chloro.With the chlorination N of gained, tolyl ammonium (sealed tube) in kapillary slowly is warmed up to 200 ℃ between N-diethyl-alpha-chloro, does not observe decomposition, is heat-staple.
With the chlorination N of gained, the tolyl ammonium carries out heat analysis by TG-DAT between N-diethyl-alpha-chloro, and fusing point is 54.6 ℃.
B) N, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine
In there-necked flask (500ml), add the N of synthetic chlorination in advance, tolyl ammonium (25g between N-diethyl-alpha-chloro, 0.1 mole) and (gloomy field chemistry (strain) manufacturing of the spray dried prod of Potassium monofluoride, 23.5g, 0.4 the mole), acetonitrile (250g), under the reflux temperature of nitrogen atmosphere and acetonitrile the reaction 18 hours.After reaction finished, cool to room temperature filtered, and obtains containing chlorination N, the acetonitrile solution of the fluorine of tolyl ammonium exchange product between N-diethyl chloro.Use the rotation belt rectifying tower of 80 grades of theoretical stages to distill this solution.Obtain the N of 130g as the cut (pressure 2mmHg:260Pa) of 50 ℃ to 60 ℃ of temperature, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine (below, abbreviate this compound as DEET-F).With chloro N, the tolyl ammonium is a benchmark between N-diethyl chloro, and the distillatory separation yield is about 60%.
The cut of gained is a colourless transparent liquid, has following proterties.
(thermostability and thermal runaway temperature)
(sealed tube) slowly is warmed up to 200 ℃ in kapillary, keeps 1 hour, do not observe problems such as decomposition, is heat-staple.In addition, use TG/DTA apparatus for thermal analysis is warmed up to 400 ℃ with 10 ℃/minute, carries out heat analysis, observes at 210 ℃ to begin heating, and weight slowly reduces.The peak temperature of heating is 280 ℃.In addition, estimate the thermally-stabilised of material under the adiabatic condition according to JIS escape reaction assay experiment (ARC experiment), the temperature that discovery begins to generate heat is 180 ℃.
(fluorine content)
Calculated value: 17.8 weight %, measured value: 17.6 weight t%
C) N, N-diethyl-2-methoxy benzamide
In there-necked flask (200ml), add and contain diethylamine (25.80g, 0.352 toluene solution (56g) mole), when flask cooled off in ice-water bath, stirs, with slowly dripping the toluene solution (30g) that contains 2-methoxy benzoyl chloride (20.00g, 0.117 mole) in 30 minutes.After dripping end, add entry, remove superfluous diethylamine and diethylamine hydrochloride.Use MgSO
4With the toluene layer dehydration of gained, distillation removes and desolvates, and obtains weak yellow liquid (output 22.81g, yield 94%).
D) chlorination N, N-diethyl-α-chloro-(2-p-methoxy-phenyl) ammonium synthetic
Under nitrogen atmosphere, in there-necked flask (200ml), add tetracol phenixin (54g) solution that contains oxalyl chloride (24.50g, 0.193 mole), at normal temperatures, with 20 minutes dropping N, N-diethyl-2-methoxy benzamide (20.05g, 0.0965 mole).After drip finishing, make the content temperature be 50 ℃ after, reacted 5 hours.Confirm to have gas to produce when reaction, afterwards, reaction solution is separated into 2 layers.After reaction finished, distillation removed and desolvates, and leaves standstill, and obtains dark brown solid.After the solid that obtains cleaned with tetracol phenixin, normal hexane, drying obtained chlorination N, N-diethyl-α-chloro-(2-p-methoxy-phenyl) ammonium (output 21.40g, yield 80%).
