US 2015O1974.73A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0197473 A1 ISHII et al. (43) Pub. Date: Jul. 16, 2015

(54) PROCESS FOR PRODUCING (30) Foreign Application Priority Data ALPHA-FLUOROALDEHYDES

Aug. 3, 2011 (JP) ...... 2011-1701.94 (71) Applicant: Central Glass Company, Limited, Feb. 28, 2012 (JP). 2012-04 1213 Ube-shi (JP) Jul. 9, 2012 (JP). 2012-153460 Publication Classification (72) Inventors: Akihiro ISHII, Kawagoe-shi (JP); Takashi OOTSUKA, Kawagoe-shi (JP); (51) Int. Cl. Mari IMAMURA, Kawagoe-shi (JP); CD7C 45/4I (2006.01) Takayuki NISHIMIYA, Kawagoe-shi (52) U.S. Cl. (JP); Kazuto KIMURA, Kawagoe-shi CPC ...... CD7C 45/4I (2013.01) (JP) (57) ABSTRACT A production process of an C-fluoroaldehyde according to the resent invention includes reaction of an O.-fluoroester with (21) Appl. No.: 14/667,753 Sir gas (H) in the presence of a ruthenium complex. It is possible in the present invention to allow relatively easy (22) Filed: Mar. 25, 2015 industrial production of the C-fluoroaldehyde and to directly obtain, as stable synthetic equivalents of the C-fluoroalde hyde, not only a hydrate (as obtained by conventional tech Related U.S. Application Data niques) but also a hemiacetal that is easy to purify and is of high value in synthetic applications. The present invention (62) Division of application No. 14/233,629, filed on Jan. provides solutions to all problems in the conventional tech 17, 2014, now Pat. No. 9,024,075, filed as application niques and establishes the significantly useful process for No. PCT/JP2012/068639 on Jul. 24, 2012. production of the C-fluoroaldehyde. US 2015/O 197473 A1 Jul. 16, 2015

PROCESS FOR PRODUCING production equipment to perform the reaction in the vapor ALPHA-FLUOROALDEHYDES phase under high-temperature conditions. 0010. It is therefore an object of the present invention to CROSS REFERENCE TO RELATED provide a process for industrially producing an O.-fluoroalde APPLICATIONS hyde by reduction of an O.-fluoroester without the need for special production equipment. As far as the present 0001. This application is a divisional of U.S. application inventors know, there has been no specific report about the Ser. No. 14/233,629, filed Jan. 17, 2014, which is a National hydrogen reduction of C-fluoroesters and particularly about Stage application of PCT International Application PCT/ the production of C.-fluoroaldehydes by hydrogen reduction JP2012/068639, filed Jul. 24, 2012, which claims priority of C-fluoroesters with the use of homogeneous catalysts. In from Japanese Patent Application Nos. 2012-153460, filed on the present specification, the term "homogeneous catalyst” is Jul. 9, 2012, 2012-04 1213 filed on Feb. 28, 2012 and 2011 a catalyst as defined in Kagaku Daijiten (Tokyo Kagaku 170194 filed on Aug. 3, 2011, the disclosures of which are expressly incorporated by reference herein. Dojin, edited by Michinori Ohki, Toshiaki Osawa, Motoharu Tanaka and Hideaki Chihara) and the like. FIELD OF INVENTION Means for Solving the Problems 0002 The present invention relates to a process for indus 0011. As a result of extensive researches, the present trial production of C-fluoroaldehydes. inventors have found that a ruthenium complex of the follow ing general formula 2, especially a ruthenium complex of BACKGROUND ART the following general formula 4, can be used as a catalyst or 0003 C-Fluoroaldehydes can be produced by reduction of precursor thereof for hydrogen reduction of an O.-fluoroester corresponding C-fluoroesters. For Such reduction reactions, it without the need for special production equipment. This is often the case to use Stoichiometric amounts of hydride ruthenium complex functions as a homogeneous ruthenium reducing agents e.g. sodium borohydride, lithium aluminum catalyst, which is different from the supported-type (hetero hydride etc. (see Patent Document 1 and Non-Patent Docu geneous) ruthenium/tin bimetal catalysts of Patent Docu ment 1). However, the processes for production of C.-fluoro ments 2 and 3. aldehydes using the Stoichiometric amounts of hydride reduc ing agents are not suitable for large-scale production applications in view of the facts that: the hydride reducing agents are expensive and need to be handled with great cau tion; and the post treatments of the resulting reaction products require complicated operations and cause large amounts of R X 1 Wastes. R N/'N 0004. On the other hand, there have been proposed, as Ru relevant techniques, process for production of fluoral hydrates by reaction of trifluoroacetic acids (including corre ( R YY sponding esters) with hydrogen gas (H) in the presence of / \. ruthenium/tin bimetal catalysts in vapor phases (see Patent Documents 2 and 3). In the general formula 2. Reach independently represents a hydrogen atom, an alkyl group, a Substituted alkyl group, an PRIOR ART DOCUMENTS aromatic ring group or a Substituted aromatic ring group; Ar each independently represents an aromatic ring group or a Patent Documents Substituted aromatic ring group; X each independently rep 0005 Patent Document 1: Japanese Laid-Open Patent resents a ligand with a formal charge of -1 or 0 (with the Publication No. H05-170693 proviso that the sum of the formal charges of three X is -2); 0006 Patent Document 2: Japanese Laid-Open Patent and in each independently represents an integer of 1 or 2. Publication No. H05-294.882 0007 Patent Document 3: International Publication No. WO 97/O17134

Non-Patent Documents 0008. Non-Patent Document 1: Journal of the American Chemical Society (U.S.), 1954, vol. 76, p. 300 SUMMARY OF THE INVENTION In the general formula 4. Ph each independently represent a Problems to be Solved by the Invention phenyl group. 0009. The production process using the hydrogen gas in 0012. The present applicant has filed, as a technique rel the presence of the bimetal catalysts provides solutions to all evant to the present invention, an application for a process for problems raised in the production process using the stoichio industrial production of a B-fluoroalcohol by reduction of an metric amount of hydride reducing agent, but lead to high C-fluoroester with a dramatic reduction in hydrogen pressure industrial manufacturing cost due to the need for special (hereinafter referred to as “relevant application'). The disclo US 2015/O 197473 A1 Jul. 16, 2015

