RU2497801C1 - Oxa- and polyoxaperfluoroalkylbromides and method of their obtaining - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of oxaperfluoroalkylbromides of formula 1: C₂F₅O-[CF₂CF(CF₃)O]_n-CF₂CF₂Br, where n has values from 1 to 5. Invention also relates to method of obtaining claimed compounds.

EFFECT: claimed compounds are characterised by specific density 1,79-1,81 g/cm³, have high dissolving ability with respect to oxygen and can be applied as base for gas-transport compositions.

3 cl, 7 ex

Description

, гдеThe invention relates to new compounds, namely oxaperfluoroalkyl bromides of the general formula

where

1a (n = 1)

1b (n = 2)

1s (n = 3)

1d (n = 4)

1e (n = 5)

These compounds have a high solubility with respect to oxygen, high density and chemical inertness, therefore, they can be most effectively used in medicine, in particular as components of gas transport compositions, temporary intraocular implants in vitreoretinal surgery, oxygenating additives for topical preparations (therapy wound surfaces, trophic ulcers, etc.), as well as visualization tools in radiation studies.

The inventive compounds, their properties and method of preparation are not described in the literature.

It is known that the compounds used as components of gas transport compositions, temporary intraocular implants in vitreoretinal surgery, retinal detachment, oxygenating additives for external use (treatment of wound surfaces, trophic ulcers, etc.), as well as visualization aids radiation studies (radiography, magnetic resonance imaging, etc.) must be chemically inert, have high dissolving power with respect to oxygen and have a specific gravity a minimum of 1.6 g / cm ³ . It is known that perfluorooctyl bromide is widely used in ophthalmic practice [Biomedical journal, 2004, v. 5, Art. 46, p. 160 .; Bulletin of the Military Medical Academy, 2007, 3, 77; U.S. Patent No. 7691051 B2 (2010); US patent No. 2004/0092861] as a component of gas transport compositions (artificial blood substitutes) [Biotechnol. Prog., 1992, 8, 454; Crit. Care, 1999, 3 (5), R93; EP 2005948 A2 (2008)], and also as a means for imaging in radiation studies (radiography, magnetic resonance imaging, etc.) [Biomaterials, v.30, 8, 1462 (2009); U.S. Patent No. 4,640,833 (1987); Adv. Funct. Mater., 2008, 18, 1].

The following methods for producing perfluorooctyl bromide are known.

a) bromination of perfluorooctyl iodide, which in turn is obtained by telomerization of tetrafluoroethylene under the action of perfluoroethyl iodide [J. Fluor Chem., 1998, v. 88. 2, 153; EP 1 380 557 A1 (2004); EP 1364934 A1 (2003)], perfluorobutyl iodide [US Patent Application No. 2011/28768 A1 (2011)] or a mixture of perfluoroethyl and perfluorobutyl iodide [US Patent Application No. 2007/249876 A1 (2007)],

b) bromination of perfluorooctanesulfonyl chloride resulting from the electrochemical fluorination of octanesulfonyl chloride [US Patent No. 2732398 (1956)],

c) bromination of perfluorooctyl hydride [US Patent Application No. 5073651 A1 (1991)], which is obtained by reduction of perfluorooctyl iodide [J. Fluor Chem., 1987, v. 36, 49; US Pat. No. 5,073,651 A1 (1991)] or

g) the anodic oxidation of perfluoropelargonic acid in the presence of bromine [Auth. Testimonial. USSR No. 1141706 (1984)].

In all of these methods, it is necessary to use explosive or highly toxic substances, namely tetrafluoroethylene, anhydrous hydrogen fluoride or perfluoropelarboxylic acid, the production and use of which is currently prohibited due to its hepatotoxic effect.

All these factors make perfluorooctyl bromide a difficult-to-reach compound, which limits its scope. In this regard, there is a need for new substances with similar properties that can replace perfluorooctyl bromide in the above areas.

The objective of the invention is the creation of new compounds with high solubility with respect to oxygen, high density and chemical inertness, low toxicity with respect to living organisms and other characteristics close to those of perfluorooctyl bromide, which determines the possibility of their similar use as components of gas-transporting media, as well as the development of a method for their production without the use of highly toxic and explosive substances.

