1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 30 grams of sevoflurane (0.15 mols) was cooled to about −36.2° C. under nitrogen. Approximately 10 mL of a 3.0 M solution of CH3Li/CH2(OC2H5)2 (0.03 mols of the base) was added over 29 minutes while maintaining a temperature between about −37.5° C. and about −30.5° C. After addition of the methyl lithium was complete, the addition funnel was washed with a few mL of diethoxymethane. The reaction mixture was then stirred for approximately 20 minutes at a temperature between about −39° C. and about −35° C. A vacuum (0.3 mmHg) applied to the reaction mixture for approximately 1 hour, 46 minutes while the reaction mixture was held at a temperature between about −38.5° C. and about 10.7° C. afforded approximately 30.0 grams of a crude liquid product. GC analysis of this liquid showed it contained 22.8% compound A, 47.1% unreacted sevoflurane, and 29.7% diethoxymethane.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 30 grams of sevoflurane (0.15 mols) was cooled to about −36.2° C. under nitrogen. Approximately 10 mL of a 3.0 M solution of CH3Li/CH2(OC2H5)2 (0.03 mols of the base) was added over 29 minutes while maintaining a temperature between about −37.5° C. and about −30.5° C. After addition of the methyl lithium was complete, the addition funnel was washed with a few mL of diethoxymethane. The reaction mixture was then stirred for approximately 20 minutes at a temperature between about −39° C. and about −35° C. A vacuum (0.3 mmHg) applied to the reaction mixture for approximately 1 hour, 46 minutes while the reaction mixture was held at a temperature between about −38.5° C. and about 10.7° C. afforded approximately 30.0 grams of a crude liquid product. GC analysis of this liquid showed it contained 22.8% compound A, 47.1% unreacted sevoflurane, and 29.7% diethoxymethane.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a reaction similar to Example 1a, about 30.0 grams of sevoflurane (0.15 mols) was placed in a 250-mL 3-neck flask under nitrogen, and cooled in a dry ice-acetone bath to about −0.1° C. Approximately 50 mL of a 3.0 M solution of CH3Li/CH2(OC2H5)2 (0.15 mols of the base) was added to the sevoflurane over about 2 hours and 38 minutes while maintaining a reaction temperature between about −8° C. and about +9° C. A violent, exothermic reaction was observed. The reaction mixture was then stirred at about −2° C. to about +6° C. for an additional 30 minutes. A vacuum (3.3 mm Hg) applied to the reaction mixture for approximately 2 hours, 17 minutes while the reaction mixture was held at a temperature between about −30° C. and about −17° C. yielded about 17.9 grams of a crude liquid product. The crude liquid contained 17.9% sevoflurane compound A, 70.6% CH2(OC2H5)2, and other side products.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The steps of combining the crude sevoflurane with water in an amount sufficient to produce a multiphase mixture comprising an aqueous phase and a sevoflurane phase, contacting the aqueous phase and the sevoflurane phase with each other under conditions and for a time sufficient to extract at least a portion of the HFIP from the sevoflurane phase into the aqueous phase, and separating the phases of the multiphase mixture without fractional distillation, may, if necessary, be repeated. Purified sevoflurane comprising an acceptable amount of HFIP is then isolated. The removal of HFIP from the crude sevoflurane occurs without contacting the crude sevoflurane with an aqueous basic solution. to produce a multiphase mixture the sevoflurane phase with each other under conditions and for a time sufficient to extract at least a portion of the HFIP from the sevoflurane phase into the aqueous phase separating the phases of the multiphase mixture without fractional distillation

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The steps of combining the crude sevoflurane with water in an amount sufficient to produce a multiphase mixture comprising an aqueous phase and a sevoflurane phase, contacting the aqueous phase and the sevoflurane phase with each other under conditions and for a time sufficient to extract at least a portion of the HFIP from the sevoflurane phase into the aqueous phase, and separating the phases of the multiphase mixture without fractional distillation, may, if necessary, be repeated. Purified sevoflurane comprising an acceptable amount of HFIP is then isolated. The removal of HFIP from the crude sevoflurane occurs without contacting the crude sevoflurane with an aqueous basic solution. to produce a multiphase mixture the sevoflurane phase with each other under conditions and for a time sufficient to extract at least a portion of the HFIP from the sevoflurane phase into the aqueous phase separating the phases of the multiphase mixture without fractional distillation

