cas 28523-86-6, Sevoflurane | Articles data

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Novel green and environment-friendly process applied to sevoflurane production
The invention discloses a novel green and environment-friendly process applied to sevoflurane production, which is characterized in that hexafluoroisopropyl methyl ether and fluorine gas are subjected to substitution reaction to generate sevoflurane, and the reaction is carried out in a micro-channel reactor. The process comprises the steps: synchronously pumping hexafluoroisopropyl methyl ether and fluorine gas into two inlets of the microreactor unit through a metering pump respectively; enabling the mixture to pass through a layer of nickel base material and then enter a micro-channel mixer for mixing and reaction; and finally, entering a collecting tank through the nickel base material and an outlet of the microreactor unit. The sevoflurane product produced by the reactor is stable in quality, the production process is green and environment-friendly, the reaction process is easy to control, and the reactor is suitable for industrial production.
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Paragraph 0026-0039

(2022/01/20)

Preparation method of chloromethyl hexafluoroisopropyl ether
The invention relates to a preparation method of chloromethyl hexafluoroisopropyl ether. In particular, the present invention relates to the preparation method of the chloromethyl hexafluoroisopropylether, wherein a solvent used in a reaction comprises chloromethyl hexafluoroisopropyl ether. The preparation method introduces a self product as the solvent, not only solves the solidification phenomenon generated in a reaction system in the reaction process, but also greatly improves the purity of the product, and is advantageous for industrial production.
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Paragraph 0025; 0026

(2018/11/03)

Production of fluormethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether
A process for removing water from a mixture comprising hydrogen fluoride and water, said process comprising: a) providing a mixture comprising hydrogen fluoride and water; and b) removing water from the mixture as a constant boiling mixture with hydrogen fluoride.
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Paragraph 0054

(2015/09/28)

PROCESS FOR THE MANUFACTURING OF SEVOFLURANE
The present invention provides a method for forming sevoflurane comprising (i) combining chlorosevo ether, a nucleophilic fluoride reagent, and a solvent comprising sevoflurane to form an initial reaction mixture and (ii) reacting the initial reaction mixture to form additional sevoflurane relative to the amount of sevoflurane present in the initial reaction mixture. The present disclosure is also directed to a method for forming sevoflurane, comprising: initiating a reaction between chlorosevo ether and a nucleophilic fluoride reagent in an initial reaction mixture further comprising a solvent comprising sevoflurane, thereby forming additional sevoflurane relative to the amount of sevoflurane present in the initial reaction mixture.
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Paragraph 0027

(2013/03/26)

Manufacture of hexafluoroisopropanol
Hexafluoroisopropanol (CF3CHOHCF3) is manufactured in two steps from monochloromalonic acid or monochlomalonic acid esters by a reaction with a fluorinating agent, notably SF4, to form CF3CHClCF3 which is hydrolyzed to form CF3CHOHCF3. The hexafluoroisopropanol can be used as such, or, preferably, it is further reacted to form Sevoflurane, an anesthetic. Compounds of the formula CF3-CH(OY)-CF3 wherein Y is OTs, OMe, OTf or OTMS are also described.
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Page/Page column 0087-0088

(2013/08/28)

Process for the manufacture of substituted malonic acid derivative compounds and of Sevoflurane
Process for the manufacture of a substituted malonic acid derivative of formula (I) or (II): ???????? R1OOC-CH(OCH2F)-COOR2?????(I) ???????? R3HNOC-CH (OCH2F)-CONHR4?????(II) by reaction of a malonic acid derivative of formula (III) or (IV): ???????? R1OOC-CHOH-COOR2?????(III) ???????? R3HNOC-CHOH-CONHR4?????(IV) with at least one CH2-electrophile selected from the group consisting of (a) bis(fluoromethyl)ether and (b) formaldehyde activated with HF and at least one additional activator. The compounds of formula (I) and (II) can be fluorinated to produce Sevoflurane.
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Paragraph 0031

(2013/07/19)

