Title of Invention	PROCESS FOR PRODUCTION OF HALOGENATED α-FLUOROETHERS
Abstract	Halogenated α-fluoroethers (or bis-derivatives thereof) can be produced by reacting a halogenated hemiacetal (or bis-derivative thereof) with sulfuryl fluoride (SO2F2) in the presence of an organic base. The reaction is conducted preferably in the presence of "a salt or complex of an organic base with hydrogen fluoride", whereby the objective dehydroxyfluorination can proceed extremely favorably. It is still preferable to use as the starting substrate a halogenated hemiacetal prepared from fluoral or 3,3,3-trifluoropyruvic acid ester. Thus, industrially important halogenated α-fluoroethers can be industrially produced with high selectivity and in high yield.

Title of Invention

PROCESS FOR PRODUCTION OF HALOGENATED α-FLUOROETHERS

Abstract

Halogenated α-fluoroethers (or bis-derivatives thereof) can be produced by reacting a halogenated hemiacetal (or bis-derivative thereof) with sulfuryl fluoride (SO2F2) in the presence of an organic base. The reaction is conducted preferably in the presence of "a salt or complex of an organic base with hydrogen fluoride", whereby the objective dehydroxyfluorination can proceed extremely favorably. It is still preferable to use as the starting substrate a halogenated hemiacetal prepared from fluoral or 3,3,3-trifluoropyruvic acid ester. Thus, industrially important halogenated α-fluoroethers can be industrially produced with high selectivity and in high yield.