Sure of the relevant application is Summarized as follows. In present invention; and the alkyl or Substituted alkyl group the relevant application, the B-fluoroalcohol is produced by used as R in the C-fluoroester of the relevant application can reaction of the C-fluoroester of the general formula 1 with be the same as the alkyl or substituted alkyl group used as R hydrogen gas in the presence of a specific ruthenium complex in the C-fluoroester of the general formula 1 of the present (as corresponding to the ruthenium complex of the following invention. general formula 2, especially the ruthenium complex of the 0016. The present invention is however clearly different following general formula 4 of the present invention). In from the relevant application in the kind of the raw substrate the production process of the relevant application, there is no material. The raw material substrate of the present invention need to use a high-pressure gas production facility as the corresponds to those in which one of R' and R of the C-fluo hydrogen pressure can preferably be set to 1 MPa or lower. roester as the raw material of the relevant application is a Further, the amount of the catalyst used can be reduced to a fluorine atom and the other is a halogen atom or a haloalkyl significantly low level (e.g. a substrate/catalyst ratio of group. It has been found that the C-fluoroaldehyde can be 20,000) in the production process of the relevant application selectively obtained as a hydrogen reduction intermediate as compared to the substrate/catalyst ratio (e.g. 1,000) in the from the raw material substrate of the present invention. conventional reduction processes of C-fluoroalcohols. It is Although the raw substrate material of the present invention is possible by these reductions in hydrogen pressure and cata included in the raw substrate material of the relevant appli lyst amount to largely reduce the production cost of the cation, not only the C-fluoroaldehyde but also a f-fluoroal B-fluoroalcohol. In addition, the reduction reaction is inert to cohol as a by-product are obtained in the present invention. unsaturated bonds (such as carbon-carbon double bond) in There is thus no limitation imposed by the present invention the production process of the relevant application so that it is on the relevant application. In the present invention, the by a preferred embodiment of the relevant application to carry produced f-fluoroalcohol can be easily separated by purifi out the reduction reaction in a functional-group-selective cation from the target C.-fluoroaldehyde because of the large manner (see Comparative Examples 1,2,3 and 4 as explained difference between the physical properties of the C-fluoroal later in the present specification). dehyde and the B-fluoroalcohol. There is thus no limitation 0013 The C-fluoroester as the raw substrate material of imposed by the relevant application onto the production pro the relevant application is represented by the following for cess of the C-fluoroaldehyde according to the present inven mula. tion. 0017. In this way, the present inventors have found the useful techniques for industrial production of the C-fluoroal O dehyde. The present invention is based on these findings. 0018. The present invention thus provides a production F R3 process of an O.-fluoroaldehyde as defined by the following SS aspects 1 to 9. R1 R2 (0019 Inventive Aspect 1 0020. A process for producing an O.-fluoroaldehyde of the In the above formula, RandR each independently represent general formula 3, comprising: reaction of an C-fluoroester a hydrogen atom, a halogen atom, an alkyl group, a Substi of the general formula 1 with hydrogen gas (H) in the tuted alkyl group, an aromatic ring group or a substituted presence of a ruthenium complex of the general formula 2 aromatic ring group; and R represents an alkyl group or a Substituted alkyl group. 0014 Further, the f-fluoroalcohol as the target product of 1. the relevant application is represented by the following for mula.

F Y-not where R' represents ahalogenatom or a haloalkyl group; and R represents an alkyl group or a substituted alkyl group, In the above formula, R' and R have the same meanings as those of the C-fluoroester. 2 0015 The present invention and the relevant application are similar to each other in that: the halogen atom used as R' and R in the C-fluoroester of the relevant application can be R -) the same as the halogen atom used as R' in the C-fluoroester R "\/N x \-ArP of the general formula 1 of the present invention; the alkyl or R N/SA substituted alkyl group used as RandR in the C-fluoroester R of the relevant application can be the same as the alkyl or ( /Y substituted alkyl group used as R in the C-fluoroester of the R /\ general formula 1 of the present invention; the aromatic ring A/ Ar or substituted aromatic ring group used as R' and R in the C-fluoroester of the relevant application can be the same as where Reach independently represents a hydrogen atom, an the aromatic ring or Substituted aromatic ring group used as R alkyl group, a Substituted alkyl group, an aromatic ring group in the ruthenium complex of the general formula 2 of the or a substituted aromatic ring group; Areach independently US 2015/O 197473 A1 Jul. 16, 2015 represents an aromatic ring group or a Substituted aromatic ring group; X each independently represents a ligand with a 5 formal charge of -1 or 0 (with the proviso that the sum of the O formal charges of three X is -2); and in each independently represents an integer of 1 or 2. F R3 XF F where R is an alkyl group,

6 O

F where R' has the same meaning as in the general formula 1). H. 0021 Inventive Aspect 2 F F 0022. The process according to Inventive Aspect 1, wherein the reaction is performed in the presence of a base. (0027. Inventive Aspect 5 0028. The process according to any one of Inventive 0023 Inventive Aspect 3 Aspects 1 to 4, wherein the reaction is performed at a hydro 0024. A process for producing an C-fluoroaldehyde of the gen pressure of 2 MPa or lower. general formula 3, comprising: reaction of an C-fluoroester (0029 Inventive Aspect 6 of the general formula 1 with hydrogen gas (H) in the 0030 The process according to any one of Inventive presence of a ruthenium complex of the general formula 4 Aspects 1 to 4, wherein the reaction is performed at a hydro gen pressure of 1 MPa or lower. 0031. Inventive Aspect 7 1. 0032. The process according to any one of Inventive Aspects 1 to 4, wherein the reaction is performed at a hydro gen pressure of 0.5 MPa or lower. 0033 Inventive Aspect 8) 0034. A process for producing an O.-fluoroaldehyde of the general formula 3, comprising: reaction of an C-fluoroester of the general formula 1 with hydrogen gas (H) in the where R' represents a halogen atom or a haloalkyl group; and presence of a ruthenium catalyst R represents an alkyl group or a substituted alkyl group,

NN/Sp P Ru

where R' represents ahalogenatom or a haloalkyl group; and R represents an alkyl group or a substituted alkyl group, where Ph represents a phenyl group,

where R' has the same meaning as in the general formula 1). 0035) Inventive Aspect 9 where R' has the same meaning as in the general formula 1). 0036. The process according to Inventive Aspect 8, wherein the ruthenium catalyst is a homogeneous catalyst. 0025 Inventive Aspect 4 0037. In the present invention, there is no need to use 0026. The process according to any one of Inventive special production equipment for hydrogen reduction of the Aspects 1 to 3, wherein the C-fluoroester of the general for C-fluoroester. There is also no need to use a high-pressure gas mula 1 is an O.-fluoroester of the general formula 5; and the production facility by adoption of the preferable hydrogen C-fluoroaldehyde of the general formula 3 is an O.-fluoroal pressure condition (1 MPa or lower) in the present invention. dehyde of the general formula I6 It is therefore possible to allow relatively easy industrial US 2015/O 197473 A1 Jul. 16, 2015

