TW201245133A - Process for the manufacture of fluoromethoxymalonic acid derivatives - Google Patents

Abstract

Process for the manufacture of a compound of formula R1OOC-CH(OCH2F)-COOR2 (I) or R3HNOC-CH(OCH2F)-CONHR4 (II) wherein R1, R2, R3, R4 are equal or different from each other and are independently selected from H; an alkyl group having from 1 to 10 carbon atoms which is optionally substituted by at least one halogen atom; an aralkyl group; or an aryl group, comprising reacting a compound of formula R1OOC-CH(OCH2X)-COOR2 (III) or R3HNOC-CH(OCH2X)-CONHR4 (IV) wherein X is a leaving group that can be substituted by nucleophilic substitution, and wherein R1, R2, R3, R4 have the same meaning as above, with at least one source of nucleophilic fluorine.

Description

201245133 VIII. OBJECTS OF THE INVENTION: [Technical Field] The present invention claims the priority of the European Application No. 11153966.4 filed on February 10, 2011, the entire content of which is hereby incorporated by reference. It relates to a process for the manufacture of a fluoromethoxymalonic acid derivative and to the use of this process in the manufacture of sevoflurane (CF3_CH(OCH2F)_cf3). The invention also relates to the use of a fluoromethoxymalonic acid derivative prepared according to the process. [Prior Art] Sevoflurane is an important volatile anesthetic and is particularly suitable for administration to patients during outpatient surgery. Sevoflurane is known to provide patients with a rate of rapid recovery from anesthesia. An additional advantage of this anesthetic is that it can be used as an inducer because it is not irritating and allows for rapid and smooth induction without apnea or throat (unlike the use of other inducers) . Smooth and accident-free induction is particularly valuable for pediatric anesthesia, where the use of intravenous inducers can cause numerous problems and is often contraindicated.

Many commercial processes for the preparation of sevoflurane utilize hexafluoroisopropanol (CF3-CH(OH)-CF3 (HFIP)) as a chemical intermediate and as a starting material. In most of these processes, unreacted HFIP will remain in the product mixture' and it is known that it is difficult to remove HFIP from the crude sevoflurane product in this technique. Total manufacturing costs are primarily based on expensive material costs for HFIP manufacturing. Several methods have therefore been developed to recover HFIP -5 - 201245133, for example from waste streams or by purification of crude sevoflurane, as exemplified in WO 2004/065340 and WO 2009/085247. Some other methods for synthesizing sevoflurane have also been described (difficult separation of sevoflurane and HFIP have been avoided), for example in US 5,969,193 and US 6,100,4 34, but the method is too complicated. Recently, the inventors of the present invention have discovered a method for producing sevoflurane, which comprises having a chemical formula of :^ΟΟ(:-(:Η((:Η2Χ)-(:ΟΟΙ12 or R3HNOC-CH(CH2X)- The fluorination of the substituted malonic acid derivative of CONHR4 is already in the international patent application EP 201 0/06 1 645 (now published as WO 201 1/01 8466) from Solvay Fluor GmbH. The above method is illustrated and incorporated herein by reference in its entirety, particularly in comparison to known methods in which HFIP is used as a chemical intermediate, which allows for improved throughput, high efficiency, and lower manufacturing costs. This international patent application also describes the use of the compound R1〇〇C-CH(Y)-COOR2 or R3HNOC-CH(Y)-CONHR4 (where Y is a leaving group 'which can be substituted by nucleophilic a method of producing the substituted malonic acid derivative by a mono-nucleophile, or a hydroxyl group having the formula RiOOC-CHiOHhCOORz or R3HNOC-CH(OH)-CONHR4 in the presence of a leaving group transfer agent Production of the substituted malonic acid derivative by a malonic acid derivative and a CH2-electrophile In this context, the object of the present invention is to provide a fluoromethoxymalonic acid compound starting from a compound having the formula Ri00C-CH(CH2X)-C00R2 or R3HNOC-CH(CH2X)-conhr4. Method of -6 -

S 201245133 SUMMARY OF THE INVENTION The present invention therefore relates to a process for the manufacture of a compound of formula (I) or (II)

Ri〇OC-CH(OCH2F)-COOR2 (I) R3HNOC-CH(OCH2F)-CONHR4 (II)