, гдеThis problem is solved by new compounds - oxperfluoroalkyl bromides of the general formula

where

1a (n = 1)

1b (n = 2)

1c (n = 3)

1d (n = 4)

1e (n = 5)

, гдеpossessing high density and high dissolving ability with respect to oxygen, as well as chemical inertness and low toxicity with respect to living organisms, as well as a method for their preparation, which involves the interaction of bromodifluoroacetyl fluoride with hexafluoropropylene oxide in a polar aprotic solvent (monoglyme, diglyme, acetonitrile) in the presence of catalytic amounts of potassium or cesium fluorides or bis (dialkylamino) methanes to form a mixture of ω-bromoxa-perfluoroacyl fluorides of the general formula

where

1a (n = 1)

1b (n = 2)

1c (n = 3)

1d (n = 4)

1e (n = 5),

its subsequent decarbonylation under the action of catalytic amounts of SbF ₅ with the formation of a mixture of target products 1a-e and the isolation of individual products by distillation.

The reaction is carried out at 0 ÷ 5 ° C, hexafluoropropylene oxide (OHPP) is gradually added to a mixture of bromodifluoroacetyl fluoride and catalyst (potassium or cesium fluoride or bis (dialkylamino) methane, (molar ratio of bromodifluoroacetyl fluoride: cat = 10-15: 1) in a polar aprotic solvent (The molecular weight distribution of telomere homologs is controlled by the ratio of the starting compounds, bromodifluoroacetyl fluoride and hexafluoropropylene oxide, taken into the reaction.) The resulting mixture of ω-bromoxaperfluoroacyl fluorides 2 (ae) is decarbonylated by the action of catal ical amounts of SbF ₅ with the formation of a mixture of the target bromides 1 (ae), characterized by a specific gravity of 1.79-1.81 g / cm ³ (20 ° C) and a solubility in relation to oxygen of 53-54 vol.%, obtained a mixture of bromides 1 is separated by distillation:

All compounds used in the synthesis of the claimed compounds are manufactured by the industry and are commercially available.

Example 1. Preparation of a mixture of 2a-c fluorohydrides.

A mixture of 17.7 g (0.1 mol) of bromodifluoroacetyl fluoride, 0.6 g (0.01 mol) bezv. Is added to a flask equipped with a stirrer, gas tube and reflux condenser cooled to -78 °. KF and 10 ml of diglyme, stirred for 0.5 hours at room temperature., Cooled to 0-5 ° C, then with vigorous stirring gradually, over 30 minutes, 33.2 g (0.2 mol) of hexafluoropropylene oxide (HFP) are added, stirred for 20 min, the reaction mass is transferred to a separatory funnel, the lower layer is separated and receive 45 g of a mixture containing dimer OHPP (DOGPP), 2- (2-bromo-1,1,2,2-tetrafluoroethoxy) -2,3,3 , 3-Tetrafluoropropanoyl fluoride (CF ₂ CF ₂ CF (CF ₃ ) C (O) F and compounds 2a-c in the ratio DOGFP: (CF ₂ CF ₂ CF (CF ₃ ) C (O) F: 2a: 2b: 2c = 8: 41.4: 35: 13: 2.6 (GC).

Example 2. Under the conditions of Example 1, by the interaction of 0.1 mol of bromodifluoroacetyl fluoride with 0.247 mol of HFP, 53 g of a mixture containing DOGFP (CF ₂ CF ₂ CF (CF ₃ ) C (O) F and 2a-d in the ratio of DOGFP are obtained: ( CF ₂ CF ₂ CF (CF ₃ ) C (O) F: 2a: 2b: 2c: 2d = 10: 12.5: 33.7: 34.8: 7: 2 (GLC).

Example 3. Under the conditions of Example 1, by the interaction of 0.1 mol of bromodifluoroacetyl fluoride with 0.32 mol of HFCP, 59 g of a mixture containing DOGFP (CF ₂ CF ₂ CF (CF ₃ ) C (O) F and compound 2a-e in the ratio of DOGFP are obtained : (CF ₂ CF ₂ CF (CF ₃ ) C (O) F: 2a: 2b: 2c: 2d: 2e = 8: 10: 12: 16: 24: 22: 8 (GLC).

Example 4. The selection of fluoride 2b-e

A mixture of organofluorine reaction products obtained under the conditions of Example 1 from 177 g (1 mol) CF ₂ CF ₂ CF (CF ₃ ) C (O) F and 500 g (3 mol) of HFP (total 610 g) was rectified using a Vigreux column and get 122 g of a fraction boiling in the range of 126-142 ° C and containing 90-92% of hydrofluoride 2a and ~ 5-6% of diglyme. 360 g of a fraction is isolated by further distillation, boiling in the range of 75 ° C / 10 Torr - 130 ° C / 1-2 Torr and containing 2b-e fluoroanhydrides, which is used to obtain the desired oxaalkyl bromides 1b-e without isolation of individual compounds 2b-e.