production of the C-fluoroaldehyde. Further, it is possible to matter of course, the alkyl group with Such an unsaturated directly obtain, as stable synthetic equivalents of the C-fluo bond or bonds may have any of the above Substituent groups.) roaldehyde (as explained later), not only a hydrate (as Depending on the kind of the Substituent group, the Substitu obtained by conventional techniques) but also a hemiacetal ent group itself may be involved in a side reaction. However, that is easy to purify and is of high value in synthetic appli the side reaction can be minimized by the adoption of suitable cations. reaction conditions. In the present specification, the term 0038. As mentioned above, the present invention provides “lower” means that the group to which the term is attached is Solutions to all problems in the conventional techniques and a group having 1 to 6 carbon atoms in the form of a straight establishes the significantly useful process for production of chain structure, a branched structure or a cyclic structure (in the C-fluoroaldehyde. the case of 3 or more carbons). The aromatic ring groups described above as “such substituent groups' may further be DETAILED DESCRIPTION OF THE INVENTION Substituted with a halogen atom, a lower alkyl group, a lower 0039. The production process of the C-fluoroaldehyde haloalkyl group, a lower alkoxy group, a lower haloalkoxy according to the present invention will be described below in group, a cyano group, a lower alkoxycarbonyl group, a car detail. It should be noted that: the scope of the present inven boxyl group, a protected carboxyl group, an amino group, a tion is not limited to the following examples; and various protected amino group, a hydroxyl group, a protected changes and modifications can be made as appropriate with hydroxyl group etc. As the protecting groups of the pyrrolyl, out impairing the scope of the present invention. All of the indolyl, carboxyl, amino and hydroxyl groups, there can be publications cited in the present specification, Such as prior used those described in “Protective Groups in Organic Syn art documents and patent documents e.g. published patents thesis”. Third Edition, 1999, John Wiley & Sons, Inc. and patent applications, are herein incorporated by reference. 0043 Among the C-fluoroester of the general formula 1. In the following description, the structures of the general the C-fluoroester of the general formula 5 is preferred formulas 1 to 6 are as defined above. because it is easily available on a large scale. In this case, the 0040. In the present invention, the C-fluoroaldehyde of the resulting C-fluoroaldehyde of the general formula I6 is general formula 3 is produced by reaction of the C-fluo important as an intermediate for pharmaceutical and roester of the general formula 1 with hydrogen gas (H) in agrichemical products. the presence of the ruthenium complex of the general formula 0044. In the ruthenium complex of the general formula 2. 2. Reachindependently representahydrogenatom, an alkyl 0041. In the C-fluoroester of the general formula 1), R' group, a Substituted alkyl group, an aromatic ring group or a represents a halogen atom or a haloalkyl group. Examples of Substituted aromatic ring group. Examples of the alkyl and the halogen atom are fluorine, chlorine, bromine and iodine. substituted alkyl groups as Rare the same as those of R in the Examples of the haloalkyl group are those obtained by sub C-fluoroester of the general formula 1). Examples of the stitution of any number of and any combination of the above aromatic ring group are those having 1 to 18 carbon atoms, halogen atoms onto any of carbon atoms of alkyl groups Such as: aromatic hydrocarbon groups as typified by phenyl, having 1 to 18 carbon atoms in the form of a straight-chain naphthyl and anthryl; and aromatic heterocyclic groups con structure, a branched structure or a cyclic structure (in the taining heteroatoms e.g. as nitrogen, oxygen or Sulfur as case of 3 or more carbons). Among others, preferred is a typified by pyrrolyl (including nitrogen-protected form), fluorine atom. pyridyl, furyl, thienyl, indolyl (including nitrogen-protected 0042. In the C-fluoroester of the general formula 1, R form), quinolyl, benzofuryl and benzothienyl. Examples of represents an alkyl group or a substituted alkyl group. the Substituted aromatic ring group are those obtained by Examples of the alkyl group are those having 1 to 18 carbon Substitution of any number of and any combination of Sub atoms in the form of a straight-chain structure, a branched stituents onto any of carbon or nitrogen atoms of the above structure or a cyclic structure (in the case of 3 or more car aromatic ring groups. As such Substituents, there can be used bons). Examples of the substituted alkyl group are those the same substituents as mentioned above. Two vicinal R obtained by substitution of any number of and any combina (except hydrogenatoms) may form a cyclic structure by cova tion of Substituents onto any of carbon or nitrogen atoms of lent bond of carbonatoms with or without a nitrogenatom, an the above alkyl groups. As such substituents, there can be oxygen atom or a Sulfur atom. In particular, it is preferable used: halogen atoms Such as fluorine, chlorine and bromine; that all of eight Rare hydrogen (in the case where each of two lower alkyl groups such as methyl, ethyl and propyl; lower n is 1). haloalkyl groups such as fluoromethyl, chloromethyland bro 0045 Areach independently represent an aromatic ring momethyl, lower alkoxy groups such as methoxy, ethoxy and group or a substituted aromatic ring group in the ruthenium propoxy; lower haloalkoxy groups such as fluoromethoxy, complex of the general formula 2. Examples of the aromatic chloromethoxy and bromomethoxy; cyano group; lower ring and Substituted aromatic ring groups as Arare the same alkoxycarbonyl groups such as methoxycarbonylmethyl, as those of R in the ruthenium complex of the general formula ethoxycarbonylethyl and propoxycarbonylpropyl; aromatic 2. In particular, it is preferable that all of four Arare phenyl. ring groups such as phenyl, naphthyl, anthryl, pyrrolyl (in 004.6 X each independently represent a ligand having a cluding nitrogen-protected form), pyridyl, furyl, thienyl, formal charge of -1 or 0 with the proviso that the sum of the indolyl (including nitrogen-protected form), quinolyl, benzo formal charges of three X is -2 (the formal charge of Ru is +2) furyl and benzothienyl; carboxyl group; protected carboxyl in the ruthenium complex of the general formula 2. groups; amino group; protected amino groups; hydroxyl Examples of the ligand having a formal charge of -1 or 0 are: group; and protected hydroxyl groups. In the Substituted alkyl ligands described in “Hegedus: Transition Metals in the Syn group, an arbitrary carbon-carbon single bond or bonds may thesis of Complex Organic Molecules (written by L. S. Hege be replaced by any number of and any combination of carbon dus, Second Edition, translated by Shinji Murai, p. 4-9, Tokyo carbon double bonds and carbon-carbon triple bonds. (As a Kagaku Dojin, 2001) and in “Organic Chemistry for Gradu US 2015/O 197473 A1 Jul. 16, 2015