Ri and R2 are the same or different from each other, and are independently selected from H; an alkyl group having 1 to 10 carbon atoms which may be optionally substituted with at least one halogen atom; an aralkyl group; and an aryl group, R3 and R4 Are the same or different from each other, and are independently selected from H; an alkyl group having 1 to 10 carbon atoms which may be optionally substituted with at least one halogen atom; an aralkyl group; and an aryl group, the method comprising the chemical formula Compound of (III) or (IV) Ri〇OC-CH(OCH2X)-COOR2 (III) R3HNOC-CH(OCH2X)-CONHR4 (IV) wherein X is a leaving group which may be substituted by nucleophilic substitution a group, R1 and R2 are the same or different from each other, and are independently selected from H; an alkyl group having 1 to 10 carbon atoms which may be optionally substituted with at least one halogen atom; an aralkyl group; and an aryl group, R3 And R4 are the same or different from each other, and are independently selected from H; an alkyl group having 1 to 10 carbon atoms which may be optionally substituted with at least one halogen atom; an aralkyl group; and an aryl group, 201245133 and at least one Source reaction of nucleophilic fluorine. In the present invention, the compound of the formula (I) or (II) is also referred to as a fluoromethoxymalonic acid derivative. The advantages of the present invention include, inter alia, the fact that it is simple, efficient, and low cost, while allowing the preparation of compounds (1) and (II), ie, fluoromethoxypropene, starting from the above compounds of formula (III) or (IV). Diacid derivative. This is especially advantageous because the fluoromethoxy compound is more stable than the above compounds of formula (III) and (IV), especially the corresponding halogenated methoxy compounds (e.g., chloromethoxy compounds). This method also has the advantage of allowing, for example, the preparation of the formula (III) or (IV) according to the method described in the unpublished international patent application EP 20 1 0/06 1 645, which is incorporated herein by reference. a chloromethoxy derivative which is easier to prepare than the corresponding fluoromethoxy compound and which is then initiated from a more stable intermediate, in a second step according to the invention Conversion from a chloromethoxy compound to a fluoromethoxy compound is carried out. For the purposes of the present invention, the term "aryl" refers to an aromatic ring group such as phenyl and naphthyl' and phenyl and naphthyl substituted by at least one halogen atom. The term "aralkyl" refers to an aromatic cyclic group substituted with an alkyl group, such as tolyl, biphenyl, and the like.

In the method of the present invention, the source of the nucleophilic fluorine is preferably a fluoride, more preferably a fluoride selected from the group consisting of inorganic fluorides and organic fluorides, especially selected from the group consisting of metal fluorides and organic fluorides. For example, a fluorinated key, more particularly selected from the group consisting of alkali metal fluorides and ammonium fluorides, is most preferably selected from alkali metal fluorides. A suitable example of a metal fluoride is silver fluoride (I) (A g F s -8- 201245133

