DE2312963A1 - DIOXOLANES - Google Patents

Description

IGI AMERICA INC., Wilmington / Delaware, V. St. A.

Dioxolanes

The invention relates to halogenated dioxolane compounds, a process for their production and veterinary medicinal products containing them.

The invention relates to agents containing dioxolanes of the general formula

R- c-

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where each R ^ group is an independently selected perhalogenated alkyl group, Rr ₇ and Rg are one of H or lower alkyl, R ^ is H, haloalkyl, alkyl, hydroxyalkyl or polyhydroxyalkyl or ARg, R £ H, haloalkyl, alkyl , Hydroxyalkyl or polyhydroxyalkyl or ARg, with the proviso that when R £ -ARg, then R ^ is H or alkyl or ARg, A is an alkylene group, Rg is one of the following substituents

ONO ₂ 0

-OCNHR, - OSOo ^f ν-Γ! Ττ 4

Il ·· ■ - -

- OCNH-

^d ■ , - - OCH

denotes where R _{2 is} a lower alkyl group, phenyl, tolyl, halophenyl or cyclohexyl, with the proviso that Rg can be a hydroxyl group when either R ₁ -, or Rq is an alkyl group or when the total number of carbon atoms in the alkylene or alky! chains, which are indicated in the -A- and Rp

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Groups is at least 6 and with the further proviso that if R ₁₇ and R "are H and R ₂ ^e ^ - ^{n is a} substituent other than Rg, then at least one of the substituents of R ₂ and R ^ is hydroxyl or haloalkyl ,

and
5 is.

the total number of carbon in

and

1 bi

The present invention also relates to compounds having the general formula

C.
O

? 7

σ-a

ι O

Ri

v / orin each R ^ group independently from a ρ obtained ο generated Alkyl group is selected, A stands for an alkylene radical, Rg a substituent from the group

- ONO-

- OSO ₂ -

0
1"

- OCNH-

Il

OCNHRj _1-

- OCHpC-GH

- OCH

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"means, where Rg can be arranged at the end of" A "(alkylene radical) or otherwise along the chain, and R ^ ₊ . is selected from the group consisting of lower alkyl groups, phenyl, -ToIyI ₁ halophenyl and cyclohexyl. R _n - is selected from from the group hydrogen, alkyl and -A-Rg. Ry and Rr are independently selected from the group hydrogen and lower alkyl groups It is also within the scope of the present invention that Rg can be a hydroxyl group when either R ₇ or R _{ß is} an alkyl group or when the total number of carbon atoms in the alley 1 en or alkyl chains present in the combined _{groups indicated by -A- and R 1} - is 6 or more.

According to a further embodiment of the present invention means are provided which a compound of the general formula

R ₀ -CH CH-Ro

/ O II

/ V

R ₁ R ₁ . ■ _

contain, wherein (each R ^ is an independently selected perhalogenated .Alkylrest, Ro and R ^ are independently selected from the group hydrogen, haloalkyl, alkyl, hydroxyalkyl or polyhydroxyalkyl so that they contain a total of 1 to 5 carbon atoms combined with the Provided that R ₀ and R ₇ are selected so that at least one hydroxyl group or haloalkyl group is present ..

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Pharmacological studies indicate that the dioxolane compounds according to the invention can be used as tranquillizers * can be used for living animals, especially for mammals. In particular, the invention Compounds that represent central nervous system dampening agents as mainly minor ones Tranquillizer because they share many pharmacological properties with the barbiturates and because they are useful for treating nervousness and calming down.

A preferred group of compounds falling within the above formula (I) are those in which each group L is independently selected from the group consisting of alkyl radicals having the formula perhalogenierteii '^ _n ^X 2n + 1 ^from £ ^ew ählt wherein η is an integer from 1 to 7; and X represents a halogen atom with an atomic weight of 80 or less. In a preferred mode, X is fluorine or chlorine, or any combination thereof.

The compounds according to the invention can with perhalogenated Alkyl groups containing mixed halogens, such as dichlorofluoromethyl groups, which are symmetrical (which means that both IL, groups are identical), as well as with perhalogenated alkyl groups, which are unsymmetrical, e.g. 2-chlorodifluoromethyl-2-dichlorofluoromethyl . The R ^ groups can also be non-mixed perhalogenated alkyl groups, the are either symmetrical or unsymmetrical.

In a further preferred embodiment of the present Invention -A- in the above formula IA is a linear or non-linear alkylene radical which is 1 to Contains 18 carbon atoms, with the proviso that the

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combined total number of carbon atoms in the alkylene or alkyl chains contained in the _{radicals indicated by: -A- and R 1} - is not more than 18, and with the further proviso that the alkylene or alkyl chains which are in the radical represented by Rf- do not contain more than 6 carbon atoms.

It has been found that a further preferred group of compounds of the formula I is obtained when -A- is either a linear or a non-linear lower alkylene radical which contains 1 to 6 carbon atoms. In a preferred group of compounds, R, - in the formula IA different from hydrogen and -AR, - represents a lower alkyl radical having 1 to 6 carbon atoms. Furthermore, R ^ is an alkyl radical containing 1 "to 4 carbon atoms and the halogen component of the Halophenyl radical is chlorine or fluorine. In a preferred type the halophenyl radical is p-halophenyl In the currently preferred group of compounds, the substituents Rr ₇ and Ro represent, independently of one another, lower alkyl radicals other than hydrogen which contain 1 to 4 carbon atoms.

The compounds of the formula II are cyclic ketals of polyhydric alcohols which contain at least three hydroxyl groups and contain at least three carbon atoms, and ketones of the general formula

J ^ G = O . III

wherein each R is a perhalogenated alkyl radical. For the sake of simplicity, this group of compounds is referred to herein as

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Dioxolanyl alcohols are designated. These are the hydroxyl derivatives of the corresponding perhalogenated ones Dioxolane compounds. The 4- or 4,5 ~ halogen derivatives of 4- or 4,5-hydroxyalkyldioxolane are also suitable according to the invention for achieving a calming.

Polyhydric alcohols of the class given above include simple sugars and polyols. Examples of polyols are alkane triols, alkane tetrols, alkane pentols and alkane hexols. In particular, such compounds as Sorbitol, "mannitol, erythritol, xylitol, glycerin, 2-methyl-2,3,4-pentanetriol, 1,2,3-butanetriol, 1,2,3,4-hexanetrol, 2,3,4-hexanetriol, 1,2,3-hexanetriol, 1,2,4-hexanetriol, 1,3,4-heptanetriol, 1,2,4-pentanetriol, 1,2,3 ~ heptanetriol and 1,2,4-butanetriol than in the classes of polyhydric alcohols considered falling, which contain at least three hydroxyl groups and at least three carbon atoms. A preferred group of polyhydric alcohols has three to six carbon atoms and includes, for example, glycerin, Sorbitol, threitol, erythritol, butanetriol and xylitol.

A preferred class of cyclic ketals according to Invention is based on polyhydric alcohols with 3 to 6 carbon atoms and 3 to 6 hydroxyl groups and ketones having 3-his about 9 carbon atoms, the halogen has an atomic weight of at most 36 and dex ^ Halogen Content Each ketone is a mixture of halogens can be. The preferred subclass of cyclic ketals is that made from glycerol carbonate or butanetriol carbonates and perhalogenated acetone from the group hexafluoroacetone, chloropentafluoroacetone, Dichlo-rtetrafluoroacetones and Trichlorotriflucracetones is formed.

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A group of cyclic ketals which can be used according to the invention can be represented by the general formula

R ₃ -

IV

are represented, wherein each EL is an independently selected perhaloalkyl radical, Ro and R ^ are independently selected from the group hydrogen, alkyl radicals, haloalkyl radicals, hydroxyalkyl or polyhydroxyalkyIresfce so that they combined contain a total of 1 to 5 carbon atoms. In formula II, the substituents R ^ and Rp are selected such that at least one free hydroxyl or haloalkyl group is present. If R2 and / or R _{7 is} a haloalkyl radical, then this is preferably a monohalosubstituted alkyl radical in which the halogen is selected from the group consisting of bromine, iodine, chlorine and fluorine.

In one, subclass of the cyclic ketals of the formula III is each R ^ independently of perhaloalkyl radicals with 1 to 7 carbon atoms and it contains halogen atoms with an atomic weight of at most about 80. With one preferred type contain the perhaloalkyl radicals fluorine or chlorine atoms or any combination from it. It is contemplated that the compounds of the invention may be substituted with perhalogenated alkyl groups containing mixed halogens, such as with

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Dichlorofluoromethyl groups that are symmetrical (which means that both IL groups are identical), as well as with perha-lo genated alkyl groups that are unsymmetrical, e.g. 2-chlorodifluoromethyl-2-dichlorofluoromethyl. Obviously, the R _x , group can also be an unmixed perhalogenated alkyl group that is either symmetrical or unsymmetrical. The R ^ - and R - ^ - radicals of this class would be an alkyl radical, a haloalkyl radical, a hydroxyalkyl or polyhydroxyalkyl radical or a hydrogen atom. When R 1 and / or R 1 are haloalkyl radicals, the halogen atoms have an atomic weight of at most about 127.

Examples of cyclic ketals according to the invention include the following compounds: 2,2-bis (trifluoromethyl ) -4-hydroxymethyl-1,3-dioxolane; 2-tribromomethyl-2-trifluoromethyl-4-hydroxymethyl-1,3-dioxolane; 2,2 ~ bis (trifluoromethyl) -4 (4-hydroxybutyl) -1,3-dioxolane; 2,2-bis (trichloromethyl) -4 (1,2-dihydroxyethyl) -1,3-dioxolane; 2-. Dichlorotrifluoroethyl ^ -tetrachlorotrifluoropropyl - ^ - hydroxymethyl-1,3-dioxolane; 2-trichlorodifluoroethyl-2-pentachlorotetrafluorobutyl-4-hydroxymethyl-1,3-dioxolane; 2-heptafluoropropyl-2-pentafluoroethyl-4-hydroxymethyl-5- (1,2-dihydroxyethyl) -1,3-dioxolane; 2,2-bis (trifluoromethyl ) -4- (2-hydroxyethyl) -1,3-dioxolane; 2,2-bis (chlorodifluoromethyl) -4-chloromethyl-1,3-dioxolane; 2,2-bis (chlorodifluoromethyl) -4- (5-hydroxypentyl) -1,3-dioxolane; and 2,2-bis (ö? rif fluoromethyl) -4-chloromethyl-1,3-dioxolane.