With the chlorination N of gained, N-diethyl-α-chloro-(2-p-methoxy-phenyl) ammonium reacts to confirm chlorination N, the chlorination ability of N-diethyl-α-chloro-(2-p-methoxy-phenyl) ammonium with phenylcarbinol in loft drier.Add chlorination N in experiment tube, N-diethyl-α-chloro-(2-p-methoxy-phenyl) ammonium (0.20g, 0.465 mole), phenylcarbinol (0.11g, 1.017 moles) and acetonitrile 1.10g at room temperature reacted 4 hours.With GC analytical reaction liquid, results verification generates benzyl chloride.
E) N, N-diethyl-α, α-two fluoro-(2-methoxyl group) benzylamine
In loft drier, in there-necked flask (100ml), add the N of synthetic chlorination in advance, (gloomy field chemical spray drying (strain) is made: 17 for N-diethyl-α-chloro-(2-p-methoxy-phenyl) ammonium (20.00g, 0.0725 mole) and Potassium monofluoride.72g, 0.3052 mole), acetonitrile (200g).Under nitrogen atmosphere, prolong and electromagnetic mixing apparatus are installed, reacted 20 hours down at 80 ℃.After reaction finished, cool to room temperature filtered in loft drier, obtains containing chlorination N, the acetonitrile solution of the fluorine quid pro quo of N-diethyl-α-chloro-(2-p-methoxy-phenyl) ammonium.
Use the rotation belt rectifying tower of 80 grades of theoretical stages to distill this solution.Obtain as under the pressure of 2mmHg (260Pa), the N of the cut of 77 ℃ to 80 ℃ of temperature, N-diethyl-α, α-two fluoro-(2-methoxyl group) benzylamine (9.86g, yield 55%).
The gained cut is a colourless transparent liquid, has following proterties.
(thermostability and thermal runaway temperature)
(sealed tube) slowly is warmed up to 200 ℃ in kapillary, keeps 1 hour, do not observe problems such as decomposition, is heat-staple.In addition, use TG/DTA apparatus for thermal analysis is warmed up to 400 ℃ with 10 ℃/minute, carries out heat analysis, observes at 200～210 ℃ to begin heating, and weight slowly reduces.The peak temperature of heating is 255 ℃.In addition, according to JIS escape reaction assay experiment (ARC experiment), find that the temperature that begins to generate heat is 159 ℃ as the material thermostability evaluation experimental that carries out under the adiabatic condition.
[embodiment 1]: methyl 2, the fluoridizing of 3-O-isopropylidene-β-D-ribofuranoside
The fluororesin-coated glass reactor of usefulness 100ml, that have whipping appts and condenser is set.Adding is as the methyl 2 of matrix, 3-O-isopropylidene-β-D-ribofuranoside (10 mmole), with N as fluorizating agent, N-diethyl-α, (12 mmoles 2.56g) and heptane (20ml), at room temperature stir α-two fluoro-(3-methyl) benzylamine, temperature is elevated to 100 ℃ simultaneously, reacted 60 minutes.After reaction finishes, in reaction solution, add 50ml water, use 20ml dichloromethane extraction 2 times.After extraction liquid dried over mgso, the filtration, underpressure distillation obtains product.Product uses gas-chromatography or liquid chromatography quantitative by evaluations such as IR, NMR, mass analyses.As the methyl 2 of product, the yield of 3-O-isopropylidene-5-deoxidation-5-fluoro-beta-D-ribofuranoside is 55%.
[embodiment 2]: methyl 2, the fluoridizing of 3-O-isopropylidene-β-D-ribofuranoside
In the microwave oven that can pass through the conical distributor uniform irradiation (wide, degree of depth 55cm, height 70cm, power 1KW, frequency 2.45GHz), the fluororesin-coated glass reactor of the usefulness that has whipping appts and condenser of 100ml is set.Adding is as the methyl 2 of matrix, and 3-O-isopropylidene-β-D-ribofuranoside (10 mmoles, 2.04g), with the N as fluorizating agent, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine (12 mmoles, 2.56g), at room temperature stir, used microwave irradiation simultaneously 10 minutes.After microwave irradiation finishes, handle similarly to Example 1, as the methyl 2 of target product, the yield of 3-O-isopropylidene-5-deoxidation-5-fluoro-beta-D-ribofuranoside is 65%.In addition, as by product fluoridize 2, the yield of 3-O-isopropylidene-5-O-methyl-β-D-ribofuranoside is 20%.