Full Text	TECHNICAL FIELD [0001] The present invention relates to a process for industrially producing halogenated a-fluoroethers which are important as an intermediate of medicines or agrichemicals or as a flon alternative compound. BACKGROUND OF THE INVENTION [0002] Halogenated a-fluoroethers, the object of the present invention, serve as an important intermediate of medicines or agrichemicals or as an important flon alternative compound. Particularly, a,ß,ß,ß-tetrafluoroethers are utilized as a useful intermediate for a volatile anaesthetic "desflurane". As conventional techniques for such a-fluoroethers, relating to the present invention, the following two techniques are exemplified. [0003] There have been disclosed: a process for reacting fluoral hemiacetals with the Yarovenko's reagent (Patent Publication 1); and a process consisting of two process steps in which fluoral hemiacetals are converted into corresponding /rtoluenesulfonic acid esters and then these are reacted with Fluoride anion (F) (Patent Publication 2). REFERENCES ABOUT PRIOR ART Patent Publication [0004] Patent Publication 1: Japanese Patent Application Publication No. 50-76007 Patent Publication 2- Japanese Patent Application Publication No. 2-104545. SUMMARY OF THE INVENTION [0005] An object of the present invention is to provide a process for industrial production of halogenated a-fluoroethers. [0006] Patent Publication 1 in which the Yarovenko's reagent is used as a dehydroxyfluorination agent requires previously preparing the reagent from chlorotrifluoroethylene and diethylamine. Furthermore, a fluorine-containing organic waste is stoichiometrically formed as a by-product, so that an industrial execution thereof had been difficult. [0007] In Patent Publication 2 where the reaction is achieved with two process steps, the operations including a post-treatment are so complicated that a high productivity cannot be expected. Additionally, the total yield is also not satisfying. [0008] Thus, there has been intensely desired a production process which can be readily and industrially accomplished and provide halogenated a-fluoroethers with high productivity and yield. [0009] As a result of eager studies the present inventors have made in view of the above, they have newly found it possible to produce halogenated a-fluoroethers represented by the general formula [2] by reacting halogenated hemiacetals represented by the general formula [1] with sulfuryl fluoride in the presence of an organic base. Furthermore, there has been also newly found that the present reaction can be applied to bis-derivatives formed through alkylene group (, in which halogenated a-fluoroether bis-derivatives represented by the general formula [2a] are obtained as the objective by using halogenated hemiacetal bis-derivatives represented by the general formula [1a] as the starting substrate). [0010] Incidentally, the present applicant has found a dehydroxyfluorination reaction of alcohols by combination of sulfuryl fluoride (SO2F2) and the organic base and has already filed an application therefor [International Publication 2006/098444 Pamphlet (Japanese Patent Application Publication No. 2006-290870)]. On the other hand, the raw materials of the present invention are relatively unstable "halogenated hemiacetals" or bis-derivatives thereof. These can be said to be "an equivalent of a compound having a carbon with which two hydroxyl groups are concurrently bonded". The present inventors have made it clear: that these raw material compounds are reacted with sulfuryl fluoride (SO2F2) in the presence of the organic base thereby selectively subjecting "free hydroxyl group" alone to fluorine substitution; and that, as opposed to this, -OR2 group, group and haloalkyl group are inducted into the halogenated a-fluoroelhcrs represented by the general formula [2] or the halogenated a-fluoroether bis-derivatives represented by the general formula [2a] with high yield without being subjected to any change. [0011] Moreover, the present invention allows the reaction to be conducted with one process step as a one-pot reaction, in which fluorosulfuric acid-esterification of the starting substrate halogenated hemiacetals (or the bis-derivatives thereof) and a succeeding fluorine substitution proceed continuously. In fluorine substitution, "a salt or complex of an organic base with hydrogen fluoride" formed as a by-product in the reaction system by the fluorosulfuric acid-esterification is usefully utilized as a Fluoride anion source, (see Scheme 1 showing an example where the halogenated hemiacetals represented by the general formula [1] are used as the starting substrate.) [0012] [Chemical Formula 1] [0013] In the present invention, it has also been made clear that the succeeding fluorine substitution enormously excellently proceeds by conducting the reaction in the additional presence of "a salt or complex of an organic base with hydrogen fluoride" in the system (see Scheme 2 showing an example where the halogenated hemiacetals represented by the general formula [1] are used as the starting substrate.) The fluorosulfuric acid-esterification of the relatively unstable halogenated hemiacetals proceeds excellently even in the presence of "a salt or complex of an organic base with hydrogen fluoride", which is a new finding. [0014] [Chemical Formula 2] [0015] Furthermore, the present invention have newly made it clear that hemiacetals of fluoral (corresponding to halogenated hemiacetals represented by the general formula [3]) or hemiacetals of 3,3.3-trifluoropyruvic acid esters (corresponding to halogenated hemiacetals represented by the general formula [o\|) are extremely preferable starting substrates. When using such starting substrates, the desired reaction can excellently proceed under mild conditions and the objective halogenated crfluoroethers are obtained with high selectivity and yield. These starting substrates can be readily prepared from fluoral or 3,3.3-trifluoropyruvic acid esters (either of which is readily available in large-scale) so as to be suilable also from the viewpoint of a starting substrate for an industrial production process. Particularly, a,ß,ß,ß-tetrafluoroethylmetnylethcr obtained from fluoral methyl hemiacetal arc useful as an intermediate for a volatile anaesthetic "desflurane", so as to bo particularly preferable. [0016] Thus, an extremely useful process has been found as a process for industrially producing the halogenated afluoroethers. thereby achieving the present invention. [0017] More specifically, the present invention includes the following 1st process to 7th process and provides an industrial production process of the halogcnated a-fluoroethers. [0018] According to the present invention, there is provided a process for producing halogcnated a-fluoroethers represented by the general formula [2] [Chemical Formula 4] by reacting halogenated hemiacetals represented by the general formula [1] [Chemical Formula 3] with sulfuryl fluoride (SO2F2) in the presence of an organic base (a 1st process). [In the formulas: haloR represents haloalkyl group; R1 represents hydrogen atom, alkyl group, substituted alkyl group, alkoxycarbonyl group or substituted alkoxycarbonyl group; and R2 represents alkyl group or substituted alkyl group.] [0019] According to the present invention, there is further provided a process for producing halogenated a-fluoroether bis-derivatives represented by the general formula [2a] [Chemical Formula 6] by reacting halogenated hemiacetal bis-derivatives represented by the general formula [1a] [Chemical Formula 5] with sulfuryl fluoride (SO2F2) in the presence of an organic base (a 2nd process). [In the formulas: haloR mutually independently represents a haloalkyl group; R1 mutually independently represents a hydrogen atom, an alkyl group, a substituted alky] group, an alkoxycarbonyl group or a substituted alkoxycarbonyl group; and n represents an integer of from 2 to 18.] [0020] The 1st or 2nd process may be a process for producing halogenated a-fluoroethers or halogenated a-fluoroether bis-derivatives, the process being characterized in that the reaction is conducted in the additional presence of "a sail or complex of an organic base with hydrogen fluoride" in a system (a 3rd process). [0021] According to the present invention, there is further provided a process for producing halogenated a-fluoroethers represented by the general formula [4] [Chemical Formula 8] by reacting halogenated hemiacetals represented by the general formula [3] [Chemical Formula 7] with sulfuryl fluoride (SO2F2) in the presence of an organic base (a 4th process). [In the formulas. R2 represents an alkyl group or a substituted alkyl group.] [0022] The 4th process may be a process for producing halogenated a-fluoroethers. the process being characterized in that the reaction is conducted in the additional presence of "a salt or complex of an organic base with hydrogen fluoride" in a system (a 5th process). [0023] According to the present invention, there is further provided a process for producing halogenated a-fluoroethers represented by the general formula L6] [Chemical Formula 10] by reacting halogenated hemiacetals represented by the general formula [5] [Chemical Formula 9] with sulfuryl fluoride (SO2F2) in the presence of an organic base (a 6th process). [In the formulas, R2 and R3 mutually independently represent an alkyl group or a substituted alkyl group.] [0024] The 6th process may be a process for producing halogenated Q'fluoroethers, the process being characterized in that the reaction is conducted in the additional presence of "a salt or complex of an organic base with hydrogen fluoride" in a system (a 7th process). DETAILED DESCRIPTION [0025] Advantageous points of the present invention over conventional techniques will be discussed below. [0026] As compared to Patent Publication 1, a dehydroxyfluorination agent used in the present invention is suitable for large-scale production. Sulfuryl fluoride is widely utilized as a fumigant and industrially available at low cost. Additionally, wastes made in the use of sulfuryl fluoride can be conveniently treated into inorganic salts such as fluorite (CaF2), calcium sulfate, etc., which reduce the load to the environment. [0027] As compared to Patent Publication 2, the reaction can be conducted with one process step (in which fluorosulfuric acid-esterification and a succeeding fluorine substitution proceed continuously as a one-pot reaction) with extremely high productivity and in high yield. [0028] Furthermore, impurities serving as by-products difficult to be separated off are hardly provided in the present invention, so that the objective product can be obtained at a high chemical purity. [0029] Thus, the present invention is a production process which can solve all problems the conventional techniques had carried and can be industrially readily conducted. [0030] A process for producing halogenated a-fluoroethers of the present invention will be discussed in detail. [0031] In the present invention, it is possible to produce halogenated a-fluoroethers represented by the general formula [2] (or halogenated a-fluoroether bis-derivatives represented by the general formula [2a]) by reacting halogenated hemiacetals represented by the general formula [1] (or halogenated hemiacetal bis-derivatives represented by the general formula [1a]) with sulfuryl fluoride (SO2F2) in the presence of an organic base. [0032] HaloR as shown in the general formula [1] denotes haloalkyl group. Examples of the haloalkyl group are those obtained by substitution caused on any carbon atom in a linear, branched or cyclic (with a carbon number of not smaller than 3) alkyl group having a carbon number of from 1 to 18 with any number of and any combination of halogen atoms including fluorine, chlorine, bromine and iodine (where the alkyl group causes substitution with at least one halogen atom). Among these, the preferable is fluoroalkyl group and chloroalkyl group, and the more particularly preferable is trifluoromethyl group. [0033] R1 of the halogenated hemiacetals represented by the general formula [1] denotes hydrogen atom, alkyl group, substituted alkyl group, alkoxycarbonyl group or substituted alkoxycarbonyl group. Examples of alkyl moieties of the alkyl group and of the alkoxycarbonyl group (the moieties corresponding to, for example. R3 of the halogenated hemiacetals represented by the general formula [5]) include a linear, branched or cyclic (with a carbon number of not smaller than 3) alkyl group having a carbon number of from 1 to 18. [0034] The alkyl group and the alkoxycarbonyl group may have, on any carbon atom in the alkyl moiety, any number of and any combination of substituents (and correspond to substituted alkyl group and substituted alkoxycarbonyl group, respectively). Examples of the substituents are: halogen atom such as fluorine, chlorine, bromine, iodine, etc.; azide group; nitro group; lower alkyl group such as methyl group, ethyl group, propyl group, etc.; lower haloalkyl group such as fluoromethyl group, chloromethyl group, bromomethyl group, etc.; lower alkoxy group such as methoxy group, ethoxy group, propoxy group, etc.; lower haloalkoxy group such as fluoromethoxy group, chloromethoxy group, bromomethoxy group, etc.; lower alkyl amino group such as dimothylamino group, diethylamino group, dipropylamino group, etc.; lower alkylthio group such as mcthylthio group, ethylthio group, propylthio group, etc.; cyano group; lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, etc.; aminocarbonyl group (CONH2); lower alkylaminocarbonyl group such as dimethylaminocarbonyl group, diethylaminocarbonyl group, dipvopylaminocarbonyl group, etc.; unsaturated group such as alkenyl group, alkynyl group, etc.; aromatic cyclic gi'oup such as phenyl group, naphthyl group, pyrrolyl group, furyl group, thienyl group, etc.; aromatic cyclic oxy group such as phenoxy group, naphthoxy group, pyrrolyloxy group, furyloxy group, thienyloxy group, etc.; aliphatic heterocyclic group such as piperidyl group, piperidino group, morpholinyl group, etc.; protected hydroxyl group; protected amino group (including amino acid and peptide residue); protected thiol group; protected aldehyde group; protected carboxyl group; etc. [0035] Incidentally, in the present specification, each of the following terms is used as having the following meaning. "Lower" means a linear, branched or cyclic (with a carbon number of not smaller than 3) chain having a carbon number of from 1 to 6. In the case that "unsaturated group" is the double bond (alkenyl group), it may be in the form of E configuration, Z configuration or a mixture of these. As "protecting groups of hydroxyl group, amino group (including amino acid and peptide residue), thiol group, aldehyde group and carboxyl group", it is possible to use protecting groups and the like described in Protective Groups in Organic Synthesis, Third Edition. 1999, John Wiley & Sons, Inc.(, in which not less than two functional groups may be protected with one protecting group). Moreover, "unsaturated group", "aromatic cyclic group", "aromatic cyclic oxy group" and "aliphatic heterocyclic group" may be subjected to substitution with halogen atom, azide group, nitro group, lower alkyl group, lower haloalkyl group, lower alkoxy group, lower haloalkoxy group, lower alkyl amino group, lower alkylthio group, cyano group, lower alkoxycarbonyl group, aminocarbonyl group, lower alkylaminocarbonyl group, protected hydroxyl group, protected amino group (including amino acid and peptide residue), protected thiol group, protected aldehyde group, protected carboxyl group or the like. [0036] Among these, hydrogen atom, alkoxycarbonyl group and substituted alkoxycarbonyl group are preferable. Particularly, hydrogen atom and alkoxycarbonyl group are more preferable. [0037] R2 of the halogenated hemiacetals represented by the general formula [1] denotes alkyl group or substituted alkyl group. [0038] The alkyl group and the substituted alkyl group are the same as the alkyl group and the substituted alkyl group as had been discussed as R1 of the halogenated hemiacetals represented by the general formula L1], and can be selected independently of R1. [0039] HaloR and R1 of the halogenated hemiacetal bis-derivatives represented by the general formula [1a] are the same as haloR and R1 as had been discussed on the halogcnatcd hemiacetals represented by the general formula [1]. n represents an integer of from 2 to 18. Among these, with regard to n, an integer of from 2 to 12 is preferable and that of from 2 to 6 in particular is more preferable. Two haloR included in the halogenated hemiacetal bis-derivatives represented by the general formula [1a] are mutually independently selected from the above substituents. However, it is preferable to select the same substituent for the two haloR if taking the preparation of the starting substrate into account. Additionally, the same thing can be said for two R1 of the halogcnatcd hemiacetal bis-derivatives represented by the general formula [1a]. [0040] Stereochemistry of the halogenated hemiacetals represented by the general formula [1] will be discussed. In the halogenated hemiacetals, a carbon atom with which hydroxyl group forms a covalent bond is an asymmetric carbon atom with the exception of the case where haloR and R1 adopt the same substituent. In the case where the starting substrate has the asymmetric carbon atom, it is not only allowed to use a racemic form (it will be understood that the racemic form can be used) but also allowed to use an optically active form (R configuration or S configuration), and its optical purity is not limited. A dehydroxyfluorination reaction of the present invention proceeds together with stereochemical reversal, stereochemical maintenance or racemization. This stereoselectivity differs according to the combination of the starting substrate and the organic base and to the adopted reaction conditions, so that the starting substrate, the organic base and the reaction conditions may be suitably selected according to the desired stereochemistry (R configuration, S configuration or racemic form) of the objective halogenated a-fluoroethers represented by the general formula [2], The same as the stereochemistry of the halogenated hemiacetals represented by the general formula [1] goes for that of corresponding two carbon atoms of the halogenated hemiacetal bis-derivatives represented by the general formula [1a], mutually independently. [0041] The halogenated hemiacetals represented by the general formula [1] (or the halogenated hemiacetal bis-derivatives represented by the general formula [1a]) can be prepared by the conventionally known method. Halogenated hemiacetals represented either by the general formula [3] or by the general formula [5], the particularly preferable starting substrate for