Patent Application: US-201515503686-A

Abstract:
the present invention relates to a process for the preparation of synthetic intermediates which may be used in the preparation of tetrahydroquinoline derivatives , which derivatives have an inhibitory activity against cholesteryl transfer protein , show effects of increasing hdl cholesterol level and decreasing ldl cholesterol level , and can be used for the treatment and / or prevention of diseases such as arteriosclerotic diseases , hyperlipidemia , dyslipidemia and the like .

Description:
a process for the preparation of tetrahydroquinoline derivatives has been described in wo 2007 / 116922 . although tetrahydroquinoline derivatives , such as compound a , may be prepared with the above mentioned process , this process was low - yielding and generated a high level of unwanted byproducts . moreover , expensive starting materials , such as ( r )- 3 - aminovaleric acid , were used in this process . it was found that in particular the preparation of the compounds according to formula i ( such as diam in the process above ) was troublesome and expensive . in order to overcome these problems an improved process for the preparation of the compounds according to formula i was developed by the present inventors . it was surprisingly found that with the so called three - component povarov reaction compounds according to formula i could be prepared . the povarov reaction is a 3 - component reaction in which a cis - 2 - alkyl - 4 - amino - 1 , 2 , 3 , 4 - tetrahydroquinoline is formed in one stereoselective step from an aniline , an aldehyde and an enamine ( tetrahedron 2009 , 65 , 2721 ). the use of this reaction has been reported in the literature , however its application in the preparation of pharmaceutically active ingredients has been limited due to concerns over storage stability and product purity . hence , a first aspect of the present invention relates to a process for preparing the compound of formula i or a salt thereof : in the presence of a solvent and optionally one or more catalysts to form the compound of formula v r 1 is h or c 1 - c 3 alkyl , preferably ch 2 ch 3 ; r 2 is h , c 1 - c 3 alkyl or with the process of the present invention it is now possible to prepare efficiently , with relatively cheap starting materials and with a good yield the compounds according to formula i without many unwanted byproducts . for the preparation of compound a it is preferred to use in the process of the present invention compounds wherein r 1 is ch 2 ch 3 and r 2 is h . in such as case the aldehyde according to formula iii is propionaldehyde and the compound according to formula iv is n - vinylformamide . after step a ) and b ) of the present process are carried out , a key intermediate according to formula i is obtained which may be used in the further preparation of tetrahydroquinoline derivatives , such as compound a . since the compounds according to formula i are chiral , it may be desirable to at least partially separate or purify the different enantiomers of the compound of formula i . such separation or purification is well known in the art and several methods are readily available to the skilled person to execute such a separation or purification . one preferred way of at least partially separating or purifying the different enantiomers is the use of chiral resolving agents , such as l - tartaric acid or a derivative thereof , such as di - p - toluoyl - l - tartaric acid . for the preparation of tetrahydroquinoline derivatives having cetp - inhibiting properties , such as compound a , the use of the 2r , 4s enantiomers of the compounds according to formula i are most often needed . hence , in a further step c ) of the process of the present invention the 2r , 4s - enantiomer according to formula i - a with respect to the preparation of compound a it is preferred to separate from the other stereoisomers the compound b ( also referred to in wo2007 / 116922 as ( 2r , 4s )- 2 - ethyl - 6 - trifluoromethyl - 1 , 2 , 3 , 4 - tetrahydroquinolin - 4 - ylamine )): preferably , the separation or purification of the compounds according to formula i is such that the compound according to formula i - a or compound b is obtained with a purity of at least 99 % enantiomeric excess ( e . e . ), preferably at least 99 . 6 % e . e ., more preferably at least 99 . 