Patent Application: US-28321508-A

Abstract:
the invention discloses the composition and preparation of various 1 , 3 , 6 - trisubstituted - 2 - carboxy - quinol - 4 - ones of the formula 1 where r is h , alkyl , haloalkyl or hydroxyalkyl , r ′ is alkyl , nitro , halogen or nr 2 ′″ where r ′″ is alkyl or cycloalkyl , and r ″ is h or alkyl . the composition of the invented compounds as methods of antagonizing the action of endothelin - 1 to treat cardiovascular , pulmonary diseases and obstetric disorders and preterm labor and preeclampsia in mammals is disclosed .

Description:
the subject invention is directed toward the treatment of a variety of diseases in a mammal by administering one or more endothelin - 1 antagonists that comprise a pharmaceutically acceptable amount of any one or combination of two or more of a novel series of 1 , 3 , 6 - trisubstituted - 2 - carboxy - quinol - 4 - ones and pharmaceutically acceptable carrier and a method of antagonizing the action of endothelin - 1 , consisting of administering to a human a pharmaceutically effective amount of any one or combination of two or more of a novel series of 1 , 3 , 6 - trisubstituted - 2 - carboxy - quinol - 4 - ones . the diseases that may be treated with the aforementioned compounds include hypertension , congestive heart failure , restenosis following arterial injury , reperfusion injury , angina , acute or chronic pulmonary hypertension , cerebral ischemia , myocardial ischemia , cerebral vasospasm , atherosclerosis , emphysema , asthma , bronchitis , bronchiectasis , pneumonia , adult respiratory distress syndrome , neonatal respiratory distress syndrome , bronchopulmonary dysplasia , interstitial pulmonary fibrosis , cystic fibrosis , persistent pulmonary hypertension of the newborn , proliferative diseases and neoplasia , especially prostate cancer , acute and chronic renal failure , cyclosporine - induced nephrotoxicity , gastric ulceration , colitis , inflammatory bowel disease , migraine , raynaud &# 39 ; s disease , erectile dysfunction , endotoxin - induced toxicity , lpl - related lipoprotein disorders , platelet aggregation , thrombosis , il - 2 mediated cardiotoxicity , preterm labor , premature rupture of membranes , placental abruption , pre - eclampsia , miscarriage , stillbirth , pain , especially cancer - related bone pain , infertility , malaria , sleeping sickness , chagas disease , cerebral malaria and leukomalacia . the endothelin - 1 antagonist may be administered orally , intravenously , topically , intramuscularly , intratracheally , or by any other route deemed efficacious . typically , the effective daily amount of endothelin antagonist is from about 1 μg / kg to 10 mg / kg of body weight . it may be given once per day or more often , until the desired daily dosage is fully administered . the endothelin receptor antagonist ( et a - ra ) is administered in a pharmaceutically acceptable carrier . such examples include saline solution , dmso , an alcohol solution , sodium carbonate solution , or water . such carriers are well known in the art , and the specific carriers employed may be varied depending upon factors such as size of the subject being treated , treatment dose , and the like . further , the time over which the endothelin receptor antagonist ( et a - ra ) is administered may vary as is well known in the art to achieve the desired results . the treatment is intended for a wide variety of human subjects , ranging from neonates to elderly subjects . endothelin - 1 , an extremely potent vasoconstrictor peptide ( yanagisawa et al . 