Process for the manufacture of sevoflurane
A process for the manufacture of Sevoflurane CF3—CH(OCH2F)—CF3 which comprises (a) manufacturing a substituted malonic acid derivative of formula (I): R1OOC—CH(OCH2X)—COOR2 or of formula (II): R3HNOC—CH(OCH2X)—CONHR4, wherein X is OH or a leaving group which can be substituted by nucleophilic substitution and wherein R1, R2 R3, R4, equal to or different from each other, are independently selected from the group consisting of H, an alkyl group having from 1 to 10 carbon atoms which is optionally substituted by at least one halogen atom, an aralkyl group, and an aryl group; and (b) further reacting said malonic acid derivative as intermediate for the manufacture of Sevoflurane CF3—CH(OCH2F)—CF3.
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Page/Page column 5

(2012/06/30)

Process for Producing Fluoromethyl Hexafluoroisopropyl Ether
There is provided according to the present invention a process for producing fluoromethyl hexafluoroisopropyl ether ((CF3)2CH—O—CH2F), including: reacting bisfluoromethyl ether with hexafluoroisopropyl alcohol in a solvent substantially immiscible with hydrogen fluoride in the presence of a catalytic amount of a strong acid selected from sulfuric acid and any other acids stronger in acidity than sulfuric acid. The process of the present invention enables industrial production of the fluoromethyl hexafluoroisopropyl ether without using hydrogen fluoride or a large amount of sulfuric acid and thereby without causing a large amount of waste as a by-product.
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Page/Page column 3-4

(2012/03/08)

METHOD OF SYNTHESIZING SEVOFLURANE
The present invention provides a method of synthesizing sevoflurane, which comprises the following steps: taking hexafluoro isopropanol as the starting material and reacting it with trioxymethylene (or paraformaldehyde) in the presence of acid to generate dihexafluoro isopropanol formal derivatives, adding anhydrous aluminum trihalide to generate halomethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether, then reacting the halomethyl compound with metal fluoride to form the sevoflurane. The method is of low cost, and the reaction condition is easy to implement, and produces sevoflurane in large scale.
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Page/Page column 6

(2011/04/25)

METHOD OF SYNTHESIZING SEVOFLURANE
The present invention provides a method of synthesizing sevoflurane, which comprises the following steps: taking hexafluoro isopropanol as the starting material and reacting it with trioxymethylene (or paraformaldehyde) in the presence of acid to generate dihexafluoro isopropanol formal derivatives, adding anhydrous aluminum trihalide to generate halomethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, then reacting the halomethyl compound with metal fluoride to form the sevoflurane. The method is of low cost, and the reaction condition is easy to implement, and produces sevoflurane in large scale.
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Page/Page column 4

(2011/05/08)

PROCESS FOR THE MANUFACTURE OF SEVOFLURANE
A process for the manufacture of Sevoflurane CF3-CH(OCH2F)-CF3 which comprises (a) manufacturing a substituted malonic acid derivative of formula (I) or (II): R1OOC-CH(OCH2X)-COOR2 (I) or R3HNOC-CH (OCH2X)-CONHR4 (II) wherein X is OH or a leaving group which can be substituted by nucleophilic substitution and R1, R2, R3, R4 equal to or different from each other, 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, (b) further reacting said malonic acid derivative as intermediate for the manufacture of Sevoflurane CF3-CH(OCH2F)-CF3
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Page/Page column 13

(2011/02/24)

METHOD OF PRODUCING FLUOROMETHYL 1,1,1,3,3,3-HEXAFLUOROISOPROPYL ETHER
The present application provides a preparation method of fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether by reacting CH2FX with 1,1,1,3,3,3-hexafluoroisopropanol in the presence of acid-binding agent. The reaction can be also preformed in the presence of solvent and/or phase-transfer catalyst. The present method has the advantages of simple reaction, manageable control condition, high material conversion and product yield, and the product can be easily separated. The obtained fluoromethyl 1,1,1,3,3,3-hexafluoroisoprophyl ether can be used as a safe inhalation anesthetics.
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Page/Page column 8

(2011/08/03)

