the present invention relates to a new synthesis of vincaminic acid derivatives , in particular of vincamine , apovincamine and deoxyvincamine and of the ethyl esters of vincaminic acid , apovincaminic acid and deoxyvincaminic acid , in the form of racemates and enantiomers . several syntheses of vincamine have already been described in the literature ; these are either partial syntheses starting from natural alkaloids ( for example from tabersonine , french pat . no . 71 / 47 , 731 ), or total syntheses ( french pat . no . 70 / 11 , 406 and u . s . pat . no . 3 , 454 , 583 ). vincamine is known for its valuable pharmacological properties as a cerebral oxygenating agent and cerebral vasoregulator and for its therapeutic activity for the treatment of cerebral insufficiencies . the synthesis of the invention is carried out starting from 1 - ethyl - 2 , 3 , 4 , 6 , 7 , 12 - hexahydroindolo [ 2 , 3 - a ] quinolizine , ## str2 ## this product being described by wenkert and wickberg ( j . am . chem . soc . 87 , 1 , 580 ( 1965 )). scheme ( 1 ) for the synthesis of vincamine and scheme ( 2 ) for the synthesis of deoxyvincamine and apovincamine are shown on the following pages . ## str3 ## to prepare vincamine according to the invention , the enamine ( 1 ) is reacted with the ( 2 , 4 - dinitrophenyl )- hydrazone of methyl or ethyl bromopyruvate ( 2 ), and then either the protective group is removed from the compound ( 3 ) in order to obtain the cyclised compound ( 4 ), which is reduced in order to obtain the cyclised compound ( 6 ), or the compound ( 3 ) is reduced in order to obtain the compound ( 5 ), from which the protective group is removed in order to obtain the cyclised compound ( 6 ), and , if appropriate , the compound ( 6 ) is transesterified ( if it is the ethyl ester ) to give (±)- vincamine ( 7 ). the first step can be carried out in a solvent , such as ethyl acetate , at ambient temperature . the removal of the protective group from the compound ( 3 ) to give the compound ( 4 ) can be carried out in a solvent such as a mixture of acetonitrile and water , adjusted to a suitable ph , e . g . about ph 8 , using preferably sodium borate and hydrochloric acid . ambient temperature can be used in this step also . the reduction of the compound ( 4 ) can be carried out by any suitable means , such as zinc in the presence of 50 % strength acetic acid or raney nickel in 50 % strength acetic acid . the reduction of the compound ( 3 ) to give the compound ( 5 ) can be carried out , for example , by means of an alkali metal hydride in an acid medium in a solvent , such as methanol or acetronitrile , or a mixture thereof . the removal of the protective group from the compound ( 5 ) is carried out by means of titanium ( iii ) chloride in a solvent , such as methanol or acetonitrile , containing formaldehyde and an acid , such as hydrochloric acid or acetic acid , in a temperature range of 20 ° to 140 ° c . if appropriate , the transesterification of the compound ( 6 ) to give (±)- vincamine ( 7 ) is carried out by heating in methanol at the reflux temperature , in the presence of sodium methylate . the cis - vincamine obtained according to the synthesis of the invention is in the (±) racemic form . the compound ( 5 ) is obtained directly in the cis form , starting from the compound ( 3 ), in a proportion of at least 80 %. the compound ( 6 ) is a mixture of the two epimers on the carbon in the 14 - position , the h - atom in the 3 - position and the ethyl in the 16 - position being in the cis position , relative to each other . to prepare apovincamine and deoxyvincamine according to the invention , the enamine ( 1 ) is reacted with the ( 2 , 4 - dinitrophenyl )- hydrazone of ethyl or methyl bromopyruvate ( 2 ), and the compound ( 3 ) is then reduced to give the compound ( 5 ), which is reacted , in formic acid , either with an approx . 