[comparative example 1]: methyl 2, the fluoridizing of 3-O-isopropylidene-β-D-ribofuranoside
Will be as the methyl 2 of matrix, 3-O-isopropylidene-β-D-ribofuranoside (10 mmole) is dissolved among the exsiccant methylene dichloride 20ml, under nitrogen gas stream, stirs the N that slowly drips simultaneously as fluorizating agent, N-diethylamino sulfur trifluoride (DAST, 10 mmoles).After dripping end, reacted 15 minutes.In reaction solution, inject 50ml water, behind the separatory, use the dried over mgso organic layer, carry out chromatographic separation.Obtain fluoridizing 2 as the tautomeric of product, the productive rate of 3-O-isopropylidene-5-deoxidation-β-D ribofuranoside is 55%.But do not obtain methyl 2 fully, 3-O-isopropylidene-5-deoxidation-5-fluoro-beta-D-ribofuranoside as target.
[embodiment 3]: ethyl 2, the fluoridizing of 3-O-isopropylidene-β-D-ribofuranoside
Except using ethyl 2,3-O-isopropylidene-β-D-ribofuranoside (10 mmole) uses N as matrix, N-diethyl-α, and α-two fluoro-(3-methyl) benzylamine (20 mmole) carries out similarly to Example 2 as beyond the fluorizating agent.Obtaining ethyl 2 as product, 3-O-isopropylidene-5-deoxidation-5-fluoridizes-and the yield of β-D-ribofuranoside is 55%, fluoridizes 2, and the yield of 3-O-isopropylidene-5-O-ethyl-β-D-ribofuranoside is 21%.
[embodiment 4]: sec.-propyl 2, the fluoridizing of 3-O-isopropylidene-β-D-ribofuranoside
Except using sec.-propyl 2,3-O-isopropylidene-β-D-ribofuranoside (10 mmole) carries out similarly to Example 3 as beyond the matrix.Obtain the sec.-propyl 2 as product, the yield of 3-O-isopropylidene-5-deoxidation-5-fluoro-beta-D-ribofuranoside is 62%, fluoridizes 2, and the yield of 3-O-isopropylidene-5-O-sec.-propyl-β-D-ribofuranoside is 22%.
[embodiment 5]: the fluoridizing of 2 ', 3 '-O-isopropylidene uridine
Except using 2 ', 3 '-O-isopropylidene uridine (10 mmole), carry out similarly to Example 3 as beyond the matrix.The yield that obtains 2 ', 3 '-O-isopropylidene-5 '-deoxidation-the 5 '-fluoro uridine as product is 55%.
[embodiment 6]: 1,2,3, the fluoridizing of 4-two-O-isopropylidene-α-D-galactopyranose
Except use N, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine (20 mmole) carries out in addition similarly to Example 3.Obtain as 1,2,3 of product, the yield of 4-two-O-isopropylidene-6-deoxidation-6-fluoro-α-D-galactopyranose is 75%.
[embodiment 7]: α-D-ribofuranose-1,3, the fluoridizing of 5-three benzoic ethers
In the hermetic type pressure vessel (200ml) that the teflon that the optical fiber temperature sensor is installed is made, add stirrer, α-D-ribofuranose-1,3,5-three benzoic ethers (11 mmoles, 5.1g), acetonitrile (50ml), under nitrogen atmosphere, slowly add N, N-diethyl-α, and α-two fluoro-(3-methyl) benzylamine (23.2 mmoles, 49.5g).Afterwards, while the speed that stirs with 20 ℃/minute is warmed up to 200 ℃, reacted 20 minutes.Reaction is injected into reaction product in the 200ml frozen water after finishing, and behind the separation organic layer, uses 50ml acetonitrile aqueous layer extracted again.2 organic layers are merged,, after dried over mgso, filter with the pure water washing.Organic solution is passed through liquid-phase chromatographic analysis after concentrating with vaporizer.The result is: obtain the 2-deoxidation-2-fluoro-α-D-ribofuranose-1,3 of 2.8g (yield 55%) as target, 5-three benzoic ethers.