1988 ) has now been implicated in a broad spectrum of physiologic and pathologic processes , including cardiovascular , respiratory , vascular , obstetrical , oncologic or pain - related disorders . for example , the peptide increases myometrial smooth muscle tone ( kaya et al . 1999 , yallampali and garfield 1994 , wollf et al . 1993 ) and it has also been shown that infection and inflammatory cytokines stimulate et - 1 production ( woods et al . 1999 ). we have found that treatment of pregnant mice with lipopolysaccharide results in increased levels of expression of both et - 1 and ece - 1 ( wang et al 2008 ). we have also shown that treating lps - stimulated pregnant mice with the ece - 1 inhibitor phosphoramidon decreases the incidence of premature delivery ( koscica et al . 2004 ). in addition , we have recently found that treating lps - stimulated pregnant mice with the selective et a - ra bq - 123 also results in decreased incidence of premature delivery and that this effect is dose dependent ( wang et al . 2008 ). finally , we have also recently found that rnai directed at endothelin - converting enzyme - 1 results in a dramatic decrease in the incidence of premature delivery ( wang et al . 2008 ). in a separate line of investigation , we have shown that inhibition of et - 1 activity with either phosphoramidon or an endothelin receptor antagonist markedly reduces lipopolysaccharide ( lps )- induced influx of neutrophils into the lung ( bhavsar et . al . 2008a , bhavsar et al . 2008b ). measurement of bronchoalveolar lavage fluid ( balf ) leukocytes demonstrated a selective recruitment of neutrophils by et - 1 . phosphoramidon is a non - specific endothelin converting - enzyme inhibitor that inactivates ece - 1 as well as ece - 2 . bq - 123 is a modified peptide , which must be administered parenterally . rna knockdown requires hydrodynamic transfection . we have synthesized a series of compounds , the prototype of which is 3 -( 3 - carboxybenzyl )- 1 -( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 - hydroxy - 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylic acid ( hjp272 ) fig2 . this novel , non - peptide , potentially orally active compound was found to bind the et a receptor selectively . furthermore , the compound effectively controlled infection - associated preterm labor and delivery in our mouse model . in addition , et - 1 plus cigarette smoke triggered selective recruitment of alveolar neutrophils was reversed by concomitant treatment with hjp - 272 , suggesting a possible role for this type of agent in reducing smoking related acute lung injury . due to the broad range of disorders with pathology now known to involve et - 1 , the compounds may be useful in the treatment of many disorders , ranging from vascular disease to cancer . synthesis of hjp272 , the prototype compound with the formula of 1a ( r , ═ h , r ′ c 1 h 5 , r ″═ h ) according to the invention we provide the method of synthesis of the prototype compound 1 -( 5 - 1 -( 5 - hydroxy - 2 - nitrophenyl ) ethanone 3 - hydroxyacetophenone , 80 g ( 0 . 