Patent Application: US-14979902-A

Abstract:
the invention provides a method for the preparation of a metallocene halide salt having at least one cyclopentadiene group substituted by a basic group , the method comprising reacting together a metal halide with a cyclopentadiene substituted by a basic group . in a preferred embodiment , the substituted cyclopentadiene is substituted with an amino group and the metal halide titanium tetrachloride . the invention provides a single step process for the preparation of metallocene derivatives which are useful in the formulation of medicaments and as polymerisation catalyst precursors .

Description:
the present invention will now be described in greater detail and with reference to fig1 and 2 of the accompanying drawings which illustrate the synthetic routes which will be described . by way of example , fig1 illustrates the known synthetic route and the method of the present invention for the preparation of an amino - functionalised titanocene ; the method of the invention is shown as step ( v ). the titanocene dihydrochloride salt 2 can be synthesised either by direct reaction of two equivalents of the neutral cyclopentadiene 1 and ticl 4 in toluene or by reaction of the sodium salt 3 with ticl 4 followed by reaction with hcl . the substituted cyclopentadiene 1 can be synthesised as previously described by herrmann and co - workers [ 9 ]. the dihydrochloride salt is isolated as a dark orange solid which is soluble in a polar solvent such as methanol , water and acetonitrile . the neutral titanocene 4 can be obtained by reaction of the dihydrochloride 2 with two equivalents of meli and by reaction by the sodium salt 3 with t cl 4 in ether . the highly air and moisture sensitive titanocene 4 can be isolated as a crystalline , deep orange solid and is soluble in aprotic , polar and non - polar solvents such as ether and toluene . an analytically pure sample can be obtained by recrystallisation from ether . reaction of the dihydrochloride 2 with four equivalents of meli results in the formation of the thermally stable dimethylated species 5 , as illustrated in fig2 . species 5 is a highly air sensitive red oil . accordingly the present invention provides a synthetic route for a titanocene dihydrochloride which is both air stable and water soluble and avoids a number of synthetic steps in which the reagents are air and water sensitive . the resultant “ protected ” titanocene can be stored indefinitely and the neutral titanocene can be generated by reaction with a base . deprotonation can be carried out in situ by a cocatalyst such as mao ( methylalumunoxane ) to give the neutral metallocene dichloride as the catalyst precursor . furthermore , reaction with four equivalents of an alkylating agent generates the dialkyl substituted titanocene . method 1 : from nacpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 and ticl 4 1 . 37 g ( 0 . 0069 mol ) of nacpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 was added as a slurry in 100 ml of thf to 0 . 38 ml ( 0 . 66 g , 0 . 0034 mol ) ticl 4 in 75 ml of thf . on addition an orange colour developed in the toluene and a colourless precipitate formed . the reaction mixture was left to stir for 1 h after which the solvent was removed in vacuo . the product was extracted in 100 ml of toluene . recrystallisation from toluene affords the product as dark orange crystals . method 2 : from ( cpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 . 