Title of Invention

"PREPARATION OF FLUORINATED 1,3-BENZODIOXANES"

Abstract

Compound of the general formula (I-a) where R1, R2, R3, R4 are each independently H, CN, NO2, NH2, OH, halogen, linear or branched, optionally partly fluorinated or perfluorinated C1-C4-alkyl radicals, linear or branched, optionally partly fluorinated or perfluorinated C1-C4-alkoxy radicals, CHO, COOH, COOR, SO2CH3, SO2Hal, optionally substituted phenyl or pyridyl radicals, fluorocarbonyl, benzoyl, trifluoroacetyl, phenoxy, isocyanato, SO2F and difluorochloromethyl radicals, where R is a C1-C4-alkyl radical and Hal is a halogen radical, X is H, C1 or F.

Full Text

Preparation of fluorinated 1,3-benzodioxanes The invention relates to novel fluorinated achiral 1,3-benzodioxanes and to the preparation thereof. Fluorinated 1,3-benzodioxanes, especially the corresponding aminobenzodioxanes, are valuable intermediates for the synthesis of life science active ingredients, especially of active pharmaceutical ingredients in cancer therapy. In the field of the fluorinated 1,3-benzodioxanes, the only compounds known to date have either borne two different substituents on one of the methylene carbons and/or not had sufficient lipophilicity for use as building blocks for active pharmaceutical ingredients (DE-A 16 43 382). In the case of the compounds which have a stereocentre, a costly and inconvenient enantiomer separation before further use is required. There is therefore a need to circumvent the problem of enantiomer separation, which cannot be solved satisfactorily with the current state of the art, and to provide fluorinated 1,3-benzodioxanes suitable for further processing to give active pharmaceutical ingredients. The object on which the present invention is based is thus to provide suitable fluorinated 1,3-benzodioxanes for which no costly and inconvenient enantiomer separation is required and which are suitable, for example, for further processing to give active pharmaceutical ingredients for cancer therapy. It has been possible, surprisingly, using a new synthesis strategy, to circumvent the chirality problem by introducing a second identical substituent on the methylene group, and to noticeably increase the lipophilicity in the active ingredient molecules. With few synthetic steps, a multitude of compounds of the general formulae (I-a) or (I-b) can be obtained. (Formula Removed) The present invention therefore provides compounds of the general formulae (I-a) or (I-b) (Formula Removed) where R1, R2, R3, R4 are each independently H, CN, NO2, NH2, OH, halogen, linear or branched, optionally partly fluorinated or perfluorinated C1-C4-alkyl radicals, linear or branched, optionally partly fluorinated or perfluorinated C1-C4-alkoxy radicals, CHO, COOH, COOR, SO2CH3, SO2Hal, optionally substituted phenyl or pyridyl radicals, fluorocarbonyl, benzoyl, trifluoroacetyl, phenoxy, isocyanato, SO2F and difluorochloromethyl radicals, where R is a C1-C4-alkyl radical and Hal is a halogen radical, X is H, Cl or F, preferably F. R1, R2, R3 and R4 are each independently H, CN, NO2, NH2, Br, CH3, CF3, OCH3, OCF3, CHO, COOH, COOR or SO2CH3, where R is preferably a C1-C4-alkyl radical. In preferred embodiments of the present invention, at least one of the R1, R2, R3 and R4 radicals is different to H. In further preferred embodiments of the present invention, at least one of the R\ R2, R3 and R4 radicals is independently CN, NO2, NH2, Br, CHO, COOH, COOR or SO2CH3, preferably NO2 or NH2, where R is a C1-C4-alkyl radical, and all further R1, R2, R3 and R4 radicals are each independently H, CH3, OCH3, OCF3 or CF3. Unless specifically stated otherwise, C1-C4-alkyl and C1-C4-alkoxy in the context of the invention are preferably each independently a straight-chain, cyclic, branched or unbranched alkyl and alkoxy radical respectively, which may optionally be further substituted. For example, C1-C4-alkyl is more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl. For example, C1-C4-alkoxy is preferably methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy or tert-butoxy. Unless specifically stated otherwise, halogen, in the context of the invention is fluorine, chlorine, bromine or iodine. For example, halogen is preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine. Exemplary compounds of the inventive 1,3-benzodioxanes are the following: (Formula Removed) Unlike most known compounds, the inventive compounds of the general formula (I-a) or (I-b) are achiral, so that the problem