To further illustrate the cyclic ketals in accordance with the present invention, the following formulas are used specified:

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OH OH- 0 0

III I

HpC - C - C - C-CHp ^c \ «T -i

HH H. OH-. V

^ ₂ Cl ₃ O ₂ ° 2 ^G1 3 ^ 2

HOO ι ι t

^: HO-CCC-

i ι t γι

HH H ₂

H ■ H

ι ..ι

H ₂ C-C-CH ₂ OH H ₂ -C-C-CH ₂ OH

0 0

CP ₃ CP

CP ₃ VII Cl ₂ FC CP ₂ Cl VIII

H
t

- C. - C - CHp - OH HpC - CH- CHpCl ClP ₂ G CP ₂ Cl. PCl ₂ C CClP ₂

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• The new dioxolane compounds according to the invention can advantageously from hydroxyl-substituted cyclic ones Ketals are described in U.S. Patent Application No. 873,660. It describes the following connections:

Cyclic ketals of a polyhydric alcohol containing at least 3 carbon atoms and at least 3 hydroxyl groups contains, and a ketone of the general formula

= 0

wherein each R is a halogenated alkyl radical having at most three non-halogenated carbon atoms, and wherein the carbon atom of the alkyl radical which is attached to the carbonyl atom of the ketone, at least 2 halogen atoms and wherein the halogen has an atomic weight of 36 or less.

A group of cyclic ketals which falls under this definition and which are used for the preparation of the invention Dioxolane compounds is very suitable, has the general formula

IV

where each R ^ is a perhaloalkyl radical, R2 and R ^ independently from the group hydrogen, alkyl radicals,

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Hydroxyalkyl and polyhydroxy alley Ires te are selected. In this embodiment of the formula IV, the substituents are R2 and H selected to include at least one free hydroxyl group is present.

In a subclass of this form of cyclic ketals of Formula IV, each R 1 subscript would be independently selected from the group consisting of perhaloalkyl radicals having from 1 to 7 carbon atoms and containing halogen atoms having an atomic weight of about 36 or less. The Rg " ^{un <a} -

Most of this class would be alkyl, hydroxyalkyl or polyhydroxyalkyl, or hydrogen.

The preparation of the cyclic ketals described above can be carried out in the V / eise that one ketone, except when Ro and / or R is a haloalkyl with the formula

X = O
R.

wherein each R is a halogenated alkyl radical having at most 3 non-halogenated carbon atoms and is the carbon atom of the alkyl groups attached to the carbonyl carbon of the ketone have at least two attached thereto Has halogen atoms, heated with a cyclic carbonate of a polyhydric alcohol, the polyhydric Alcohol contains at least 3 hydroxyl groups and 3 carbon atoms, and wherein the cyclic carbonate is a or contains several cyclic carbonate groups. If that cyclic carbonate does not contain free hydroxyl groups, then the reaction occurs in the presence of a lower alcohol or carried out by water. The molar ratio of

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Ketone to cyclic carbonate can be as high as about 10 Moles of ketone per cyclic carbonate group. V / enn a lower alcohol is used, an amount sufficient to dissolve the cyclic carbonate is used. Alternatively, the cyclic ketals can also be prepared in such a way that a low Alcohol or water is reacted with a ketone of the formula (a) above and a hydrate or a hemiketal forms, and that this product is then reacted with a cyclic carbonate, as described above. If a cyclic carbonate containing more than one carbonate group is reacted, then products are formed which contain both carbonate and ketal rings.

Suitable polyhydric alcohols for carrying out the above reaction are, for example, alkane triols, alkane tetrols, alkane pentols and alkarihexols. In particular, compounds such as sorbitol, mannitol, erythritol, xylitol, glycerin, 1,2,3-butanetriol, 1,2,3,4-hexanetrol, 2,3,4-hexanetriol, 1,2,3-hexane ~ triol, 1,2,4-hexanetriol, 1,2,3-heptanetriol, 1,3, ^ - heptanetriol, 1,2,4-pentanetriol, 2-methyl-2,3,4-pentanetriol and 1,2,4-butanetriol as in the class of polyhydric alcohols considered falling, which contain at least 3 hydroxyl groups and at least 3 carbon atoms. One preferred group of polyhydric alcohols have 3 to 6 carbon atoms and contain at most one hydroxyl group per carbon atom. This group includes e.g. glycerine, sorbitol, threitol, erythritol, butanetriols and xylitol a.

Ketones of the formula φ.) Can, for example, preferably include perhalogenated alkyl radicals of the general formula C Xp _{n +} Xi, in which η is an integer from 1 to 7

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and X for a halogen core with an atomic weight of at most 80, preferably 36, is. The halogen content of the ketones can also be a mixture of halogens be.

Examples of these ketones are: bis (trifluoromethyl) ketone ·; bis (chlorodifluoromethyl) ketone; Chlorodifluoromethyl dichlorofluoromethyl ketone ; bis (pentafluoroethyl) ketone; bis (dichlorotrifluoroethyl) ketone; 1,1,1-tribromo-3,3,3-trifluoropropanone; and 3,3-dibromo-i, 1,1,3-tetrafluoroacetone.

In particular, a hydroxyl-containing cyclic carbonate of a polyhydric alcohol can be reacted with one of the aforementioned ketones in a two-stage reaction to form the cyclic ketal. The first stage of the reaction forms an intermediate which is an eemiketal of the ketone. This reaction can be initiated at temperatures as low as about 10G or as high as about 120C. When the temperature ^{falls below 10 °} C., the initiation and the reaction become more difficult. If the temperature ^{goes above 120 °} C., the reaction proceeds, progressively worse, and there is a loss of the intermediate product. The final reaction stage is mainly an intramolecular reaction in which the hemiketal function attached to the cyclic carbonate reacts with a carbonate group to form the cyclic ketal. This stage usually takes at least an hour to complete, depending on the reactants. The temperatures for this stage are generally from 100 ^° C. to about 170 ^° C. If the temperature falls below 100 ^° C., the reaction becomes sluggish. When the temperature rises above 170 ^° C., a begins

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Loss of yield and a loss of reactants to occur.

An alternative process for making compounds of Formula IV that does not require the cyclic carbonate containing a free hydroxyl group begins by having one of the ketones with a low Reacts alcohol to form a hemiketal or with water to form a hydrated ketone. These The reaction proceeds at temperatures from about 10 to about 120 ° C. Then the product, namely the hydrate or the Hemiketal, with a cyclic carbonate at about 100 ° C to about 170 ° C to form the cyclic ketal, the temperature ranges as in the above process be chosen to optimize the response. Naturally, if a suitable hemiketal or hydrate is available, the stage of formation can be omitted and the reaction can be carried out directly with the carbonate take place.

In a preferred method for preparing these ketals, the number of moles of the ketone Qe cyclic carbonate group is from about 0.3 to about 3, and the cyclic tanninate used contains up to about 3 cyclic carbonate groups and at least one free hydroxyl group. The temperature is maintained from 0.5 to 30 hours at 25 to 70 ⁰ C and then raised to 120 ° C to 160 ° C, is no longer released to carbon dioxide.

Examples of lower alcohols that can be used are saturated aliphatic monohydric alcohols, saturated aliphatic diols and saturated aliphatic Triols in which the aliphatic chain contains up to 4 carbon atoms. Examples are: ethanol, 1,2-butanediol, methanol, 1,2,3 ^ butanetriol.

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Examples of suitable carbonates are: mono- and mscyclic tetritol carbonates, cyclic glycerine carbonate, mono-bis- and tris-cyclic hexitol carbonates, mono- · and bis-hexanetetritol carbonates, cyclic butanetriol carbonates and cyclic heptane triol carbonates.

The preparation of the above-described hydroxyl-substituted cyclic ketals, which are also used as precursors to Preparation of some of the compounds of the invention and which are referred to herein as dioxolanyl alcohols can be exemplified as follows will.

example 1

118 g of glycerol carbonate (1 mole) is placed in a 500 ml three-necked flask fitted with a thermometer, magnetic stirrer, gas inlet tube and condenser which is cooled with a dry ice-isopropyl alcohol bath. Hexafluoroacetone gas is added to the vigorously stirred glycerine carbonate at 27 to 60 ° C. until 14-2 g (0.85 mol) have been absorbed. The dry ice condenser is now replaced by a water condenser which is connected to a dry ice trap so that the hexafluoroacetone that is released during the reaction can be condensed. The temperature is slowly raised to about 118 ° C, at which point COp begins to evolve. The temperature is allowed to rise to 148 ^° C. in the course of a 40 hour reaction period. The resulting product is mixed with water (50 ml) and the organic layer is separated and diluted with chloroform. The chloroform solution is washed several times with water and 5 # NaHCO ^ solution. The evaporation

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in vacuo gives crude 2,2-bis (trifluoromethyl) -4-hydroxymethyl-1,3-dioxolane. This is distilled at 78 to 80 ° C / 25 mm Hg. The yield of the pure product is $ 92, based on the hexafluoroacetone used. The twice distilled product has a refractive index of 0.3504-6 (20 ⁰ G). Analysis gives $ 4-7.19 fluorine, $ 30.02 carbon, and $ 2.22 hydrogen.

Example 2

Following the procedure of Example 1, 41.8 g Ethylene glycol ~ (the glycerine carbonate is replaced by ethylene glycol replaced) in 54 g of hexafluoroacetaone for 4 hours 26 to 35 ° G implemented. 95 »8 g of the product are obtained. ;

8.5 g of this Hydroxyäthylhemiketal of hexafluoroacetone are then reacted with 3 g of glycerol carbonate for 103 hours at 115 to 141 ° C. The yield of 2,2-bis (trifluoroethyl) -4-bydroxymethyl-1,3-dioxolane is $ 66.

Example 3

14.8 g of absolute ethanol are reacted according to the procedure of Example 1 (the glycerol carbonate is replaced by absolute ethanol) at 26 to 35 ^° C. with 57.5 g of hexafluoroacetone for 6 hours. This product is then ^{degassed at 30 °} C. and a pressure of 100 to 150 mm Hg (absolute) for a further 1.5 hours. This product is the ethyl hemiketal of hexafluoroacetone.