the present invention, can be readily prepared from fluoral [CF3CHO (or an equivalent thereof)] and 3,3,3-trifluoropyruvic acid esters [CF3COCO2R (R denotes alkyl group or substituted alkyl group)], respectively. Furthermore, ethylhomiacetal or hydrate of fluoral, and ethyl 3,3,3-trifluoropyruvate are commercially available. [0042] The amount of the used sulfuryl fluoride (SO2F2) is required only to be not lower than 0.7 mole, preferably from 0.8 to 10 moles in general, more preferably from 0.9 to 5 moles in particular, relative to 1 mole of the halogenated homiacotals represented by the general formula [1]. In the case of using the halogenated hemiacetal bis-derivatives represented by the general formula [1a] as the starting substrate, it is required only to use it in the same manner in an amount two times that of the halogenated hemiacetals represented by the general formula [1]. [0043] As a dehydroxyfluorination agent for the present invention, trifluoromethanesulfonyl fluoride (CF3SO2F) or perfluorobutanesulfonyl fluoride (C4F9SO2F) may be used. However, a conscious employment of these reactants is not so advantageous in view of their availability in large scale; their fluorine atom economy; waste treatment (by which a fluorine-containing organic waste is stoichiometrically formed as a by product): etc. [0044] Examples of the organic base for the present invention are trimethylamine, dimethylethylamine. diethylmethylamine, triethylamine, di-n-propylmcthylamine, dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylaminc, diisopropylisobutylamine, dimethyl-n-nonylamine, tri-n-butylamine, di-n-hexylmethylamine, dimethyl-n-dodecylamine, tri-n-pentylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), dimethylaminopyridine (DMAP), l,5diazabicyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2.4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine, etc. [0045] Among these, the preferable are triethylamine, dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4.6-collidine and 3,5.6-collidine. The more preferable are triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,4-lutidine, 2,6-lutidine, 3,5-lutidine and 2,4,6-collidine, in particular. These organic bases may be used singly or in combination. Additionally, an organic base having a carbon number of not less than 8 is high in fat-solubility so as to be readily recovered at a post-treatment using water, thereby being reused without being lowered in reactivity. Accordingly, such an organic base is suitable for an industrial production process. In the present specification, "carbon number" means the total number of carbon atoms contained in an organic base. [0046] The amount of the used organic base is required only to be not lower than 0.7 mole, preferably from 0.8 to 15 moles in general, more preferably from 0.9 to 10 moles in particular, relative to 1 mole of the halogenated hemiacetals represented by the general formula [1]. In the case of using the halogenated hemiacetal bis-dcrivatives represented by the general formula [1a] as the starting substrate, it is required only to use it in the same manner in an amount two times that of the halogenated hemiacetals represented by the genera] formula [1]. [0047] Then, "a salt or complex of an organic base with hydrogen fluoride" to be used in the 3rd process, the 5th process and the 7th process will be discussed in detail. [0048] Examples of the organic base of "a salt or complex of an organic base with hydrogen fluoride" include trimethylamine, dimethylethylamine, diethylmethylamine, triethylamine, di-n-propylmethylamine, dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine, diisopropylisobutylamine, dimethyl-n-nonylamine, tri-n-butylamine, di-n-hexylmethylamine. dimethyl-n-dodccylamino, tri-irpentylamine, 1.4-diazabicyclo[2.2.2]octane (DABCO), dimethylaminopyridine (DMAP), 1 ,5-diazabicyclo[4.3.0]non-o-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine. 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine, etc.. [0049] Among these, the preferable are triethylamine, dimethylcyclohexylamine. diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3.5-lutidine, 2,4,6-collidine and 3,5,6-collidine. The more preferable are triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,4-lutidine, 2,6-lutidine, 3,5-lutidine and 2,4,6-collidine in particular. [0050] The mole ratio of the organic base of "a salt or complex of an organic base with hydrogen fluoride" to hydrogen fluoride is within a range of from 100:1 to 1:100, preferably within a range of from 50:1 to 1:50 in general, and more preferably within a range of from 25:1 to 1:25 in particular. Furthermore, it is convenient to use "a complex comprising 1 mole of triethylamine and 3 moles of hydrogen fluoride" and "a complex comprising up to 30% (up to 10 mol%) of pyridine and up to 70% (up to 90 mol%) of hydrogen fluoride", both of which are placed on sale from Aldrich (Aldrich, 2007-2008 Comprehensive Catalogue). [0051] The amount of "a salt or complex of an organic base with hydrogen fluoride" to be used is required only to be not less than 0.3 mole as Fluoride anion (F-), preferably within a range of from 0.5 to 50 moles in general and more preferably within a range of from 0.7 to 25 moles in particular, relative to 1 mole of the halogenated hemiacetals represented by the general formula [1]. When using the halogenated hemiacetal bis-derivatives represented by the general formula [1a] as the starting substrate, it is required only to use it in the same manner in an amount two times that of the halogenated hemiacetals represented by the general formula [1]. [0052] Examples of a reaction solvent are: aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane, etc.; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, mesitylene. etc; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc; ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tertrbutyl methyl ether, etc; esters such as ethyl acetate, n-butyl acetate, etc; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2imidazolidinone, etc; nitriles such as acetonitrile, propionitrile, etc; and dimcthylsulfoxide, etc. [0053] Among these, the preferable are n-hexane, n-heptane, toluene, xylene, mesitylene, methylene chloride, tetrahydrofuran, diisopropyl ether, tert-butyl metlryl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile and dimethylsulfoxide. Particularly, the more preferable are toluene, xylene, methylene chloride, tetrahydrofuran, diisopropyl ether, ethyl acetate, N,N-dimethylformamide and acetonitrile. It is possible to use these reaction solvents singly or in combination. Furthermore, the present invention may be performed without the solvent. [0054] In the case of using the reaction solvent, the amount thereof is required only to be not less than 0.1 L (liter), preferably within a range of from 0.2 to 10 L in general, and more preferably within a range of from 0.3 to 5 L in particular, relative to 1 mole of the halogenated hemiacetals represented by the general formula [1] (or the halogenated hemiacetal bis-derivatives represented by the general formula [1a]). [0055] The temperature condition is required only to be conducted within a range of from 100 to +100 °C, preferably within a range of from 60 to +60 °C in general, more preferably within a range of from -50 to +50 °C in particular. In the case of conducting the reaction under a temperature condition of not lower than the boiling point of sulfuryl fluoride (-49.7 °C), it is possible to use a pressure-proof reaction vessel. [0056] The pressure condition is required only to be conducted within a range of from atmospheric pressure to 2 MPa, preferably within a range of from atmospheric pressure to 1.5 MPa in general, more preferably within a range of from atmospheric pressure to 1 MPa in particular. Therefore, it is preferable to conduct the reaction in the use of a pressure-proof reaction vessel made of a material such as stainless steel (SUS) or glass (glass lining). Furthermore, for infusion of sulfuryl fluoride in large-scale, the effective is a process for causing a negative pressure in a pressure-proof reaction vessel first of all, and then introducing gaseous or liquid sulfuryl fluoride into therein while recovering the pressure under a reduced pressure. [0057] The reaction time is within 72 hours; however, it differs according to the combination of the starting substrate and the organic base and to the adopted reaction conditions. It is therefore preferable to determine a temporal point at which the starting substrate is generally completely consumed as the endpoint of the reaction, upon tracking the progress of the reaction by an analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance (NMR), etc. The objective halogenated a-fluoroethers represented by the general formula [2] (or the halogenated a-fluoroether bis-derivatives represented by the general formula [2a]) can be obtained by conducting an usual operation on a reaction-terminated liquid as a post-treatment. The objective product can be purified at a high chemical purity by activated carbon treatment, distillation, rccrystallization. column chromatography or the like as necessary. [0058] Such an operation as to directly distill the reaction-terminated liquid is particularly effective. By conducting such a post-treatment (defluorination, fractional distillation or the like, as necessary), it becomes possible to obtain a product of quality sufficient either for an intermediate of medicines or agrichemicals or for a flon alternative compound. [0059] In the present invention, the halogenated hemiacetals represented by the general formula [1] (or the halogenated hemiacetal bis-derivatives represented by the general formula [1a]) are reacted with sulfuryl fluoride in the presence of the organic base, thereby producing the halogenated a fluoroethers represented by the general formula [2] (or the halogenated crfluoroether bis-derivatives represented by the general formula [2a]). [0060] It is preferable to conduct the reaction in the presence of "a salt or complex of an organic base with hydrogen fluoride", by which the objective dehydroxyfluorination reaction can proceed extremely favorably. [0061] It is more preferable to use. as the starting substrate, halogenated hemiacetals represented by the general formula [3] or the general formula [5] and able to be prepared from fluoral or 3,3,3-trifluoropyruvic acid esters. With this, the industrially important halogenated a-fluoroethers can be industrially produced with high yield and selectivity. [0062] [Examples] Embodiments of the present invention are specifically explained by examples. The present invention is, however, not limited to these examples. Incidentally, omission marks discussed in the examples are as follows. Et; Ethyl group Me: Methyl group [0063] [Example 1] A pressure-proof reaction vessel made of stainless steel (SUS) was charged with 500 mg (3.47 mmol, 1.00 eq) of halogenated hemiacetals represented by the following formula [Chemical Formula 11] 3.5 mL of acetonitrile, 1.756 mg (17.35 mmol, 5.00 eq) of triethylamine and 839 mg (5.20 mmol, 1.50 eq) of triethylamine tris(hydrogen fluoride) complex, followed by immersing it in a coolant bath of -78 °C. Then, 708 mg (6.94 mmol, 2.00 eq) of sulfuryl fluoride (SO2F2) was blown thereinto by using a bomb, followed by stirring at room temperature throughout the night. The reaction-terminated liquid was confirmed by 1H-NMR and 19F NMR to have a conversion rate and a selectivity of 100 % and not less than 70 %, respectively. By directly distilling the reaction-terminated liquid (at normal pressure), halogenated a-fluoroethers represented by the following formula [Chemical Formula 12] can be obtained as a mixture of triethylamine and acetonitrile. The yield was confirmed by the conversion rate and the selectivity of the reaction-terminated liquid to be not less than 70 %. A molecular weight of 147 (M+1) was observed by GC-MS (CI method). 1H-NMR and 19F-NMR will be discussed below. [0064] 1H-NMR [Standard substance; (CH3)4Si, Deuteration solvent; CDCl8]; d ppm/1.34 (t, 7.0Hz, 3H), 3.86 (m. 1H), 4.03 (m, 1H), 5.41 (dq, 61.9Hz, 3.0Hz, 1H). 19F-NMR [Standard substance; C6-F6, Deuteration solvent; CDCl3]; d ppm/19.60 (dq, 61.9Hz, 6.4Hz, 1F), 78.03 (dd, 6.4Hz, 3.0Hz, 3F). [0065] [Example 2] In conformity with YUKIGOSEIKYOKAISHI (Japan), 1999, Vol. 57, No. 10, p. 102-103, fluoral (gas) was generated from an excessive amount of fluoral monohydrate, followed by blowing it into allyl alcohol. Stirring was conducted for 2 hours at room temperature, thereby obtaining halogenated hemiacetals represented by the following formula [Chemical Formula 13] at a quantitative yield. [0066] A pressure-proof reaction vessel made of stainless steel (SUS) was charged with 1.56 g (9.99 mmol, 1.00 eq) of halogenated hemiacetals represented by the above formula, 10 mL of acetonitrile, 4.05 g (40.02 mmol, 4.01 eq) of triethylamine and 1.61 g (9.99 mmol, 1.00 eq) of triethylamine tris(hydrogen fluoride) complex, followed by immersing it in a coolant bath of -78 °C. Then, 2.04 g (19.99 mmol, 2.00 eq) of sulfuryl fluoride (SO2F2) was blown thereinto by using a bomb, followed by stirring at room temperature throughout the night. The reaction-terminated liquid was confirmed by 1H-NMR and 19F-NMR to have a conversion rate and a selectivity of 100 % and not less than 70 %, respectively. The reaction-terminated liquid was directly distilled (at normal pressure) thereby obtaining halogenated a-fluoroethers represented by the following formula [Chemical Formula 14] as a mixture of triethylamine and acetonitrile. The yield was confirmed by the conversion rate and the selectivity of the reaction-terminated liquid to be not less than 70 %. 1H-NMR and 19F-NMR will be discussed below. 10067] 1H-NMR [Standard substance; (CH3)1Si, Dcuteration solvent; CDCl3l; d ppm/4.30 (dd, 13.2Hz, 6.0Hz, 1H), 4.47 (dd, 13.2Hz, 4.2Hz, 1H), 5.36 (dd, 16.8Hz, 0.4Hz. 1H), 5.40 (dd. 16.8Hz, 1.2Hz, 1H), 5.42 (dq, 60.7Hz, 3.2Hz, 1H), 5.92 (m, 1H). 19F-NMR [Standard substance; C6F6, Deuteration solvent: CDCl3]; d ppm/17.95 (dq, 60.7Hz, 6.0Hz, 1F), 78.29 (dd, 6.0Hz, 3.2Hz, 3F). [0068] [Example 3] An excessively small amount of methanol was added to ethyl 3,3,3-trifluoropyruvate and then stirred at room temperature throughout the night, thereby obtaining halogcnated hemiacetals represented by the following formula [Chemical Formula 15] at a quantitative yield. [0069] A pressure-proof reaction vessel made of stainless steel (SUS) was charged with 500 mg (2.47 mmol, 1.00 eq) of halogenated hemiacetals represented by the above formula, 2.5 mL of acetonitrile, 1.000 mg (9.88 mmol, 4.00 eq) of triethylamine and 399 mg (2.47 mmol, 1.00 eq) of triethylamine tris(hydrogen fluoride) complex, followed by immersing it in a coolant bath of -78 °C. Then, 505 mg (4.95 mmol, 2.00 cq) of sulfuryl fluoride (SO2F2) was blown thereinto by using a bomb, followed by stirring at room temperature throughout the night. The reaction-terminated liquid was confirmed by 1H-NMR and 19F-NMR to have a conversion rate and a selectivity of 100 % and not less than 70 %. respectively. The reaction-terminated liquid was directly distilled (at from normal pressure to 23 kPa) thereby obtaining halogenated a-fluoroethers represented by the following formula [Chemical Formula 16] as a mixture of triethylamine and acetonitrile. The yield was confirmed by the conversion rate and the selectivity of the reaction-terminated liquid to be not less than 70 %. 1H-NMR and 19F-NMR will be discussed below. [0070] 1H-NMR [Standard substance; (CH3)-1Si, Deuteration solvent; CDCl3]; d ppm/1.38 (t, 7.2Hz, 3H), 3.59 (s, 3H), 4.41 (q, 7.2Hz, 2H). 19F-NMR [Standard substance; C6F6, Deuteration solvent; CDCl3]; d ppm/26.70 (s, 1F), 80.51 (s, 3F). WE CLAIM: 1. A process for producing a halogenated a-fiuoroether represented by a general formula [2] by reacting a halogenated hemiacetal represented by a general formula [1] with sulfuryl fluoride (SO2F2) in the presence of an organic base. wherein haloR represents haloalkyl group; R1 represents one of hydrogen atom, alkyl group, substituted alkyl group, alkoxycarbonyl group and substituted alkoxycarbonyl group; and R2 represents one of alkyl group and substituted alkyl group. 2. A process for producing a halogenated a-fiuoroether bis-derivative represented by a general formula [2a] by reacting halogenated hemiacetal bis-derivative represented by the general formula [1a] with sulfuryl fluoride (SO2F2) in the presence of an organic base, wherein haloR mutually independently represents a haloalkyl group; R1 mutually independently represents one of a hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxycarbonyl group and a substituted alkoxycarbonyl group; and n represents an integer of from 2 to 18. 3. A process for producing one of a halogenated a-fluoroether and a halogenated a-fluoroether bis-derivative, as claimed in Claim 1 or Claim 2, wherein a reaction of Claim 1 or Claim 2 is conducted in the additional presence of "one of a salt and a complex of an organic base with hydrogen fluoride" in a system. 4. A process for producing a halogenated a-fluoroether represented by a general formula [4] by reacting a halogenated hemiacetal represented by a general formula [3] with sulfuryl fluoride (SO2F2) in the presence of an organic base. wherein, R2 represents one of an alkyl group and a substituted alkyl group. 5. A process for producing a halogenated a-fluoroether as claimed in Claim 4, wherein a reaction of Claim 4 is conducted in the presence of "one of a salt and a complex, of an organic base with hydrogen fluoride" in a system. 6. A process for producing a halogenated a-fluoroether represented by a general formula [6] by reacting a halogenated hemiacetal represented by a general formula [5] with sulfuryl fluoride (SO2F2) in the presence of an organic base, wherein R2 and R3 mutually independently represent one of an alkyl group and a substituted alkyl group. 7. A process for producing a halogenated a-fluoroether as claimed in Claim 6, wherein a reaction of Claim 6 is conducted in the additional presence of "one of a salt and a complex, of an organic base with hydrogen fluoride" in a system. Halogenated α-fluoroethers (or bis-derivatives thereof) can be produced by reacting a halogenated hemiacetal (or bis-derivative thereof) with sulfuryl fluoride (SO2F2) in the presence of an organic base. The reaction is conducted preferably in the presence of "a salt or complex of an organic base with hydrogen fluoride", whereby the objective dehydroxyfluorination can proceed extremely favorably. It is still preferable to use as the starting substrate a halogenated hemiacetal prepared from fluoral or 3,3,3-trifluoropyruvic acid ester. Thus, industrially important halogenated α-fluoroethers can be industrially produced with high selectivity and in high yield.