7 % e . e . after having obtained these compounds they may be reacted into tetrahydroquinoline derivatives having cetp inhibiting properties , such as compound a , by using the same process as has been described in wo2007 / 116922 . in one preferred embodiment of the invention , the stoichiometry of the reaction between the aldehyde compound with formula iii , the amide compound with formula iv and the 4 - aminobenzotrifluoride with formula ii ranges from 0 . 5 - 5 (:) 1 (:) 0 . 5 - 1 , respectively . the yield of the compounds according to formula i may also be dependent from the solvent used in step a ). preferably , the solvent used is dichloromethane , acetonitrile , ethyl acetate , toluene or a mixture thereof . if r 1 is ch 2 ch 3 and r 2 is h , the reaction of step a ) is preferably conducted in dichloromethane , acetonitrile or in a mixture of toluene and dichloromethane . in a preferred embodiment of the present invention the catalyst used in step a ) of the present invention is an acid , preferably a brønsted acid , or a lewis acid . in an even more preferred embodiment according to the invention , the reaction between the aldehyde compound with formula iii , the compound with formula iv and the 4 - aminobenzotrifluoride with formula ii is conducted in the presence of the acid catalyst 4 - toluenesulfonic acid . there are a number of addition modes that can successfully result in the desired product . a simultaneous addition mode is preferred so as to prevent formation of difficult to remove product related impurities . preferably , in step a ) of the process of the present invention a mixture of 4 - aminobenzotrifluoride according to formula ii and catalyst are added , simultaneously , to the addition of the compound according to formula iv and to the aldehyde according to formula iii . alternatively , the aldehyde according to formula iii , the compound according to formula iv and the 4 - aminobenzotrifluoride according to formula ii are first mixed in a solvent according to the invention , before contacting the compounds with the catalyst . alternatively , the aldehyde according to formula iii and the 4 - aminobenzotrifluoride according to formula ii are first dissolved in a solvent according to the invention , before contacting them with the compound according formula iv and a catalyst according to the invention . for the purpose of further improving the yield and purity of the compounds according to formula i , the inventors found that it is beneficial to separate the compound of formula v ( i . e . the povarov product ) formed in step ( a ) from the reaction mixture before carrying out the subsequent step ( b ). preferably , the compound of formula v is separated prior to step ( b ), by means of precipitation and / or filtration procedures . precipitation of the compound of formula v from the reaction product may be carried out by means of the addition of a non - polar solvent to said reaction mixture . preferred non - polar solvents are heptanes , cyclohexane or a mixture thereof . if required , purification is achieved by means of a two - step precipitation process with the compound of formula v . for this purpose , the compound with formula v is preferably in a first step precipitated with heptanes or cyclohexane or a mixture thereof and subsequently recrystallized with acetone , isopropanol , ethyl acetate or methyl tert - butyl ether in a second precipitation step . further precipitation and / or recrystallization may be carried out to further increase the purity of the compound with formula v . in step b ) of the process of the present invention the compound with formula v is hydrolyzed to form the compound of formula i . preferably , such hydrolysis is carried out by warming a mixture comprising compound v for 1 to 3 hours at a temperature of 45 to 80 ° c . in the presence of an aqueous acid , preferably hydrochloric acid . in a preferred embodiment of the process of the present invention , the compound according to formula v is hydrolyzed in the presence of an alcohol , preferably ethanol , and an aqueous acid . the compounds according to formula i - a and in particular the compound b are preferably used further in the preparation of tetrahydroquinoline derivatives having cetp inhibiting properties , such as compound a , by using the same kind of process as has been described in wo2007 / 116922 . a second aspect of the present invention