[embodiment 8]: 2,3,5, the fluoridizing of 6-two-O-isopropylidene-D-sweet dew furanose
Except using 2,3,5,6-two-O-isopropylidene-D-sweet dew furanose (10 mmole) is as matrix, and beyond at room temperature reacting 1 hour, carries out similarly to Example 1.Do not separate fully as the acetonide of protecting group, obtain as product fluoridize 2,3,5, the yield of 6-two-isopropylidene-D-sweet dew furanose is 94%.
[comparative example 2]: 2,3,5, the fluoridizing of 6-two-O-isopropylidene-D-sweet dew furanose
Except using HF (20 mmole), carry out similarly to Example 8 as the fluorizating agent.The result is that protecting group is separated, and fluoridizes, does not obtain fluoridizing 2,3,5 fully, 6-two-O-isopropylidene-D-sweet dew furanose for 1 that can't produce as target.
[embodiment 9]: 2,3,4, the fluoridizing of 5-four-O-ethanoyl-D-Glucopyranose
Except using 2,3,4,5-four-O-ethanoyl-D-Glucopyranose (10 mmole) is as matrix, and in methylene dichloride, at room temperature reacted 1 hour beyond, carry out similarly to Example 1.The result does not separate fully as the ethanoyl of protecting group, obtain as product fluoridize 2,3,4, the yield of 5-four-O-ethanoyl-D-Glucopyranose is 84%.
[comparative example 3]: 2,3,4, the fluoridizing of 5-four-O-ethanoyl-D-Glucopyranose
Except using HF (20 mmole), carry out similarly to Example 9 as the fluorizating agent.The result is that protecting group is separated, and fluoridizes, does not obtain fluoridizing 2,3,4 fully, 5-four-O-ethanoyl-D-Glucopyranose for 1 that can't produce as target.
[embodiment 10]: 2,3,4, the fluoridizing of 5-four-O-ethanoyl-D-Glucopyranose
Except using 2,3,4,5-four-O-ethanoyl-D-Glucopyranose (10 mmole) carries out similarly to Example 2 as beyond the matrix.Do not separate fully as the ethanoyl of protecting group, obtain as product fluoridize 2,3,4, the yield of 5-four-O-ethanoyl-D-Glucopyranose is 84%.
[embodiment 11]: α-D-ribofuranose 1,3, the fluoridizing of 5-three benzoic ethers
Except using α-D-ribofuranose 1,3,5-three benzoic ethers (11 mmole) are as matrix, use N, N-diethyl-α, α-two fluoro-(2-methoxyl group) benzylamine (23.2 mmole) is as fluorizating agent, beyond reaction under 120 ℃ 30 minutes, carry out similarly to Example 7.Obtain the 2-deoxidation-2-fluoro-α-D-ribofuranose-1,3 as product, the yield of 5-three benzoic ethers is 85%.
[embodiment 12]: the fluoridizing of D-xylopyranose
Except using D-xylopyranose (10 mmole), and use fluorizating agent (80 mmole) in addition, carry out similarly to Example 9 as matrix.Obtain as product fluoridize 2,3, the yield of 4-three-O-(3 '-methyl benzoyl)-D-xylopyranose is 57%.
[embodiment 13]: 1,2,3, the fluoridizing of 4-two-O-isopropylidene-α-D-galactopyranose
Except using N, N-diethyl-α, α-two fluoro-(2-methoxyl group) benzylamine (20 mmole) are as fluorizating agent, and irradiating microwaves beyond reaction under 120 ℃ 48 hours, does not carry out similarly to Example 6.Obtain as 1,2,3 of product, the yield of 4-two-O-isopropylidene-6-deoxidation-6-fluoro-α-D-galactopyranose is 58%.