And fluorine (silver (11) (A g F 2 ). Suitable examples of alkali metal fluorides are sodium fluoride (NaF), potassium fluoride (KF), lithium fluoride (LiF), and fluorinated planing ( CsF) is advantageously potassium fluoride. Examples of ammonium fluorides are nH4F and R4NF, wherein R is an alkyl group such as methyl, ethyl, propyl or butyl. In the process of the invention, in the chemical formula ( In I) to (IV), r, r2, R3 and R4 may be the same or different from each other, and are preferably selected from the group consisting of ruthenium, optionally at least one halogen atom. a substituted C1-C4 alkyl group, and an aryl group (e.g., a phenyl group). R1, r2, R3 and R4 are more preferably independently selected from the group consisting of: H, optionally at least one halogen Atom-substituted linear or branched C1-C4 alkyl; particularly preferred is selected from the group consisting of: H; methyl 'ethyl, n-propyl and isopropyl groups, each The group may be optionally substituted with at least one halogen atom; very preferably selected from the group consisting of hydrazine; methyl and ethyl groups, each group being Desirably, at least one halogen atom is substituted. It is especially preferred that h and R2 or R3 and R4 are the same; most preferably, R! and R2 are the same and are oxime or ethyl. R3 and R4 are preferably The same and are oxime or ethyl. In the chemical formulae (ΙΠ) and (IV) used in the method of the present invention, X may be typically selected from the group consisting of halogens other than fluorine; and oxygen-containing functional groups. ' Preferred is selected from the group consisting of bromine, chlorine, iodine, 0-toluenesulfonate (OTo), oxime-methanesulfonate (OMe), 0-trifluoromethanesulfonate (OTf), and Ο-trimethyl Mercapto (0TMS), more preferably selected from the group consisting of chlorine, Oto, OMe and 0TMS, especially chlorine. 201245133 In a particularly good aspect, 'R1 and R2 are germanium atoms and are fluorene-based, so they have a chemical formula (I And the compounds of (III) are diacids HOOC-CH(OCH2F)-COOH and H00C-CH(0CH2C1)-C00H, respectively. In another particularly preferred aspect, R, and R2 are ethyl and X is chlorine, so The compounds of formula (I) and (III) are the diesters EtOOC-CH(0CH2F)-C00Et and Et00C-CH(0CH2Cl)-C00Et, respectively. The process of the invention is typically carried out in the liquid phase. This method is usually carried out in the presence of a solvent, preferably a polar solvent, more preferably a polar aprotic solvent. Examples of suitable solvents are alkyl nitriles or alkyl dinitrites or alkylenes. Dicarbonitriles (such as acetonitrile), dialkyl sulfoxides (such as dimethyl hydrazine (DMS0)), dialkyl hydrazines (such as dimethylhydrazine (DMS02) 'cyclic guanidines (such as guanidine) Formamides (eg dimethylformamide (DMF)), pyrrolidone (eg N.methyl.2. pyrrolidone (NMF) 'ketones (eg acetone), esters (eg ethyl acetate), rings Ethers (e.g., tetrahydrofuran) may optionally include hydrogen as one or more substituents of a halogenated carbon (e.g., dichloromethane), an aromatic compound (e.g., toluene), a fluorine-substituted aromatic compound (e.g., CF3). -Toluene), as well as ionic liquids (such as those described in U.S. Patent Application Publication No. 20090242 840). In this paragraph, the term "alkyl" preferably means methyl, ethyl, n-propyl or isopropyl; the term "alkyl" preferably means methyl, ethyl or propyl. . In the process of the invention, the fluoride is generally used in at least one stoichiometric amount, in particular wherein the molar ratio of the fluoride to the compound of the formula (ΠΙ) or (IV) is from 4:1 to 1: Especially from 3: to 1: 1

S -10- 201245133 ' Especially from 2: 1 to 丨: 1, for example about 1.5. In the process of the invention, the reaction is generally carried out under atmospheric pressure. Temperatures often range from 40 ° C to 200 °. (:, usually from 50. (: to 150 ° C, more usually from 70 ° C to 160 ° C. Most usually, the reaction is carried out near the reflux temperature, which will therefore depend on the nature of the solvent used. The method of the invention The duration of the reaction is typically from 15 minutes to 24 hours, in many cases from 30 minutes to 12 hours, for example from 1 to 8 hours. In the process of the invention, it can be in an acid, in an acid In a neutral or alkaline medium, it is preferred to carry out the reaction in a neutral or basic medium, more preferably in a neutral medium. The medium can be added by adding in the art. Any suitable pH modifier known to be acidified, neutralized or alkalized. Acidic pH modifiers such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, ascorbic acid 'citric acid, or tartaric acid. Alkaline pH modification The agent is, for example, sodium hydroxide, potassium hydroxide, soda ash, ammonia, or triethylamine. In the process of the invention, the starting material of formula (III) or (IV) can also be acidified prior to its use, Neutralization or alkalization, preferably neutralization or alkalization' Preferably, the neutralization is carried out using the same pH modifier as described above. Thus, in the process of the invention, the starting material can be further washed, in particular with water or with an organic solvent, and dried prior to its use. An embodiment of the invention may be present in the presence of at least one alkali metal halide other than an alkali metal fluoride, for example in an alkali metal iodide such as potassium iodide (KI) or iodide (C s I) Next, and preferably -11-201245133 is the addition of at least one other alkali metal halide in the presence of potassium iodide, and in particular the alkali metal iodide 'especially potassium iodide, which is advantageous for accelerating the reaction. Indeed 'alkali metal iodine The compound (such as KI or Csi) dissolves better than KF and dissolves faster (more soluble) than KF, thereby initiating the reaction. Usually about 〇1 to 0.5 mol per mol of fluoride, in many cases The use of such added alkali metal halides from 〇.〇5 to 〇.2 mol per m〇l of fluoride, for example about 0.1 mol per mol of fluoride, is used in a further embodiment The method of producing a compound of formula (I) or (II) as defined above may further comprise by a separation process (e.g., distillation, precipitation, and/or crystallization, preferably by distillation, especially by vacuum) Fractionation) The separation of the compound of formula (I) or (II) from the reaction mixture. In another embodiment, the process of the invention may further comprise recovering at least a portion of the reaction medium, particularly by-products of recovery. A typical by-product is a compound R of the following formula (V) or (VI), OOC-CH(OH)-COOR2 (V) R3HNOC-CH(OH)-CONHR4 (VI) wherein Ri, R2, R3 and R4 Have the same meaning as defined above. In the present invention, these compounds having the chemical formulas (V) and (VI) are also referred to as hydroxymaleic acid derivatives. A first possibility is, for example, converting a hydroxyl group of the compounds of formula (V) or (VI) to a leaving group which can be substituted by nucleophilic substitution, in particular a hydrazine-tosylate ( OTo), 0-A