5.3 g of the Hemiketalprodukts are mixed with 2.95 g of glycerol and until a gasflüssigkeitschromatografische analysis, a yield of the 50 # Ketalprodukts Toggle 21 hours at 110-118 ⁰ C or heated as long as

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The product is then separated off by extraction with 20 ml of CKbraßrm and washed three times with 5 ml of the above bicarbonate solution and once with water. By taking place in the vacuum removal of the Chloiiforms at 50 ⁰ C of the product are obtained 4 g. ·

The product 2,2-bis (trifluoromethyl) -4-hydroxymethyl-1,3-dioxolane is then ^{absolutely distilled at 70 to 75 °} C. and 20 mm Hg. It has an index of refraction of 1.34988 at 20 ⁰ C.

Example 4

1> 34 g of sorbitol dicarbonate are added to 3.5 g of the hemiketal product of Example 3 dissolved, -This mixture is Reacted for 24 hours at 105 ° C. The clear liquid phase is decanted from the reaction mixture.

A yield of the product of 1.04 g is obtained after completely taking place in vacuo removal of dekandierten solution at 50 ° C to 90 ⁰ C and a pressure of I5 mm Hg. This product _N is soluble in acetone and chloroform. Analysis shows it contains $ 36.3 of carbon, $ 3.91 of hydrogen, and $ 20.4 of fluorine. The product is a monoketal: the cyclic monocarbonate of sorbitol,

Example 5

5.2 g of mannitol tricarbonate and 23 g of ethylene glycol hemiketal of hexafluoroacetone are reacted under reflux at 139 ° C. for 70 hours. The reaction mixture is then cooled to 80 to 90 ⁰ C. 5 ml of water are stirred in. Another 7 ml of water are added and the mixture is made five times with 25 ml portions of chloroform

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extracted, yielding a water fraction and a chloroform fraction is obtained. Evaporation of the chloroform gives 2.59 g of product.

The evaporation product is distilled at 80 Ms 105 ° C and a pressure of 0.5 mm Hg absolute further purified to give 2.0 g of a colorless syrup. After extracting a small amount of the ~ remaining ethylene glycol with water has the product, predominantly mannitol monocarbonate monoketal, the fouling composition: $ 33.52 carbon, $ 3.19 hydrogen and $ 38.35 fluorine.

The water fraction from the first separation is completely evaporated under vacuum at final conditions of 140 to 15O ⁰ C under a pressure of 0.5 mm Hg. The remainder, 3 * 21 g of a viscous syrup, is dissolved in 7 ml of acetone, from which 0.56 g of solids are filtered off. The acetone is then evaporated off and the product is absolutely distilled at 140 to 175 ° C. and a pressure of 0.3 mm Hg. The product, 1.16 grams of predominantly mannitol monoketal, has the following composition: $ 38.28 carbon, $ 5.16 hydrogen, and $ 25.35 fluorine.

Example 6

86.7 S dichlorotetrafluoroacetone are added dropwise to 50.7 g of G-lycerol carbonate at 27 to 35 ° C., with cooling. The product is stirred at 35 ° C. for one hour. There are added to 50 ml glycerol, and further the temperature is raised to 115 to 123 ⁰ C. Then the evolution of CO ₂ begins. The temperature is increased to 150 to 170 ° C. over a total period of 42 hours. The product is isolated as in Example 1. That

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Product is a liquid having a boiling point of 119 "to 121 ° C / 20 mm Hg, the refractive index is 1.4 to 1844 at 2O ⁰ C. The analysis shows f ofendes. Hydroxyl number 190, from 26.4 to 7 carbon $, 2 , $ 57. Hydrogen, $ 26.0 chlorine, and ~ 27.5 # fluorine. The product is 2,2-bis- (chlorodifluoromethyl) -4-hydroxymethyl-1,3-dioxolane.

Example 7 ■

Cyclic carbonate of 1,2,4 ~ butanetriol (38.4 g) is treated with 57.9 g Dichlortetrafluoraeeton at 25 to 40 ⁰ C. The product is then reacted under reflux at 129 ° C. for 114 hours after 8 g of butanetriol has been added to give a higher reaction temperature. The product isolated according to Example 1 is mainly 2,2-bis (chlorodifluoromethyl) -4- (2-hydroxyethyl) -1,3-dioxolane. It boils at 73 to 81 ° C / 0.15 mm Hg and has a refractive index: 1.42180 at 20 ° C. Analysis shows the following: 29, carbon, $ 2.95 hydrogen, $ 25.0 fluorine, and 23, chlorine.

Example 8

Glycerine carbonate (3554 g) is ^{treated dropwise at 26 to 40 °} C. with 76 g of trichlorotrifluoroacetone. The hemiketal precursor is diluted with more glycerine carbonate (total carbonate present is 115.4 g) and refluxed as the temperature gradually increases. The reaction time is 40 hours at 110 to 123 ° C and 48 hours at 123 to 143 ° C. The weight loss is about 20 g during this period. The isolated product is 2-chlorodifluoromethyl-2-fluorodichloromethyl-4-hydroxymethyl-T, 3-dioxolane. It distills at 92 ° C / 0.20 mm

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2312363

Hg and has a refractive index of 1.4-4-885 at 20 ° C.

Example 9

0.66 g of solid hexafluoroacetone monohydrate, obtained by passing hexafluoroacetone through distilled water, become 1.5 g of cyclic! Glycerine carbonate given. The reaction is then carried out at 100 to 111 ^° C. for 64 hours. The reaction product is 2,2 ~ bis (örifluoromethyl) -4 ~ hydroxymethyl-1,3-dioxolane.

Example 10

11.8 g of glycerol carbonate are mixed with 36.2 g of bis (trichlorodifluoroethyl) ketone mixed and reacted for JO hours at 55 ° C.

The temperature of the reaction mixture then increases to 125 ° 0 increased and it is implemented for a further 25 hours. The product is predominantly 2,2-bis (trichlorodifluoroethyl) -4-hydroxymethyl-1,3-dioxolane.

Another general method of working for the preparation of the dioxolanyl alcohols precursors is described in U.S. Patent 2 925 424. This method builds up on the conversion of glycol half-esters, e.g. chlorohydrins, with perhalogenated ketones in the presence of a base.

Compounds, e.g., halohydrins, according to the present invention Invention can be obtained from olefinic alcohols by reaction with hypochlorite, for example according to the procedure described in Bull. Soc. Chim. France, 1962 (177-182). The implementation of N-bromosuccinimide according to the is also suitable for this purpose

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known procedures. Examples of olefinic alcohols, which can be converted into chlorohydrins, which are used as starting materials for the invention are: 2-methyl-2-propen-1-ol; 3-buten-1-ol; 4 ~ penten-1-ol; 4-pentene-2-ol; 3-methyl-3-buten-1-ol; 3-methyl ~ 3-buten-2-ol; 5-hexen-1 ~ ol; 5-hexen-3-ol; 4— Methyl-4-pentene-2-oil; 2,3-dimethyl-3-buten-2-ol; 6-hepten-3-ol; 2-methyl-5-hexen-2-ol; 2,3-dimethyl-4-penten-2-ol; • I-octene - ^ - oil; ^ -Methyl-i-hepten - ^ - oil; 3-ethyl ~ 5-hexen-3-ol; 2,3-dimethyl-5-hex: en-3-ol; 1-non-4-ol; 2,3, ^ - i-trimethyl-5-hexen-3-ol; 9-decen-1-ol; 4-propyl-1-hepten-4-ol; 5,9-dimethyl-8-decen-3-ol; and 3,7,1 ^, 15-tetramethyl-2-hexadecen-1-ol.

The above-described production method of the hydroxyl-substituted cyclic ketals is carried out by reaction stage III _; of Example 1 and illustrated by Example 2. Steps I and II of Example 2 show an alternative method that can be used to prepare the desired Chlorälkaiidiole,

example ΛΛ

Production of 2,2-bis (trifluoromethyl) -4- (2-hydroxyethyl) -1,3 -dioxolane

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ι O.

GP.

-CH - CH ₂ -CH ₂ OH

CP

I «CHp = CH-CHpCl Parafoi ^ ialdehyäv C

- «2 ^Si V

- CH ₂ - CH - CH - CH ₂ Cl

CH

-l, 3-dioxane

II. CH ₂ -CH ₂ -CH-CH ₂ Cl CH ₃ OH

H ₂ SOJi ₁ .

CII ₂ -CH ₂ -CH-CH ₂ CT

OH

CH ₂

Chloro-1,3-butanediol

CPn

■ X

C «

II.

CF

OH

OH

! Ethanol CH ₂ CH - CH ₂ - CH ₂ OH

'Benzene.:- »'

Kfin (\ Γ)

4-chloromethyl-1,3-dioxane was obtained in about $ 25 according to a method given in the literature (C. C. Price, et al, J. Am. Chem. Soc. £ 2., 5335-5336 (195O)).

Because it was expected that the intermediate 4-chloro-1 ', 3-butanediol was unstable, reactions II and III were carried out in a single step as above, the 4-chloro-1,3-butanediol was not isolated. Details of the manufacturing process illustrated above are as follows:

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A 27.4 x g sample of 4 ~ chloromethyl-1,3-dioxane (0.2 mole) is dissolved in 100 ml of methanol and 3.6 g of concentrated sulfuric acid is added. The solution is brought to the boil and thereby concentrated to half the volume. This is repeated several times until the hydrolysis is complete. The solvent is then evaporated off at atmospheric pressure. 60 ml of benzene are added and the mixture is stirred magnetically. A hexafluoroacetone / ethanol adduct containing 0.8 g of hexafluoroacetone per gram is then added (52 g = 0.225 mol), followed by 26.0 g of potassium carbonate (0.19 mol). The mixture is stirred at room temperature for 4-8 hours. The product is divided with the help of 100 ml of water and 4-0 ml of benzene. The aqueous phase is extracted with 50 ml of benzene. The benzene phases are combined. The benzene phase is washed three times with 50 ml of 5 # sodium carbonate solution and three times with 100 ml of water. The benzene is evaporated in a moderate vacuum at 40 to 50 ° 0, whereby 27.3 g of product (yield $ 53.7) are obtained. The product, 2,2-bis (trifluoromethyl) -4- (2-hydroxyethyl) -1,3-dioxolane, is distilled at 94 ° to 96 ° C./18 mm Hg. The yield of the distilled product is 4-5 %. The refractive index is 1.36053 (20 ° C). The analysis of the double distilled product is as follows:

Found: σ - 33, $ 18 Calculated: 33 .08% H ~ 3, 3 , $ 17 Έ - 44-, $ 40 4-4- , $ 86

The purity was checked by gas liquid chromatography and thin layer chromatography ($ 100). the Structure was confirmed by mass spectrometry.