B. use the situation of the fluorizating agent shown in the general formula (III)
Fluoridizing of＜primary alconol 〉
[embodiment 14]: 1-dodecanol
In the microwave oven that can pass through the conical distributor uniform irradiation (wide, degree of depth 55cm, height 70cm, power 1KW, frequency 2.45GHz), the fluororesin-coated glass reactor of the usefulness that has whipping appts and condenser of 100ml is set.Adding as the 1-dodecanol of matrix (10 mmoles, 1.86g) with as the N of fluorizating agent, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine (12 mmoles, 2.25g), at room temperature stir on the limit, the limit was with microwave irradiation 10 minutes.After microwave irradiation finishes, in reaction solution, add 50ml water, use 20ml dichloromethane extraction 2 times.After extraction liquid dried over mgso, the filtration, underpressure distillation obtains product.Product uses gas-chromatography or liquid chromatography quantitative by evaluations such as IR, NMR, mass analyses.The result is that the yield as the 1-fluoro dodecane hydrocarbon of product is 93%.
[comparative example 4]: 1-dodecanol
Except the irradiating microwaves not, according to step reaction similarly to Example 14.Under 110 ℃ of temperature of reaction, 10 minutes condition, the yield of 1-fluoro dodecane hydrocarbon is 45%, and when at room temperature reacting 17 hours, the yield of 1-fluoro dodecane hydrocarbon is 12%.
[embodiment 15]: 10-undecene-1-alcohol
Use device similarly to Example 14, in heptane solvent, add 10-undecene-1-alcohol (10 mmoles as matrix, 1.7g) and as the N of fluorizating agent, N-diethyl-α, α-two fluoro-(3-methyl) benzylamine (12 mmoles, 2.56g), at room temperature stir on the limit, and microwave irradiation 10 minutes are used on the limit.The yield that obtains as the 1-fluoro-10-undecylene of product is 91%.
[embodiment 16]: ethylene glycol
Except making spent glycol (10 mmole) as matrix, do not use beyond the solvent normal heptane, react according to the method identical with embodiment 15.Only a hydroxyl of ethylene glycol is fluoridized by microwave irradiation 10 minutes.Just, the yield that obtains 2-((3-methyl) the benzoyloxy)-1-fluoroethane as product is 83%.
Fluoridizing of＜secondary alcohol 〉
[embodiment 17]: suitable-hexanaphthene-1, the 2-glycol
Suitable except using-hexanaphthene-1,2-glycol (10 mmole) is as beyond the matrix, reacts according to the method identical with embodiment 16.The yield that obtains as anti--1-fluoro-2-((3-methyl) benzoyloxy) hexanaphthene of product is 89%.
[embodiment 18]: cyclododecanols
Except using cyclododecanols (10 mmole), react according to the method identical with embodiment 16 as the matrix.Obtain being respectively 16%, 84% as the fluoro cyclododecane hydrocarbon of product and the yield of ring dodecylene.
Fluoridizing of＜tert-hydroxyl 〉
[embodiment 19]: Alpha-hydroxy isobutyric acid methyl esters
Except using Alpha-hydroxy isobutyric acid methyl esters (10 mmole), react according to the method identical with embodiment 16 as the matrix.The yield that obtains as the alpha-fluoro methyl isobutyrate of product is 93%.
[comparative example 5]: Alpha-hydroxy isobutyric acid methyl esters
The fluororesin-coated glass reactor of the usefulness that has whipping appts and condenser of 100ml is set.Adding is as the Alpha-hydroxy isobutyric acid methyl esters (10 mmole) of matrix, as the N of fluorizating agent, N-diethyl-α, and (12 mmoles 2.56g) with as the normal heptane 20ml of solvent, reacted under 20 ℃ 5 hours α-two fluoro-(3-methyl) benzylamine while stirring.The yield of alpha-fluoro methyl isobutyrate is 80%.