relates to the compound according to formula v wherein r 2 is h , c 1 - c 3 alkyl or the compound of formula v is the so called povarov product , which compound has not been synthesized before . the compound according to formula v wherein r 1 is ch 2 ch 3 and r 2 is h is particularly preferred for reasons that it is very efficient to use this compound in the preparation of compound a . a third aspect of the present invention relates to the use of these compounds in the preparation of a compound according to formula i - a , in particular in the preparation of the compound b . a last aspect of the present invention relates to the use of a compound of formula v in the preparation of compound a . the present invention will be illustrated further by means of the following non - limiting examples . example 1a ) 3 mol % toluene sulfonic acid ( tsoh ) catalyzed 3 - component povarov reaction using simultaneous addition ( 50 g scale ) to a reactor a was added propionaldehyde ( 90 g , 5 eq ) and acetonitrile ( 50 ml ), to a reactor b was added p - toluenesulfonic acid ( 1 . 77 g , 3 % mol ), 4 - trifluoromethylaniline ( 50 g , 1 eq ) and acetonitrile ( 100 ml ) and to a reactor c was added n - vinylformamide ( 26 . 5 g , 1 . 2 eq ) and acetonitrile ( 100 ml , 2 vols ). the contents of reactor b and reactor c were added simultaneously to reactor a over ˜ 4 hours whilst keeping the temperature of the contents of reactor a at 20 - 30 ° c . after addition , the reaction mixture in reactor a was stirred at 20 - 25 ° c . for 16 hours . the mixture was then cooled to 0 - 5 ° c . and stirred for 3 hours . the precipitate was filtered off and washed with cold acetonitrile ( 100 ml ). the solid was then dried under vacuum at 40 ° c . for 16 hours to give 31 g of the povarov product ( 37 % yield ). example 1b ) 2 mol % p - toluenesulfonic acid ( tsoh ) catalyzed 3 - component povarov reaction in dichloromethane overnight ( 100 g scale ) 4 - aminobenzotrifluoride ( 100 g , 78 ml , 0 . 62 mol ) was dissolved in ch 2 cl 2 ( 200 ml ) at room temperature . propionaldehyde ( 44 . 7 ml , 0 . 62 mol ) was added , followed by ch 2 cl 2 ( 200 ml ). the clear solution was stirred at room temperature for 1 hour to give a pale - yellow solution of the imine . the reaction mixture was further diluted with ch 2 cl 2 ( 300 ml ) and cooled on ice . n - vinylformamide ( 86 . 8 ml , 1 . 24 mol , 2 . 0 eq ) was added in one portion to the in situ prepared imine solution , as described above . tsoh ( 2 . 36 g , 12 . 4 mmol , 2 mol %) was added to the reaction mixture which was stirred overnight on ice at 0 ° c . to room temperature . heptanes ( 700 ml ) were added to the suspension . after 5 minutes the slurry was filtered over a glass filter under suction . the off - white crystals were washed on the filter with heptanes ( 2 × 200 ml ) under suction . the obtained solids were dried under reduced pressure at 50 ° c . with a rotary evaporator to give the product ( 99 g , 59 % yield ) as an off - white solid . liquid chromatography - mass spectrometry ( lcms ) and 1 h - nuclear magnetic resonance ( nmr ) confirm the product . next , the crude solid was recrystallized from hot acetone . solids that did not dissolve were removed from the hot acetone solution by filtration . the resulting clear solution was stored at 5 ° c . overnight . the resulting thick slush was filtered using a glass filter and washed with heptanes ( 2 × 200 ml ). this yielded 52 . 5 g of a white solid ( 32 % yield ). the mother liquor was evaporated and recrystallized from isopropanol ( ipa ) (+ 100 ml ), yielding 13 . 5 g of a white solid . both batches combined gave a yield of 66 g ( 39 % yield ). 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 40 ( s , 1h ), 7 . 34 ( t , 1h ), 7 . 26 ( d , j = 7 . 7 hz , 1h ), 6 . 52 ( d , j = 8 . 4 hz , 1h ), 5 . 88 - 5 . 54 ( m , j = 26 . 6 hz , 1h ), 5 . 52 - 5 . 36 ( m , 1h ), 4 . 85 - 4 . 67 ( m , j = 16 . 3 , 10 . 8 hz , 1h ), 4 . 14 ( s , 1h ), 3 . 58 - 3 . 31 ( m , 1h ), 2 . 45 - 2 . 30 ( m , 1h ), 1 . 80 - 1 . 36 ( m , 4h ), 1 . 03 ( t , 3h ). a mixture of the povarov product ( 20 g , 73 . 5 mmol ), concentrated hcl ( 22 . 