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-25- 2312983

Example 12

dioxolane-4-pentanol

i / Jtio On "

0 0 'OH

A sample of 0.1 mol of 5 _} 9-dimethyl-8-decen-3-ol is prepared according to the method described in Bull. Soc. Chim. France, 1962 (177-182), converted into the 8,9-chlorohydrin. The reaction was carried out in aqueous solution in the presence of monopotassium phosphate and a hypochlorite solution at temperatures below 5 ° C. The product is purified by extraction with water and dissolved in about three parts of benzene. An adduct of hexafluoroacetone ethanol, which contains about 0.8 g of hexafluoroacetone per gram, is then added (50 # excess, 0.15 mol). The solution is stirred vigorously in the presence of finely ground potassium carbonate (0.15 mol) for 48 hours at room temperature. The product is partitioned between benzene and water and the benzene layer is washed several times with 5 # sodium carbonate solution and water. Evaporation of the solvent gives the product. This can be purified by distillation in a high vacuum.

The compounds of the above formula IV, in which Ro and / or R, are haloalkyl and Rr, and R _{g are} hydrogen, can be prepared from the corresponding DioxoIany! Alcohol or the above-described hydroxyl-substituted cyc-

$ 09840/1210

lischen ketals are produced. These are illustrated in the examples by various different reactions. When R p and / or R 1 is chloroalkyl then the following general reaction is applicable, using an equimolar weight amount of pyridine and a slight molar excess of thionyl chloride at about 10 ⁰ O. The reaction is completed by raising the temperature is raised to 10O ⁰ O. ·

- ■ ■. H -

_ C-A-OK 'H

ι ^ t t

^ O + pyridine + thionyl, CHo - C - AQ \ / '. Chloride " ^f

(A)

In the above formulas, A is a linear or non-linear lower alkylene group containing 1 to 5 carbon atoms means. Q stands for chlorine and R ^ is as defined above with respect to formula IV. The product B is purified by its aqueous extraction and vacuum distillation.

To prepare the dioxolane compounds where Q in Formula B above is iodine or fluorine, it is advantageous to go through the tosylate derivative of a suitable dioxolane compound. For example, a sample of 2,2-bis (chlorodifluoromethyl) -4-p-toluene-sulfonyloxymethyl-1,5-dioxolan dissolved in 4 parts of dimethylacetamide and treated for 24 hours with an excess of potassium fluoride at about 15O ⁰ C. Das.Produkt is isolated by filtration and vacuum distillation. The iodine derivative (i.e. when Q is iodine in formula B) can

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be prepared, for example, by dissolving a suitable dioxolantosylate derivative in acetone and heating it to 100 ° C. for hours with an excess of sodium iodide PA. The resulting product is then filtered off and distilled in vacuo. Another solvent that can be used in the above reaction is, for example, dimethylformamide.

The tosylate compounds used in the above reaction can be made by the following general method:

GH ₂ CA-OH

O _n ^ ^ O + CH ₃ ~ { _{x 7} ) -SO ₂ Cl + pyridine-

..Atrao- '*

spheres- i. pressure

CH ₂
0 H
t
- C-A
t
0 ^Vr i

OSO ₂ ~ / V- CH ₃ + pyridine hydrochloric

A and R ^ have the same meaning as in the formula A.

If Q in Formula B is bromine then preparation can be accomplished by treating an appropriate dioxolanyl alcohol take place with an excess of H Br at elevated temperature (60 to 100 ° C). The resulting product is then purified by aqueous extraction and vacuum distillation.

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It will be apparent to those skilled in the art that the above-described preparation method for the 4-substituted perhalogenated Dioxolane compounds also directly affect the preparation of the 5-haloalkyl- and 4-, 5-bis (haloalkyl) substituted ones Dioxolane is applicable by a simple substitution of the starting dioxolane and an obvious setting the molar concentration of the reactants is made in such a way that a mono- or Disubstitution will result. For example, a suitable 5-hydroxyalkyl substituted perhalogenated dioxolane can be used or a 4,5-bis (hydroxyalkyl) substituted perhalogenated one Dioxolane can be used as a starting material.

The following Examples 13 to 15 describe the preparation of compounds according to the invention, which are described in 4-position contain a Haiοgenalkylgruppe.

Example 13

2,2-bis (trifluoromethyl) -4-chloromethyl-1,3-dioxolane

CH-CH Cl

0 0

^GP 3 ^CP 3

Commercially available glycerol-1,2-dichlorohydrin is purified by distillation (boiling point 80 ° C./20 mm Hg). A sample of 25.5 B (0.2 mol) is ^{treated with Hexafluoroacetpn at 30 to 40 0} C until 28.5 g have been absorbed (86 # of theory). Potassium carbonate (0.2 mol) and 120 ml of hexane are added at 30 ^° C. and the reaction mixture is stirred vigorously for 16 hours at room temperature. The product is mixed with water / water and the aqueous phase

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is extracted with hexane. The hexane solution is diluted with water washed and evaporated in vacuo. In this way, 12.6 g of a colorless liquid product are obtained. That Product is distilled at 51 to 53 ° C./22 mm Hg, giving 2,2-bis (trifluoromethyl) -4-chloromethyl-1,3-dioxolane will.

analysis

(in percent) c, 27.52; H, 2.14; Cl, 13.93;

F, 43.75

Calculated for C ₆ H ₅₆₂
(MW 258.6) C, 27.8 ?; H, 1.95; Cl, 13.71;

F, 4-4.09

Example 14

2-chlorodifluoromethyl-2-dichlorofluoromethyl-4-chloromethyl ■ 1,3-dioxolane

GH-CHpGl ι

CGl ₂ P CClP ₂

A 6.0 g sample of 2-chlorodifluoromethyl-2-dichlorofluoromethyl-4-hydroxymethyl-1,3-dioxolane (0.021 mol) is mixed with 1.9 g of pyridine (0.024 mol) and, dropwise, with 2.8 g of thionyl chloride (0.024 Mol) at 0 to 8 ⁰ C treated. After a period of 16 hours at 25 ⁰ C the temperature is increased about 6 hours at 90 to 105 ° C. The Rea-

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tion product is dissolved in 35 ml benzene and the solution is washed with several portions of 10 ml water and 3 # strength sodium carbonate solution. The vacuum evaporation of the solvent gives 5.8 g of the crude product (91 #) · ^T he fractional distillation at 72 ⁰ C /. 1.0 mm Hg gives 3.3 g of 2-chlorodifluorometh.yi-2-dichlorofluoromethyl-4-chloromethyl-1,3-dioxolane.

analysis

(in percent) C, 23.74; H, 2.06; Cl, 45.82

F ₁ 18.56

Calculated for C ₆ H ₅ Cl ^ F ₅ O ₂

(MW 275.90) C, 23.40; H, 1.64-; Cl, 46.05

F, 18.51

Refractive index : 1.45088 (20 ° C)
Example 15

2,2-bis (chlorodifluoromethyl) -4-chloromethyl-1,3-dioxolane

CH-GHpCl 0

C.
CClF ₂ CClF ₂

A sample of 6.0 g of 2,2-bis (chlorodifluoromethyl) -4-hydroxymethyl-1,3-dioxolane (0.022 mol) is mixed with 1.9 6 pyridine (0.024 mol) and with. 2.8 g of thionyl chloride (0.024 mol) at 0 to 10 ⁰ C treated. After a 16-hour period at 25 ⁰ C, the temperature

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increased to 90 to 105 ° C for about 6 hours. The reaction mixture is dissolved in 35 ml of benzene and mixed with several portions of 10 ml of water and 3 # strength sodium carbonate solution washed. Vacuum evaporation and distillation at 53 ° C./1.1 mm Hg yields 3.6 g of 2,2-bis (chlorodifluoromethyl) -4-chloromethyl-1,3-dioxolane.

analysis

(in percent) C, 24.53; H, 2.06; Cl ₁ 36.36;

F, 26.28

Calculated for C ₆ H ₅ Cl ₅ F ^ O ₂

(291.45 mg). C, 24.73; H, 1.73; Ci, 36.9;

P, 26.08

Refractive index ; 1.41856 (20 ° C)

U.S. Patent 3,488,335 also teaches a manufacturing method for 4-hydroxyl-substituted dioxolane compounds which are used as precursors for production of some of the compounds of the invention can be used. This patent describes compounds with the following structure:

H
t

C - CHpOR t

XY

wherein X and Y are perfluoroalkyl or perchlorofluoroalkyl, each having 1 to 5 carbon atoms, and R is Hydrogen stands. Examples of perchlorofluoroalkyl radicals in the X and Y positions are:

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-CP ₂ Cl -CCl ₂ P -CF ₂ CP ₂ Cl

The compounds of the invention are prepared by several different reactions, which one conversion one of the above defined hydroxyl derivatives of perhalogenated Dioxolane compounds (also referred to herein as dioxolanyl alcohols) with one or more suitable reactants include.

The compounds according to the present invention in which R ^

- OCH ₂ C = CH or -OCH y

is can suitably according to the Williamson ether synthesis using a suitable dioxolanyl alcohol, an alkynyl or arylalkyl halide, and an alkali source is used. In particular, it has been found that a suitable source of alkali is a sodium hydride dispersion is in mineral oil. This response can be represented by the following general equations:

(I) H.

CH _P CA-OH, ...

t ■ «space

0 0+ sewing temperature / atmospheric

"C pressure

^R l ^R l
(ID H.

CH ₉ CA-ONa. '. . ...

ι ^d \ ■ i

0 0+ RX increased ■

\ / Temperature '

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In the above formulas, X is a halogen atom with an atomic weight of at most about 80. R is a suitable alkynyl or arylalkyl radical. R ^ and A have the same meaning as defined above in connection with the formal IA. The series of reactions described above is carried out using substantially equimolar ratios of the reactants. If appropriate, an excess of the halide can be used. In general, the above reaction II is carried out at atmospheric pressure at a temperature in the range from about 40 to 150 ° C. depending on the boiling point of the halide starting material or the solvent used. For example, toluene can be used as the reaction solvent. The products made in the above manner
are generally purified by distillation.