ate Students Vol. II: Molecular Structure & Reaction/Organic ide, lithium ethoxide, Sodium ethoxide, ethoxide, Metal Chemistry (Ryoji Noyori et al., p. 389-390, Tokyo lithium isopropoxide, Sodium isopropoxide, potassium iso Kagaku Dojin, 1999)” etc.; BH; and RCO. (Herein, R propoxide, lithium tert-butoxide, sodium tert-butoxide and represents a hydrogen atom, an alkyl group or a substituted potassium tert-butoxide; organic bases such as triethylamine, alkyl group. Examples of the alkyl and substituted alkyl diisopropylethylamine, 4-dimethylaminopyridine and 1.8- groups as Rare the same as those of R in the C-fluoroester diazabicyclo5.4.0]undec-7-ene; alkali metal bis(trialkylsily of the general formula 1.) In particular, it is preferable that l)amides such as lithium bis(trialkylsilyl)amide, sodium bis the three ligands are hydrogen, chlorine and carbon monox (trialkylsilyl)amide and potassium bis(trialkylsilyl)amide: ide, respectively. and alkali metal borohydrides such as lithium borohydride, Sodium borohydride and potassium borohydrode. Among 0047. The reaction can be performed in the absence of the others, alkali metal alkoxides are preferred. Particularly pre base in the case where at least one of three X ligands is BH ferred are lithium methoxide, Sodium methoxide and potas in the ruthenium complex of the general formula 2. (As a sium methoxide. matter of course, it is alternatively feasible to perform the reaction in the presence of the base). Among others, it is 0054. It suffices to use the base in an amount of 0.001 mol preferable to use the ruthenium complex of the general for or more per 1 mol of the C-fluoroester of the general formula mula 4 in which the C1 ligand has been replaced by BH 1. The amount of the base is preferably 0.005 to 5 mol, more (H BH) (see International Application Publication No. preferably 0.01 to 3 mol, per 1 mol of the C-fluoroester of the 2011/048727). general formula 1. 0055 As it is assumed that the true catalytic active species 0048. Further, in each independently represent an integer is derived from the ruthenium catalyst of the general formula of 1 or 2 in the ruthenium complex of the general formula 2. 2 optionally in the presence of the base, the case where the In the case where n is 1, a nitrogen atom and a phosphorus catalytic active species (including isolated form) is prepared atom are bonded to each other via two carbon atoms in the in advance and used in the reduction reaction is included in ruthenium complex. In the case where n is 2, a nitrogenatom the scope of the present invention. and a phosphorus atom are bonded to each other via three carbon atoms in the ruthenium complex. It is preferable that 0056. It suffices to use the hydrogen gas in an amount of 1 each of two n is 2. mol or more per 1 mol of the C-fluoroester of the general formula 1. The hydrogen gas is preferably used in a large 0049. In the ruthenium complex of the general formula excessive amount, more preferably in a large excessive 4. Ph represents a phenyl group. amount under the following pressurized conditions. 0050. Among the ruthenium complex of the general for 0057 There is no particular limitation on the hydrogen mula 2, the ruthenium complex of the general formula 4 is pressure. The hydrogen pressure is preferably 2 to 0.001 MPa, preferred. There can be used, as the ruthenium complex of the more preferably 1 to 0.01 MPa. It is particularly preferred that general formula 4, a commercially available complex Ru the hydrogen pressure is 0.05 MPa or lower in order to maxi MACHOTM (manufactured by Takasago International Corpo mize the effects of the present invention. ration). 0.058 Examples of the reaction solvent usable in the reac 0051. The ruthenium complex of the general formula 2 tion are: aliphatic hydrocarbon Solvents such as n-hexane and can be prepared in a similar manner with reference to the n-heptane; aromatic hydrocarbon solvents such as toluene preparation process of the above complex Ru-MACHOTM. and Xylene; halogenated Solvents such as methylene chloride Further, the ruthenium complex of the general formula 2 can and 1,2-dichloroethane; ether solvents such as diethyl ether, be used even when water or organic solvent Such as toluene is 1.2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 2-meth contained in the ruthenium complex. It suffices that the purity yltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, of the ruthenium complex is 70% or higher. The purity of the diethylene glycol dimethyl ether and anisole; alcohol sol ruthenium complex is preferably 80% or higher, more pref vents such as , ethanol, n-propanol, isopropanol, erably 90% or higher. n-butanol, tert-butanol, n-pentanol, n-hexanol and cyclohex anol; amide solvents such as N,N-dimethylformamide and 0052. It suffices to use the ruthenium complex of the gen 1,3-dimethyl-2-imidazolidinone; nitrile solvents such as eral formula 2 in an amount of 0.000001 mol or more per 1 acetonitrile and propionitrile; dimethyl sulfoxide; and water. mol of the C-fluoroester of the general formula 1). The Among others, ether solvents and alcohol solvents are pre amount of the ruthenium complex of the general formula 2 ferred. Alcohol solvents are more preferred as the reaction is preferably 0.00001 to 0.005 mol, more preferably 0.00002 solvent. These reaction solvents can be used solely or in to 0.002 mol, per 1 mol of the C-fluoroester of the general combination of two or more thereof. It is particularly prefer formula 1. able to use methanol, ethanol or propanol, each of which is 0053 Examples of the base usable in the reaction are: easy to separate by fractional distillation, for production of alkali metal hydrogencarbonates such as lithium hydrogen the C-fluoroaldehyde of the general formula I6 (or the after carbonate, sodium hydrogencarbonate and potassium hydro mentioned synthetic equivalent thereof) as the preferred tar gencarbonate; alkali metal carbonates such as lithium carbon get compound. ate, Sodium carbonate and potassium carbonate; alkali metal 0059. It suffices to use the reaction solvent in an amount of hydroxides such as lithium hydroxide, and 0.01 L (liter) or more per 1 mol of the C-fluoroester of the ; tetraalkyl ammonium hydroxides Such general formula 1. The amount of the reaction solvent is as tetramethyl ammonium hydroxide, tetraethyl ammonium preferably 0.03 to 10L, more preferably 0.05 to 7 L. per 1 mol hydroxide, tetra-n-propyl ammonium hydroxide and tetra-n- of the C-fluoroester of the general formula 1). The reaction butyl ammonium hydroxide; alkali metal alkoxides such as can alternatively be performed under neat conditions without lithium methoxide, sodium methoxide, potassium methox the use of the reaction solvent. US 2015/O 197473 A1 Jul. 16, 2015

0060. It suffices that the reaction temperature is +150° C. intended to limit the present invention thereto. In the follow or lower. The reaction temperature is preferably +125 to -50° ing description, the abbreviations “Me”, “Ph', and “Et” refer C., more preferably +100 to -25° C. to methyl, phenyl and ethyl, respectively. 0061 Further, it suffices that the reaction time is 72 hours or less. As the reaction time varies depending on the raw Substrate material and reaction conditions, it is preferable to Example 1 determine the time at which there is seen almost no decrease of the raw substrate material as the end of the reaction while 0066. A pressure-proof reaction vessel of stainless steel monitoring the progress of the reaction by any analytical (SUS) was charged with 2.6 g (20 mmol. 1 eq) of C-fluo means such as gas chromatography, liquid chromatography roester of the following formula, 6.1 mg (purity: 94.2%; 9.5 or nuclear magnetic resonance. umol, 0.0005 eq) of ruthenium complex of the following 0062. The C-fluoroaldehyde of the general formula 3 can formula, 270 mg (5.0 mmol, 0.25 eq) of sodium methoxide be obtained by any ordinary post treatment operation for and 10 mL (0.5 L/mol) of methanol. organic synthesis. 0063 As the C-fluoroaldehyde of the general formula 3 is an aldehyde having directly bonded thereto a strong elec tron-attracting group, it is often the case that the C-fluoroal dehyde of the general formula 3 is obtained as stable syn thetic equivalents such as a self-polymerization product, hydrate and hemiacetal. (As a matter of course, the C-fluoro aldehyde of the general formula 3 can be obtained in the form of an aldehyde.) These synthetic equivalents are thus included in the C-fluoroaldehyde of the general formula 3 as the scope of the present invention. (The same applies to that of the general formula (6.) Herein, the alcohol function of the "Q/ \Ph hemiacetal is derived from the alkali metal alkoxide used as N H P the base, the alcohol used as the reaction solvent (see C N/YPhRu Example 6), the ester moiety of the raw material substrate (i.e. OR in the C-fluoroester of the general formula 1)) or the / No like. It is feasible to replace the alcohol function of the hemi p/ Y, acetal with an arbitrary alcohol function by shifting the equi librium of the reaction system upon the addition of the arbi trary alcohol during post treatment (see Example 8). (The The inside of the reaction vessel was replaced five times with “arbitrary alcohol function” refers to those having 1 to 18 hydrogen gas. The hydrogen pressure inside the reaction ves carbon atoms in the form of a straight-chain structure, a sel was then set to 1.0 MPa. The resulting solution inside the branched structure or a cyclic structure (in the case of 3 or reaction vessel was stirred all night at 35°C. It was confirmed more carbons).) Similarly, the hydrate can be obtained upon by F-NMR analysis of the reaction completed solution that the addition of water. the conversion rate of the reaction and the selectivity of 0064. Further, the crude product can be purified to a high C-fluoroaldehyde equivalent of the following formula were purity, as needed, by activated carbon treatment, fractional 96% and 62.3%, respectively. distillation, recrystallization, column chromatography or the like. It is convenient to recover the target compound by directly subjecting the reaction completed Solution to recov ery distillation in the case where the target compound has a OH low boiling point. In the case where the reaction is performed in the presence of the base, the relatively highly acidic target compound (such as self-polymerization product, hydrate, hemicacetal etc.) tends to form a salt or complex with the base and remain in the residue of distillation. In Such a case, it is feasible to obtain the target compound with high yield by It was also confirmed that the selectivity of B-fluoroalcohol of neutralizing the reaction completed Solution with an organic the following formula as an excessive reduction product was acid Such as formic acid, acetic acid, citric acid, oxalic acid, 37.7%. benzoic acid, methanesulfonic acid or paratoluenesulfonic acid oran inorganic acid Such as hydrogen chloride, hydrogen bromide, nitric acid or Sulfuric acid in advance, and then, F Subjecting the neutralized reaction completed Solution to recovery distillation (including recovery by washing the dis Xnot tillation residue with an organic solvent Such as diisopropyl F F ether). The H- and 'F-NMR data and gas chromatographic data of EXAMPLES the obtained C-fluoroaldehyde equivalent was in agreement 0065. The present invention will be described in more with those of the reference standard. For reference purposes, detail below by way of the following examples. It should be the reaction procedure and reaction results of the present noted that the following examples are illustrative and are not example are Summarized in the following scheme. US 2015/O 197473 A1 Jul. 16, 2015