Example 5. Obtaining oxperfluoroalkyl bromides 1b-e.

A mixture of compounds 2b-e (360 g) was purified from diglyme traces by stirring with 6-7 g of SbF ₅ for 30 minutes, kept for 15 minutes without stirring, the liquid part of the reaction mixture was decanted from the precipitate, 8-10 g of SbF _{5 was} added and stirred , gradually increasing the reaction temperature to 90-100 ° C (5-6 hours). After gas evolution is completed, the mixture is cooled, washed with dilute hydrochloric acid, water, dried with P ₂ O ₅ and distilled in vacuo, collecting products boiling to 110 ° C / 1-2 Torr. Obtain 305 g of a distillate containing bromides 1b-e in the ratio 1b: 1c: 1d: 1e = 2: 3: 3: 1. Further distillation of the obtained distillate gives analytical samples of bromides 1b-e. 237.5 g (92%) of bromide 1b are obtained, b.p. 88-92 ° / 75 Torr and 72 g (90%) bromide 1 s, b.p. 86-90 ° / 11 Torr.

Bromide 1b, b.p. 88-92 ° / 75 Torr. Found%: C 18.64; F 61.71; Br 12.10. C ₁₀ BrF ₂₁ O ₃ . Calculated%: C 18.54; F 61.66; Br 12.36.

¹⁹ F NMR spectrum of bromide 1b:

1 2 3 4 5 6 7 8 9 10

BrCF ₂ CF ₂ OCF (CF ₃ ) CF ₂ OCF (CF ₃ ) CF ₂ OCF ₂ CF3: -6.6 (s, 2F ¹ ), 3.7-4.7 (m, 8F ^{4 + 5 + 7} ), 6 , 5-8.5 (m, 4F ^{2 + 8} ), 11.5 (s, 3F ¹⁰ ), 12.8 (s, 2F ⁹ ), 69.1 (m) and 69.5 (m) (2F ^{3 + 6} ).

Bromide 1c, b.p. 86-90 ° / 11 Torr. Found%: C 18.76; F 62.52; Br 9.60. C ₁₃ BrF ₂₇ O ₄ . Calculated%: C 19.19; F 63.10; Br 9.84.

¹⁹ F NMR spectrum of bromide 1c:

1 2 3 4 5 6 7 8 9 10 11 12 13

BrCF ₂ CF ₂ OCF (CF ₃ ) CF ₂ OCF (CF ₃ ) CF ₂ OCF (CF ₃ ) CF ₂ OCF ₂ CF3: -6.6 (s, 2F ¹ ), 3.2-4.8 (m, 13F ^{4 + 5 + 7 + 8 + 10} ), 6.5-8.6 (m, 4F ^{2 + 11} ), 11.6 (s, 3F ¹³ ), 12.8 (m, 2F ¹² ), 68, 6-69.5 (m, 3F ^{3 + 6 + 9} ).

Bromide 1d, bp 73-78 ° C / 1-2 Torr. Found%: C 19.69; F 64.32; Br 8.13. C ₁₆ BrF ₃₃ O ₅ . Calculated%: C 19.61; F 64.04; Br 8.17.

¹⁹ F NMR spectrum of 1d bromide:

1 2 4, 5, 7, 8, 10, 11 13 14 15 16

BrCF ₂ CF ₂ O [CF (CF) CF ₂ O] ₃ CF (CF ₃ ) CF ₂ OCF ₂ CF ₃ :

3, 6, 9 12

CF: 3, 6, 9, 12

CF ₂ O: 2, 5, 8, 11, 14, 15

CF ₃ : 4, 7, 10, 13, 16

-6.75 (s, 2F ¹ ); 3.2-4.8 (m, 18F ^{4 + 5 + 7 + 8 + 10 + 11} ), 6.5-8.6 (m, 4F ^{2 + 14} ), 11.6 (s, 3F ¹⁶ ), 12.8 (m, 2F ¹⁵ ), 68.6-69.5 (m, 4F ^{3 + 6 + 9 + 12} ).