[embodiment 20]: 1-adamantanol
Except using 1-adamantanol (10 mmole), react according to the method identical with embodiment 16 as the matrix.The yield that obtains as the 1-fluoroadamantane of product is 96%.
[comparative example 6]: 1-adamantanol
Except using the device identical with comparative example 4, use 1-adamantanol (10 mmole) is as beyond the matrix, reacts according to the method identical with comparative example 4.After reacting 5 hours while stirring under 20 ℃, be 68% as the yield of the 1-fluoroadamantane alcohol of product.
Fluoridizing of＜epoxy compounds 〉
[embodiment 21]: 2-(positive decyl)-oxyethane
Except using 2-(positive decyl)-oxyethane (10 mmole) as matrix, use the dodecane hydrocarbon as solvent, microwave irradiating time is beyond 30 minutes, reacts according to the method identical with embodiment 16.Obtain as 1 of introducing 2 atomic fluorine of product, the yield of 2-two fluoro dodecane hydrocarbon is 65%.
Fluoridizing of＜carbonyl compound 〉
[embodiment 22]: phenyl aldehyde
Except using phenyl aldehyde (10 mmole), react according to the method identical with embodiment 16 as the matrix.The yield that obtains as two fluoro methylbenzene of product is 86%.
[embodiment 23]: pimelinketone
Except using pimelinketone (10 mmole), react according to the method identical with embodiment 16 as the matrix.Obtain two fluoro hexanaphthenes (yield 32%%) and fluoro tetrahydrobenzene (yield 58%) as product.
[embodiment 24]: phenylformic acid
Except using phenylformic acid (10 mmole), react according to the method identical with embodiment 16 as the matrix.The yield that obtains as the benzoyl fluoride of product is 99%.
[comparative example 7]: pimelinketone
Except using pimelinketone (10 mmole) as matrix, use 10 mmoles 1,3-dimethyl-2,2-two fluoro tetrahydroglyoxalines (DFI, Mitsui Chemicals) be as fluorizating agent, similarly to Example 16 irradiating microwaves.But, because reaction has danger out of control at once, so stopped reaction.Do not obtain target product fully.
C. the complex compound that is formed by HF and alkali is as the situation of fluorizating agent
[embodiment 25]
Can be continuously in the microwave oven of uniform irradiation (wide, degree of depth 55cm, height 70cm, power 1KW, frequency 2.46GHz) by conical distributor, the reactor that the fluoro-resin that has reflux exchanger (PFA) of 5ml is made is set, carry out fluoridation.
(1 mmole, 0.1g) and as the triethylamine-3HF of fluorizating agent (0.6 mmole 0.1g), did not stir, with microwave irradiation 2 minutes as the cyclohexene oxide of matrix in adding.After microwave irradiation finished, cool to room temperature added 15ml water in reaction solution, use 15ml extracted with diethyl ether 3 times.Extraction liquid neutralizes with sodium bicarbonate aqueous solution, adds an amount of Anhydrous potassium carbonate drying.After the removal of solvent under reduced pressure, with column chromatography (Hexane: Et
2O=1: 1) refining.The yield that obtains as anti--2-fluoro hexalin (trans-2-Fluorocyclohexanol) of product is 71% (purity is more than 98%).
[comparative example 8]
Except irradiating microwaves not, down beyond the reaction 4 hours, carry out similarly to Example 25 115 ℃ of temperature of reaction.Yield as anti--2-fluoro hexalin (trans-2-Fluorocyclohexanol) of product is 61%.
[embodiment 26]
Except using device similarly to Example 25, add oxidation ring dodecylene (1 mole: 0.17g, ratios of the isomers=31: 69) and Et
3N-3HF (0.6 mole 0.1g), beyond the microwave irradiation 10 minutes, is carried out similarly to Example 25.The yield that obtains as the 2-fluoro cyclododecanols (2-Fluorocyclododecanol) of product is 76%.