2hcl two equivalents of meli ( 0 . 0018 mol , 1 . 26 ml , 1 . 4m solution in et 2 o were added dropwise to a suspension 0 . 48 g of ( cpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 . 2hcl ( 0 . 00088 mol ) in 100 ml of toluene . the mixture was stirred for 2 h after which an orange colour had developed in the toluene . the solution was filtered and the solvent removed in vacuo . the residue was extracted in 50 ml of toluene and the solvent was removed in vacuo leaving 1 as a dark orange solid . 1 h nmr ( c 6 d 6 ): δ 2 . 54 ( t , 4h , cpch 2 ), δ 2 . 07 ( t , 4h , cpch 2 ch 2 ), δ 2 . 3689 ( m , 8h , n ( ch 2 ) 2 ) δ 1 . 55 ( m , 8h , n ( ch 2 ) 2 ( ch 2 ) 2 ), δ 1 . 37 ( m , 4h , n ( ch 2 ) 2 ( ch 2 ) 2 ( ch 2 ), 6 . 26 , 5 . 89 ( pt , 8h , cph ). 13 c nmr ( c 6 d 6 ): δ 29 . 16 ( cpch 2 ), δ 59 . 6 ( cpch 2 ch 2 ), δ 55 . 10 ( n ( ch 2 ) 2 , δ 26 . 74 ( n ( ch 2 ) 2 ( ch 2 ) 2 ), δ 25 . 16 ( n ( ch ) 2 ( ch 2 ) 2 ( ch 2 ), δ 114 . 98 , 123 . 31 ( cp ring c , δ 136 . 65 ( cp ring quaternary ). anal . calcd for ( cpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 ( 449 . 32 ); c , 61 . 16 ; h , 7 . 70 ; n , 5 . 94 . found : c , 61 . 4 ; h , 7 . 85 ; n , 6 . 10 . synthesis of ( cpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 . 2hcl ( 2 ) method 1 ( illustrative of the method of the invention ): from ticl 4 and hcpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 two equivalents of freshly distilled hcp ch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ( 3 . 0 g , 0 . 0169 mol ) in toluene ( 50 ml ) were added dropwise to a solution of ticl 4 ( 1 . 6 g , 0 . 0085 mol ) in toluene ( 150 ml ) at − 78 ° c . the solution was stirred for 30 minutes during which time a dark orange solid had precipitated . the mixture was warmed to room temperature and stirred for an additional 4 h . the toluene was removed in vacuo and the solid was washed with ether and dried in vacuo leaving 2 as a dark orange solid . method 2 : from ( cpch 2 ch 2 n ( ch 2 ) n ( ch 2 ) 2 ) 2 ticl 2 and hcl to a solution of 0 . 10 g of 1 ( in deuterated benzene in an nmr tube ) was added an excess of hcl ( 40 % solution . immediately a dark orange solid precipitated . the benzene was removed in vacuo and the solid was dissolved in cd 3 n . 1 h nmr meod ): 1 h nmr ( c 6 d 6 ): δ 3 . 31 ( t , 4h , cpch 2 ), δ 3 . 45 ( t , 4h , cp ch 2 ch 2 ), δ 3 . 61 , 3 . 00 ( m , 8h , n ( ch 2 ) 2 ) δ 1 . 95 , 1 . 87 ( m , 8h , n ( ch 2 ) 2 ( ch 2 ) 2 ), δ 1 . 54 ( m , 4h , n ( ch 2 ) 2 ( ch 2 ) 2 ch 2 ), 6 . 72 , 6 . 48 ( pt , 8h , cph ). 13 c nmr ( c 6 d 6 ): δ 26 . 43 ( cpch 2 ), δ 57 . 10 ( cpch 2 ch 2 ), δ 54 . 39 ( n ( ch 2 ) 2 ) δ 24 . 23 ( n ( ch 2 ) 2 ( ch 2 ) 2 ), δ 22 . 64 ( n ( ch 2 ) 2 ( ch 2 ) 2 ch 2 ), δ 124 . 64 , 116 . 95 ( cp ring c ), δ 133 . 33 ( cp ring quaternary ). ms ( fab ; m / z ( relative intensity , %): 472 ([ cpch 2 ch 2 nh ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ) ticl 2 ] + , 7 . 43 ). to a suspension of 2 in et 2 o ( 0 . 5 g , 0 . 92 mmol , 50 ml et 2 o ) was added two equivalents of meli ( 1 . 4 m , 1 . 3 ml , 1 . 