Full Text

TECHNICAL FIELD
[0001] The present invention relates to a process for industrially producing
halogenated a-fluoroethers which are important as an intermediate of
medicines or agrichemicals or as a flon alternative compound.
BACKGROUND OF THE INVENTION
[0002] Halogenated a-fluoroethers, the object of the present invention,
serve as an important intermediate of medicines or agrichemicals or as an
important flon alternative compound. Particularly, a,ß,ß,ß-tetrafluoroethers
are utilized as a useful intermediate for a volatile anaesthetic "desflurane". As
conventional techniques for such a-fluoroethers, relating to the present
invention, the following two techniques are exemplified.
[0003] There have been disclosed: a process for reacting fluoral hemiacetals
with the Yarovenko's reagent (Patent Publication 1); and a process consisting
of two process steps in which fluoral hemiacetals are converted into
corresponding /rtoluenesulfonic acid esters and then these are reacted with
Fluoride anion (F) (Patent Publication 2).
REFERENCES ABOUT PRIOR ART
Patent Publication
[0004] Patent Publication 1: Japanese Patent Application Publication No.
50-76007
Patent Publication 2- Japanese Patent Application Publication No.
2-104545.
SUMMARY OF THE INVENTION
[0005] An object of the present invention is to provide a process for
industrial production of halogenated a-fluoroethers.
[0006] Patent Publication 1 in which the Yarovenko's reagent is used as a