[comparative example 9]
Except irradiating microwaves not, beyond carrying out under 155 ℃ of temperature of reaction, 4 hours the condition, carry out similarly to Example 26.The yield that obtains as the 2-fluoro cyclododecanols (2-Fluorocyclododecanol) of product is 54%.
[embodiment 27]
Except using device similarly to Example 25, add oxidation cyclooctene (1 mole) and Et
3Beyond the N-3HF (1 mole), microwave irradiation 10 minutes, carry out similarly to Example 25.(anti--2-Fluorocyclohexanol) yield is 68% to obtain anti--2-fluoro hexalin as product.
[comparative example 10]
Except irradiating microwaves not, beyond carrying out under 155 ℃ of temperature of reaction, 4 hours the condition, carry out similarly to Example 27.The yield that obtains as anti--2-fluoro ring octanol (trans-2-Fluorocyclooctanol) of product is 54%.
[embodiment 28]
Except adding cyclo-dodecyl-1,4,8-triolefin list oxide compound (1 mole) and Et
3N-3HF (1 mole) is as matrix, beyond the microwave irradiation 2 minutes, carries out similarly to Example 25.Obtain the 2-fluoro cyclo-dodecyl-6 as product, (2-Fluorocyclododecane-6, yield 10-diene-1-ol) are 78% to 10-diene-1-alcohol.
[comparative example 11]
Except irradiating microwaves not, beyond carrying out under 155 ℃ of temperature of reaction, 4 hours the condition, carry out similarly to Example 28.Obtain the 2-fluoro cyclo-dodecyl-6 as product, (2-Fluorocyclododecane-6, yield 10-diene-1-ol) are 51% to 10-diene-1-alcohol.
[embodiment 29-36 and comparative example 12-19]
In device similarly to Example 25, matrix and fluorizating agent that use table 1 is put down in writing carry out the fluoridation (embodiment) under the microwave irradiation and the comparative example of thermal response.The result is as shown in table 1.
[embodiment 37]
Except in embodiment 25, use the reaction vessel of the PFA manufacturing of 10ml, add 3-phenyl propyl methanesulfonate ester (1 mmole) and Et
3N-3HF (1.2 mmole) shines beyond 2 minutes microwaves, carries out similarly to Example 25.The yield that obtains the 1-fluoro-3-phenyl-propane (1-Fluoro-3-phenirupropane) as product is 80%.
[embodiment 20]
In embodiment 37, in acetonitrile solvent (1ml), make 3-phenyl propyl methanesulfonate ester (1 mmole) and Et
3N-3HF (10 mmole) reacted 100 hours down at 80 ℃, the yield of research product.The yield of 1-fluoro-3-phenyl-propane (1-Fluoro-3-phenirupropane) is as follows respectively.
The yield 20% of yield after 10 hours after 12% 20 hours
The yield 74% of yield after 38 hours after 44% 54 hours
The yield 80% of yield after 79 hours after 80% 100 hours
Table 1
According to the present invention, as medical material, the carbohydrate that the performance chemicals of makeup and heath food etc. is useful, has position by α, the compound of the substituting group labilized hydrogen atom of β position or γ position, silyl ether compound or have unsaturated group, hydroxyl, halogen radical, amino, diazo, triazenyl or isocyano-are as the compound of functional group, the above various matrix such as ring compound of 3 yuan of rings with heteroatomic situation are perhaps arranged, can highly selective, effectively and safely the specific position as the difficult point of prior art is fluoridized in short period of time.
Claims (3)
1. fluorination process is characterized in that: use the fluorizating agent shown in the general formula (I) to fluoridize to monose or with the monose of nucleic acid base bonding,
In the formula, Y represents nitrogen-atoms, R
0Expression tolyl or p-methoxy-phenyl, R
1And R
2The expression ethyl.
2. the fluorination process of putting down in writing according to claim 1, wherein R
0Be 3-aminomethyl phenyl or 2-p-methoxy-phenyl.