S -12- 201245133 Sulfonate (OMe), 〇-trifluoromethanesulfonate (〇Tf) or 〇-trimethylsulfonyl (OTMS). This type of conversion can be easily carried out by reacting a hydroxyl group with p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trimethylchlorodecane, or bis(trimethyldecyl)acetamide, respectively. It is also possible to replace the hydroxyl groups of the compounds of formula (V) or (VI) with a halogen other than a parent, especially bromine, chlorine, or iodine, more particularly chlorine. Such a reaction is described in detail in the International Patent Application No. 20 1 0/06 1 645, the entire disclosure of which is hereby incorporated by reference. This is especially advantageous as it allows for an increase in the final total yield of the compound of formula (I) or (II). The compounds of the formulae (I) and (Π) prepared according to the invention can be used for the preparation of chemical compounds, in particular chemical compounds other than sevoflurane, more particularly for the preparation of biologically active compounds, in particular for the preparation of medicaments. A structural unit of a chemical compound or agrochemical. Malonic acid and malonate derivatives are indeed commonly used as building blocks for the preparation of biologically active compounds, for example as in WO 20 1 0/1 3 3 724, WO 20 1 0/1 1 8992 or WO 2010/ 1 0 9468 As explained in the above. In the present invention, the expression "structural unit" is preferably intended to mean a component which is suitable for being integral with at least one other block, i.e., reacting with at least another organic compound to form a new compound. The organic starting material, the new compound includes more carbon atoms than the original organic compound used as the starting material. Accordingly, the present invention provides a process for the manufacture of a chemical compound other than sevoflurane, in particular for the manufacture of a biologically active compound, in particular for the preparation of a pharmaceutical or agrochemical compound, the process comprising providing a chemical formula prepared according to the above process. a step of the compound of (I) or (II)-13-201245133, and further comprising reacting a compound of formula (I) or (II) with at least one other reactant to provide the chemical compound other than sevoflurane A first step, especially for the manufacture of biologically active compounds, especially for the preparation of pharmaceutical or agrochemical compounds. The compounds of the formulae (1) and (II) prepared according to the invention can also be used as foam blowing agents, in particular for the production of foams, and in particular for polyurethane foams. Accordingly, the present invention also provides a process for making a foam, especially a plastic foam, and more preferably a polyurethane foam, wherein the chemical formula (I) is used as a foam blowing agent. The foamable starting material, such as a foamed thermoplastic or a precursor material (for example, a polyol composition and a composition comprising a compound having an isocyanate group) is converted into a foam in the presence of a compound of (II) . The compounds of formula (I) and (II) prepared in accordance with the present invention may also be used in the manufacture of sevoflurane (CF3-CH(OCH2F)-CF3). In a preferred embodiment, the invention therefore also relates to a process for the manufacture of sevoflurane (CF3-CH(OCH2F)-CF3), the process comprising the steps of: U) manufacturing a chemical formula according to the method as defined above a compound of (I) or (II), and (b) fluorinating the compound of formula (I) or (π). This method is particularly advantageous because the compounds of the formulae (I) and (II), ie the fluoromethoxy compounds, correspond to the compounds of the formulae (III) and (IV), and in particular to other halo The oxy compound is especially stable than the chloromethoxy compound, -14-