of enantiomer separation does not occur in their preparation. The inventive compounds can therefore be prepared in a simpler manner than the known chiral compounds. Compounds of the general formula (I-a) may begin, for example, with reaction of a phenol with hexafluoroacetone to give the ketal, followed by a ring-building reaction with dihalomethanes, formaldehyde or other C1 units. Subsequent chlorination on the methylene group and subsequent fluorination lead to the inventive compound which can then optionally be subjected to further substitutions on the aromatic ring. Further reactions of the substituents on the aromatic ring, for example oxidations, reductions, esterifications or amidations, etc., are also possible. The present invention therefore further provides a process for preparing an inventive compound, wherein a) a dihydroxy compound of the general formula (II-a) (Formula Removed) where R5, R6, R7, R8 are each as defined for R1, R2, R3 and R4 and is reacted with an optionally substituted dihalomethane, formaldehyde or another C1 unit, b) optionally chlorinated subsequently on the methylene group, and c) subsequently fluorinated on the methylene group. As already detailed, the ketals of the general formula (I) may be prepared, for example, by reacting a phenol with hexafluoroacetone. Compounds of the general formula (I-b) may be prepared, for example, starting from hydroxy- or halobenzyls which bear a hydroxyl group or a halogen in the ortho-position, with the reaction with hexafluoroacetone and subsequent ring-closure reaction with acids or under Buchwald conditions, i.e., for example, with palladium(dibenzylideneacetone) and tris(tert-butyl)phosphine as a catalyst in boiling toluene and sodium tert-butoxide as a base. The further derivatization via chlorination and chlorine-fluorine exchange is effected analogously to the preparation of the compounds of the general formula (I-a). The chlorination may be effected, for example, with a series of chlorinating agents, for example chlorine, PC13, PCl5 and combinations thereof. However, preference is given to effecting the chlorination with chlorine, more preferably under irradiation with an Hg vapour lamp. The chlorination is effected in substance or in at least one solvent, at at least one temperature of ± 30°C above and below the boiling point of the substance or of any solvent(s) used. The solvents used are preferably those which are inert towards the chlorinating agent(s), especially towards chlorine, under the conditions of the chlorination. These are, for example, halogenated solvents, for example chlorobenzotrifluoride, dichlorobenzotrifluoride. The fluorination may be effected by means of a series of fluorinating agents, for example HF, alkali metal and transition metal fluorides and main groups element fluorides, for example KF or SbF3, or else ammonium fluorides of the R4N+F" type, where R is C1-C4-alkyl. However, preference is given to effecting the fluorination with anhydrous HF. Preference is further given to carrying out the fluorination at a temperature of, for example, -10°C to 20°C, more preferably with an excess of anhydrous HF. The variations mentioned of substituents and functional groups in the aromatic ring of the benzodioxane system may be achieved by three different strategies. One is to provide the phenol reactant with different substituents which remain unchanged on the molecule throughout the entire synthesis and can later if appropriate be converted to further derivatives. In order to be able to ensure regioselectivity in the case of unsymmetric starting compounds, it is sensible in some cases to introduce reversible protecting groups in the ortho-position before the reaction with hexafluoroacetone. A further possibility available for achieving a particular substitution pattern on the aromatic ring is that of electrophilic aromatic substitution on the finished fluorinated 1,3-benzodioxane system, for example a nitration, from which a further derivatization, for example via reduction to the amino group and subsequent conversion to the amide, is possible. A third possibility is the nucleophilic attack on the finished fluorinated 1,3-benzodioxane systems, for example with lithium alkyls and the subsequent classic derivatization of the organometallic compounds. The present invention therefore further provides a process for preparing the inventive compounds, wherein a substitution on the aromatic ring and/or a reaction on at least one of any substituents