15 % aqueous solution of titanium ( iii ) chloride in order to obtain ethyl apovincaminate ( 8 , r ═ c 2 h 5 ) or apovincamine ( 8 , r ═ ch 3 ), or with an approx . 30 % aqueous solution of titanium ( iii ) chloride in order to obtain ethyl deoxyvincaminate ( 9 , r ═ c 2 h 5 ) or deoxyvincamine ( 9 , r ═ ch 3 ). the strengths of the solutions are weight / volume . the vincamine obtained in accordance with reaction scheme 1 is cis - vincamine in the (±) racemic form . now , the applicant company has succeeded in resolving the compound ( 5 ) ( itself also in the racemic form ) in order to obtain the dextrorotatory and laevorotatory enantiomers and to lead directly , starting from this compound , to optically active vincaminic acid derivatives , especially cis -(+)- vincamine and cis -(-)- vincamine . according to the invention , the resolution of the compound ( 5 ) is carried out using an optically active acid , such as dibenzoyl - l - tartaric acid , in a solvent , such as acetonitrile . the analyses and the ir and nmr spectra confirmed the structure of the compounds . the starting compound ( 2 ) is new . if r is c 2 h 5 , it is obtained in the following manner : 39 g ( 0 . 2 mol ) of ethyl bromopyruvate are added to 41 g ( 0 . 2 mol ) of ( 2 , 4 - dinitrophenyl )- hydrazine in an acid , such as hydrochloric or acetic acid . the temperature is allowed to return to 20 ° c . and the precipitate formed is filtered off , washed copiously with water and then dried in vacuo at 60 ° c . 29 g ( 77 . 35 mmols ) of the starting compound ( 2 ) are dissolved in 1 . 7 liters of ethyl acetate . 8 . 95 g ( 88 . 6 mmols ) of triethylamine , dried over koh , are added to the solution , whilst stirring , and a solution of 15 . 7 g ( 62 . 4 mmols ) of the enamine ( 1 ) in 500 ml of ethyl acetate is then added . the reaction mixture is stirred at ambient temperature overnight . the precipitate formed is filtered off and washed with ethyl acetate . the resulting product is dried in vacuo at 40 ° c . this yields 39 g ( yield 99 . 6 %) of an orange powder which melts at 200 ° c . with decomposition . 1 . 56 g ( 2 . 48 mmols ) of the compound ( 3 ) obtained above are dissolved in 50 ml of acetonitrile . 150 ml of water are added and 50 ml of a buffer at ph 8 , consisting of a concentrated solution of sodium borate and hydrochloric acid , are then added . the reaction mixture is stirred overnight . the small amount of precipitate formed is filtered off . the aqueous phase is washed three times with 50 ml of toluene and extracted with methylene chloride . the organic phase is dried over sodium sulphate and filtered and the filtrate is concentrated . this yields 1 g ( yield 100 %) of the compound ( 4 ), which is used as such for the following step . 1 g ( 2 . 48 mmols ) of the compound ( 4 ) obtained above is dissolved in 65 ml of 50 % strength acetic acid . the solution is heated to 88 ° c . in the course of 4 minutes and 5 g of zinc are then added in small amounts . heating is maintained for 5 minutes . the reaction mixture is poured onto 65 g of ice and treated with 50 ml of 28 % strength ammonia solution . the precipitate is filtered off and dried in vacuo at 60 ° c . this yields 0 . 55 g of the compound ( 6 ), which is taken up in 3 ml of methanol . the mixture is heated at the reflux temperature , in the presence of sodium methylate ( 0 . 1 ml of a 30 % strength solution in methanol ), for 5 hours . this yields 0 . 33 g ( yield 38 %) of (±)- vincamine . 10 . 5 g ( 167 mmols ) of nabh 3 cn are added , whilst stirring , to a solution of 35 g of the compound ( 3 ) in 40 ml of acetic acid , 200 ml of methanol , 200 ml of acetonitrile and 200 ml of water . after one hour at ambient temperature , the solution is treated with 80 ml of 28 % strength ammonia solution and 200 ml of water . the aqueous phase is extracted with methylene chloride . the organic phases are concentrated and the residue is taken up in 150 ml of methanol . the mixture is heated at the reflux temperature for 15 minutes , left to cool and filtered . this yields 24 . 