84 mmol ) in et 2 o with vigorous stirring . evolution of a gas was immediately apparent . the mixture was left to stir at room temperature for 2 h , during which a deep orange solution had formed and a colourless solid precipitated . the et 2 o was removed in vacuo and the product was extracted in toluene to leave the product as a dark red - brown oil . synthesis of [( cp ch 2 ch 2 n ( me )( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 ] cl − 2 ( 4 ) two equivalents ( 0 . 19 g , 0 . 0013 mol ) of methyl iodide were added to 0 . 30 g ( 0 . 00067 mol ) of cpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 in 50 ml of toluene . the reaction mixture was stirred for 30 minutes after which a bright orange precipitate had formed and no colour remained in the toluene . the toluene was filtered from the product which was washed with diethyl ether to leave 4 as a powder red solid . 1 h nmr ( meod ): 1 h nmr ( c 6 d6 ): δ 3 . 31 ( t , 4h , cpch 2 ), δ 3 . 45 ( t , 4h , cp ch 2 ch 2 ), δ 3 . 61 , 3 . 00 ( m , 8h , n ( ch 2 ) 2 ) δ 1 . 95 , 1 . 87 ( m , 8h , n ( ch 2 ) 2 ( ch 2 ) 2 ), δ 1 . 54 ( m , 4h , n ( ch 2 ) 2 ( ch 2 ) 2 ch 2 ), 6 . 72 , 6 . 48 ( pt , 8h , cph ). 13 c nmr ( c 6 d 6 ): δ 26 . 43 ( cpch 2 ), δ 57 . 10 ( cpch 2 ch 2 ), δ 54 . 39 ( n ( ch 2 ) 2 ) δ 24 . 23 ( n ( ch 2 ) 2 ( ch 2 ) 2 ), δ 22 . 64 ( n ( ch 2 ) 2 ( ch 2 ) 2 ch 2 ), δ 124 . 64 , 116 . 95 ( cp ring c ), δ 133 . 33 ( cp ring quaternary ). ms ( fab ; m / z ( relative intensity , %): 472 ([ cpch 2 ch 2 nh ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ) ticl 2 ] + , 7 . 43 ). to a suspension of 2 in et 2 o ( 0 . 5 g , 0 . 92 mmol , 50 ml et 2 o ) was added two equivalents of meli ( 1 . 4 m , 1 . 3 ml , 1 . 84 mmol ) in et 2 o with vigorous sting . evolution of a gas was immediately apparent the mixture was left to stir at room temperature for 2 h , during which a deep orange solution had formed and a colourless solid precipitated . the et 2 o was removed in vacuo and the product was extracted in toluene to leave the product as a dark red - brown oil . synthesis of [( cp ch 2 ch 2 n ( me )( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 ] cl − 2 ( 4 ) two equivalents ( 0 . 19 g , 0 . 0013 mol ) of methyl iodide were added to 0 . 30 g ( 0 . 00067 mol ) of cpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 in 50 ml of toluene . the reaction mixture was stirred for 30 minutes after which a bright orange precipitate had formed and no colour remained in the toluene . the toluene was filtered from the product which was washed with diethyl ether to leave 4 as a powder red solid . analogous to the preparation of ( cpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 , the sodium salt nacpch ( ch 2 ) 2 ( ch 2 ) 2 nch 3 ( 0 . 73 g , 3 . 92 mmol in 50 ml of thf ) was added to a solution of ticl 4 ( 0 . 38 g , 1 . 96 mmol in 100 ml of thf ). the mixture was stirred for 2 hours after which a brown precipitate had formed and the solution had turned a deep red colour . the solution was filtered and solvent removed under vacuum to leave a dark orange solid synthesis of ( cpch ( ch 2 ) 2 ( ch 2 ) 2 nch 3 ) 2 ticl 2 . 2hcl ( 6 ) analogous to the preparation of ( cpch 2 ch 2 n ( ch 2 ) 2 ( ch 2 ) 2 ) 2 ticl 2 . 2hcl , the product can be synthesised by the direct reaction of nacpch ( ch 2 ) 2 ( ch ) 2 nch 3 and ticl 4 in toluene and by reaction of ( cpch ( ch 2 ) 2 ( ch 2 ) 2 nch 3 ticl 2 with hcl . 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