588 mole ) was dissolved in 320 ml of glacial acetic acid and placed in 3 - neck flask , with one neck fitted with thermometer and other with condenser . with efficient stirring , at 70 ° c ., 47 . 8 ml ( 0 . 676 mole ) of nitric acid ( d 1 . 4 ) is added drop wise carefully assuring that temperature is not deviating from 70 ° c . by more than ± 2 ° c . after addition , reaction was stirred for another 2 hrs at 65 - 70 ° c . and then poured into around 300 ml of ice - water and kept overnight in the refrigerator . next day precipitates were filtered and allowed to dry . precipitates were then taken in to 500 ml round bottom flask and were boiled in 200 ml of benzene for 1 hour . benzene was decanted while hot leaving sticky black residue in the round bottom flask and then allowed to cool to room temperature resulting in 38 . 4 g of mixture of nitration products . column chromatography ( chcl 3 : etoac ; 85 : 15 ) resulted in 14 . 3 g ( 17 . 9 %) of the desired 1 -( 5 - hydroxy - 2 - nitrophenyl ) ethanone regioisomer , 8 . 4 g ( 10 . 4 %) of 1 -( 5 - hydroxy - 6 - nitrophenyl ) ethanone and 1 . 5 g ( 1 . 9 %) of 1 -( 5 - hydroxy - 4 - nitrophenyl ) ethanone . mp . 146 - 148 ° c . ( klinke et . al . 1961 , 148 - 149 ° c . ), tlc ( 80 % chcl 3 : 20 % etoac ) r f = 0 . 5100 . ms : m / z 181 ( m + ); 166 [( m - ch 3 ) + , c 7 h 4 no 4 ]; 139 [( m - ch 2 ═ c ═ o ) + , c 6 h 5 no 3 ]; 122 ( 139 - oh .) + ; 109 [( 139 - no ) + , c 6 h 5 o 2 ]; 92 ( 139 - hno 2 + , c 6 h 4 o ); 80 c 5 h 4 o ; c 6 h 5 + ; 63 c 5 h 3 + , 53 c 4 h 5 + , 52 c 4 h 4 + ; 43 ch 3 -+ c ═ o ( base peak ). ir : 1711 cm − ( ketone c ═ o ), 1523 and 1341 cm − 1 ( aromatic nitro ). 1 h - nmr ( dmso - d 6 , 8 ppm ): a : 2 . 49 , s , 3h ; b : 6 . 85 , s , 1h ; c : 6 . 99 , d , 1h , j cd = 7 . 8 hz ; d : 8 . 09 , d , 1h , j = 7 . 8 hz ; e : 11 . 39 , s , 1h . 13 c - nmr ( dmso - d 6 , δ ppm ): c 1 : 30 . 24 , c 2 : 113 . 37 , c 3 : 116 . 55 , c 4 : 127 . 48 , c 5 : 136 . 32 , c 6 : 141 . 10 , c 7 : 163 . 55 , c 8 : 200 . 22 . 1 -( 5 - hydroxy - 2 - nitrophenyl ) ethanone , 13 g ( 0 . 0718 mole ) was dissolved in 150 ml of methanol and placed in 500 ml round - bottomed flask . to this 23 ml ( 3 equiv .) of 10 n naoh was added and allowed to stir at room temperature for 15 mins , followed by addition of 10 . 77 g ( 0 . 0718 mole ) of 3 - carboxybenzaldehyde . reaction mixture was refluxed for 12 hrs and monitored on tlc . the reaction mixture was allowed to cool and neutralized with 23 ml of 10 n hcl , resulting in the formation of a precipitate . the precipitate was filtered , washed thoroughly with water and allowed to dry , to give 21 . 2 g of crude product . recrystallization from methanol - water ( 5 %) resulted in 19 . 4 g ( 86 . 3 %) of pure product , m . p . 253 - 254 ° c ., tlc ( 90 % ch 2 cl 2 : 10 % etoac ) r f = 0 . 306 . ms : m / z 313 ( m + ), 296 , 284 , 268 , 250 , 163 ( base peak ), 150 , 135 , 131 , 120 , 107 , 92 , 91 , 77 , 65 , 51 . ir : 3408 and 3215 cm − 1 (— oh ), 1702 cm − 1 ( α , β unsaturated ketone c ═ o ), 1627 cm − 1 ( aromatic carboxylic acid c ═ o ), 1575 and 1332 cm − 1 ( aromatic nitro ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 6 . 84 , d , 1h , j = 2 . 2 hz ; b : 7 . 07 , dd , 1h , j bh = 8 . 8 ; c : 7 . 26 , d , 1h , j cd = 16 . 4 hz ; d : 7 . 46 , d , 1h , j dc = 16 . 