3. according to claim 1 or 2 fluorination process of being put down in writing, wherein be carbohydrate to be fluoridized by thermal response.
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| JP352968/2002 | 2002-12-04 | ||
| JP2002352968A JP4577478B2 (en) | 2002-12-04 | 2002-12-04 | Carbohydrate fluorination method |
| JP358249/2002 | 2002-12-10 |
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| CN100432086C true CN100432086C (en) | 2008-11-12 |
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| CNA2006101640227A Pending CN1974588A (en) | 2002-12-04 | 2003-12-01 | Method of fluorination |
| CNB2003801046799A Expired - Fee Related CN100432086C (en) | 2002-12-04 | 2003-12-01 | Method of fluorination |
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| KR20120046718A (en) * | 2009-06-19 | 2012-05-10 | 오메가켐 아인엔씨. | Disubstituted-aminodifluorosulfinium salts, process for preparing same and method of use as deoxofluorination reagents |
| EP2812311B1 (en) * | 2012-02-09 | 2016-04-20 | UBE Industries, Ltd. | Processes for isolating fluorinated products |
| ES2818736T3 (en) * | 2016-05-02 | 2021-04-13 | Dow Global Technologies Llc | Aromatic fluorination method |
Citations (5)
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|---|---|---|---|---|
| US3101357A (en) * | 1962-03-09 | 1963-08-20 | Syntex Corp | 19-halo androstenes |
| WO1997041083A1 (en) * | 1996-05-01 | 1997-11-06 | Rhodia Limited | Process for the preparation of fluoro compounds from the corresponding amines |
| WO2000058240A1 (en) * | 1999-03-31 | 2000-10-05 | Rhodia Chimie | Method for activating aromatic substrates by microwaves |
| WO2001002320A1 (en) * | 1999-07-02 | 2001-01-11 | Rhodia Chimie | Use of nitriles as polar aprotic solvents |
| EP1172369A1 (en) * | 2000-07-13 | 2002-01-16 | Air Products And Chemicals, Inc. | Synthesis of 2-deoxy-2-fluoro-arabinose derivates |
-
2002
- 2002-12-04 JP JP2002352968A patent/JP4577478B2/en not_active Expired - Fee Related
-
2003
- 2003-12-01 CN CNA2006101640227A patent/CN1974588A/en active Pending
- 2003-12-01 CN CNB2003801046799A patent/CN100432086C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3101357A (en) * | 1962-03-09 | 1963-08-20 | Syntex Corp | 19-halo androstenes |
| WO1997041083A1 (en) * | 1996-05-01 | 1997-11-06 | Rhodia Limited | Process for the preparation of fluoro compounds from the corresponding amines |
| WO2000058240A1 (en) * | 1999-03-31 | 2000-10-05 | Rhodia Chimie | Method for activating aromatic substrates by microwaves |
| WO2001002320A1 (en) * | 1999-07-02 | 2001-01-11 | Rhodia Chimie | Use of nitriles as polar aprotic solvents |
| EP1172369A1 (en) * | 2000-07-13 | 2002-01-16 | Air Products And Chemicals, Inc. | Synthesis of 2-deoxy-2-fluoro-arabinose derivates |
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| Title |
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| Dialkyl-α,α-DifluorobenzylaminesandDialkyl(Trifluoromethyl)Amines-Novel FluorinatingReagents. Dmowski,W.et al.Journal of Fluorine Chemistry,Vol.23 No.3. 1983 |
| Dialkyl-α,α-DifluorobenzylaminesandDialkyl(Trifluoromethyl)Amines-Novel FluorinatingReagents. Dmowski,W.et al.Journal of Fluorine Chemistry,Vol.23 No.3. 1983 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1720256A (en) | 2006-01-11 |
| JP4577478B2 (en) | 2010-11-10 |
| CN1974588A (en) | 2007-06-06 |
| JP2004182664A (en) | 2004-07-02 |
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