dehydroxyfluorination agent requires previously preparing the reagent from
chlorotrifluoroethylene and diethylamine. Furthermore, a fluorine-containing
organic waste is stoichiometrically formed as a by-product, so that an
industrial execution thereof had been difficult.
[0007] In Patent Publication 2 where the reaction is achieved with two
process steps, the operations including a post-treatment are so complicated
that a high productivity cannot be expected. Additionally, the total yield is
also not satisfying.
[0008] Thus, there has been intensely desired a production process which
can be readily and industrially accomplished and provide halogenated
a-fluoroethers with high productivity and yield.
[0009] As a result of eager studies the present inventors have made in
view of the above, they have newly found it possible to produce halogenated
a-fluoroethers represented by the general formula [2] by reacting halogenated
hemiacetals represented by the general formula [1] with sulfuryl fluoride in
the presence of an organic base. Furthermore, there has been also newly
found that the present reaction can be applied to bis-derivatives formed
through alkylene group (, in which halogenated a-fluoroether bis-derivatives
represented by the general formula [2a] are obtained as the objective by using
halogenated hemiacetal bis-derivatives represented by the general formula
[1a] as the starting substrate).
[0010] Incidentally, the present applicant has found a
dehydroxyfluorination reaction of alcohols by combination of sulfuryl fluoride
(SO2F2) and the organic base and has already filed an application therefor
[International Publication 2006/098444 Pamphlet (Japanese Patent
Application Publication No. 2006-290870)]. On the other hand, the raw
materials of the present invention are relatively unstable "halogenated
hemiacetals" or bis-derivatives thereof. These can be said to be "an equivalent
of a compound having a carbon with which two hydroxyl groups are
concurrently bonded". The present inventors have made it clear: that these
raw material compounds are reacted with sulfuryl fluoride (SO2F2) in the
presence of the organic base thereby selectively subjecting "free hydroxyl
group" alone to fluorine substitution; and that, as opposed to this, -OR2 group,
group and haloalkyl group are inducted into the halogenated
a-fluoroelhcrs represented by the general formula [2] or the halogenated
a-fluoroether bis-derivatives represented by the general formula [2a] with
high yield without being subjected to any change.
[0011] Moreover, the present invention allows the reaction to be conducted
with one process step as a one-pot reaction, in which fluorosulfuric
acid-esterification of the starting substrate halogenated hemiacetals (or the
bis-derivatives thereof) and a succeeding fluorine substitution proceed
continuously. In fluorine substitution, "a salt or complex of an organic base
with hydrogen fluoride" formed as a by-product in the reaction system by the
fluorosulfuric acid-esterification is usefully utilized as a Fluoride anion source,
(see Scheme 1 showing an example where the halogenated hemiacetals
represented by the general formula [1] are used as the starting substrate.)
[0012] [Chemical Formula 1]

[0013] In the present invention, it has also been made clear that the
succeeding fluorine substitution enormously excellently proceeds by
conducting the reaction in the additional presence of "a salt or complex of an
organic base with hydrogen fluoride" in the system (see Scheme 2 showing an
example where the halogenated hemiacetals represented by the general
formula [1] are used as the starting substrate.) The fluorosulfuric
acid-esterification of the relatively unstable halogenated hemiacetals proceeds
excellently even in the presence of "a salt or complex of an organic base with
hydrogen fluoride", which is a new finding.
[0014] [Chemical Formula 2]

[0015] Furthermore, the present invention have newly made it clear that
hemiacetals of fluoral (corresponding to halogenated hemiacetals represented
by the general formula [3]) or hemiacetals of 3,3.3-trifluoropyruvic acid esters
(corresponding to halogenated hemiacetals represented by the general
formula [o|) are extremely preferable starting substrates. When using such
starting substrates, the desired reaction can excellently proceed under mild
conditions and the objective halogenated crfluoroethers are obtained with
high selectivity and yield. These starting substrates can be readily prepared
from fluoral or 3,3.3-trifluoropyruvic acid esters (either of which is readily
available in large-scale) so as to be suilable also from the viewpoint of a
starting substrate for an industrial production process. Particularly,
a,ß,ß,ß-tetrafluoroethylmetnylethcr obtained from fluoral methyl hemiacetal
arc useful as an intermediate for a volatile anaesthetic "desflurane", so as to
bo particularly preferable.
[0016] Thus, an extremely useful process has been found as a process for
industrially producing the halogenated afluoroethers. thereby achieving the
present invention.
[0017] More specifically, the present invention includes the following 1st
process to 7th process and provides an industrial production process of the
halogcnated a-fluoroethers.
[0018] According to the present invention, there is provided a process for
producing halogcnated a-fluoroethers represented by the general formula [2]
[Chemical Formula 4]

by reacting halogenated hemiacetals represented by the general formula [1]
[Chemical Formula 3]

with sulfuryl fluoride (SO2F2) in the presence of an organic base (a 1st process).
[In the formulas: haloR represents haloalkyl group; R1
represents hydrogen atom, alkyl group, substituted alkyl group,
alkoxycarbonyl group or substituted alkoxycarbonyl group; and R2 represents
alkyl group or substituted alkyl group.]
[0019] According to the present invention, there is further provided a process
for producing halogenated a-fluoroether bis-derivatives represented by the
general formula [2a]
[Chemical Formula 6]

by reacting halogenated hemiacetal bis-derivatives represented by the general
formula [1a]
[Chemical Formula 5]

with sulfuryl fluoride (SO2F2) in the presence of an organic base (a 2nd
process).
[In the formulas: haloR mutually independently represents a
haloalkyl group; R1 mutually independently represents a hydrogen atom, an
alkyl group, a substituted alky] group, an alkoxycarbonyl group or a
substituted alkoxycarbonyl group; and n represents an integer of from 2 to
18.]
[0020] The 1st or 2nd process may be a process for producing halogenated
a-fluoroethers or halogenated a-fluoroether bis-derivatives, the process being
characterized in that the reaction is conducted in the additional presence of "a
sail or complex of an organic base with hydrogen fluoride" in a system (a 3rd
process).
[0021] According to the present invention, there is further provided a
process for producing halogenated a-fluoroethers represented by the general
formula [4]
[Chemical Formula 8]

by reacting halogenated hemiacetals represented by the general formula [3]
[Chemical Formula 7]

with sulfuryl fluoride (SO2F2) in the presence of an organic base (a 4th
process).
[In the formulas. R2 represents an alkyl group or a substituted alkyl
group.]
[0022] The 4th process may be a process for producing halogenated
a-fluoroethers. the process being characterized in that the reaction is
conducted in the additional presence of "a salt or complex of an organic base
with hydrogen fluoride" in a system (a 5th process).
[0023] According to the present invention, there is further provided a
process for producing halogenated a-fluoroethers represented by the general
formula L6]
[Chemical Formula 10]

by reacting halogenated hemiacetals represented by the general formula [5]
[Chemical Formula 9]

with sulfuryl fluoride (SO2F2) in the presence of an organic base (a 6th
process).
[In the formulas, R2 and R3 mutually independently represent an alkyl
group or a substituted alkyl group.]
[0024] The 6th process may be a process for producing halogenated
Q'fluoroethers, the process being characterized in that the reaction is
conducted in the additional presence of "a salt or complex of an organic base
with hydrogen fluoride" in a system (a 7th process).
DETAILED DESCRIPTION
[0025] Advantageous points of the present invention over conventional
techniques will be discussed below.
[0026] As compared to Patent Publication 1, a dehydroxyfluorination agent
used in the present invention is suitable for large-scale production. Sulfuryl
fluoride is widely utilized as a fumigant and industrially available at low cost.
Additionally, wastes made in the use of sulfuryl fluoride can be conveniently
treated into inorganic salts such as fluorite (CaF2), calcium sulfate, etc., which
reduce the load to the environment.
[0027] As compared to Patent Publication 2, the reaction can be conducted
with one process step (in which fluorosulfuric acid-esterification and a
succeeding fluorine substitution proceed continuously as a one-pot reaction)
with extremely high productivity and in high yield.
[0028] Furthermore, impurities serving as by-products difficult to be
separated off are hardly provided in the present invention, so that the
objective product can be obtained at a high chemical purity.
[0029] Thus, the present invention is a production process which can solve
all problems the conventional techniques had carried and can be industrially
readily conducted.
[0030] A process for producing halogenated a-fluoroethers of the present
invention will be discussed in detail.