Ru-MACHO (0.0005 eq)* F Sodium methoxide (0.25 eq) xnot O Methanol (0.5 L/mol) F F H2 (1.0 MPa) F Me -> O1 350 C. The H- and 'F-NMR data and gas chromatographic data of All night the obtained C-fluoroaldehyde equivalent was in agreement with those of the reference standard. For reference purposes, the reaction procedure and reaction results of the present example are Summarized in the following scheme.

Ru-MACHO (0.0005 eq)* Sodium methoxide (0.25 eq) O Methanol (0.5 L/mol) H (0.5 MPa) O1 350 C. All night

Conversion rate: 96% Selectivity: 37.7% Selectivity: 62.3%

Example 2 0067. A pressure-proof reaction vessel of stainless steel (SUS) was charged with 2.6 g (20 mmol. 1 eq) of C-fluo roester of the following formula, 6.1 mg (purity: 94.2%; 9.5 umol, 0.0005 eq) of ruthenium complex of the following formula, 270 mg (5.0 mmol, 0.25 eq) of sodium methoxide Conversion rate: 97% Selectivity: 27.6% and 10 mL (0.5 L/mol) of methanol. Selectivity: 72.4%

Example 3 0068 A pressure-proof reaction vessel of stainless steel (SUS) was charged with 5.8 g. (40 mmol. 1 eq) of C-fluo roester of the following formula, 13 mg (purity: 94.2%; 20 umol, 0.0005 eq) of ruthenium complex of the following formula, 540 mg (10.0 mmol, 0.25 eq) of sodium methoxide The inside of the reaction vessel was replaced five times with and 20 mL (0.5 L/mol) of methanol. hydrogen gas. The hydrogen pressure inside the reaction ves sel was then set to 0.5 MPa. The resulting solution inside the reaction vessel was stirred all night at 35°C. It was confirmed by F-NMR analysis of the reaction completed solution that the conversion rate of the reaction and the selectivity of C Me Ru C-fluoroaldehyde equivalent of the following formula were 97% and 72.4%, respectively.

OH The inside of the reaction vessel was replaced five times with hydrogen gas. The hydrogen pressure inside the reaction ves sel was then set to 1.0 MPa. The resulting solution inside the reaction vessel was stirred all night at 35°C. It was confirmed by F-NMR analysis of the reaction completed solution that It was also confirmed that the selectivity of B-fluoroalcohol of the conversion rate of the reaction and the selectivity of the following formula as an excessive reduction product was C-fluoroaldehyde equivalent of the following formula were 27.6%. 83% and 89.4%, respectively. US 2015/O 197473 A1 Jul. 16, 2015

The inside of the reaction vessel was replaced five times with OH hydrogen gas. The hydrogen pressure inside the reaction ves sel was then set to 0.8 MPa. The resulting solution inside the C Me reaction vessel was stirred all night at 38°C. It was confirmed by F-NMR analysis of the reaction completed solution that the conversion rate of the reaction and the selectivity of C-fluoroaldehyde equivalent of the following formula were It was also confirmed that the selectivity of B-fluoroalcohol of 91% and 83.0%, respectively. the following formula as an excessive reduction product was 10.6%. OH

F Et C Xnot F F The H- and 'F-NMR data and gas chromatographic data of It was also confirmed that the selectivity of B-fluoroalcohol of the obtained C-fluoroaldehyde equivalent was in agreement the following formula as an excessive reduction product was with those of the reference standard. For reference purposes, 17.0%. the reaction procedure and reaction results of the present example are Summarized in the following scheme. F

Ru-MACHO (0.0005 eq)* F X.noF Sodium methoxide (0.25 eq) O Methanol (0.5 L/mol) H2 (1.0 MPa) The H- and 'F-NMR data and gas chromatographic data of C Me the obtained C-fluoroaldehyde equivalent was in agreement O1 350 C. with those of the reference standard. For reference purposes, All night the reaction procedure and reaction results of the present 5.8 g. H example are Summarized in the following scheme. (40 mmol) \ H \-Ph N/ Yph Ru-MACHO (0.0001 eq)* N Potassium ethoxide (0.15 eq) K l, CO O Ethanol (0.4L/mol) p/ Ph H (0.8 MPa) OH o1 38° C. All night C Me + Cl : 14g H F F F F (100 mmol) \\ H \-Ph Conversion rate: 83% Selectivity: 10.6% N/ NPh Selectivity: 89.4% ''Q p/K Ph CO Example 4 OH

0069. A pressure-proof reaction vessel of stainless steel F Et - F (SUS) was charged with 14 g (100 mmol. 1 eq) of C-fluo roester of the following formula, 6.4 mg (purity: 94.2%; 10 Fx F - F X.F umol, 0.0001 eq) of ruthenium complex of the following formula, 840 mg (10.0 mmol, 0.1 eq) of potassium ethoxide Conversion rate: 91% Selectivity: 17.0% and 44 mL (0.4L/mol) of ethanol. Selectivity: 83.0%

H / V Ph O YN H PC Example 5 - Et Ru 0070 A pressure-proof reaction vessel of stainless steel (SUS) was charged with 8.9 g (50 mmol. 1 eq) of C-fluo SksF F O n OK”(INo roester of the following formula, 6.4 mg (purity: 94.2%; 10 p/ Y. umol, 0.0002 eq) of ruthenium complex of the following formula, 270 mg (5.0 mmol, 0.1 eq) of sodium methoxide and 25 mL (0.5 L/mol) of methanol. US 2015/O 197473 A1 Jul. 16, 2015

-continued F F OH F F F O1 Me + ^^. F F F F Conversion rate: 84% Selectivity:20.0% Selectivity: 80.0%