The carbamate derivatives of the present invention in which Il

R -0-C-NH ₀ , can be in a simple manner after the

fc> d. '

drive from Loew and Komendy (J. Org. G hem. 28, 3421
(1963)). With this procedure goes
so that about 1 mole of one of the above-described suitable dioxolanyl alcohols in a suitable solvent such as methylene dichloride with about 2
Reacts mol of sodium cyanate, whereupon about 2 mol of a strong acid such as trifluoroacetic acid is slowly added. This response can be expressed by the following general equation
be given:

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+ CP ^ COOH

HO

t ι '

CII ₀ - CA-

Room- O O + CPoCOONa

temperature

A and Ry have the same meaning as defined in connection with the formula IA. This reaction can be carried out at atmospheric pressure at a temperature in the range from about 20 ° C. to the boiling point of methylene dichloride. The carbamates, if solid, can be recrystallized from an aromatic solvent or a lower alkanol. If they are liquid then they can be purified by extraction or by chromatography.

The nitrate compounds according to the invention can easily be produced using standard nitration methods. A suitable dioxolanyl alcohol as described above is reacted with a mixture of nitric acid and acetic anhydride at room temperature or below. These Implementation can be illustrated by the following general equation will:

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+ HNO ₃ + (CH ₃ GO) ₂ O 0 ⁰ G,

H
t

_CH GA-ONOp

t t

0 0 + CHoCOOH

R ₁

A and It | have the same meaning wb in context defined by the formula IA. The nitrates indulge in purified by washing with water and treating with activated charcoal will.

The azide derivatives of the dioxolanyl compounds according to the invention can be prepared by replacing the ester group with an azide anion. This reaction can be in simply with an equimolar ratio of Reactants in a polar solvent such as dimethylformamide at the boiling point of the polar used Solvent or just below it. The reaction can be illustrated by the following equation will:

3098-40 / 1 2 1 Q

H .1 λττ .. Γ t ² t O O

-A-Y

CH ₂ 0

o + dimethylformamide

. · Atmospheric pressure

H j C j

- AT-

Y in the above formula is a halogen atom such as chlorine or

OSO.

^. A and R ^ are as above together

defined with the formula IA. The azide compounds can be purified by vacuum distillation.

The ester derivatives, e.g. those in which Rg

- OSO

is can in a simple way

can be made by adding about 1 mole of the Snurechlorids with about 1 mole of a suitable dioxolany! alcohol in the presence is implemented by pyridine. This can be illustrated by the following general equation:

309840 / 121Q

CA- OSO ₂ -

-SOpCl + pyridine 2 $ ° C

Atmospheric pressure

-CH3

+ Pyridine— 'Hydrοchior iά

A and R ^ j have the meanings as they are related above with formula I was defined. The ester derivatives can be obtained by recrystallization from a lower alcohol or cleaned with an aromatic solvent.

The N-substituted ^ carbamate compounds can be in a simple Way to be prepared by using one of the dioxolanyl alcohols described above depending on the de.m desired Product is reacted with an equimolar amount by weight of a suitable isocyanate compound. The reaction can be carried out with or without the use of a further reaction medium. When a reaction solvent indicated, then such as benzene can be used and the reaction will be around the boiling point of benzene. Examples of isocyanate compounds that can be used are p-chlorophenyl isocyanate, Isopropyl isocyanate, cyclohexyl isocyanate and p-tolyl isocyanate.

It will be apparent to those skilled in the art that the above-described Manufacturing methods for the 4 — substituted

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perhalogenated dioxolane compounds also directly on the Preparation of the 4- and 5-substituted dioxolanes applicable by simply replacing the initial dioxolane compound with a suitable difunctional starting compound and an obvious adjustment of the molar concentration of the reactants is made, ' so that double substitution is obtained. For example, a suitable 4-, 5- bis (hydroxyalkyl) substituted perhalogenated Dioxolane can be used as the initial compound when appropriate.

Examples of the new substituted halogenated dioxolane compounds of the present invention are: 2,2-bis (chlorodifluoromethyl) -4-carbamoyloxymethyl-1,3-dioxolane; 2,2-bis (trifluoromethyl) -4-diphenylmethoxymethyl-1,3-dioxolane; 2,2-bis (trifluoromethyl) -4 ~ (2-propynyloxymethyl) -Λ , 3-dioxolane; 2,2-bis (trifluoromethyl) -4- (N-phenylcarbamoyloxymethyl) -1,3-dioxolane; 2,2-bis (trifluoromethyl) -4-carbamoyloxyr methyl-1,3-dioxolane; 2,2-bis (trifluoromethyl) -4-azidomethyl-1,3-dbxolane; 2,2-bis (trifluoromethyl) -1,3-dioxolan-4-ylmethyl-p-toluenesulfonate; 2,2-bis (chlorodifluoromethyl) -1,3-dioxolan-4-ylmethyl nitrate; 2-chlorodifluoromethyl-2-dichlorofluoromethyl-4-carbamoyloxymethyl-1,3-dioxolane; 2,2-bis (trifluoromethyl) -4- (3-carbamoyloxypropyl) ^ 1,3-dioxolane; 2,2-bis (trifluoromethyl) -4 - (6-carbamoyloxyhexyl) -1,3-dioxolane; 2,2-bis (trifluoromethyl) - ^, 5-bis (2-carbamoyloxyethyl) -1,3-dioxolane; 2,2-bis (trifluoromethyl) -4- (3-carbamoyloxypropyl) -5-methyl-1,3-dioxolane; 2-a? Ribromomethyl-2-trifluoromethyl-4-carbamdyloxymethyl-Ί, 3-dioxolane; 2-chlorodifluoromethyl-dichlorofluoromethyl-'l · - (2-carbamoyloxyethyl) -1,3-dioxolane; 2,2-bis (chlorodifluoromethyl) -4- ~ (3-carbamoyloxypropyl) -1,3-dioxolane; 2,2-bis (trifluoromethyl) -4- (10-carbamoyloxydecyl) ^, 3-dioxolane; 2,2-bis (trifluoromethyl) -4,5-bis (N-phenylcarbamoyloxyethyl) -1,3-dioxolane; 2 _{tons of} 2-bis (trifluoromethyl) - ^ - (2-azidoethyl) -1,3-dioxolane. .

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-59- 2312983

The following examples further illustrate the preparation of the compounds of the invention.

Example 16

Oil ethyl 7,5,5-trimethyl-2,2-bis (trifluoromethyl) -1,3- dioxolane-4-pentanol carbamate

ι 3

CH ₃ -C CH-CH ₂ -CH ₂ -CH-CH ₂ -CH-CH ₂ -Ch ₃ .

O-C-HHp u * ~

A sample of 0.1 mol ^ -
(Trifluoi'methyl) ^, 3-dioxolane-4-pentanol (product of Example 8) is dissolved in 5 parts of methylene dichloride and treated with 0.2 mol of sodium cyanate and dropwise with 0.2 mol of trifluoroacetic acid. The reaction mixture is stirred for 24 hours at 35 to 4-0 ⁰ C and filtered. The filtrate is washed several times with water until neutral. On evaporation of the solvent from the piltrate, the product is obtained. The product is purified by passing it through a column of silica gel and eluting with benzene and methanol.

Example 1?

2,2-bis (chlorodifluoromethyl) -1,5-dioxolan-4-ylmethyl ititrate

ml of nitric acid ($ 96) are slowly cooled to 43 ml Acetic anhydride added. 14.8 g of 2,2-bis (chlorodifluoromethyl) -4-hydroxymethyl-1,3-dioxolane are then added dropwise with magnetic stirring over a time

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2312983

Added space of 30 minutes to the cooled mixed acid (0 to 10 ° C). It is stirred for a further 25 minutes. The reaction mixture is poured into 250 ml of cold tap water, whereby a small lower liquid layer is formed. Extraction with ether (3 x 75 nil) removes the lower layer and all of the yellow color. The ether solution is washed several times with water and then _{dried over ..Na 2} SO ^, filtered and evaporated in a rotary evaporator. The cloudy residue is _{redissolved in ether, treated with Na 2} SO ₂ , decanted and evaporated as described above. The shiny yellow liquid is redissolved in ether and treated with activated carbon (DARCO G-60). It is then filtered (colorless) and evaporated again to give the product identified above.

Analysis found N, $ 4.15

Calculated for C ₆ H ₅ Cl ₂ F ^ ₅

(MW 318.02) N, 4.40 #

Example 18

2,2-bis (trifluoromethyl) -1,3-dioxolan-4-ylmethyl-p- toluenesulfonate

30.0 g of 2,2-bis (trifluoromethyl) -4-hydroxymethyl-1,3-dioxolane (0.125 mol) are dissolved in 40 tnl pyridine. To do this will be 26.2 g of p-toluenesulfonyl chloride were added. The mixture is kept at room temperature for 16 hours.

The product is dissolved in chloroform, extracted with water and sodium carbonate solution and the solvent is evaporated. The resulting product is then recrystallized from isopropyl alcohol to give 2,2-bis (trifluoromethyl) -1 ^ -dioxolane ^ -ylinethyl-p-toluenesulfonate (m.p. 57 Ms 58.5 ° C) is obtained.

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-4-

Analysis found (in percent)

Calculated for (MG 394.3)

Example 19

C, 39.68; H, 3.10; F, 28.90; S, 8.15

C, 39.60; H, 3.07; F, 28.91; S, 8.13

2,2-bis (Qrifluorinethyl) -4-azidomethyl-1,3-dioxolane

A sample of 14,00g 2,2-bis (! Trifluoromethyl) -4-tosyloxymethyl-1,3-dioxolane (Pp- 58 to 6O ⁰ C) is dissolved in 40 ml of dimethylformamide. To this end, 4.85 NaN _{3 is} added. The mixture is stirred magnetically at 140-149 ° C for 3.5 hours. The product is diluted with benzene and filtered. The filtrate is washed thoroughly with water, evaporated in vacuo and distilled. The product, 2,2-bis (trifluoromethyl) -4-azidomethyl- ~ 1,3-dioxolane, has a boiling point of 78 ° C / 20 mm Hg and a refractive index of 1.37447 at 20 ° C.