[0031] In the present invention, it is possible to produce halogenated
a-fluoroethers represented by the general formula [2] (or halogenated
a-fluoroether bis-derivatives represented by the general formula [2a]) by
reacting halogenated hemiacetals represented by the general formula [1] (or
halogenated hemiacetal bis-derivatives represented by the general formula
[1a]) with sulfuryl fluoride (SO2F2) in the presence of an organic base.
[0032] HaloR as shown in the general formula [1] denotes haloalkyl group.
Examples of the haloalkyl group are those obtained by substitution caused on
any carbon atom in a linear, branched or cyclic (with a carbon number of not
smaller than 3) alkyl group having a carbon number of from 1 to 18 with any
number of and any combination of halogen atoms including fluorine, chlorine,
bromine and iodine (where the alkyl group causes substitution with at least
one halogen atom). Among these, the preferable is fluoroalkyl group and
chloroalkyl group, and the more particularly preferable is trifluoromethyl
group.
[0033] R1 of the halogenated hemiacetals represented by the general
formula [1] denotes hydrogen atom, alkyl group, substituted alkyl group,
alkoxycarbonyl group or substituted alkoxycarbonyl group. Examples of alkyl
moieties of the alkyl group and of the alkoxycarbonyl group (the moieties
corresponding to, for example. R3 of the halogenated hemiacetals represented
by the general formula [5]) include a linear, branched or cyclic (with a carbon
number of not smaller than 3) alkyl group having a carbon number of from 1
to 18.
[0034] The alkyl group and the alkoxycarbonyl group may have, on any
carbon atom in the alkyl moiety, any number of and any combination of
substituents (and correspond to substituted alkyl group and substituted
alkoxycarbonyl group, respectively). Examples of the substituents are:
halogen atom such as fluorine, chlorine, bromine, iodine, etc.; azide group;
nitro group; lower alkyl group such as methyl group, ethyl group, propyl group,
etc.; lower haloalkyl group such as fluoromethyl group, chloromethyl group,
bromomethyl group, etc.; lower alkoxy group such as methoxy group, ethoxy
group, propoxy group, etc.; lower haloalkoxy group such as fluoromethoxy
group, chloromethoxy group, bromomethoxy group, etc.; lower alkyl amino
group such as dimothylamino group, diethylamino group, dipropylamino
group, etc.; lower alkylthio group such as mcthylthio group, ethylthio group,
propylthio group, etc.; cyano group; lower alkoxycarbonyl group such as
methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, etc.;
aminocarbonyl group (CONH2); lower alkylaminocarbonyl group such as
dimethylaminocarbonyl group, diethylaminocarbonyl group,
dipvopylaminocarbonyl group, etc.; unsaturated group such as alkenyl group,
alkynyl group, etc.; aromatic cyclic gi'oup such as phenyl group, naphthyl
group, pyrrolyl group, furyl group, thienyl group, etc.; aromatic cyclic oxy
group such as phenoxy group, naphthoxy group, pyrrolyloxy group, furyloxy
group, thienyloxy group, etc.; aliphatic heterocyclic group such as piperidyl
group, piperidino group, morpholinyl group, etc.; protected hydroxyl group;
protected amino group (including amino acid and peptide residue); protected
thiol group; protected aldehyde group; protected carboxyl group; etc.
[0035] Incidentally, in the present specification, each of the following terms
is used as having the following meaning. "Lower" means a linear, branched or
cyclic (with a carbon number of not smaller than 3) chain having a carbon
number of from 1 to 6. In the case that "unsaturated group" is the double bond
(alkenyl group), it may be in the form of E configuration, Z configuration or a
mixture of these. As "protecting groups of hydroxyl group, amino group
(including amino acid and peptide residue), thiol group, aldehyde group and
carboxyl group", it is possible to use protecting groups and the like described
in Protective Groups in Organic Synthesis, Third Edition. 1999, John Wiley &
Sons, Inc.(, in which not less than two functional groups may be protected
with one protecting group). Moreover, "unsaturated group", "aromatic cyclic
group", "aromatic cyclic oxy group" and "aliphatic heterocyclic group" may be

subjected to substitution with halogen atom, azide group, nitro group, lower
alkyl group, lower haloalkyl group, lower alkoxy group, lower haloalkoxy
group, lower alkyl amino group, lower alkylthio group, cyano group, lower
alkoxycarbonyl group, aminocarbonyl group, lower alkylaminocarbonyl group,
protected hydroxyl group, protected amino group (including amino acid and
peptide residue), protected thiol group, protected aldehyde group, protected
carboxyl group or the like.
[0036] Among these, hydrogen atom, alkoxycarbonyl group and substituted
alkoxycarbonyl group are preferable. Particularly, hydrogen atom and
alkoxycarbonyl group are more preferable.
[0037] R2 of the halogenated hemiacetals represented by the general
formula [1] denotes alkyl group or substituted alkyl group.
[0038] The alkyl group and the substituted alkyl group are the same as the
alkyl group and the substituted alkyl group as had been discussed as R1 of the
halogenated hemiacetals represented by the general formula L1], and can be
selected independently of R1.
[0039] HaloR and R1 of the halogenated hemiacetal bis-derivatives
represented by the general formula [1a] are the same as haloR and R1 as had
been discussed on the halogcnatcd hemiacetals represented by the general
formula [1]. n represents an integer of from 2 to 18. Among these, with regard
to n, an integer of from 2 to 12 is preferable and that of from 2 to 6 in
particular is more preferable. Two haloR included in the halogenated
hemiacetal bis-derivatives represented by the general formula [1a] are
mutually independently selected from the above substituents. However, it is
preferable to select the same substituent for the two haloR if taking the
preparation of the starting substrate into account. Additionally, the same
thing can be said for two R1 of the halogcnatcd hemiacetal bis-derivatives
represented by the general formula [1a].

[0040] Stereochemistry of the halogenated hemiacetals represented by the
general formula [1] will be discussed. In the halogenated hemiacetals, a
carbon atom with which hydroxyl group forms a covalent bond is an
asymmetric carbon atom with the exception of the case where haloR and R1
adopt the same substituent. In the case where the starting substrate has the
asymmetric carbon atom, it is not only allowed to use a racemic form (it will be
understood that the racemic form can be used) but also allowed to use an
optically active form (R configuration or S configuration), and its optical
purity is not limited. A dehydroxyfluorination reaction of the present
invention proceeds together with stereochemical reversal, stereochemical
maintenance or racemization. This stereoselectivity differs according to the
combination of the starting substrate and the organic base and to the adopted
reaction conditions, so that the starting substrate, the organic base and the
reaction conditions may be suitably selected according to the desired
stereochemistry (R configuration, S configuration or racemic form) of the
objective halogenated a-fluoroethers represented by the general formula [2],
The same as the stereochemistry of the halogenated hemiacetals represented
by the general formula [1] goes for that of corresponding two carbon atoms of
the halogenated hemiacetal bis-derivatives represented by the general
formula [1a], mutually independently.
[0041] The halogenated hemiacetals represented by the general formula [1]
(or the halogenated hemiacetal bis-derivatives represented by the general
formula [1a]) can be prepared by the conventionally known method.
Halogenated hemiacetals represented either by the general formula [3] or by
the general formula [5], the particularly preferable starting substrate for the
present invention, can be readily prepared from fluoral [CF3CHO (or an
equivalent thereof)] and 3,3,3-trifluoropyruvic acid esters [CF3COCO2R (R
denotes alkyl group or substituted alkyl group)], respectively. Furthermore,
ethylhomiacetal or hydrate of fluoral, and ethyl 3,3,3-trifluoropyruvate are
commercially available.
[0042] The amount of the used sulfuryl fluoride (SO2F2) is required only to
be not lower than 0.7 mole, preferably from 0.8 to 10 moles in general, more
preferably from 0.9 to 5 moles in particular, relative to 1 mole of the
halogenated homiacotals represented by the general formula [1]. In the case of
using the halogenated hemiacetal bis-derivatives represented by the general
formula [1a] as the starting substrate, it is required only to use it in the same
manner in an amount two times that of the halogenated hemiacetals
represented by the general formula [1].
[0043] As a dehydroxyfluorination agent for the present invention,
trifluoromethanesulfonyl fluoride (CF3SO2F) or perfluorobutanesulfonyl
fluoride (C4F9SO2F) may be used. However, a conscious employment of these
reactants is not so advantageous in view of their availability in large scale;
their fluorine atom economy; waste treatment (by which a fluorine-containing
organic waste is stoichiometrically formed as a by product): etc.
[0044] Examples of the organic base for the present invention are
trimethylamine, dimethylethylamine. diethylmethylamine, triethylamine,
di-n-propylmcthylamine, dimethylcyclohexylamine, diisopropylethylamine,
tri-n-propylaminc, diisopropylisobutylamine, dimethyl-n-nonylamine,
tri-n-butylamine, di-n-hexylmethylamine, dimethyl-n-dodecylamine,
tri-n-pentylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO),
dimethylaminopyridine (DMAP), l,5diazabicyclo[4.3.0]non-5-ene (DBN),
l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,3-lutidine, 2,4-lutidine,
2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine,
2.4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine,
etc.
[0045] Among these, the preferable are triethylamine,
dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine,
tri-n-butylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine,
3,5-lutidine, 2,4.6-collidine and 3,5.6-collidine. The more preferable are

triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine,
pyridine, 2,4-lutidine, 2,6-lutidine, 3,5-lutidine and 2,4,6-collidine, in
particular. These organic bases may be used singly or in combination.
Additionally, an organic base having a carbon number of not less than 8 is
high in fat-solubility so as to be readily recovered at a post-treatment using
water, thereby being reused without being lowered in reactivity. Accordingly,
such an organic base is suitable for an industrial production process. In the
present specification, "carbon number" means the total number of carbon
atoms contained in an organic base.
[0046] The amount of the used organic base is required only to be not lower
than 0.7 mole, preferably from 0.8 to 15 moles in general, more preferably
from 0.9 to 10 moles in particular, relative to 1 mole of the halogenated
hemiacetals represented by the general formula [1]. In the case of using the
halogenated hemiacetal bis-dcrivatives represented by the general formula
[1a] as the starting substrate, it is required only to use it in the same manner
in an amount two times that of the halogenated hemiacetals represented by
the genera] formula [1].
[0047] Then, "a salt or complex of an organic base with hydrogen fluoride"
to be used in the 3rd process, the 5th process and the 7th process will be
discussed in detail.
[0048] Examples of the organic base of "a salt or complex of an organic base
with hydrogen fluoride" include trimethylamine, dimethylethylamine,
diethylmethylamine, triethylamine, di-n-propylmethylamine,
dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine,
diisopropylisobutylamine, dimethyl-n-nonylamine, tri-n-butylamine,
di-n-hexylmethylamine. dimethyl-n-dodccylamino, tri-irpentylamine,
1.4-diazabicyclo[2.2.2]octane (DABCO), dimethylaminopyridine (DMAP),
1 ,5-diazabicyclo[4.3.0]non-o-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine,
3,4-lutidine, 3,5-lutidine. 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine,
2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine, etc..
[0049] Among these, the preferable are triethylamine,
dimethylcyclohexylamine. diisopropylethylamine, tri-n-propylamine,
tri-n-butylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine,
3.5-lutidine, 2,4,6-collidine and 3,5,6-collidine. The more preferable are
triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine,
pyridine, 2,4-lutidine, 2,6-lutidine, 3,5-lutidine and 2,4,6-collidine in
particular.
[0050] The mole ratio of the organic base of "a salt or complex of an organic
base with hydrogen fluoride" to hydrogen fluoride is within a range of from
100:1 to 1:100, preferably within a range of from 50:1 to 1:50 in general, and
more preferably within a range of from 25:1 to 1:25 in particular. Furthermore,
it is convenient to use "a complex comprising 1 mole of triethylamine and 3
moles of hydrogen fluoride" and "a complex comprising up to 30% (up to 10
mol%) of pyridine and up to 70% (up to 90 mol%) of hydrogen fluoride", both of
which are placed on sale from Aldrich (Aldrich, 2007-2008 Comprehensive
Catalogue).
[0051] The amount of "a salt or complex of an organic base with hydrogen
fluoride" to be used is required only to be not less than 0.3 mole as Fluoride
anion (F-), preferably within a range of from 0.5 to 50 moles in general and
more preferably within a range of from 0.7 to 25 moles in particular, relative
to 1 mole of the halogenated hemiacetals represented by the general formula
[1]. When using the halogenated hemiacetal bis-derivatives represented by
the general formula [1a] as the starting substrate, it is required only to use it
in the same manner in an amount two times that of the halogenated
hemiacetals represented by the general formula [1].
[0052] Examples of a reaction solvent are: aliphatic hydrocarbons such as
n-hexane, cyclohexane, n-heptane, etc.; aromatic hydrocarbons such as
benzene, toluene, ethylbenzene, xylene, mesitylene. etc; halogenated
hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc;
ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tertrbutyl
methyl ether, etc; esters such as ethyl acetate, n-butyl acetate, etc; amides
such as N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidone, 1,3-dimethyl-2imidazolidinone, etc; nitriles such as
acetonitrile, propionitrile, etc; and dimcthylsulfoxide, etc.
[0053] Among these, the preferable are n-hexane, n-heptane, toluene,
xylene, mesitylene, methylene chloride, tetrahydrofuran, diisopropyl ether,
tert-butyl metlryl ether, ethyl acetate, N,N-dimethylformamide,
N,N-dimethylacetamide, acetonitrile, propionitrile and dimethylsulfoxide.
Particularly, the more preferable are toluene, xylene, methylene chloride,
tetrahydrofuran, diisopropyl ether, ethyl acetate, N,N-dimethylformamide
and acetonitrile. It is possible to use these reaction solvents singly or in
combination. Furthermore, the present invention may be performed without
the solvent.
[0054] In the case of using the reaction solvent, the amount thereof is
required only to be not less than 0.1 L (liter), preferably within a range of from
0.2 to 10 L in general, and more preferably within a range of from 0.3 to 5 L in
particular, relative to 1 mole of the halogenated hemiacetals represented by
the general formula [1] (or the halogenated hemiacetal bis-derivatives
represented by the general formula [1a]).
[0055] The temperature condition is required only to be conducted within a
range of from 100 to +100 °C, preferably within a range of from 60 to +60 °C
in general, more preferably within a range of from -50 to +50 °C in particular.
In the case of conducting the reaction under a temperature condition of not
lower than the boiling point of sulfuryl fluoride (-49.7 °C), it is possible to use
a pressure-proof reaction vessel.
[0056] The pressure condition is required only to be conducted within a
range of from atmospheric pressure to 2 MPa, preferably within a range of
from atmospheric pressure to 1.5 MPa in general, more preferably within a
range of from atmospheric pressure to 1 MPa in particular. Therefore, it is
preferable to conduct the reaction in the use of a pressure-proof reaction
vessel made of a material such as stainless steel (SUS) or glass (glass lining).
Furthermore, for infusion of sulfuryl fluoride in large-scale, the effective is a
process for causing a negative pressure in a pressure-proof reaction vessel
first of all, and then introducing gaseous or liquid sulfuryl fluoride into
therein while recovering the pressure under a reduced pressure.
[0057] The reaction time is within 72 hours; however, it differs according to
the combination of the starting substrate and the organic base and to the
adopted reaction conditions. It is therefore preferable to determine a temporal
point at which the starting substrate is generally completely consumed as the
endpoint of the reaction, upon tracking the progress of the reaction by an
analytical means such as gas chromatography, thin layer chromatography,
liquid chromatography, nuclear magnetic resonance (NMR), etc. The objective
halogenated a-fluoroethers represented by the general formula [2] (or the
halogenated a-fluoroether bis-derivatives represented by the general formula
[2a]) can be obtained by conducting an usual operation on a
reaction-terminated liquid as a post-treatment. The objective product can be
purified at a high chemical purity by activated carbon treatment, distillation,
rccrystallization. column chromatography or the like as necessary.
[0058] Such an operation as to directly distill the reaction-terminated
liquid is particularly effective. By conducting such a post-treatment
(defluorination, fractional distillation or the like, as necessary), it becomes
possible to obtain a product of quality sufficient either for an intermediate of
medicines or agrichemicals or for a flon alternative compound.
[0059] In the present invention, the halogenated hemiacetals represented
by the general formula [1] (or the halogenated hemiacetal bis-derivatives
represented by the general formula [1a]) are reacted with sulfuryl fluoride in
the presence of the organic base, thereby producing the halogenated
a fluoroethers represented by the general formula [2] (or the halogenated
crfluoroether bis-derivatives represented by the general formula [2a]).
[0060] It is preferable to conduct the reaction in the presence of "a salt or
complex of an organic base with hydrogen fluoride", by which the objective
dehydroxyfluorination reaction can proceed extremely favorably.
[0061] It is more preferable to use. as the starting substrate, halogenated
hemiacetals represented by the general formula [3] or the general formula [5]
and able to be prepared from fluoral or 3,3,3-trifluoropyruvic acid esters. With
this, the industrially important halogenated a-fluoroethers can be industrially
produced with high yield and selectivity.
[0062] [Examples]
Embodiments of the present invention are specifically explained by
examples. The present invention is, however, not limited to these examples.
Incidentally, omission marks discussed in the examples are as follows.
Et; Ethyl group
Me: Methyl group
[0063] [Example 1]
A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 500 mg (3.47 mmol, 1.00 eq) of halogenated hemiacetals
represented by the following formula
[Chemical Formula 11]