METHOD OF PRODUCING FLUOROMETHYL 1,1,1,3,3,3-HEXAFLUOROISOPROPYL ETHER
The present invention provides a preparation method of fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether by reacting CH2FX with 1,1,1,3,3,3-hexafluoroisopropanol in the presence of acid-binding agent. The reaction can be also preformed in the presence of solvent and/or phase-transfer catalyst. The present method has the advantages of simple reaction, manageable control condition, high material conversion and product yield, and the product can be easily separated. The obtained fluoromethyl 1,1,1,3,3,3-hexafluoroisoprophyl ether can be used as a safe inhalation anesthetics.
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Page/Page column 5

(2011/10/31)

NOVEL CARBOXYLIC ACID ESTER, USE OF THE SAME, AND METHOD FOR PRODUCING THE SAME
The present invention provides a process for producing a novel compound, i.e., α-chloromethoxycarboxylic acid ester represented by General Formula (1): (CF3)2C (OCH2Cl) COOR, wherein R is a hydrocarbon group which may be substituted with at least one atom selected from the group consisting of halogen, oxygen, nitrogen, and sulfur atoms, comprising reacting an α-methoxycarboxylic acid ester represented by General Formula (2): (CF3)2C(OCH3)COOR, wherein R is as defined above, with molecular chlorine; and a process for producing 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether represented by a chemical formula (CF3)2CH(OCH2F), comprising fluorinating and decarboxylating the α-chloromethoxycarboxylic acid ester. According to the present invention, 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether (sevoflurane), which is known as a compound having an anesthetic property, can be produced efficiently and at a low cost.
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Page/Page column 6

(2010/08/18)

NOVEL ALPHA-FLUOROMETHOXYCARBOXYLIC ESTER, PROCESS FOR PRODUCING THE ALPHA-FLUOROMETHOXYCARBOXYLIC ESTER, AND PROCESS FOR PRODUCING SEVOFLURANE
The present invention provides a novel α-fluoromethoxycarboxylic ester represented by Formula (1): (CF3)2C(OCH2F)COOR wherein R is a hydrocarbon group that may have a substituent; a process for producing 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether, the process including hydrolyzing and decarboxylating the α-fluoromethoxycarboxylic ester; and a process for producing an α-fluoromethoxycarboxylic ester represented by Formula (1): (CF3)2C (OCH2F)COOR, the process including reacting an α-hydroxycarboxylic ester represented by Formula (2): (CF3)2C(OH)COOR with a halofluoromethane in the presence of an alkaline compound. According to the present invention, 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether (sevoflurane), which is known as an anesthetic compound, can be efficiently produced at low cost.
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Page/Page column 4-5

(2010/02/17)

NOVEL ALPHA -FLUOROMETHOXYCARBOXYLIC ESTER, PROCESS FOR PRODUCING THE ALPHA -FLUOROMETHOXYCARBOXYLIC ESTER, AND PROCESS FOR PRODUCING SEVOFLURANE
The present invention provides a novel α-fluoromethoxycarboxylic ester represented by Formula (1): (CF3)2C(OCH2F)COOR wherein R is a hydrocarbon group that may have a substituent; a process for producing 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether, the process including hydrolyzing and decarboxylating the α-fluoromethoxycarboxylic ester; and a process for producing an α-fluoromethoxycarboxylic ester represented by Formula (1) : (CF3)2C(OCH2F)COOR, the process including reacting an α-hydroxycarboxylic ester represented by Formula (2): (CF3)2C(OH)COOR with a halofluoromethane in the presence of an alkaline compound. According to the present invention, 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether (sevoflurane), which is known as an anesthetic compound, can be efficiently produced at low cost.
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Page/Page column 7-8

(2009/04/23)