S 201245133 In general, the fluorination reaction is carried out in the liquid phase. In this embodiment, the fluorination reaction is typically carried out using a fluorinating agent. Preferably, the fluorinating agent permits fluorination of a halogen, a hydroxy group, a carboxy group, and other oxygen containing functional groups, particularly a carbon-oxygen group. For example, a typical example of the fluorinating agent is sulfur tetrafluoride (SF4): diethylaminosulfur trifluoride (DAST), dimethylaminosulfur trifluoride (DMAST), 4-tert-butyl-2,6-di Methylphenyl trifluoride (

FluoleadTM) and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor), the best fluorinating agent for SF4. The production of SF4 can be carried out according to the procedure described in British Patent No. 1,374,054. According to one embodiment of the invention, fluorination with SF4 is carried out in the presence of anhydrous HF. HF is typically used in an amount of from about 1 to about 1 mole, and more preferably from about 1 to about 500 moles per mole of 8 to 4. In this embodiment, the fluorination can be carried out in the presence or absence of a solvent. For example, suitable solvents may be selected from aromatic hydrocarbons (for example benzene, toluene or xylene): aliphatic hydrocarbons (for example pentane or hexane); halogenated hydrocarbons (for example dichloromethane 'chloroform, ethylene dichloride) Hydrofluorocarbon (eg, l,l,3,3-pentafluorobutane (Solkane® 3 65 nlfc)): perfluorocarbon (eg perfluorocyclohexane): ethers (eg diethyl ether, dibutyl) Ether or tetrahydrofuran): and mixtures thereof. Among them, halogenated hydrocarbons are preferred, and dichloromethane is preferred. These solvents may be used singly or in combination as a mixture. If appropriate, the solvent is usually from 50% to 99% by weight, based on the total weight of the reaction medium, preferably from 60% to 99% by weight, more preferably based on the weight of the solvent. Use from 7 5 % to 9 9 % -15 - 201245133. If the reaction mixture is a liquid under the reaction conditions, no solvent is required. It is also possible to use the starting compound or the reaction product C as a solvent if desired. The use of sevoflurane as a solvent system is particularly preferred. Preferably, if sevoflurane is used as a solvent, it is present in the reaction mixture from the beginning. The pressure and temperature of the fluorination reaction are typically selected such that the reaction mixture remains in the liquid phase. For example, it is usually equal to or higher than 30. (:, preferably, the fluorination reaction is carried out at a temperature equal to or higher than 40 ° C, more preferably equal to or higher than 50 ° C. It is generally equal to or lower than 90 ° C, preferably It is equal to or lower than 80 ° C, more preferably equal to or lower than 70. The temperature is preferably in the range of from 50 ° C to 70 ° C. In general, the fluorination reaction is The pressure is advantageously carried out at a pressure equal to or greater than about 5 bar (absolute enthalpy), preferably equal to or greater than about 1 bar (absolute enthalpy) up to or less than about 25 bar (absolute enthalpy). Computationally, converting one C(O) group to a CF2 group consumes one molecule of SF4. Converting a C-OR丨 or C-OR2 group to a CF group and converting an OCH2X group to an OCH2F group Like a group, a half molecule of SF4 is consumed. Therefore, in the fluorination step according to this embodiment, the range of the molar ratio of the compound of the formula (I) or (II) to SF4 is preferably from 1: 3 to 1: 5, particularly preferably from 1: 3 · 5 to 1: 4.5. In a particularly preferred embodiment, the method for producing sevoflurane can be further stepped a) before (b) and, between, and / or after the purification step comprises, preferably is between steps (a) and (b) at least both after step (b).