57 g ( yield 80 %) of compound ( 5 ) melting at 214 ° c . 1 g ( 1 . 82 mmols ) of the compound ( 5 ) obtained above is dissolved in 20 ml of acetone and 10 ml of acetic acid . the solution is degassed with argon and added , in the course of 2 minutes , to a solution , kept at 67 ° c ., containing 30 ml of a 15 % strength solution of titanium chloride in water , 30 ml of a 37 % strength solution of formaldehyde in degassed water , and 10 ml of degassed acetic acid . after a reaction time of 20 minutes at 67 ° c ., 200 ml of iced water are added to the reaction mixture and the resulting mixture is extracted with methylene chloride . the combined organic phases are concentrated . the residue is taken up in 30 ml of iced water . the resulting solution is treated with 28 % strength ammonia solution . the mixture is filtered and the precipitate is dried at 60 ° c . in vacuo . this yields 0 . 460 g ( 68 %) of a mixture of epimers ( in the 14 - position ) of the compound ( 6 ). a solution of the compound ( 6 ) in methanol is heated at the reflux temperature for 5 hours in the presence of sodium methylate . this yields 0 . 326 g of (±)- vincamine . nmr : ( cdcl 3 , dmso ): 0 . 95 ( t , 3h ), 1 . 40 ( m , 6h ), 2 . 60 ( m , 3h ), 3 . 30 ( m , 2h ), 3 . 78 ( s , 3h ), 3 . 86 ( broad s , 1h ), 7 . 07 ( m , 3h ), 7 . 36 ( m , 1h ). ir : ( kbr , cm - 1 ): 3 , 440 ( oh , broad ), 2 . 920 ( m ), 2 , 840 ( sh ), 1 , 730 ( coome ). 1 . a solution containing 6 . 88 g ( 27 mm ) of enamine and 2 . 9 g ( 29 mm ) of triethylamine in 60 ml of ethyl acetate is added to a suspension of 10 g ( 29 mm ) of the ( 2 , 4 - dinitrophenyl )- hydrazone of methyl bromopyruvate in 140 ml of ethyl acetate . the mixture is stirred for 16 hours and filtered and the product is washed with ethyl acetate . it is dried in vacuo at 70 ° c . this yields 15 . 2 g of 1 -[ 2 -( 2 , 4 - dinitrophenyl )- hydrazono - 2 - methoxycarbonylethyl ]- 1 - ethyl - 1 , 2 , 3 , 4 , 6 , 7 - hexahydro -( 12h )- indolo [ 2 , 3 - a ] quinolizin - 5 - ium bromide . ( yield : 92 %). 2 . 4 . 9 g ( 7 . 98 mm ) of the latter compound are reduced with 1 . 29 g ( 24 mm ) of potassium borohydride in order to obtain 1 -[ 2 -( 2 , 4 - dinitrophenyl )- hydrazono - 2 - methoxycarbonylethyl ]- 1 - ethyl - 1 , 2 , 3 , 4 , 6 , 7 , 12 , 12b - octahydroindolo [ 2 , 3 - a ] quinolizine ( 3 . 6 g ; yield : 74 %). 3 . 2 g ( 2 . 74 mm ) of the product obtained above , in 28 ml of acetone , are added to a solution , at 55 °- 60 ° c ., containing 60 ml of acetone , 10 ml of a 37 % strength aqueous solution of formaldehyde , 20 ml of acetic acid and 60 ml of titanium ( iii ) chloride solution ( 15 % strength ). the reaction is kept at 60 ° c . for 15 minutes and ice is then added . 5 g ( 72 mm ) of nano 2 are added and nitrogen is bubbled for 15 minutes . extraction is carried out with methylene chloride , the organic phase is concentrated and the residue is taken up in 10 ml of water . the solution is rendered basic with ammonia and filtered and the (±)- vincamine is dried ( 0 . 974 g ; yield : 74 %). 29 g ( 77 . 35 mmols ) of the starting compound ( 2 ) are dissolved in 1 . 7 liters of ethyl acetate . 8 . 95 g ( 88 . 6 mmols ) of triethylamine , dried over koh , are added to the solution , whilst stirring , and a solution of 15 . 7 g ( 62 . 4 mmols ) of the enamine ( 1 ) in 500 ml of ethyl acetate is then added . the reaction mixture is stirred at ambient temperature overnight . the precipitate formed is filtered off and washed with ethyl acetate . the resulting product is dried in vacuo at 40 ° c . this yields 39 g ( yield 99 . 6 %) of an orange powder which melts at 200 ° c . with decomposition . 10 . 