PROCESS FOR THE PREPARATION OF FLUOROMETHYL 2,2,2-TRIFLUORO-1-(TRIFLUOROMETHYL) ETHYL ETHER
The present invention refers to a process for the preparation of fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether (sevoflurane) which includes a step that consists of reacting hexafluoroisopropanol with a formaldehyde equivalent selected among paraformaldehyde or 1,3,5-trioxane, a chlorinating agent selected from the group consisting of oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, sulfuryl chloride and thionyl chloride, and a strong acid selected from the group consisting of concentrated or fuming sulfuric acid resulting in the formation of the intermediate sevochlorane which is converted to sevoflurane in a second step which consists of reacting sevochlorane with an alkali metal fluoride, or a linear or branched chain tetra-alkyl quarternary ammonium fluoride in the presence of a sub-stoichiometric quantity of an alkali metal iodide, or a linear or branched alkyl chain tetra-alkyl quarternary ammonium iodide, preferably in a solvent.
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Page/Page column 26-29

(2008/06/13)

Direct electrophilic monofluoromethylation
Monofluoromethyl derivatives of various nucleophiles have been synthesized using a new electrophilic monofluoromethylating reagent developed. The S-(monofluoromethyl)diarylsulfonium tetrafluoroborate has been shown to be effective for the introduction of an electrophilic monofluoromethyl group into C, S, O, N, and P nucleophiles. This methodology has been expanded for the synthesis of various biologically important compounds.
Prakash, G. K. Surya,Ledneczki, Istvan,Chacko, Sujith,Olah, George A.
p. 557 - 560
(2008/04/12)

PURIFICATION OF FLUOROMETHYL 1,1,1,3,3,3-HEXAFLUOROISOPROPYL ETHER (SEVOFLURANE)
Crude sevoflurane product comprising unacceptably high levels of HFIP can be purified by combining the crude sevoflurane product with sufficient water to produce a multiphase mixture, fractionally distilling the multiphase mixture, and removing substantially pure sevoflurane from the distilling multiphase mixture. It is emphasized that this abstract is provided to comply with the rules requiring an abstract which will allow a searcher or other reader quickly to ascertain the subject matter of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the appended issued claims.
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Page/Page column 9

(2008/06/13)

Preparation of Monofluoromethyl Ether
The invention relates to a method for preparing a monofluoromethyl ether, in particular fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (i.e. Sevoflurane), wherein hexafluoroisopropanol is used as a reactant reacting with trioxymethylene in the presence of fluorine-containing catalyst.
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Page/Page column 2

(2008/06/13)

METHOD FOR THE PREPARATION OF SEVOFLURANE
A method for the preparation of (CF3)2CHOCH2F (Sevoflurane) is presented, which comprises providing a mixture of (CF3)2CHOCH2Cl, potassium fluoride, water, and a phase transfer catalyst and reacting the mixture to form (CF3)2CHOCH2F.
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Page/Page column 13-14

(2008/06/13)

PROCESS FOR PURIFYING FLUOROMETHYL 1,1,1,3,3,3-HEXAFLUOROISOPROPYL ETHER
A process for purifying fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether containing at least 1,1,1,3,3,3-hexafluoroisopropyl alcohol. The purifying process comprises the treatment of causing fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether containing at least 1,1,1,3,3,3-hexafluoroisopropyl alcohol, to contact with a basic aqueous solution. The basic aqueous solution contains a basic substance in an amount providing a chemical equivalent ratio of the basic substance to 1,1,1,3,3,3-hexafluoroisopropyl alcohol being within a range of not less than 1.
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Page/Page column 4-5

(2008/06/13)

Diisopropylethylamine mono(hydrogen fluoride) for nucleophilic fluorination of sensitive substrates: Synthesis of sevoflurane
Diisopropylethylamine mono(hydrogen fluoride) (8), which can be prepared by addition of two equivalents of diisopropylethylamine to the complex diisopropylethylamine tris(hydrogen fluoride) (7), is shown to be an effective and selective nucleophilic fluorinating reagent when applied to halogen-exchange reactions of chloromethyl ethers, in particular the conversion of 1,1,1,3,3,3-hexafluoroisopropyl chloromethyl ether (3) to the volatile anesthetic sevoflurane (1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether). The amine portion of the reagent does not react with the starting material to give a troublesome quaternary ammonium salt, as is the case for the species formed by addition of two equivalents of triethylamine to triethylamine tris(hydrogen fluoride). These particular chloromethyl ether substrates require a 1:1 stoichiometry of diisopropylethylamine to hydrogen fluoride to give useful rates of reaction and yields when solventless conditions are desired. Two other complexes, diisopropylethylamine bis(hydrogen fluoride) and 7, are ineffective for conversion of 3 to sevoflurane.
Kudzma,Huang,Lessor,Rozov,Afrin,Kallashi,McCutcheon,Ramig
p. 11 - 16
(2007/10/03)