-16- S 201245133 The advantages of this particularly preferred embodiment include, inter alia, the possibility of reducing the risk of the sevoflurane product being contaminated by impurities, in particular by halogenated and more particularly by chlorinated impurities. Indeed, if sevoflurane is prepared by direct fluorination of a chloromethoxy derivative, chlorinated impurities may be present in the resulting product. In contrast, if the chloromethoxy derivative is first converted to the corresponding fluoromethoxy compound of formula (I) or (II) before fluorination to sevoflurane, using an intermediate purification step, then Chlorine is removed prior to one step and the final product will be less contaminated. The presence of an additional purification step will improve the removal of chlorine-containing impurities. The purification steps according to this particularly preferred embodiment are typically separated from the reaction mixture by a separation process (e.g., distillation, precipitation, and/or crystallization), preferably by distillation, particularly vacuum fractionation, respectively. A compound of formula (I) or (II) and/or sevoflurane. In the process for producing sevoflurane, the compound of the formula (I) or (II) prepared in the step (a) is preferably a diacid HOOC-CH(OCH2F)-COOH or has a fluorination reaction. a diacetate of the formula RiOOC-CH(OCH2F)-COOR2, wherein Ri and R2 are the same or different from each other, and are independently selected from an alkyl group having 1 to 10 carbon atoms which may be optionally substituted by at least one halogen atom, Aralkyl or aryl, especially a diester of formula (I) wherein R! and R2 are ethyl, ie Et00C_CH(OCH2F)-COOEt. In one embodiment, the compound of formula (1) or (Π) prepared in step (a) is diacid H00C-CH(0CH2F)-C00H or diamine H2NOC-CH(OCH2F)-CONH2, preferably Is a diacid H00C· -17- 201245133 CH(OCH2F)-COOH » In a further preferred embodiment, the invention therefore relates to a process for the manufacture of sevoflurane (CF3-CH(OCH2F)-CF3), The method comprises the steps of: (a) producing a compound of formula (I) or (II)

Ri00C-CH(0CH2F)-C00R2 (I) R3HNOC-CH(OCH2F)-CONHR4 (II) wherein R1 and R 2 are the same or different from each other and are independently selected from those which are optionally substituted by at least one halogen atom An alkyl group having 1 to 10 carbon atoms; an aralkyl group; and an aryl group; preferably, R1 and R2 are an ethyl group, and R3 and R4 are the same or different from each other, and are independently selected from the group consisting of An alkyl group having 1 to 10 carbon atoms substituted by at least one halogen atom; an aralkyl group; and an aryl group, ie a fluoromethoxymalonic acid diester according to the method of the invention as defined in the present invention Or diamine, (b) Hydrolyzing the diester or diamine of step (a) to the corresponding diacid H00C-CH(0CH2F)-C00H, and (C) fluorinating the diacid. This method has the following advantages. First, the fluoromethoxymalonic acid (or diamine) can be formed according to the method of the present invention. This product has good stability, and then it can be Easily converted to the corresponding diacids. The fluorination of these diacids is more prevalent than the fluorination of such diesters.