Analysis found

(in percent)

Calculated for Cg (MW 265.1)

C, 26..95; H, 1.73; N, 16.06; C, 27.18; H, 1.90; N, 15.84

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2312983

Example 20

2,2-bis (trifluoromethyl) -4-carbamoyloxymethyl-1,3-dioxolane

A mixture of 15 g of 2,2-bis (trifluoromethyl) -4 ~ hydroxymethyl-1,3-dioxolane (0.0625 mol), 8.12 g of NaOCN (0.125 col) and 75 ml of methylene dichloride is added at 25 to 35 ° C., 14.3 S trifluoroacetic acid being added dropwise. The mixture is ^{stirred at 40 °} C. for 16 hours. The product is filtered and the filter cake is washed with methylene dichloride. The filtrate is washed with water and dried over NaoSOy. dried before vacuum evaporation, the reaction product is recrystallized from 1 part benzene, whereby 2,2-bis (trifluoromethyl) -4-carbamoyloxymethy1-1,3-dioxolane (mp. 52 to 5 ^ ° ^) is obtained.

Analysis found.

(in percent)

Calculated for C _n H _n FJTO

(MG 283.13)

/ / ό 4

C, 29.77; H _s 2.65; F, 40.40; N, 4.92

C, 29.69; H, 2.49; F, 40.26; N, 4,

Example 21

2,2-bis (trifluoromethyl) -4- (N-phenylcarbamoyloxymethyl) - 1,3-dioxolane -

60 g of 2,2-bis (0? Rifluoromethyl) -4-hydroxymethyl-1,3-dioxol5ji (0.25 mol) are mixed with 28.3 g (0.24 mol) of phenyl isocyanate under a reflux condenser with a dry motor. The reaction mixture is heated to 75 "to 80 ^° C. for 17 hours. The product solidifies after it has reached room temperature.

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temperature is left to stand. It is taken up in 1 part hot in benzene and filtered hot (insoluble substances 3.6 g). 1 part of hexane is added to the filtrate and the product is ^{crystallized at 0} ° C. Filtration, drying and solvent washing with hexanobenzene gives a white crystalline product. The filtrate is evaporated to give 21.2 g of solids. This is washed with benzene hexane, dissolved while hot, treated with activated charcoal and crystallized at 0.degree. Both crystalline products are combined and after 24 - aialysiert hour vacuum drying at 50 ^0C. The product was identified as 2,2-bis (trifluoromethyl) -4 ~ (N-phenylcarbamoyloxymethyl) -1,3-dioxolane (mp. 71 to 72.5 ⁰ C).

Analysis found

(in percent) C, 43.42; H, 2.91; F, 31.65;

N, 3.86

Calculated for C ^ H ^ Fg ^
(MW 359.2) C, 43.45; H, 3.09; F, 31.74;

N, 3.90

Example 22 2,2-bis (trifluoromethyl) -4- (2-propynylpxymethyl) -1,3-dioxolane

A solution of 12.0 g (0.05 mol) of 2,2-bis (trifluoro ~ methyl) -4-hydroxymethyl-1,3-dioxolane in 50 ml of toluene. At 24 to 33 ° C, 2.24 g of sodium hydride mineral oil are produced (Active ingredient $ 53.5, 0.05 mol) added. The resulting The mixture is stirred until the foaming subsides. Excess propargyl bromide (15.6 ml "is then calculated 3.9 ml) is added and the mixture becomes about 6.5

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Heated to 55 Ms 65 ° 0 hours. The resulting solution is filtered, washed with water, filtered through. Super gel clarified and evaporated in vacuo (on Final 70 ° C / 70 mm Hg).

The reaction product is at 4-8 ° C / 0.2 mm Hg in a 7.5 cm column distilled, which comes with a packing stainless steel is filled. In this way, 2,2-bis (trifluoromethyl) -4- (2-propynyloxymethyl) -1,3-dioxolane is obtained.

Analysis found

(in percent) C, 39.09; H, 3.29; F, 4-1,14-

Calculated for CgHgPgO,
. (MW 278.15) C, 38.85; H, 2.9; P, 4-1.0

Refractive index : 1.36986 (20 ⁰ G)

Example 23

2,2 bis (trifluoromethyl) -4-diphenylmethoxymethyl-1,3-dioxolane

A sample of 12 g (0.05 mol) of 2,2-bis (trifluoromethyl) -4 ~ hydroxymethyl-1,3-dioxolane in 50 ml of toluene is mixed with 1.93 g of sodium hydride mineral oil (53.4- $ .0 , 04-3 mol) at 25 to 33 ° G. The sodium salt is stirred at 35 ° C. for 2 hours. There are 10.6 g of benzhydryl bromide (0.04 to 3 mol) at 37 ° C was added, and then the temperature is raised for 3 hours at 75 ° C to 95 ⁰ G. The mixture is filtered and the piltrate is washed with water. Vacuum evaporation gives an oil which is dissolved in methanol and clarified by filtration through Super CeI. The yield of the

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• Product is 17.0 g at this point. One advance is distilled in a 12 cm column, which with a Stainless steel packing is filled. The remainder is distilled without a packed column. The received Product is at 137 ° C under a pressure of 0.4-5 mm Hg distilled, giving 2,2-bis (trifluoromethyl) -4-diphenylmethoxymethyl-1,3-dioxolane is obtained.

Analysis found

(in percent) C, 55.99; H, 4.4-5; F, 28.51

Calculated for O ₁₉ H ₁₆ F ₆ O ₅

(MW 406.32) C, 56.1; H, 3.97; F, 28.1

Refractive index : 1.48003 (20 ° C)
Example 24

2,2-bis (chlorodifluoromethyl) -4-carbamoyloxymethyl-1,3- dioxolane

A sample of 15 g of 2,2-bis (chlorodifluoromethyl) -4-hydroxymethyl-1,3-dioxolane (0.055 mol) is dissolved in 75 ml of methylene chloride. 7 * 16 g of sodium cyanate are used for this (0.11 moles). Trifluoroacetic acid (12.6 g, 0.11 mol) is added dropwise with stirring at 23 to 33 ° C. The temperature is then increased to 40 ° C and it becomes stirred for a further 18 hours. The product is filtered and the filtrate is washed with water until neutral is. In the case of vacuum evaporation, a quantitative yield of the crude products is obtained, some of which can be obtained solidify. Filtration and recrystallization from a mixture of benzene hexane and once from cyclohexane gives 2,2-bis (chlorodifluoromethyl) -4-carbamoyloxymethyl-1,3-dioxolane (M.p. 56-57 ° C).

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Analysis found (in percent)

C, 27.88; H, 2.28; Cl, 22.88; F, 24.34; N, 4.44

Calculated for (MG 316.03)

C, 27.16; H, 2.28; Cl, 22.90; F, 24.55; N, 4.43

Example 25

2,2-bis (chlorodifluoromethyl) ~ 4- / N- (p-chlorophenyl) carbamoyl oxyme thy Xj-Λ , 3-dioxolane _

68.0 g of 2,2-bis (chlorodifluoromethyl) -4-hydroxymethyl-1,3-dioxolane (0.25 mol) are mixed with 36.8 g (0.24 mol) of p-chlorophenyl isocyanate at 73 to 80 ° C. over a Treated period of 15 to 20 hours. The product, 2,2-bis (chlorodifluoromethyl) .- 4- / N- (p-chlorophenyl) -carbamoyloxymethylT "-1,3-dioxolane, is purified by crystallization from benzene or a mixture of benzene and hexane. It can can be decolorized by treatment with activated charcoal.

The procedure of Example 24 can be used to prepare other N-substituted carbamates, where isopropyl isocyanate, cyclohexyl isocyanate and p-tolyl isocyanate instead of p-chlorophenyl isocyanate used .. ^

Example 26

<&, <*, 5-trimethyl -2,2-bis (chlorodifluoromethyl) -1,3-dioxolane-4-methanol carbamate

A solution of 31.5 S (0.1 mol) oC, rt, 5-trimethy1-2,2-bis

30984071210

(Chlorodifluoromethyl) -i, 3 ~ <3.ioxolane - ^ - methanol in'BO ml of methylene dichloride is treated with 13.0 g of sodium cyanate (0.2 mol), with 22.8 g of trifluoroacetic acid (0.2 mol) being added dropwise will. The reaction is carried out at 25 to 35 ° C for 24 hours. When the reaction is complete, a small amount of water is added to dissolve salts. The methylene hybrid solution is separated off and extracted again with water / water. In the case of vacuum evaporation, the product ^, a ^ -trimethyl ^^ - bisichlordifluormethyl) -Λ , J-dioxolane - ^ - methanol carbamate is obtained. The product is purified by crystallization from a mixture of benzene and hexane.

The dioxolanyl alcohol used in this example can according to the method of U, S. patent application 873,660 or by reacting the oxido alcohol V with the appropriate perhaloketone by the method of the US patent 3,488,335. The latter method can be illustrated by the following reaction scheme:

^f * Kther ■

CH ₃ -CH id

₃ -CH-CH-C-CHo

O OH

\ C. \ GH-C-CHn
»Ι -5 CH-
I. O OH O R ₁

Darm means R _x , the desired perhalogenated alkyl radical.

30 9 8 AO / 1 21Q

Example 27

2,2-bUs (chlorodifluoromethyl) -4,5-Ms (1-carbamoyloxyethyl-

1, 3-dioxolane _ ^ - _inii -

A solution of 33.1 g (0.1 mol) of 2,2-bis (chlorodifluoromethyl) ■ 4,5-Ms (1-hydroxy-ethyl) -1,3-dioxolane in 200 ml of methylene dichloride is with 13.0 g of sodium cyanate (0.2 mol) and 22.8 g Trifluoroacetic acid (0.2 mol) treated in the same manner as in Example 26. The product, 2,2-bis (chlorodifluoromethyl) -4, 5-bis (1-carbamoyloxyethyl) -1,3 ~ dioxolane is isolated and purified as in Example 26.

The dioxolanyl alcohol used in this example is from 3-hexene-2,5-d-iol by a reaction according to the following Equation made:

CH ₀ -GH-GH = GH-CH-GH iMLPSS ^^

.3 ι t -> Chloi-Of or.si

OH- OH V.

·. CH _O -CH-GH-CH-CH-CH_

■ * ■ ³ ι \ / ^{! 3}

VIII OH 0 OH

The above oxidodiol (VIII) is treated with the appropriate per halo ketone by the method of U.S. Patent 3 488 335 converted into cLas Dioxolanyldiol.