present on the aromatic ring is carried out either after above-described fluorination or in another stage of the above-described process for preparing the inventive compounds. The present invention further provides a process for preparing an inventive compound, wherein a compound of the general formula (I-a) or (I-b) is substituted on the aromatic ring and/or a reaction is carried out on at least one of any substituents present on the aromatic ring. The inventive compounds are outstandingly suitable for use as intermediates or building blocks in active pharmaceutical ingredients, especially for cancer therapy. Examples; Example 1: a) Preparation of 2-[2,2,2-trifluoro-l-hydroxy-l-(trifluoromethyl)ethyl]phenol (Formula Removed) 94.11 g (1000 mmol) of phenol and 166.02 g (100mmol) of A1C13 were initially charged in 1200 ml of 1,2-dichloroethane and cooled to -35°C. At this temperature, the precalculated amount of 166.02 g (1000 mmol) of hexafluoroacetone was metered in from a bomb. Subsequently, the reaction mixture was allowed to come to room temperature (20°C, RT) and stirred at RT for a further 36 h. The reaction flask was subsequently flushed with N2 and the offgas passed into a wash bottle containing water. For workup of the remaining reaction solution, 500 ml of water were added cautiously and the mixture was stirred well. Subsequently, the organic phase was removed, the aqueous phase was extracted with CH2C12 and dried over magnesium sulphate, and the solvent was removed on a rotary evaporator. As this was done, the residue crystallized out. For purification, the resulting crystals were slurried in n-hexane and filtered off, and 230 g (842 mmol, yield: 82.4% of theory) of a white, crystalline solid were obtained. b) Preparation of 4,4-bis(trifluoromethyl)-4H-1,3 –benzodioxane (Formula Removed) 100.00 g (380 mmol) of the product from example la) and 111.67 g (1920 mmol) of potassium fluoride were initially charged in 1200 ml of dry N,N-dimethylformamide (DMF) and heated to 130°C. Over 75 min, 73.51 g (420 mmol) of dibromomethane were metered in and the mixture was stirred for a further 2 h. GC monitoring was used to detect full conversion. After cooling to RT, the reaction mixture was admixed with 3 1 of dist. H20. Subsequently, the mixture was divided and extracted in each case with 3 x 300 ml of methyl tert-butyl ether (MTBE), the organic phases were combined, washed 1 x with 100 ml of 1 M aqueous NaOH, washed 2 x with 11 of dist. H2O and dried over magnesium sulphate, and the solvent was removed on a rotary evaporator. A red liquid was obtained. After distillation through a horizontal condenser at 6.7 mbar and a top temperature of 68°C, 57 g (205 mmol, yield: 52.86% of theory at a purity of 98%) of the product distilled over as a clear liquid. c) Preparation of 2,2-dichloro-4,4-bis(trifluoromethyl)-4H-l,3-benzodioxane by chlorination of 4,4-bis(trifluoromethyl)-4H-l,3-benzodioxane (Formula Removed) 57 g (205 mmol) of the product from example lb) were initially charged, 5 g (37 mmol) of PC13 were added and chlorine was introduced at 165°C for 6 hours under irradiation of a Hg vapour lamp. At 5.6-5 mbar, a bath temperature of 130°C and a top temperature of 80-85°C, the dichlorine compound was distilled over a small horizontal condenser. Yield: 34 g (99.7 mmol), 41.77% of theory at a purity of 86%) of colourless liquid d) Preparation of 2,2-difluoro-4,4-bis(trifluoromethyl)-4H-l,3-benzodioxane by fluorination of 2,2-dichloro-4,4-bis(trifluoromethyl)-4H-1,3-benzodioxane (Formula Removed) 150 ml of anhydrous HF were initially charged at -4°C and 34 g (99.70 mmol) of product from example lc) were added dropwise at -5°C depending on the HCl evolution. On abatement of gas evolution, the temperature was allowed to rise to RT and the mixture was stirred for a further 4 h. Subsequently, the reaction mixture was added to a mixture of 350 g of ice and 650 g of CH2C12. The aqueous and the organic phase were separated from one another, the aqueous phase was re-extracted 1 x with 200 ml of CH2C12, the organic phases were dried over magnesium sulphate, and the solvent was removed on a rotary evaporator. 