S 201245133. It is preferred to produce the diester in step (a). This process is therefore particularly advantageous for the manufacture of sevoflurane on an industrial scale. In this further preferred embodiment, the hydrolysis of step (b) of the diester or diamine to form the corresponding diacid can be carried out in the presence of water in any of the art known in the art for the hydrolysis of esters or guanamines. It is carried out under the conditions of, or by transesterification with an organic acid, in particular with a fatty acid (for example like acetic acid or trifluoroacetic acid) or even with an aromatic carboxylic acid. The hydrolysis reaction can be catalyzed by acid or city, especially in the practice of using water. Typical acids are, for example, dilute mineral acids (such as dilute HC1 or H2S〇4), or organic acids (such as p-toluenesulfonic acid (pTSA) or small amounts of trifluoromethanesulfonic acid (or trifluoromethanesulfonic acid). ). Typical urban systems are, for example, sparse inorganic cities (such as NaOH). The hydrolysis reaction is usually carried out under atmospheric pressure, or under vacuum and under heating, for example, from 40 ° C to 100 ° C, typically at reflux temperature. In this further preferred embodiment, the fluorination step (c) can be carried out under the same conditions as above. In another specific embodiment, the process for making sevoflurane may further comprise a separation process (eg, distillation, precipitation, and/or crystallization, preferably by distillation, particularly by fractional distillation), The sevoflurane is isolated from the reaction mixture obtained according to any of the preferred embodiments disclosed herein. The methods of the invention and preferred embodiments can be carried out batchwise or continuously. The process can be carried out in any suitable reactor (e.g., in a high pressure -19-201245133 kettle). The invention is further described below, and the scope is not limited thereto. In the event that any of the disclosures of the patents, patent applications, and publications cited herein are inconsistent with the description of the present application to the extent that it may render the term unclear, the description should be preferred. EXAMPLES Example 1: Preparation of diethyl-2-(fluoromethoxy)malonate from acidic diethyl-2-(chloromethoxy)malonate 18 g (0.08 mol) from Production of diethyl-2-(chloromethoxy)malonate having pH 1 (acidity is derived from hydrolysis of SOC12 to h2so4 during aqueous separation and purification in its manufacturing reaction (ie, after chloromethylation)) 55 ml of acetonitrile, 7 g of KF (0.12 mol) and 2 g of KI (0.012 mol) were placed in a 100 ml Teflon® three-necked flask equipped with a reflux condenser. The mixture was boiled and refluxed under a N2- atmosphere. After the reaction, all the solids were removed by filtering the reaction medium sample by a syringe filter before being injected into the gas chromatograph, and then subjected to gas chromatography (GC). After about 6 hours, GC analysis showed The starting material has been nearly quantitatively reacted to form about 55 wt% of diethyl-2-(fluoromethoxy)malonate and about 37 wt% of hydroxymaleate as a by-product. These compounds were characterized by gas chromatography coupled with mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR).

-20-S 201245133 The product was purified by evaporating the solvent with a rotary evaporator, followed by vacuum fractionation. Its l3C NMR spectrum measured at 126 MHz in deuterated chloroform showed the following peak (ppm): 14.0 (q > 2 C ) - 62.5 (t > 2 C ) , 76.8 (d, lC) > 102.3 ( t, J = 220.6 Hz > 1 C ) - 165.4 ( s > 2 ° C ). Its 19F NMR spectrum measured at 471 MHz in deuterated chloroform showed the following peak (ppm): -154.3 (t > J = 5 4.9 Hz, 1 F). The structure of the product was also confirmed by i-NMR together with the MS spectrum. Example 2: Preparation of diethyl-2-(fluoromethoxy)malonate from pre-neutralized diethyl-2-(chloromethoxy)malonate under the same conditions as in Example 1. Example 2, except that before the reaction was carried out, the still acidic 2-ethyl (chloromethoxy) malonate from the production was first washed with 10 wt% NaOH solution, then with water, and then used. Na2S04 is dry. After about 2 hours, GC analysis showed that the starting material had reacted almost quantitatively, forming about 78 wt% of diethyl-2-(fluoromethoxy)malonate and about 22 wt% as a pair. The hydroxy maleate of the product. Example 3: Preparation of diethyl-2-(fluoromethoxy)malonate from acidic diethyl-2-(chloromethoxy)malonate in the presence of NEt3 in the same conditions as in Example 1. Example 3 was carried out, except that 4 ml of NEt3 was added twice to the reaction mixture, the first time the reaction mixture had reached reflux conditions to accelerate the reaction, and the second time after i hours 21 - 201245133 was obtained and examples. Similar results in 2.

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Claims (1)