Example 28

1- / 2,2-bis (chlorodifluoromethyl) -1,3-dioxolan-4-yl7-butyl nitrate

34 ml of nitric acid ($ 96) are slowly distilled to 43 ml Acetic anhydride given. 17.1 g of 2,2-bis (chlorodifluoromethyl) -4- (1-hydroxybutyl)

309840/12 10

1,3-dioxolane with stirring over a period of 30 minutes at ⁰ ° C to -10 ⁰ G added. The dioxolanyl alcohol is prepared from 1,2,3-hexanetriol and the corresponding perhalogenated ketone by the process of US patent application 873i660. An additional 25 minute response period is allowed. The reaction mixture is added to 250 ml of cold water and extracted with several 75 ml portions of ether. The ether solution of the product is washed thoroughly with water, treated with activated charcoal and dried over sodium sulfate. Filtration and evaporation yields 1/2 ", 2-bis (chlorodifluoromethyl) -1,3-dioxolan-4-yl7-butyl nitrate.

Example 29

2,2-bis (heptafluoropropyl) -4-carbamoyloxymethyl-1,3-dloxolane

A solution of 44.0 g (0.1 mol) of 2,2-bis (heptafluoropropyl) -4-hydroxymethyl-1,3-dioxolane, prepared by the method of US patent application 873,660, in 25Ο ml of methylene dichloride "is with 13 , 0 g of sodium cyanate treated while 22.8 g of trifluoroacetic acid are added dropwise. The reaction is carried out for 24 hours at 25 to 35 ^° C. After the reaction has ended, a small amount of water is added in order to dissolve the salts The desired product is obtained by vacuum evaporation The product, 2,2-bis (heptafluoropropyl) -4-carbamoyloxymethyl-1,3-dioxolane, is purified by crystallization from a mixture of benzene and hexane.

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Example 30

Production of 2,2-bis (trifluoromethyl) -4- (2-carhamoyloxyethyl) -1,3-dioxolane _ -

"- ■ uj

- CH - CH ₀ -CHp-OG- NH _O tc - _f 2 c- u 2

OO *** 0

CF ^ ■ CF.
.J--

A sample of 10 g of 2,2-bis (trifluoromethyl) -4- (2-hydroxyethyl) -1,3-dioxolane (39.4 millimoles) is dissolved in 50 ml of methylene chloride and mixed with 5.2 g of sodium cyanate and dropwise with 9jO g trifluoroacetic acid .. The reaction is carried out for 1.5 hours at 25'bis 41 ⁰ C and 66 hours at Eaumtemperatur. The product is filtered and the piltrate is washed five times with 25 ml of water. The solvent is evaporated in vacuo and the crude product is treated at 75-115 ° C / 0.14 mm Hg to remove the by-product and starting materials. The yield of the syrupy product is 8.4 g (71 ^ 5 $ ') * The product is purified by passing it through a column of silica gel and eluting with benzene and methanol. The yield of the pure product is 7 »· 4 g (63 ^). The refractive index is 1.38662 (20.4 ° C). The analysis is as follows: "

Found: C - $ 32.34 Calculated: $ 32.35

H - 2.91 # 3.04 #

i ¹ - $ 38.00 $ 38.41

N - $ 4.79. $ 4.72

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Example 31

2-chlorodifluoromethyl-2-dichlorofluoromethyl-4-carbamoyloxy methyl-1,3-dioxolane

20 g of 2-chlorodifluoromethyl-2-dichlorofluoromethyl-4-hydroymethyl-1,3-dioxolane (0.069 mol) are dissolved in 100 ml of methylene dichloride. It becomes sodium cyanate. (9 g, 0.138 Mol) added. The solution is stirred for 15.7 sec Trifluoroacetic acid can be added dropwise. The reaction is carried out at 40 ° C. for 16 hours. The mixture is filtered and the filtrate is washed with water until neutral. The removal of the solvent by vacuum evaporation gives a quantitative yield of the product, some of which is released on standing solidified. The product is filtered and recrystallized from a 1: 1 mixture of benzene and cyclohexane The yield of the pure product is 12.4 g ($ 54). The product is a white solid that is at 76 to 78 ° C melts.

Analysis found

(in percent) C, 25.38; H, 2.14; Cl, 31.86;

F, 17.18; N, 4.14

Rained ■ for

(MW 332.5) ^J C, 25.29; H, 2.12; Cl, 31.99;

F, 17.14; N, 4.21

Various test methods were carried out in the laboratory to investigate tranquilizing activity. These included the shock-induced aggression test and the amphetamine toxicity antagonism test. These l'ests are carried out as follows:

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Shock-induced expression test (in the mouse)

In this method, two mice are placed on a grid and the grid is electrified for 2 minutes. This causes the animals to be aggressive towards one another Show behavior. The fighting period of each pair of control mice (injection with water) is coincident with the fighting period of the pairs injected with the test compound. Connections are made inside administered. Tranqui-llizers reduce the fighting period, by reducing aggressiveness.

Results:

The compound, 2,2-bis (chlorodifluoromethyl) -4-carbamoyloxymethyl-1,3-dioxolane, Reduces fight time by $ 87 at mg / kg and by $ 100 at 100 mg / kg

The compound, 2,2-bis (chlorodifluoromethyl) -4-chloromethyl-1,3-dioxolane, Reduces fight time by $ 83 at 200 mg / kg and by $ 29 at 25 mg / kg.

Amphetamine toxicity antagonism test (in the mouse)

In this test, 10 mice are administered orally either water (control animals) or the test substance An hour later, amphetamine is injected intraperitoneally. The dosage of the amphetamine is what causes death in $ 80 to $ 100 of control animals by overstimulating the sympathetic nervous system. 2 and 4 hours after the amphetamine injection, the Number of still living animals in each group compared.

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Results:

The compound, 2,2-bis (chlorodifluoromethyl) -4-carbamoyloxymethyl-1,3 ~ dioxolane, reduced amphetamine toxicity by $ 100 at 200 mg / kg and gave one at 50 mg / kg Protection of

The compound, 2,2-bis (chlorodifluoromethyl) -4-chlorinethyl-1,3-dioxolane, reduced amphetamine toxicity by $ 100 at 200 mg / kg and gave protection at 25 mg / kg from $ 50.

The evaluation of the laboratory tests indicates that the dioxolane compounds according to the invention have a tranquillizing activity when they are administered in a therapeutically effective amount. The activity and dosage required will vary as usual depending on the species being treated, the disorder being treated, the weight of the animal and the route of administration. Suitable dosages and routes of administration for animals which are responsive to the compounds of the invention can readily be found through routine studies. According to the invention, the compounds according to the invention are administered 1 to 4 times a day in doses of about 1.0 mg to 5 mg per kilogram of body weight. As stated above, the effective dosage will vary in individual cases depending on the species and the other variables indicated above. By way of example, a preferred oral dosage of 2,2-bis (trifluoromethyl) - ^z} ~ hydroxymethyl-1,3 <iioxolan and 2,2-bis (chlorodifluoromethyl) -4-hydroxymethyl-1,3-dioxolane for the mouse about 200 to 300 mg / kg body weight. A preferred dosage of 2,2-Ms (dichlorofluoromethyl) -4-c-chloromethyl-1,3-dioxolane for rats is about 300 to 400 mg / kg body weight by intraperitoneal injection. Furthermore, a preferred dosage of 2 r-chlorodifluoromethyl-2-dichlorofluoromethyl-4-hydroxymethyl-1,3-dioxolane for rats is about 180 "to 300 mg /

309840/1210

kg body weight by intraperitoneal injection. A preferred dosage of 2,2-bis (trifluoromethyl) -4- (2-carbamoyloxyethyl) -1,3-dioxolane and 2,2-bis (chlorodifluoromethyl I) -4-carbamoyloxymethyl-1,3-dioxolane for rats is about 50 to 325 mg / kg body weight by intraperitoneal injection. A preferred peroral dosage for 2,2-bis (chlorodifluoromethyl) -4 ~ carbamoyloxymethyl-1,3-dioxolane for Monkeys is about 5 ° to 100 mg / kg body weight. One preferred oral dosage of 2-chlorodifluoromethyl-2- dichlorofluoromethyl-4-carbamoyloxymethyl-1,3-dioxolane for monkeys is about 100 to 200 mg / kg body weight. Furthermore, a preferred oral dosage is 2,2-bis (trifluoromethyl) -4-carbamoyloxymethyl-1,3-dioxolane and from 2,2-bis (chlorodifluoromethy 1) -1,3-dioxolan ~ 4-ylmethyl nitrate for mice about 200 to 300 mg / kg body weight. A preferred one oral dosage of 2,2-bis (chlorodifluoromethyl) -4-carbamoyloxymethyl-1,3-dioxolane for mice is about 50 to 300 mg / kg body weight.

Since the compounds according to the invention are effective when administered orally, they can be formulated in any suitable oral dosage form as tablets, capsules, syrups, elixirs, suspensions or other solid or liquid preparation forms which are obtainable by the known manufacturing methods. Thus dünnungsmitteln compounds of this invention with suitable encryption · ¹ such as lactose or kaolin are mixed and encapsulated or they may be combined with suitable binders and expanding agents and compressed into tablets. In addition, liquid preparation forms can be obtained by dissolving or suspending the compounds according to the invention in a suitably flavored liquid. The compounds of the invention are also active when administered parenterally or rectally.

309840/1210

Some examples for the production of tablets, capsules, liquids, parenteral preparation forms, suppositories containing the new dioxolane compounds of the invention are described below. It will be apparent to the person skilled in the art that the following formulations show only one method for the production of such pharmaceutical preparations, whereby, of course, the size of the tablets or capsules or the strength of the dosage can be suitably varied to meet the respective requirements, for example the dosage unit indicated, To take into account. For example, each Dosierungseinheitgpeigneterweise about 15 tfe 5OOO mg of the active ingredient in admixture with an \ ^r erdünnenden amount of a pharmaceutically acceptable carrier contained. The known suitable pharmaceutical carriers can be used for the production of preparation forms, so that an effective amount or a therapeutically effective amount of the substance to be administered is obtained.

Tablets containing 100 mg 2,2-bis (Tri- 1000Tablet-

fluoromethyl) -4- (N-phenylearbamoyloxymethyl) - th (g)

1, 3-dioxola n

2,2 ~ bis (trifluoromethyl) -4- ~ (N-phenylcarba-

moyloxymethyl-1,3-dioxolane 100

Strength 80

Powdered lactose 80

Talk 20

Granulation weight 280

All ingredients are mixed and then pressed into spheres. The beads should then be ground in such a way that that they form a granulate which passes through a sieve with a mesh size of 1.4-1 to 1.19 mm. The granulate can then be processed using a

309840/1210

suitable printing form for tablets with a weight of each 280 mg are recompressed.