3.5 mL of acetonitrile, 1.756 mg (17.35 mmol, 5.00 eq) of triethylamine and
839 mg (5.20 mmol, 1.50 eq) of triethylamine tris(hydrogen fluoride) complex,
followed by immersing it in a coolant bath of -78 °C. Then, 708 mg (6.94 mmol,
2.00 eq) of sulfuryl fluoride (SO2F2) was blown thereinto by using a bomb,
followed by stirring at room temperature throughout the night. The
reaction-terminated liquid was confirmed by 1H-NMR and 19F NMR to have a
conversion rate and a selectivity of 100 % and not less than 70 %, respectively.
By directly distilling the reaction-terminated liquid (at normal pressure),
halogenated a-fluoroethers represented by the following formula
[Chemical Formula 12]

can be obtained as a mixture of triethylamine and acetonitrile. The yield was
confirmed by the conversion rate and the selectivity of the
reaction-terminated liquid to be not less than 70 %. A molecular weight of 147
(M+1) was observed by GC-MS (CI method). 1H-NMR and 19F-NMR will be
discussed below.
[0064] 1H-NMR [Standard substance; (CH3)4Si, Deuteration solvent;
CDCl8]; d ppm/1.34 (t, 7.0Hz, 3H), 3.86 (m. 1H), 4.03 (m, 1H), 5.41 (dq, 61.9Hz,
3.0Hz, 1H).
19F-NMR [Standard substance; C6-F6, Deuteration solvent; CDCl3]; d
ppm/19.60 (dq, 61.9Hz, 6.4Hz, 1F), 78.03 (dd, 6.4Hz, 3.0Hz, 3F).
[0065] [Example 2]
In conformity with YUKIGOSEIKYOKAISHI (Japan), 1999, Vol. 57,
No. 10, p. 102-103, fluoral (gas) was generated from an excessive amount of
fluoral monohydrate, followed by blowing it into allyl alcohol. Stirring was
conducted for 2 hours at room temperature, thereby obtaining halogenated
hemiacetals represented by the following formula
[Chemical Formula 13]

at a quantitative yield.
[0066] A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 1.56 g (9.99 mmol, 1.00 eq) of halogenated hemiacetals
represented by the above formula, 10 mL of acetonitrile, 4.05 g (40.02 mmol,
4.01 eq) of triethylamine and 1.61 g (9.99 mmol, 1.00 eq) of triethylamine
tris(hydrogen fluoride) complex, followed by immersing it in a coolant bath of
-78 °C. Then, 2.04 g (19.99 mmol, 2.00 eq) of sulfuryl fluoride (SO2F2) was
blown thereinto by using a bomb, followed by stirring at room temperature
throughout the night. The reaction-terminated liquid was confirmed by
1H-NMR and 19F-NMR to have a conversion rate and a selectivity of 100 %
and not less than 70 %, respectively. The reaction-terminated liquid was
directly distilled (at normal pressure) thereby obtaining halogenated
a-fluoroethers represented by the following formula
[Chemical Formula 14]
as a mixture of triethylamine and acetonitrile. The yield was confirmed by the
conversion rate and the selectivity of the reaction-terminated liquid to be not
less than 70 %. 1H-NMR and 19F-NMR will be discussed below.
10067] 1H-NMR [Standard substance; (CH3)1Si, Dcuteration solvent;
CDCl3l; d ppm/4.30 (dd, 13.2Hz, 6.0Hz, 1H), 4.47 (dd, 13.2Hz, 4.2Hz, 1H), 5.36
(dd, 16.8Hz, 0.4Hz. 1H), 5.40 (dd. 16.8Hz, 1.2Hz, 1H), 5.42 (dq, 60.7Hz, 3.2Hz,
1H), 5.92 (m, 1H).
19F-NMR [Standard substance; C6F6, Deuteration solvent: CDCl3]; d
ppm/17.95 (dq, 60.7Hz, 6.0Hz, 1F), 78.29 (dd, 6.0Hz, 3.2Hz, 3F).
[0068] [Example 3]
An excessively small amount of methanol was added to ethyl
3,3,3-trifluoropyruvate and then stirred at room temperature throughout the
night, thereby obtaining halogcnated hemiacetals represented by the
following formula
[Chemical Formula 15]

at a quantitative yield.
[0069] A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 500 mg (2.47 mmol, 1.00 eq) of halogenated hemiacetals
represented by the above formula, 2.5 mL of acetonitrile, 1.000 mg (9.88 mmol,
4.00 eq) of triethylamine and 399 mg (2.47 mmol, 1.00 eq) of triethylamine
tris(hydrogen fluoride) complex, followed by immersing it in a coolant bath of
-78 °C. Then, 505 mg (4.95 mmol, 2.00 cq) of sulfuryl fluoride (SO2F2) was
blown thereinto by using a bomb, followed by stirring at room temperature
throughout the night. The reaction-terminated liquid was confirmed by
1H-NMR and 19F-NMR to have a conversion rate and a selectivity of 100 %
and not less than 70 %. respectively. The reaction-terminated liquid was
directly distilled (at from normal pressure to 23 kPa) thereby obtaining
halogenated a-fluoroethers represented by the following formula
[Chemical Formula 16]

as a mixture of triethylamine and acetonitrile. The yield was confirmed by the
conversion rate and the selectivity of the reaction-terminated liquid to be not
less than 70 %. 1H-NMR and 19F-NMR will be discussed below.
[0070] 1H-NMR [Standard substance; (CH3)-1Si, Deuteration solvent;
CDCl3]; d ppm/1.38 (t, 7.2Hz, 3H), 3.59 (s, 3H), 4.41 (q, 7.2Hz, 2H).
19F-NMR [Standard substance; C6F6, Deuteration solvent; CDCl3]; d
ppm/26.70 (s, 1F), 80.51 (s, 3F).
WE CLAIM:
1. A process for producing a halogenated a-fiuoroether represented by a
general formula [2]

by reacting a halogenated hemiacetal represented by a general formula [1]

with sulfuryl fluoride (SO2F2) in the presence of an organic base.
wherein haloR represents haloalkyl group; R1 represents one of
hydrogen atom, alkyl group, substituted alkyl group, alkoxycarbonyl group
and substituted alkoxycarbonyl group; and R2 represents one of alkyl group
and substituted alkyl group.
2. A process for producing a halogenated a-fiuoroether bis-derivative
represented by a general formula [2a]

by reacting halogenated hemiacetal bis-derivative represented by the general
formula [1a]

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein haloR mutually independently represents a haloalkyl
group; R1 mutually independently represents one of a hydrogen atom, an alkyl
group, a substituted alkyl group, an alkoxycarbonyl group and a substituted
alkoxycarbonyl group; and n represents an integer of from 2 to 18.
3. A process for producing one of a halogenated a-fluoroether and a
halogenated a-fluoroether bis-derivative, as claimed in Claim 1 or Claim 2,
wherein a reaction of Claim 1 or Claim 2 is conducted in the additional
presence of "one of a salt and a complex of an organic base with hydrogen
fluoride" in a system.
4. A process for producing a halogenated a-fluoroether represented by a
general formula [4]

by reacting a halogenated hemiacetal represented by a general formula [3]

with sulfuryl fluoride (SO2F2) in the presence of an organic base.
wherein, R2 represents one of an alkyl group and a substituted alkyl
group.
5. A process for producing a halogenated a-fluoroether as claimed in
Claim 4, wherein a reaction of Claim 4 is conducted in the presence of "one of a
salt and a complex, of an organic base with hydrogen fluoride" in a system.
6. A process for producing a halogenated a-fluoroether represented by a
general formula [6]
by reacting a halogenated hemiacetal represented by a general formula [5]

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein R2 and R3 mutually independently represent one of an
alkyl group and a substituted alkyl group.
7. A process for producing a halogenated a-fluoroether as claimed in
Claim 6, wherein a reaction of Claim 6 is conducted in the additional presence
of "one of a salt and a complex, of an organic base with hydrogen fluoride" in a
system.

Halogenated α-fluoroethers (or bis-derivatives thereof) can be
produced by reacting a halogenated hemiacetal (or bis-derivative thereof) with
sulfuryl fluoride (SO2F2) in the presence of an organic base. The reaction is
conducted preferably in the presence of "a salt or complex of an organic base
with hydrogen fluoride", whereby the objective dehydroxyfluorination can
proceed extremely favorably. It is still preferable to use as the starting
substrate a halogenated hemiacetal prepared from fluoral or
3,3,3-trifluoropyruvic acid ester. Thus, industrially important halogenated
α-fluoroethers can be industrially produced with high selectivity and in high
yield.

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Patent Number

271236

Indian Patent Application Number

4968/KOLNP/2010

PG Journal Number

07/2016

Publication Date

12-Feb-2016

Grant Date

10-Feb-2016

Date of Filing

27-Dec-2010

Name of Patentee

CENTRAL GLASS COMPANY, LIMITED

Applicant Address

5253, OAZA OKIUBE, UBE-SHI, YAMAGUCHI 755-0001 JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	AKIHIRO ISHII	C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151 JAPAN
2	MANABU YASUMOTO	C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151 JAPAN

PCT International Classification Number

C07C 41/22

PCT International Application Number

PCT/JP2009/058967

PCT International Filing date

2009-05-14

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2008-141119	2008-05-29	Japan