3 ml ) and ethanol ( 60 ml ) was heated at 50 ° c . for 5 hours . after cooling to 30 - 40 ° c ., the mixture was evaporated to a total volume of 60 ml . the mixture was then cooled and dichloromethane ( 160 ml ) added , followed by basification with 6m naoh ( 60 ml ) to ph 12 - 13 . the layers were separated and the aqueous phase extracted with dichloromethane ( 40 ml ). the combined organic layers were washed with water ( 40 ml ), dried over sodium sulphate and evaporated to dryness to yield 17 . 6 g of racemic compound b ( 95 % yield ). example 2b ) racemic 2 - ethyl - 6 -( trifluoromethyl )- 1 , 2 , 3 , 4 - tetrahydroquinolin - 4 - amine ( rac - compound b ) ( in acetonitrile followed by sulfuric acid hydrolysis ) 4 - aminobenzotrifluoride ( 6 . 3 ml , 50 . 0 mmol ) was dissolved in ch 3 cn ( 40 ml ) at rt . propionaldehyde ( 4 . 3 ml , 60 mmol , 1 . 2 eq . ; stored at 4 ° c .) was added in one portion . the temperature rose to 25 ° c . the clear solution was stirred at rt ( in a water bath for cooling ) for 5 minutes to give a pale - yellow solution of the imine . n - vinylformamide ( 4 . 4 ml , 63 mmol , 1 . 25 eq . ; stored at 4 ° c .) was added in one portion to the in situ prepared imine solution followed by tsoh ( 160 mg , 0 . 017 eq .). the temperature rose to 27 ° c . after 5 min . a precipitate formed . the mixture was stirred under nitrogen atmosphere at rt overnight . nmr analysis showed full conversion of the components into the povarov product . to the mixture water ( 140 ml ) was added , followed by h 2 so 4 ( 14 ml ) and the mixture was warmed at 60 ° c . after 0 . 5 hr nmr revealed full conversion of the povarov product into the racemic compound b . the mixture was extracted with toluene ( 50 ml ). the aqueous layer was basified with conc . aq . naoh to ph 10 . the basic water layer was extracted with toluene ( 200 ml ) and the toluene layer was dried ( na 2 so 4 ) and concentrated to give 7 . 3 g ( 60 %) of crude 2 - ethyl - 6 -( trifluoromethyl )- 1 , 2 , 3 , 4 - tetrahydroquinolin - 4 - amine ( racemic compound b ) as a brown solid , 80 - 90 % pure by nmr . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 62 ( s , 1h ), 7 . 28 ( d , 1h ), 6 . 45 ( d , j = 8 . 4 hz , 1h ), 4 . 03 ( s , 2h ), 4 . 00 ( s , 1h ), 3 . 48 - 3 . 28 ( m , j = 2 . 8 hz , 1h ), 2 . 27 - 2 . 08 ( m , 1h ), 1 . 67 - 1 . 32 ( m , 6h ), 1 . 00 ( t , 3h ). di - p - toluoyl - l - tartaric acid monohydrate ( 134 . 7 g , 0 . 33 mol , 0 . 75 eq ) was added to a solution of crude racemic compound b ( 108 . 4 g ) in methanol ( 1 l , 9 v ) and stirred until crystals formed . the resulting slush was heated to reflux , allowed to cool to rt and then cooled on ice . crystals formed , which were collected by filtration and dried ( 99 . 9 g solids ). this material was crystallized again from methanol ( 750 ml , 7 v ) and washed with methyl tert - butyl ether ( tbme ) ( 200 ml , 2v ) to give 81 . 6 g compound b ditoluoyltartaric acid ( b - dtta ) salt ( 27 % yield ) with 99 . 5 % e . e . example 2d ) conversion of compound b di - p - toluoyl - l - tartaric acid salt to methanesulfonic acid salt to 10 g compound b - dtta salt ( 94 % e . e .) was added toluene ( 100 ml ) and 2n naoh ( 100 ml ). the mixture was stirred for 10 min . after which the layers were separated . the water phase was extracted with toluene ( 2 × 100 ml ). next , the combined toluene layers were washed with brine , dried over na 2 so 4 and evaporated to dryness . this resulted in a brown oil , to which 3 v of isopropanol was added . methanesulfonic acid ( msoh ) ( 1 ml ) was added dropwise to the resulting suspension . first the suspension became a clear mixture . after a few min solids started to form . these solids were collected , washed with tbme ( 2 ×) and dried . this furnished 4 g ( 75 % yield from enriched compound b - ta salt ) of compound b msoh salt with an e . e . of 98 . 6 %. 10 v of isopropanol ( ipa ) ( 40 ml ) was added and the resulting suspension was heated to reflux for 5 min . after which it was allowed to cool to rt . solids formed which were collected by filtration and washed with tbme . this resulted in 2 . 58 g ( 48 % yield ) of compound b msoh salt with an e . e . of 99 . 7 %. example 2e ) conversion of compound b methanesulfonic acid salt into compound a for the conversion of compound b methanesulfonic acid salt into compound a the similar process as described in wo2007 / 116922 was used . 1 . the emerging risk factors collaboration . major lipids , apolipoproteins , and risk of vascular disease . jama . 2009 ; 302 : 1993 - 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