Capsules containing 200 mg of 2,2-bis (chloro-difluoromethyl) -4-carbamoyloxymethyl-1,3- dioxolane

2,2-bis (chlorodifluoromethyl) ~ 4 ~ earbamoyl-

oxymethyl-1,3-dioxolane 200 mg

Powdered lactose 100 mg

D.T.D. Capsules No. 1000

The ingredients are mixed so that the active ingredient is uniformly distributed in the lactose. The powder is in empty gelatine capsules No. 1 packed.

Suspension containing 50 mg of 2,2-bis (trifluoromethyl) -4 ~ carbamoyloxymethyl-1,3 ~ di-

OXOlan, each 5 ecm

2,2-bis (trifluoromethyl) -4- carbamoyloxyme-

thy1-1,3-dioxolane 10 g

Tragacanth 50 g

Amaranth 10g

Wild cherry syrup. 60 ml

'' Distilled water to 1000 ml

The tragacanth is soaked in enough water to form a smooth paste. For this purpose, 2,2-bis (trifluoromethyl) -4-carbamoyloxymethyl-i, 3-dioxolane, followed by the amaranth, given. The latter was previously dissolved in water. Then the wild cherry syrup is added and water is added to 1000 ml.

309840/1210

Injectable preparation containing 5 nil 2,2-bis (trifluoromethyl) -4-azidomethyl-1,3-dioxolane per ml, suitable for intramuscular intramuscular intrapr3 -toneal and subcutaneous injection

2,2-bis (trifluoromethyl) -4-azidomethyl-i, 3-

dioxolane 5> 0 6

Chlorobutanol 3.0 g

Propylene glycol 20.0 g

Water for injection to 1000.0 ml

The above ingredients are combined, clarified by filtration, vials, sealed and autoclaved treated.

Suppositories containing 200 mg of 2,2-bis (trifluoromethyl) -4- (2-carbamoyloxyethyl) -1,3-di ~ oxolane

2.2 ~ bis (trifluoromethyl) -4 - (2-carbamoyloxy- 0.2 g ethyl) -1,3-dioxolane

Cocoa butter. ^: "1.8 g

The production of such No. 100

The cocoa butter is melted. In the melted cash register, the 2,2-bis (trifluoromethyl) -4- (2-carbamoyloxyethyl) -1,3-dioxolane dispersed. Stir until the product is uniform. The resulting molten mass will poured into a suppository mold and allowed to cool. The suppositories are taken out of the mold and packaged.

Tablets containing 100 mg 2,2-bis. (Trifluor- 1000 Tablet methyl) -4-hydroxymethyl-1,3-dioxolan th (g)

2,2-bis (trifluoromethyl) -4 ~ hydroxymethyl-1,3-

dioxolane 100

Strength 80

Powdered lactose 80

Talk. '20

Granulation weight 280

309840/1210

All of the ingredients are combined, mixed and then pressed into beads. The beads are then ground to form granules, which pass through a sieve with a mesh size of 1.4-1 "to 1.19 mm. The granules can then, using a suitable compression mold, form tablets each weighing 280 mg be re-pressed.

Capsules containing 200 mg of 2,2-bis (Trifluormethyl) - 4-hydroxymethyl -1,3-dioxolane ___ "___

2,2-bis (trifluoromethyl) -4-hydroxymethyl-

1,3-dioxolane. 200 mg

Powdered lactose 100 mg

D.T.D. Capsules No. 1000

The ingredients are mixed so that the active ingredient is uniformly distributed throughout the lactose. The powder will into the empty Gelsbine capsule No. 1 packed.

Suspension containing 50 mg of 2,2-bis (chlorine dif iuormethyl) - ^ - hr / droxymethyl-i, 5-dioxolane, 5 each

2,2-bis (chlorodifluoromethyl) -4-hydroxymethyl-1,3-dioxolane

Traganth Amaranth V / ild cherry syrup Distilled water on

The tragacanth is soaked with enough water that a smooth paste is formed. To do this, 2.2-bis (Chlorodifluoromethyl) -4-hydroxymethy1-1,3-dioxolane followed of the amaranth, which was previously dissolved in water. The wild cherry syrup is then used for this purpose added and distilled water / water added to 100 ml.

10 ε 50 G 10 G 60 ml 1000 ml

309840/12 10

Injectable preparation containing 5 mg of 2,2-bis (chlorodifluoromethyl) -4-hydroxymethyl-1,3-dioxolane per ml, suitable for intramuscular , intraperitoneal and subcutaneous injection

2,2-bis (chlorodifluoromethyl) -4-hydroxymethyl-

1,3-dioxolane 5 »0 g

Chlorobutanol 5.0 g

Propylene glycol 20.0 ml

Water for injection to Ί000.0 el

The above ingredients are combined, by filtration clarified, vials, sealed and autoclaved.

Suppositories containing 200 mg of 2-chlorodifluoromethyl-2-dichlorofluoromethyl-4-hydroxy methyl-1,3-dioxolane ___ ^

2-chlorodifluoromethyl-2-dichlorofluoromethyl-4-

hydroxymethyl-1,3-dioxolane 0.2 g

Cocoa butter 1.8 g

Manufacture of such No. 100

D5's cocoa butter is melted. In the molten mass the 2-chlorodifluoromethyl-2-dichlorofluoromethyl-dihydroxy methyl-1,3-dioxolane is dispersed. It is stirred until a uniform product is obtained anyway. The resulting molten mass is converted into a suppository shape given and cooled. The suppositories are taken out of the mold and packaged.

309840/1210

Claims (1)

Patent to claims 1. Veterinary medicinal products containing at least one dioxolane compound of the general formula as active ingredient - - - - K ₂ - C - GR ₃ O ^ J) I wherein each R ^ group is an independently selected perhalogenated alkyl group, R ₇ and Rg are one of H or lower alkyl, R- is H, haloalkyl, alkyl, hydroxyalkyl or polyhdroxyalkyl or ARg, R _{2 is} H, haloalkyl, alkyl, Hydroxyalkyl or polyhydroxyalkyl or ARg, with the proviso that when R _{2 is} -ARg, then R, H or alkyl or -ARg, A is an alkylene group, R ^ - one of the following substituents - ONO ₂ - .OSOo - OCNH, - OCNHR ₁ - OCH 309840/1210 - 61 - denotes where JU is a lower alkyl group, phenyl, tolyl, halo'genphenyl or cyclohexyl, with the proviso that Rg can be a hydroxyl group when either R ₇ or Rn is an alkyl group or when the total number of carbon atoms is in the alkylene or alkyl chains, which in the _{groups indicated by -A- and R 2} is at least 6 and with the further proviso that if R ₇ and Ro are H and R _{2 is} a substituent other than Rg, then at least is one of the substituents of R ₂ and R-, hydroxyl or haloalkyl, and the total number of carbons in R ₂ and R ^ is 1 to 5, 2. Veterinary medicinal product according to claim 1, characterized in that it contains a dioxolane compound, in which R. contains 1 to 7 carbon atoms. 5. Veterinary medicinal product according to claim 1 or 2, characterized characterized in that it contains a dioxolane compound in which A contains 1 to 6 carbon atoms. 4. Veterinary medicinal product according to claim 1, characterized in that the active ingredient 2,2-bis (Trifluorme thy I) -4-hydroxymethy1-1,3-dioxolane, 2,2-bis (chlorodifluoromethyl) ■ 4-hydroxymethyl -ljjJ-dioxolane, 2-chlorodifluoromethyl-2-hydroxymethyl-diehlorfluormethy1-4-1,5-dioxolane, 2,2-bis (Trichlordifluor-äthy]) - 4-hydroxymethyl-l _i-dioxolan 3, 2,2-bis (Trifluoromethyl) -4-chloromethyl-1,5-dioxolane, 2-chlorodifluoromethyl-1,5-dichlorofluoromethyl-1,4-chloromethyl-1,3-dioxolane, 2,2-bis (chlorodifluoromethyl) -4-chloromethyl-1,5 dioxolane and / or 2,2-bis (trifluoromethyl) -4- (2-hydroxyethyl) -1,5-dioxolane. 5. Dioxolane compound of the general formula j 1 OO - A ~ R ₆ \ 309840/1210 , wherein each R group is independently selected from a perhalogenated alkyl group, A is an alkylene radical, small ones Substituents from the group - OEfO. ~ OSO, 11 OCKH, ^X 3 0 ti . «OCH ₂ C === CH denotes, R ^ denotes a lower alkyl group., denotes phenyl, tolyl, halophenyl or cyclohexyl, R ₁ - denotes hydrogen, alkyl or A-Rg and R "and Rg independently of one another denote hydrogen or a lower alkyl group, with the proviso that Rg be a hydroxyl group when either R1 or Ro is an alkyl group or when the total number of carbon atoms in the alkylene or alkyl chains present in the combined groups indicated by A and Rt is 6 or more. 6. Dioxolane compound according to Claim 5 *, characterized in that
contains. that R. 1 to ¹ J carbon atoms Dioxolane compound according to claim 5 or 6, characterized marked contains. that A has 1 to 6 carbon atoms 3 0 9 8 4 0/1210 8. dioxolane compound according to any one of claims 5 to 7, ^ characterized in that R ₁ - is a lower alkyl group having 1 to 6 carbon atoms. 9. Dioxolane compound according to claim 5 *, characterized in that each R 1 group contains a carbon atom, that R ", R ₇ and Rg are hydrogen and that R, - the group 0
ο ti ■ -0-G-NH ₂
is. 10. Dioxolane compound according to claim 5 *, characterized in that it contains 2,2-bis (chlorodifluoromethyl) -l, 3-dioxolan-4-yl-methyl-nitrate, 2,2-bis (trifluoromethyl) -4-az ± inethyl-l, 5-dioxolan, 2,2-bis (trifluoromethyl) - ⁱ lcarbamoyloxymethyl-l, '3-dioxolan, 2,2-bis (trifluoromethyl) -4-N-phenylcarbamoyloxymethyl) -l, 3-dioxolane, 2 , 2-bis (chlorodifluoromethyl-1,3-dioxolane) -4-carbamoyloxymethyl-1,5-dioxolane, 2-chlorodifluoromethyl-2-dichlorofluoromethyl-4-carbamoyloxymethyl-1,3-dioxolane or 2,2-bis (trifluoromethyl) - ⁱ ! - (2-Carbamoyloxy-ethyl) -l, 5-dioxolane is. 309840/1210