Example 6 0071. A pressure-proof reaction vessel of stainless steel (SUS) was charged with 61 g (480 mmol. 1 eq) of C-fluo The inside of the reaction vessel was replaced five times with roester of the following formula, 62 mg (purity: 94.2%; 96 hydrogen gas. The hydrogen pressure inside the reaction ves umol, 0.0002 eq) of ruthenium complex of the following sel was then set to 0.5 MPa. The resulting solution inside the formula, 3.3 g (48 mmol, 0.1 eq) of sodium ethoxide and 220 reaction vessel was stirred all night at 35°C. It was confirmed mL (0.5 L/mol) of ethanol. by F-NMR analysis of the reaction completed solution that the conversion rate of the reaction and the selectivity of C-fluoroaldehyde equivalent of the following formula were F Me 84% and 80.0%, respectively. O1 F F HQ / \ Ph N H R N / Ph /NCO PS C1 It was also confirmed that the selectivity of B-fluoroalcohol of the following formula as an excessive reduction product was The inside of the reaction vessel was replaced five times with 20.0%. hydrogen gas. The hydrogen pressure inside the reaction ves sel was then set to 0.9 MPa. The resulting solution inside the reaction vessel was stirred all night at 38°C. It was confirmed F F by F-NMR analysis of the reaction completed solution that the conversion rate of the reaction, the selectivity of C.-fluo roaldehyde equivalent (ethyl hemiacetal) of the following ^^.F F formula and the selectivity of C-fluoroaldehyde equivalent (methyl hemiacetal) of the following formula were 95%, 60.9% and 7.9%, respectively. The H- and F-NMR data and gas chromatographic data of the obtained C-fluoroaldehyde equivalent was in agreement with those of the reference standard. For reference purposes, OH the reaction procedure and reaction results of the present example are Summarized in the following scheme.

Ru-MACHO (0.0002 eq)* Sodium methoxide (0.1 eq) F F O Methanol (0.5 L/mol) H (0.5 MPa) Me F O1 350 C. All night It was also confirmed that the selectivity of B-fluoroalcohol of F F : the following formula as an excessive reduction product was 8.9 g H 31.2%. (50 mmol) \\ H \-Ph N/ NPh "Q F xnot p/K Ph CO F F US 2015/O 197473 A1 Jul. 16, 2015

The H- and 'F-NMR data and gas chromatographic data of the obtained C-fluoroaldehyde equivalents (ethyl hemiacetal OH and methyl hemiacetal) was in agreement with those of the reference standards. For reference purposes, the reaction pro cedure and reaction results of the present example are Sum marized in the following scheme. It was also confirmed that the selectivity of B-fluoroalcohol of Ru-MACHO (0.0002 eq)* the following formula as an excessive reduction product was 4.0%. Sodium ethoxide (0.1 eq) O Ethanol (0.5 L/mol) H2 (0.9 MPa) F F Me -ss O1 38°C. Xnot All night F F F F : 61 g H (480 mmol) Y/ H \-Ph The H- and 'F-NMR data and gas chromatographic data of the obtained C-fluoroaldehyde equivalent was in agreement with those of the reference standard. For reference purposes, the reaction procedure and reaction results of the present example are Summarized in the following scheme.

Ru-MACHO (0.00005 eq)* Sodium methoxide (0.2 eq) O Methanol (0.5 L/mol) H (0.9 MPa) F Me -- Conversion rate: 95% Selectivity: 7.9% Selectivity: 31.2% O1 350 C. Selectivity: 60.9% All night

: 130 g H (1.0 mol) V / \-Ph NQ PQ Example 7 N/ Ph 0072 A pressure-proof reaction vessel of stainless steel N (SUS) was charged with 130 g (1.0 mol. 1 eq) of C-fluoroester K CO of the following formula, 32 mg (purity: 94.2%; 50 umol. p/ Ph 0.00005 eq) of ruthenium complex of the following formula, 11 g (200 mmol, 0.2 eq) of sodium methoxide and 500 mL (0.5 L/mol) of methanol. OH

F Me -- F O1 Xnot F F F F Conversion rate: 89% Selectivity: 4.0% Selectivity: 96.0%

To the reaction completed solution, 4.5 g (75 mmol, 0.075 eq) of acetic acid was added. The resulting Solution was directly subjected to recovery distillation (oil bath temperature: ~63° C., Vacuum degree: ~1.6 kPa) so that the target compound was recovered in the form of a methanol solution thereof. The methanol solution was then subjected to fractional distillation (theoretical plate number: 20, distillation temperature: 93 The inside of the reaction vessel was replaced five times with C., atmospheric pressure). By this, 93 g of C-fluoroaldehyde hydrogen gas. The hydrogen pressure inside the reaction ves equivalent of the above formula was obtained. The yield of sel was then set to 0.9 MPa. The resulting solution inside the C-fluoroaldehyde equivalent was 67% as determined by inter reaction vessel was stirred all night at 35°C. It was confirmed nal standard method (internal standard material: C.C.C.-trif by F-NMR analysis of the reaction completed solution that luorotoluene, quantitative value: 87 g). The F-NMR purity the conversion rate of the reaction and the selectivity of of C-fluoroaldehyde equivalent was 98.0% or higher. The C-fluoroaldehyde equivalent of the following formula were contents of methanol content and water were 7.0% or lower 89% and 96.0%, respectively. and 0.05% or lower, respectively. US 2015/O 197473 A1 Jul. 16, 2015

Example 8 Ru-MACHO (0.0002 eq)* 0073. A pressure-proof reaction vessel of stainless steel Sodium methoxide (0.1 eq) (SUS) was charged with 154 g (1.2 mol. 1 eq) of C-fluoroester O Methanol (0.4L/mol) of the following formula, 150 mg (purity: 94.2%; 240 umol. H (0.9 MPa) F Me -> 0.0002 eq) of ruthenium complex of the following formula, O1 38° C. 6.5 g (120 mmol, 0.1 eq) of sodium methoxide and 530 mL 8 hours (0.4L/mol) of methanol.

OH

F Me + F

F F F F Conversion rate: 92% Selectivity: 8.8% Selectivity: 91.2%

To the reaction completed solution, 6.5 g (110 mmol, 0.09 eq) of acetic acid was added. The resulting Solution was directly subjected to recovery distillation (oil bath temperature: ~80° C., Vacuum degree: ~1.8 kPa) so that the target compound was The inside of the reaction vessel was replaced five times with recovered in the form of a methanol solution thereof. The hydrogen gas. The hydrogen pressure inside the reaction ves methanol solution was then subjected to fractional distillation sel was then set to 0.9 MPa. The resulting solution inside the (theoretical plate number: 10, distillation temperature: 106° reaction vessel was stirred for 8 hours at 38°C. It was con C., atmospheric pressure). (The distillation was continued firmed by F-NMR analysis of the reaction completed solu with the addition of 120 g (2.6 mol, 2.2 eq) of ethanol to the tion that the conversion rate of the reaction and the selectivity distillation still (i.e. the distillation residue containing the of C.-fluoroaldehyde equivalent (methyl hemiacetal) of the target compound) at the time the major portion of methanol following formula were 92% and 91.2%, respectively. was distilled.) By this, 97 g of C-fluoroaldehyde equivalent (ethyl hemiacetal) of the following formula was obtained.