Synthetic method for the fluoromethylation of alcohols
A method for fluoromethylating halogenated alcohols. The method includes the step of providing an alpha-halogenated alcohol of the formula R1C(CX3)2OH, wherein R1is selected from the group consisting of hydrogen and alkyl groups. The alpha-halogenated alcohol is reacted with a first compound of the formula CH2(OR2)2in the presence of an acid catalyst to form an acetal. The resulting acetal is then chlorinated with a chlorinating agent to form a chloride compound of the formula R1C(CX3)2OCH2Cl. The chloride compound is then converted to a fluoride compound of the formula R1C(CX3)2OCH2F using a fluorinating agent.
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(2008/06/13)

Method for fluoromethylation of alcohols via halogenative decarboxylation
A method for fluoromethylation of an alcohol via halogenative decarboxylation. The method includes the step of reacting an alcohol of the formula R1C(CX3)2OH with an alpha-haloester of the formula X2CH2CO2R2to form an alpha-alkoxy ester, wherein R1is selected from the group consisting of hydrogen and alkyl groups, wherein R2is selected from the group consisting of hydrogen and alkyl groups, wherein X, at each occurrence, is independently selected from the group consisting of hydrogen, bromine, fluorine, and chlorine, and wherein X2is selected from the group consisting of bromine and chlorine. The resulting alpha-alkoxy ester is saponified to form an alpha-alkoxy acid which is heated at reflux with lead tetraacetate and a chlorinating agent to form a chloride compound of the formula R1C(CX3)2OCH2Cl. The chloride compound is converted to a fluoride compound of the formula R1C(CX3)2OCH2F with a fluorinating agent.
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(2008/06/13)

A safe and efficient process for the synthesis of the inhalation anesthetic sevoflurane
A novel method for the synthesis of 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane (sevoflurane) is described. Starting from commercially available 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), the process involves a novel, safe and efficient fluoro-methylation protocol in a two-step, one-vessel procedure. The method avoids many of the hazards and complications of the current process for sevoflurane manufacture. The new method is easily scaled up to afford 10-kg batches of 99.4% pure sevoflurane.
Ramakrishna, Kornpati,Behme, Chris,Schure, Ralph M.,Bieniarz, Christopher
p. 581 - 584
(2013/08/07)

An efficient and environmentally friendly synthesis of the inhalation anesthetic sevoflurane
We report a new, high yield, single vessel synthesis of the general anesthetic sevoflurane. The new synthesis consists of a two-stage fluoromethylation of hexafluoroisopropanol. In the first stage, hexafluoroisopropanol is chloromethylated using aluminum trichloride and trioxane. In the second stage fluorine exchange is carried out using potassium fluoride and poly(ethylene glycol). Sevoflurane is distilled directly from the reaction vessel yielding material of 99.95% purity. The overall yield of the process is 65-70%.
Bieniarz, Christopher,Behme, Chris,Ramakrishna, Kornepati
p. 99 - 102
(2007/10/03)

Method of preparing monofluoromethyl ethers
A method of preparing fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (sevoflurane) and structurally related monofluoromethyl ethers in which the monochloromethyl ether precursor thereof is reacted with a sterically hindered tertiary amine hydrofluoride salt.
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(2008/06/13)

Method for the preparation of fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether
Fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether is prepared by reacting bromine trifluoride and methyl 1,1,1,3,3,3-hexachloro-2-propyl ether or chloromethyl 1,1,1,3,3,3-hexachloro-2-propyl ether. The mixed fluorochloro ether intermediates having the formula of STR1 (wherein x+y=3, a+b=3, and Z=H Cl, or F) are converted to fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether by reactions with bromine trifluoride.
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(2008/06/13)