2,2-Difluoro-4,4-bis(trifluoromethyl)-4H-l,3-benzodioxane was obtained in 95% purity in a yield of 17 g (52% of theory). e) Preparation of 2,2-difluoro-4,4-bis(trifluoromethyl)-4H-l,3-(6-nitrobenzo)dioxane by nitration of 2,2-difluoro-4,4-bis(trifluoromethyl)-4H-1,3-benzodioxane (Formula Removed) 7.9 ml of H2SO4 were initially charged and 6.5 ml of HNO3 were added dropwise with cooling. At 10°C, 17 g of the product from example Id) were added dropwise within 5 minutes and the mixture was stirred for a further 10 minutes, in the course of which the nitrated target product precipitated out. The reaction mixture was added to 400 ml of ice, extracted 3x with 80 ml each time of ethyl acetate, washed 3 x with 10% NaHC03 and dried over magnesium sulphate, and the solvent was removed. Yield: 18 g of yellow solid (95% of theory) f) Preparation of 2,2-difluoro-4,4-bis(trifluoromethyl)-4H-1,3-(6-aminobenzo)dioxane (Formula Removed) 18 g of the product from example le) were initially charged in 250 ml of acetic acid and 6.4 g of iron were metered in at reflux temperature (internal temperature 105°C) within 2 hours. The reaction mixture was subsequently poured onto 500 ml of ice, extracted 3 x with 300 ml of ethyl acetate, dried over magnesium sulphate and freed of solvent. The crude product was distilled over a small horizontal condenser. The target product distilled over at 0.1 mbar and a bath temperature of 90-110°C. 2,2-Difluoro-4,4-bis(trifluoromethyl)-4H-l,3-(6-aminobenzo)dioxane was obtained with a yield of 60% of theory. WE CLAIM: 1. Compound of the general formula (I-a) (Formula Removed) where R1, R2, R3, R4 are each independently H, CN, NO2, NH2, OH, halogen, linear or branched, optionally partly fluorinated or perfluorinated C1-C4-alkyl radicals, linear or branched, optionally partly fluorinated or perfluorinated C1-C4-alkoxy radicals, CHO, COOH, COOR, SO2CH3, SO2Hal, optionally substituted phenyl or pyridyl radicals, fluorocarbonyl, benzoyl, trifluoroacetyl, phenoxy, isocyanato, SO2F and difluorochloromethyl radicals, where R is a C1-C4-alkyl radical and Hal is a halogen radical, X is H, C1 or F. 2. The compound as claimed in claim 1, wherein X is F. 3. The compound as claimed in claim 1 or 2, wherein R1, R2, R3 and R4 are each independently H, CN, NO2, NH2, Br, CH3, CF3, OCH3, OCF3, CHO, COOH, COOR or SO2CH3, where R is a C1-C4-alkyl radical. 4. The compound as claimed in any one of claims 1 to 3, wherein at least one of the R1, R2, R3 and R4 radicals is different to H. 5. The compound as claimed in any one of claims 1 to 4, wherein at least one of the R1 , R2 , R3 and R4 radicals is independently CN, NO2, NH2, Br, CHO, COOH, COOR or SO2CH3, where R is a C1-C4-alkyl radical, and all further R1, R2, R3 and R4 radicals are each independently H, CH3, OCH3, OCF3 or CF3. 6. A process for preparing a compound as claimed in any one of claims 1 to 5, wherein d) a dihydroxy compound of the general formula (11-a) (Formula Removed) where R5, R6, R7, R8 are each as defined for R1, R2, R3 and R4 in claim 1 is reacted with an optionally substituted dihalomethane, formaldehyde or another C1 unit, e) is optionally chlorinated subsequently on the methylene group, and f) is subsequently fluorinated on the methylene group; wherein the chlorination is effected under irradiation with chlorine in at least one solvent at least one temperature of ± 30°C above and below the boiling point of this/these solvent(s); wherein the fluorination is effected using anhydrous HF. 7. The process as claimed in claim 6, wherein the fluorination is effected with an excess of anhydrous HF at least one temperature of -10°C to 20°C. 8. The process as claimed in claim 6, wherein R5, R6, R7 and R8 are each H. 9. The process as claimed in claim 6, wherein a substitution is subsequently carried out on the aromatic ring and/or a reaction on at least one of any substituents present on the aromatic ring. 10. The process as claimed in claim 6, wherein the compound as claimed in any of claims 1 to 5 is substituted on the aromatic ring and/or a reaction is carried out on at least one of any substituents present on the aromatic ring. 11. The compound as claimed in any of claims 1 to 5 as and when used for preparing active pharmaceutical ingredients or medicaments.

Documents:

1959-DEL-2005-Abstract-(23-03-2012).pdf

1959-del-2005-abstract.pdf

1959-DEL-2005-Claims-(23-03-2012).pdf

1959-del-2005-claims.pdf

1959-DEL-2005-Correspondence Others-(23-03-2012).pdf

1959-DEL-2005-Correspondence Others-(28-11-2011).pdf

1959-del-2005-correspondence-others.pdf

1959-del-2005-description (complete).pdf

1959-del-2005-form-1.pdf

1959-del-2005-form-18.pdf

1959-del-2005-form-2.pdf

1959-DEL-2005-Form-3-(23-03-2012).pdf

1959-DEL-2005-Form-3-(28-11-2011).pdf

1959-del-2005-form-3.pdf

1959-del-2005-form-5.pdf

1959-DEL-2005-GPA-(23-03-2012).pdf