OH OH

The contents of methanol, ethanol, C-fluoroaldehyde equiva It was also confirmed that the selectivity of B-fluoroalcohol of lent (methyl hemiacetal) of the above formula and C.-fluoro the following formula as an excessive reduction product was aldehyde equivalent (ethyl hemiacetal) of the above formula 8.8%. were determined by gas chromatographic analysis to be <0.1%, 14.8%, 0.1% and 84.5%, respectively. The yield of C-fluoroaldehyde equivalent (ethyl hemiacetal) was 48% in view of the gas chromatographic purity. F xnot F F Example 9 0074. A pressure-proof reaction vessel of stainless steel The H- and F-NMR data and gas chromatographic data of (SUS) was charged with 1.6 g (10 mmol. 1 eq) of C-fluo the obtained C-fluoroaldehyde equivalent was in agreement roester of the following formula, 0.9 mg (purity: 94.2%; 1.4 with those of the reference standard. For reference purposes, umol, 0.00014 eq) of ruthenium complex of the following the reaction procedure and reaction results of the present formula, 54 mg (1.0 mmol, 0.10 eq) of sodium methoxide and example are Summarized in the following scheme. 10 mL (1.0 L/mol) of methanol. US 2015/O 197473 A1 Jul. 16, 2015 12

-continued OH

F F Conversion rate: 24% Selectivity: 10.0% Selectivity: 90.0%

Comparative Example 1 0075. A pressure-proof reaction vessel of stainless steel The inside of the reaction vessel was replaced five times with (SUS) was charged with 53 g (480 mmol. 1 eq) of C-fluo hydrogen gas. The hydrogen pressure inside the reaction ves roester of the following formula, 15 mg (purity: 94.2%; 24 sel was then set to 0.5 MPa. The resulting solution inside the umol, 0.00005 eq) of ruthenium complex of the following reaction vessel was stirred all night at 36°C. It was confirmed formula, 8.4 g (120 mmol, 0.25 eq) of potassium methoxide by F-NMR analysis of the reaction completed solution that and 240 mL (0.5 L/mol) of methanol. the conversion rate of the reaction and the selectivity of C-fluoroaldehyde equivalent of the following formula were 24% and 90.0%, respectively. "Q/ \Ph O NN1 H PSYPh F - Me Ru O /INo H. H. p/ VPh

The inside of the reaction vessel was replaced five times with It was also confirmed that the selectivity of B-fluoroalcohol of hydrogen gas. The hydrogen pressure inside the reaction ves the following formula as an excessive reduction product was sel was then set to 1.0 MPa. The resulting solution inside the reaction vessel was stirred all night at 40°C. It was confirmed 10.0%. by gas chromatographic analysis of the reaction completed solution that the conversion rate of the reaction and the selec F F tivity of B-fluoroalcohol of the following formula were 100% and 97.6%, respectively. F F F Xnot The H- and F-NMR data and gas chromatographic data of F H the obtained C-fluoroaldehyde equivalent was in agreement with those of the reference standard. For reference purposes, For reference purposes, the reaction procedure and reaction the reaction procedure and reaction results of the present results of the present example are indicated in the following example are Summarized in the following scheme. scheme.

Ru-MACHO (0.00014 eq)* Ru-MACHO (0.00005 eq)* Sodium methoxide (0.1 eq) Potassium methoxide (0.25 eq) F F O Methanol (1.0 L/mol) Methanol (0.5 L/mol) H (0.5 MPa) H2 (1.0 MPa) Me Me -- H O1 36° C. 40° C. All night All night F F F H : : 1.6 g. H 53g (10 mmol) VN / H \-PhP (480 mmol) F. / \-Ph N/ NPh NQN/ PQYPh "Q ''Q K. CO p/ Ph p/K Ph CO US 2015/O 197473 A1 Jul. 16, 2015 13

-continued F Xnot Ru-MACHO (0.0004 eq)* F H Potassium methoxide (0.25 eq) Methanol (0.5 L/mol) Conversion rate: 100% Selectivity: 97.6% H2 (1.0 MPa) 37o C. All night The above reaction operation was repeated five times to obtain the reaction completed Solution equivalent to 2.4 mol 5.0 g of C.-fluoroester. Then, 36 g (600mmol, 0.25 eq) of acetic acid (40 mmol) was added to the reaction completed Solution. The resulting solution was directly subjected to recovery distillation (oil bath temperature: 55° C., vacuum degree: ~1.5 kPa) so that the target compound was recovered in the form of a methanol solution thereof. The distillation residue (i.e. the solid matter containing the target compound and potassium acetate) was washed by stirring with 200 mL of diisopropyl ether and filtered out. The thus-obtained solid matter was further washed with 200 mL of diisopropyl ether. In each of these washing operations, the target compound was recovered in F Me the form of a diisopropyl ether solution thereof. The recov Conversion rate: 92% ered solutions were combined and subjected to fractional Selectivity: 98.9% distillation (theoretical plate number: 20, distillation tem perature: 92 C., atmospheric pressure). By this, 158 g of B-fluoroalcohol of the above formula was obtained. The yield Comparative Example 3 of B-fluoroalcohol was 80%. The gas chromatographic purity of B-fluoroalcohol was 99.6%. The content of water was 0077. A pressure-proof reaction vessel of stainless steel O.05%. (SUS) was charged with 4.0 g (20 mmol. 1 eq) of C-fluo Comparative Example 2 roester of the following formula, 4.3 mg (purity: 94.2%; 6.7 umol, 0.0003 eq) of ruthenium complex of the following 0076 A pressure-proof reaction vessel of stainless steel formula, 270 mg (5.0 mmol, 0.25 eq) of sodium methoxide (SUS) was charged with 5.0 g (40 mmol. 1 eq) of C-fluo and 10 mL (0.5 L/mol) of methanol. roester of the following formula, 10 mg (purity: 94.2%; 16 umol, 0.0004 eq) of ruthenium complex of the following formula, 700 mg (10 mmol, 0.25 eq) of potassium methoxide and 20 mL (0.5 L/mol) of methanol. H / V O YN H pa" N1 NPh H M N F -Et Ru O YN H P<" O /Nco N1 NPh F Ph F Me Ru p/ Y, O /INco H Me p/ Y, The inside of the reaction vessel was replaced five times with hydrogen gas. The hydrogen pressure inside the reaction ves The inside of the reaction vessel was replaced five times with sel was then set to 1.0 MPa. The resulting solution inside the hydrogen gas. The hydrogen pressure inside the reaction ves reaction vessel was stirred all night at 40°C. It was confirmed sel was then set to 1.0 MPa. The resulting solution inside the by gas chromatographic analysis of the reaction completed reaction vessel was stirred all night at 37°C. It was confirmed solution that the conversion rate of the reaction and the selec by gas chromatographic analysis of the reaction completed tivity of B-fluoroalcohol of the following formula were 100% solution that the conversion rate of the reaction and the selec and 98.2%, respectively. tivity of B-fluoroalcohol of the following formula were 92% and 98.9%, respectively.