Conditions: temp:185.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1 liter stainless steel autoclave (Parr) was charged with 127.3 g (2.19 mole) of potassium fluoride and 434.6 g (2.01 mole) of (CF3)2CHOCH2Cl. The autoclave was then sealed and the reaction mass heated at 185° C. for 19 hours, during which time a pressure of 280 psi developed. The reactor was then cooled, the contents treated with water and the organic material distilled to afford 241 g (1.21 mole) of (CF3)2CHOCH2F and 80 g (0.4 mole) of (CF3)2CHOCH2Cl, corresponding to a 60% conversion (75% yield). The structure of (CF3)2CHOCH2F (Sevoflurane), b.p. 56° C., may be confirmed by the following instrumental data: The autoclave was then sealed The reactor was then cooled the organic material distilled

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: U.S. Pat. No. 6,271,422 describes the synthesis of sevoflurane by fluoromethylation of alcohols via decarboxylative halogenation. In this way, hexafluoroisopropanol is submitted to reaction with ethyl alpha-bromoacetate providing alpha-(hexafluoroisopropoxy) acetic acid in a yield of 66%. This intermediate is subjected to reaction with the highly toxic lead tetra-acetate, using the carcinogenic benzene as the solvent. In the reaction sequence, the homogeneous benzene/sevochlorane solution, which is inseparable by distillation, is reacted with potassium fluoride providing at the end of the process sevoflurane with a low yield of 28%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: U.S. Pat. No. 6,100,434 describes the synthesis of sevoflurane through the preparation of sevochlorane and subsequent fluorination of this intermediate with potassium fluoride in a high molecular weight solvent. Sevochlorane is prepared from hexafluoroisopropanol, aluminum trichloride and 1,3,5-trioxane. An excess of aluminum trichloride in the reaction medium results predominantly in the formation of 2,2′-[methylenebis(oxy)]bis-(1,1,1,3,3,3-hexafluoropropane)—hereinafter denominated P1. The reaction is interrupted by addition of a 6N HCl solution to decompose the gel of hydroxydichloroaluminate. The authors relate that the isolated product contained 95% sevochlorane, <5% of P1 and <1% of polyacetals of higher molecular weight. The crude yield described was 87%. Among the disadvantages of this process is the fact that large quantities of aluminum trichloride must be handled, which is a highly hygroscopic solid and whose reaction with atmospheric humidity or with residual water present tends to be violent. The fact that this reagent easily reacts with water, resulting in the formation of acidic gasses, causes a reduction in its content, compromising considerably the yield of the reaction and the purity of the isolated product. The addition of a 6N hydrochloric acid solution to interrupt the reaction is an additional disadvantage of the process, violently elevating the reaction temperature, resulting in partial product loss by decomposition, volatilization and polymerization. Finally, this reaction generates as a residue, an aqueous phase containing hydroxyaluminates that require incineration for disposal, incurring additional costs.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: U.S. Pat. No. 6,271,422 describes the synthesis of sevoflurane by fluoromethylation of alcohols via decarboxylative halogenation. In this way, hexafluoroisopropanol is submitted to reaction with ethyl alpha-bromoacetate providing alpha-(hexafluoroisopropoxy)acetic acid in a yield of 66%. This intermediate is subjected to reaction with highly toxic lead tetra-acetate, using carcinogenic benzene as the solvent. In the reaction sequence, the homogeneous benzene/sevochlorane solution, which is inseparable by distillation, is reacted with potassium fluoride providing at the end of the process sevoflurane with a low yield of 28%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: U.S. Pat. No. 6,100,434 describes the synthesis of sevoflurane through the preparation of sevochlorane and subsequent fluorination of this intermediate with potassium fluoride in a high molecular weight solvent. Sevochlorane is prepared from hexafluoroisopropanol, aluminum trichloride and 1,3,5-trioxane. An excess of aluminum trichloride in the reaction medium results predominantly in the formation of 2,2′-[methylenebis(oxy)]bis-(1,1,1,3,3,3-hexafluoropropane)—hereinafter denominated P1. The reaction is interrupted by addition of a 6N HCl solution to decompose the gel of hydroxydichloroaluminate. The authors relate that the isolated product contained 95% sevochlorane, <5% of P1 and <1% of higher molecular weight polyacetals. The crude yield described was 87%. Among the disadvantages of this process is the fact that large quantities of aluminum trichloride must be handled, which is a highly hygroscopic solid and whose reaction with atmospheric humidity or with residual water present tends to be violent. The fact that this reagent easily reacts with water, resulting in the formation of acidic gasses, causes a reduction in its content, compromising considerably the yield of the reaction and the purity of the isolated product. The addition of 6N hydrochloric acid to interrupt the reaction is an additional disadvantage of the process, violently elevating the reaction temperature, resulting in partial product loss by decomposition, volatilization and polymerization. Finally, this reaction generates as a residue, an aqueous phase containing hydroxyaluminates that require incineration for disposal, incurring additional costs.