201245133 VII. Patent application scope: 1. A method for producing a compound of formula (I) or (II) Ri00C-CH(0CH2F)-C00R2 (I) R3HNOC-CH(OCH2F)-CONHR4 (II) where Ri and R2 They are the same or different from each other, and are independently selected from H; an alkyl group having 1 to 10 carbon atoms which may be optionally substituted by at least one halogen atom; an aralkyl group; and an aryl group, R3 and R4 are the same as each other Or different, and independently selected from H; an alkyl group having from 1 to 10 @ atoms, optionally substituted by at least one halogen atom; an aralkyl group; and an aryl group, the method comprising the formula (III) Or the compound of (IV) R, OOC-CH(OCH2X)-COOR2 (III) R3HNOC-CH(OCH2X)-CONHR4 (IV) wherein X is a leaving group which can be substituted by nucleophilic substitution, Ri and R 2 are the same or different from each other, and are independently selected from H; an alkyl group having 1 to 10 carbon atoms which may be optionally substituted by at least one halogen atom; an aralkyl group; and an aryl group, R 3 and R 4 are each other The same or different, and independently selected from H; optionally taken by at least one halogen atom Alkyl group having 1 to 10 carbon atoms; aralkyl; and aryl, is reacted with at least one source of nucleophilic fluorine. 2. The method of claim 1, wherein X is selected from the group consisting of halogens other than fluorine of -23 to 201245133; and the group consisting of oxygen-containing functional groups, preferably selected from the group consisting of bromine, chlorine, iodine, and 0- Tosylate (〇To), 0-methanesulfonate (OMe), 0. triflate (OTf) and 〇-trimethylsulfonyl (0TMS). 3. The method of claim 2, wherein X is selected from the group consisting of chlorine, OTo, OMe, and 0TMS»4. The method of claim 3, wherein X is chlorine. 5. The method of claim 1, wherein R! and R2 or R3 and R4 are respectively the same and are selected from the group consisting of H, methyl, ethyl, n-propyl or isopropyl. 6. The method of claim 5, wherein R3 and R4 are selected from hydrazine or ethyl. 7. The method of claim 1, wherein the source of the nucleophilic fluorine is fluoride. 8. The method of claim 7, wherein the source of the nucleophilic fluorine is potassium fluoride. 9. The method of claim 1, wherein the reaction is carried out in the presence of a solvent. 10. The method of claim 1, wherein the reaction is carried out in the presence of at least one alkali metal halide other than an alkali metal fluoride. The method of claim 1 wherein the reaction is Performed in a neutral or alkaline medium. 12. The method of claim 1, wherein the method further comprises the step of separating the compound of formula (I) or (II) from the reaction mixture by vacuum fractionation from -24-S 201245133. The use of a compound of the formula (I) or (II) as prepared in any one of claims 1 to 12, as a building block for the preparation of a biologically active compound. A use of a compound of the formula (I) or (II) as prepared in any one of claims 1 to 12, which is a foam blowing agent. A method for producing sevoflurane (CF3-CH(OCH2F)-CF3), comprising the steps of: (a) producing a chemical formula of the method of any one of claims 1 to 12 ( a compound of I) or (II), and (b) fluorinating the compound of formula (I) or (II). 1 6 - The method of claim 15 wherein the fluorinating agent is SF4. 17. The method of claim 15 wherein the compound of formula (I) or (Π) prepared in step (a) is a diacid HOOC-ch(och2f)-cooh or a decylamine h2noc-ch (och2f)-conh2. 1 8 The method of claim 17, wherein the compound is diacid H00C-CH(0CH2F)-C00H. 19. The method of claim 15 wherein the compound of formula (I) or (Π) prepared in step (a) is a diester of formula Ri00C-CH(0CH2F)-C00R2 or has Diamines of the formula R3HNOC-CH(OCH2F)-CONHR4 wherein -25-201245133 1 and R2 are identical or different from each other and independently selected from 1 to 10 optionally substituted with at least one halogen atom An alkyl group, an aralkyl group and an aryl group of one carbon atom, R3 and R4 are the same or different from each other, and are independently selected from an alkyl group having 1 to 10 carbon atoms which may be optionally substituted by at least one halogen atom. An aralkyl group and an aryl group, and wherein before the fluorination step (b), the diester or diamine is hydrolyzed to the corresponding diacid hooc-ch(och2f)-cooh. 20. The method of claim 19, wherein the compound of formula (I) or (Π) prepared in step (a) is a diester of the formula Ri〇OC-CH(OCH2F)-COOR2, wherein Ri and R2 are the same or different from each other, and are independently selected from an alkyl group having 1 to 10 carbon atoms which may be optionally substituted by at least one halogen atom; an aralkyl group and an aryl group, preferably wherein Ri And R2 is an ethyl group. -26- S 201245133 Four designated representative drawings: (1) The representative representative of the case is: No (2) The representative symbol of the representative figure is a simple description ··201264133 If there is a chemical formula in the case, please reveal the characteristics that can best show the invention. Chemical formula: no-4-S