F F xnot xnot F Ph F Me

The reaction procedure and reaction results of the present The reaction procedure and reaction results of the present example are indicated in the following scheme for reference example are indicated in the following scheme for reference purposes. purposes. US 2015/O 197473 A1 Jul. 16, 2015 14

Ru-MACHO (0.0003 eq)* Ru-MACHO (0.0004 eq)* Sodium methoxide (0.25 eq) Sodium methoxide (0.25 eq) O Methanol (0.5 L/mol) Methanol (1.0 L/mol) H2 (1.0 MPa) H2 (1.0 MPa) Et -- F Et -- O1 40° C. 350 C. All night All night F Ph : 4.0 g H 38 g (20 mmol) V / \-Ph (250 mmol) NN/ H PQYPh / 'NC CO Ph / \Ph

F X.no F Ph Conversion rate: 100% Conversion rate: 100% Selectivity: 98.0% Selectivity: 98.2% The above reaction operation was repeated twice to obtain the reaction completed solution equivalent to 470 mmol of Comparative Example 4 C-fluoroester. Then, 7.1 g (120 mmol, 0.25 eq) of acetic acid and an appropriate amount of methoduinone (polymerization 0078. A pressure-proof reaction vessel of stainless steel inhibitor) were added to the reaction completed solution. The (SUS) was charged with 38 g (250 mmol. 1 eq) of C-fluo resulting solution was directly subjected to recovery distilla roester of the following formula, 64 mg (purity: 94.2%; 100 tion (oil bath temperature: ~63°C., vacuum degree: ~7.9 kPa) umol, 0.0004 eq) of ruthenium complex of the following so that the target compound was recovered in the form of a formula, 3.4 g (63 mmol, 0.25 eq) of sodium methoxide and methanol solution thereof. The distillation residue (i.e. the 250 mL (1.0 L/mol) of methanol. Solid matter containing the target compound and Sodium acetate) was washed by stirring with 400 mL of diisopropyl ether and filtered out. The thus-obtained solid matter was H / \ further washed with a small amount of diisopropyl ether. In O YN H P<" each of these washing operations, the target compound was N1 YPh recovered in the form of a diisopropyl ether solution thereof. F -Et Ru The recovered solutions were combined and subjected to O /INoo fractional distillation (theoretical plate number: 4, distillation F o V C temperature: 57 to 62° C., 13 to 12 kPa). By this, 40 g of p/ Ph B-fluoroalcohol of the above formula was obtained. The yield of B-fluoroalcohol was 78%. The gas chromatographic purity The inside of the reaction vessel was replaced five times with of B-fluoroalcohol was 98.9%. The H- and 'F-NMR mea hydrogen gas. The hydrogen pressure inside the reaction ves surement results of B-fluoroalcohol are indicated below. sel was then set to 1.0 MPa. The resulting solution inside the 0079 'H-NMR (reference material: MeSi, deuterated reaction vessel was stirred all night at 35°C. It was confirmed solvent: CDC1) 8 ppm; 2.21 (br. 1H), 3.81 (t, 2H), 5.55 (d. by F-NMR analysis of the reaction completed solution that 1H), 5.74 (m, 1H), 5.97 (m. 1H). the conversion rate of the reaction and the selectivity of 0080 F-NMR (reference material: CF, deuterated sol B-fluoroalcohol of the following formula were 100% and vent: CDOD) 8 ppm; 55.44 (m. 2F). 98.0%, respectively. I0081. As described above, there is no need to use special production equipment for hydrogen reduction of the C-fluo roester in the present invention. There is also no need to use a F high-pressure gas production facility by adoption of the pref erable hydrogen pressure condition (1 MPa or lower) in the XCOF v. present invention. It is therefore possible to allow relatively easy industrial production of the C-fluoroaldehyde. Further, it is possible to directly obtain, as stable synthetic equivalents of The reaction procedure and reaction results of the present the C-fluoroaldehyde, not only a hydrate (as by conventional example are indicated in the following scheme for reference techniques) but also a hemiacetal that is easy to purify and is purposes. of high value in synthetic applications. US 2015/O 197473 A1 Jul. 16, 2015

INDUSTRIAL APPLICABILITY acid, citric acid, oxalic acid, benzoic acid, methane Sulfonic acid and paratoluenesulfonic acidor at least one 0082. The C-fluoroaldehydes produced by the production kind of inorganic acid selected from the group consist method according to the present invention are usable as inter ing of hydrogen chloride, hydrogen bromide, nitric acid mediates for pharmaceutical and agrichemical products. and Sulfuric acid; and 1. A process for producing an O.-fluoroaldehyde of the Subjecting the neutralized reaction solution to recovery general formula 3, comprising: reaction of an C-fluoroester distillation. of the general formula 1 with hydrogen gas (H) in the 12. A process for producing an C-fluoroaldehyde of the presence of a homogeneous ruthenium catalyst, general formula 3, comprising: reaction of an C-fluoroester of the general formula 1 with hydrogen gas (H) in the presence of a homogeneous ruthenium catalyst and a base,

1. where R' represents a halogen atom or a haloalkyl group; and R represents an alkyl group or a substituted alkyl group, where R' represents a fluorine atom, a chlorine atom, a CF, group or a CFH group; and R represents an alkyl group,

where R' has the same meaning as in the general formula 1). 2. The process according to claim 1, wherein the reaction is performed in the presence of a base. where R' has the same meaning as in the general formula 1). 3. The process according to claim 2, wherein the base is an 13. The process according to claim 12, wherein the base is alkali metal alkoxide and is used in an amount of 0.005 to 5 lithium methoxide, Sodium methoxide or potassium methox mol per 1 mol of the C-fluoroester of the general formula 1. ide and is used in an amount of 0.01 to 3 mol per 1 mol of the 4. The process according to claim 1, wherein the C-fluo C-fluoroester of the general formula 1. roaldehyde of the general formula 3 is in the form of an 14. The process according to claim 12, wherein the C-fluo C-fluoroaldehyde equivalent of the following formula roaldehyde of the general formula 3 is in the form of an C-fluoroaldehyde equivalent of the following formula OH OH where R' and R have the same meanings as in the general formula 1. where R' and R have the same meanings as in the general 5. The process according to claim 1, wherein the reaction is formula 1. performed at a hydrogen pressure of 2 MPa or lower. 15. The process according to claim 12, wherein the reaction 6. The process according to claim 5, wherein the reaction is is performed at a hydrogen pressure of 1 MPa or lower. performed at a hydrogen pressure of 1 MPa or lower. 16. The process according to claim 15, wherein the reaction 7. The process according to claim 6, wherein the reaction is is performed at a hydrogen pressure of 0.5 MPa or lower. performed at a hydrogen pressure of 0.5 MPa or lower. 17. The process according to claim 12, wherein the reaction 8. The process according to claim 1, wherein the reaction is is performed at a temperature of +100 to -25°C. performed at a temperature of +125 to -50° C. 18. The process according to claim 1, wherein the reaction 9. The process according to claim 1, wherein the reaction is is performed with the use of methanol, ethanol or n-propanol performed with the use of an alcohol reaction solvent. as a reaction solvent. 10. The process according to claim 9, wherein the reaction 19. The process according to claim 18, wherein the reaction solvent is used in an amount of 0.03 to 10 L per 1 mol of the solvent is used in an amount of 0.05 to 7 L per 1 mol of the C-fluoroester of the general formula 1. C-fluoroester of the general formula 1. 11. The process according to claim 1, further comprising: 20. The process according to claim 12, further comprising: neutralizing a reaction Solution obtained after the comple neutralizing a reaction solution obtained after the comple tion of the reaction with at least one kind of organic acid tion of the reaction with at least one kind of organic acid Selected from the group consisting of formic acid, acetic Selected from the group consisting of formic acid, acetic US 2015/O 197473 A1 Jul. 16, 2015 16

acid, citric acid, oxalic acid, benzoic acid, methane Sulfonic acid and paratoluenesulfonic acidor at least one kind of inorganic acid selected from the group consist ing of hydrogen chloride, hydrogen bromide, nitric acid and Sulfuric acid; and Subjecting the neutralized reaction solution to recovery distillation.