Bromide 1e, bp 106-109 ° C / 1-2 Torr. Found%: C, 20.11; F 64.81; Br 6.85. C ₁₉ BrF ₃₉ O ₆ . Calculated%: C 19.91; F 64.72; Br 6.99.

¹⁹ F NMR spectrum of Ie bromide:

1 2 4, 5, 7, 8, 10, 11, 13, 14 16 17 18 19

BrCF ₂ CF ₂ O [CF (CF) CF ₂ O] ₄ CF (CF ₃ ) CF ₂ OCF ₂ CF ₃ :

3, 6, 9, 12, 15

CF: 3, 6, 9, 12, 15

CF ₂ O: 2, 5, 8, 11, 14, 17, 18

CF ₃ : 4, 7, 10, 13, 16, 19

-6.75 (s, 2F ¹ ); 3.2-4.8 (m, 23F ^{4 + 5 + 7 + 8 + 10 + 11 + 13 + 14 + 16} ), 6.5-8.6 (m, 4F ^{2 + 17} ), 11.45 ( s, 3F ¹⁹ ), 12.7 (m, 2F ¹⁸ ), 68.5-69.5 (m, 5F ^{3 + 6 + 9 + 12 + 15} ).

Example 6. Obtaining oxaalkyl bromide 1a.

The increased content of diglyme in acid fluoride 2a suggests an increase in the consumption of expensive SbF ₅ at the stage of decarbonylation. In this regard, an alternative method for preparing 2a solvent free is provided below.

a) To 122 g of the fraction (boiling range 126-142 ° C) (see example 4), when cooling with ice water, 100 ml of anhydrous are gradually added. MeOH, heated with stirring to 25 ° C, poured into water, the organic layer is separated, washed successively with water, an aqueous solution of NaHCO ₃ , dried over Na ₂ SO ₄ and 101 g (90%) of 8-bromo-3 methyl ether are isolated by distillation, 6-dioxo-perfluoro-2,5-dimethylacrylic acid (3) (mixture of diastereomers), b.p. 89-91 ° C / 40 Torr. Found%: C 20.44; H 0.58; F 51.02; Br 15.02. C ₉ H ₃ F ₁₄ BrO ₄ . Calculated%: C 20.73; H 0.58; F 51.06; Br 15.36.

b) To a mixture of 101 g (198 mmol) of ether 3 and 20 ml of water, a 50% aqueous solution of NaOH (~ 10-12 ml) is gradually added with stirring until an alkaline reaction of the reaction mixture (phenolphthalein) appears, the resulting solution is acidified with 20% aq. H ₂ SO ₄ , the lower layer is separated and distillation over conc. H ₂ SO ₄ gives 91 g (91%) of 8-bromo-3,6-dioxo-perfluoro-2,5-dimethylcaprylic acid (4), bp. 103-104 ° C / 15 Torr. Found%: C 18.48; H, 0.30; F 52.58; Br 15.93. C ₈ HF ₁₄ BrO ₄ . Calculated%: C 18.95; H 0.20; F 52.46; Br 15.76.

NMR spectrum of ¹⁹ F acid 4:

1 2 3 4 5 6 7

BrCF ₂ CF ₂ OCF (CF ₃ ) CF ₂ OCF (CF ₃ ) CO ₂ H: -6.9 (s, 2F ¹ ), 1.2-2.5 and 8.1-9.5 (m, 2F ⁵ ), 3.9 and 6.3 (s, 6F ^{4 + 7} ), 7.5 (m, 2F ² ), 56.1 and 68.9 (m, 2F ^{3 + 6} ).

c) To a mixture of 25.9 g (56.6 mmol) and 3 drops of quinoline, 15 g (126 mmol) of SOCl _{2 are} gradually added, with vigorous stirring, the reaction mixture is heated to boiling, boiled until gas evolution ceases, excess SOCl _{2 is} distilled off, from the residue By distillation, 24.5 g (91%) of 3,6-dioxo-8-bromoperfluoro-2,5-dimethyl-caprylic acid chloride (5) are isolated, b.p. 153-155 ° C.