5 g ( 167 mmols ) of nabh 3 cn are added , whilst stirring , to a solution of 35 g of compound ( 3 ) in 40 ml of acetic acid , 200 ml of methanol , 200 ml of acetonitrile and 200 ml of water . after one hour at ambient temperature , the solution is treated with 80 ml of 28 % strength ammonia solution and 200 ml of water . the aqueous phase is extracted with methylene chloride . the organic phases are concentrated and the residue is then taken up in 150 ml of methanol . the mixture is heated at the reflux temperature for 15 minutes , left to cool and filtered . this yields 24 . 57 g ( yield 80 %) of compound ( 5 ) melting at 214 ° c . 2 . 5 g ( 4 . 5 mmols ) of the compound obtained above , in 75 ml of formic acid , are heated to the reflux temperature and 60 ml of 15 % strength solution of titanium ( iii ) chloride are added . the reaction mixture is heated for 20 minutes under reflux and ice is then added . the titanium dioxide is removed by filtration and the product is extracted with methylene chloride . the organic phases are washed with ammonia solution and then with water and are then dried over sodium sulphate . the solvent is removed and the solid residue is recrystallised from petroleum ether . this yields 1 . 24 g of ethyl apovincaminate in the form of a pale yellow solid . (±)- apovincamine can be prepared in the same manner starting from the compound ( 3 ) obtained from methyl bromopyruvate and the enamine ( 1 ). a solution of 5 g ( 9 mmols ) of the compound obtained in example 4 , paragraph 1 , in 150 ml of formic acid is heated to the reflux temperature and 125 ml of a 30 % strength solution of titanium ( iii ) chloride are added . reflux is maintained for 20 minutes . ice is added to the reaction mixture and the precipitate of titanium dioxide is removed by filtration . the product is extracted from the filtrate with methylene chloride and the organic phase is washed with ammonia solution and water . after drying over sodium sulphate and removing the solvent , a viscous oil ( 3 . 2 g ) is obtained , which consists solely of a mixture of the two c 14 epimers of ethyl deoxyvincaminate ( spectral and chromatographic data are in agreement ) ( yield : 100 %). (±)- deoxyvincamine can be prepared in the same manner starting from methyl bromopyruvate and the enamine ( 1 ). 100 ml ( 0 . 0187 mm ) of the compound ( 5 ) and 70 mg of dibenzoyl - l - tartaric acid in 3 ml of ch 3 cn are heated to the reflux temperature . after cooling , the crystals formed are filtered off and washed with acetonitrile ( 1 ml ). the filtrate is concentrated , the residue is treated with dilute ammonia solution and the mixture is extracted with methylene chloride . the organic phases are washed with water , dried over na 2 so 4 and concentrated . the residue is taken up in 2 ml of acetonitrile . the solution is left to crystallise for 24 hours and the crystals formed are filtered off . these crystals consist of 46 mg of the laevorotatory enantiomer of the compound ( 5 ), of optical rotation [ α ] d 20 =- 77 . 9 ° ( c = 0 . 1 ; acoh ). the filtrate is concentrated and the residue is crystallised from 3 ml of meoh . this yields 36 mg of the dextrorotatory enantiomer of the compound ( 5 ), of optical rotation [ α ] d 20 =+ 77 . 9 ° ( c = 0 . 1 ; acoh ). 6 ml of 37 % strength formaldehyde solution and 5 ml of titanium ( iii ) chloride solution ( 15 % strength ) are introduced into a round - bottomed flask . the mixture is heated to 60 ° c . a solution of 310 mg of the (+)- enantiomer of the compound ( 5 ) in 2 ml of acetone and 2 ml of acetic acid is added . the mixture is left to react for 30 minutes at 55 °- 60 ° c . it is treated with nano 2 . a stream of argon is passed through for 3 minutes . extraction is carried out several times with methylene chloride . the extracts are concentrated and the residue is taken up in ice and an ammoniacal solution . the mixture is filtered and the product is recrystallised from methanol in the presence of sodium methylate . this yields (+)- vincamine which melts at 227 °- 230 ° c . the laevorotatory enantiomer of the compound ( 5 ) is reacted under the same conditions as in paragraph 2 and this yields (-)- vincamine .