NMR spectrum of ¹⁹ F acid chloride 5:

1 2 3 4 5 6 7

BrCF ₂ CF ₂ OCF (CF ₃ ) CF ₂ OCF (CF ₃ ) COCl: -6.9 (s, 2F ¹ ), 0.5-2.0 and 5.9-7.3 (m, 2F ⁵ ) 3.8 and 5.0 (s, 6F ^{4 + 7} ), 7.5 (m, 2F ² ), 49.2 and 68.6 (m, 2F ^{3 + 6} ).

g) A mixture of 17.8 g (34 mmol) of acid chloride 5, 3.5 g (56 mmol) of freshly calcined KF and 2.8 g of tetramethylene sulfone is boiled under vigorous stirring for 1.5 hours (the temperature of the reaction mixture drops to 133 ° C), the product the reaction is distilled off, gradually reducing the pressure to 110-100 Torr and get 15.7 g (91%) of 3,6-dioxo-8-bromoperfluoro-2,5-dimethylacrylic acid fluoride (2b), b.p. 128-130 ° C. Found%: C 18.79; F 55.98; Br 15.46. C ₈ F ₁₅ BrO ₃ . Calculated%: C 18.86; F 55.99; Br 15.72.

¹⁹ F NMR Spectrum of Fluorohydride 2a:

1 2 3 4 5 6 7 8

BrCF ₂ CF ₂ OCF (CF ₃ ) CF ₂ OCF (CF ₃ ) COF: -102.4 (s, 1F ⁸ ), -7.0 (s, 2F ¹ ), 0.4-1.8 and 5, 7-6.8 (m, 2F ⁵ ), 3.7 and 4.9 (s, 6F ^{4 + 7} ), 7.3 (m, 2F ² ), 49.0 and 68.5 (m, 2F ^{3 +6} ).

d) A mixture of 26.4 g (52 mmol) of hydrofluoride 2a and 1.6 g of SbF _{5 is} stirred at 55-100 ° C until gas evolution ceases, the reaction mass is washed successively with 10% hydrochloric acid solution, 5% aq. a solution of K ₂ CO ₃ , distilled under reduced pressure over P ₂ O ₅ , followed by distillation of the distillate, 20.6 g (83%) of bromide (1a) are obtained, b.p. 108-110 ° C. Found%: C 17.71; F 59.23; Br 16.30. C ₇ BrF ₁₅ O ₂ . Calculated%: C 17.46; F 59.25; Br 16.63.

¹⁹ F NMR spectrum of bromide 1a:

1 2 3 4 5 6 7

BrCF ₂ CF ₂ OCF (CF ₃ ) CF ₂ OCF ₂ CF ₃ : -6.7 (s, 2F ¹ ), 4.2 (m, 3F ⁴ ), 6.2-8.6 (m, 4F ^{2+ 5} ), 11.4 (s, 3F ⁷ ), 12.7 (t, 2F ⁶ , ⁴ J _FF = 13.1 Hz), 69.4 (t, 1F ³ , ³ J _FF = 21.4 Hz) .

Example 7. Determination of the solubility of 3,6,9-trioxerfluoro-5,8-dimethylundecyl bromide 1 s with respect to oxygen.

The determination was carried out in a flask with a capacity of 100 ml, equipped with a reflux condenser (-78 °), two taps and the armature of a magnetic stirrer; the total volume of the device is 225 ml. 118.1 g (66 ml) of bromide 1c (d = 1.79 g / cm ³ ) was placed in the flask; the free volume of the device was 159 ml. Bromide 1c was degassed with stirring at 8–9 Torr for 15 min, the vacuum pump was disconnected, the temperature in the refrigerator was returned to room temperature, oxygen was introduced into the evacuated device from the gas burette with stirring for 1 s until the absorption ceased (~ 15 min). 195 ml of oxygen entered the device, which is 36 ml more than the free volume of the device. Thus, the specific dissolving power of bromide 1 s with respect to oxygen is 0.54.

Claims (3)

1. Oxperfluoroalkyl bromides

,
where 1a (n = 1), 1b (n = 2), 1c (n = 3), 1d (n = 4), 1e (n = 5). 2. Compounds according to claim 1, having a high solubility with respect to oxygen, as the basis for gas transportation compositions. 3. The method of producing oxperfluoroalkyl bromides according to claim 1, comprising reacting bromodifluoroacetyl fluoride with hexafluoropropylene oxide in a polar aprotic solvent (monoglyme, diglyme, acetonitrile), catalyzed by potassium or cesium fluorides or bis (dialkylamino) methanes to form a mixture of ω-bromo perfluoride fluorides

,
where 2a (n = 1), 2b (n = 2), 2c (n = 3), 2d (n = 4), 2e (n = 5),
their subsequent decarbonylation under the action of catalytic amounts of SbF ₅ with the formation of a mixture of the target bromides 1 (ae) and the isolation of the target products by distillation.