3 hz ; e : 7 . 566 , t , 1h , j = 7 . 7 hz ; f : 7 . 99 , d , 1h , j fb = 8 hz ; g : 8 . 04 , d , 1h , j ge = 7 . 6 hz ; h : 8 . 19 , d , 1h , j he = 9 . 2 ; i : 8 . 23 , s , 1h ; j : 12 . 32 ( exchangeable with d 2 o ), s , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c 1 : 114 . 73 , c 2 : 116 . 82 , c 3 : 127 . 27 , c 4 : 127 . 72 , c 5 : 129 . 30 , c 6 : 129 . 90 , c 7 : 131 . 35 , c 8 : 131 . 64 , c 9 : 132 . 30 , c 10 : 134 . 51 , c 11 : 137 . 38 , c 12 : 139 . 06 , c 13 : 144 . 28 , c 14 : 163 . 45 , c 15 : 166 . 84 , c 16 : 192 . 77 . anal . : calc . for c 16 h 11 no 6 : c , 61 . 35 ; h , 3 . 54 ; n , 4 . 47 . found : c , 61 . 06 ; h , 3 . 54 ; n , 4 . 41 . ( e )- 3 -( 3 -( 5 - hydroxy - 2 - nitrophenyl )- 3 - oxoprop - 1 - enyl ) benzoic acid , 25 g ( 0 . 0799 mole ) was dissolved in 450 ml of anhydrous ethanol ( dried over molecular sieves overnight ). anhydrous hydrochloric acid gas was bubbled in the reaction mixture at 0 ° c . and allowed to stir overnight at room temperature . at the end of reaction ( disappearance of starting material on tlc ) ethanol and excess hcl gas were evaporated on rotary evaporation to get crude product . recrystallization from hexane - etoac resulted in 26 . 0 g ( 95 %) of white crystalline product , m . p . 157 - 159 ° c ., tlc ( 90 % chcl 3 : 10 % etoac ) r f = 0 . 414 . ms : m / z 341 ( m + ), 312 ( m - c 2 h 5 ) + , 296 ( m - o c 2 h 5 ) + , 268 ( m - coo c 2 h 5 ) + , 250 ( 296 - no 2 ) + , 196 c 9 h 6 no 4 , 179 c 8 h 5 no 4 , 163 ( base peak , c 10 h 11 o 2 ), 150 c 7 h 4 no 3 , 135 [( 163 - c 2 h 4 ) + , c 8 h 7 o 2 ], 120 ( 150 - no ) + , c 7 h 4 o 2 , 107 c 7 h 70 , 92 c 6 h 4 o , 91 c 7 h 7 + , 77 c 6 h 5 + , 65 c 5 h 5 + , 51 c 4 h 3 + . ir : 3376 cm − 1 (— oh ), 1714 cm − 1 ( aromatic ester , c ═ o ), 1672 cm − 1 ( α , β unsaturated ketone c ═ o ), 1590 and 1340 cm − 1 ( aromatic nitro ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 1 . 33 , t , 3h , j ab = 7 . 1 hz ; b : 4 . 33 , q , 2h , j ba = 7 hz ; c : 6 . 85 , d , 1h , j = 2 . 2 hz ; d : 7 . 08 , dd , 1h , j dj = 9 . 0 ; e : 7 . 27 , d , 1h , j cf = 16 . 4 hz ; f : 7 . 46 , d , 1h , j dc = 16 . 3 hz ; g : 7 . 58 , t , 1h , j = 7 . 7 hz ; h : 8 . 00 , d , 1h , j hg = 7 . 6 hz ; i : 8 . 08 , d , 1h , j ig = 7 . 5 hz ; j : 8 . 19 , d , 1h , j jd = 9 . 1 ; k : 8 . 22 , s , 1h ; l : 11 . 42 ( exchangeable with d 2 o ), s , 1h . 13 c - nmr ( dmso - d 6 , 8 ppm ): c 1 : 14 . 12 , c 2 : 60 . 95 , c 3 : 114 . 71 , c 4 : 116 . 79 , c 5 : 127 . 48 , c 6 : 127 . 70 , c 7 : 129 . 39 , c 8 : 129 . 68 , c 9 : 130 . 70 , c 10 : 131 . 09 , c 11 : 132 . 49 , c 12 : 134 . 65 , c 13 : 137 . 39 , c 14 : 138 . 97 , c 15 : 144 . 12 , c 16 : 163 . 38 , c 17 : 165 . 22 , c 18 : 192 . 76 . anal . : calc . for c 18 h 15 no 6 : c , 63 . 28 ; h , 4 . 43 ; n , 4 . 10 . found : c , 63 . 28 ; h , 4 . 46 ; n , 4 . 14 . sodium hydride dispersion ( 60 % in mineral oil ), 3 . 03 g equivalent to 1 . 81 g of nah ( 0 . 0756 mol , 1 . 2 equiv .) was weighed and placed in the three - neck flask under nitrogen . mineral oil was washed out with 10 ml of hexane for three times followed by addition of 15 ml of dry dimethyl formamide ( dried over molecular sieves overnight ). three - neck flask was then kept in the ice - water bath . when the temperature of the reaction has reached 0 ° c ., 21 . 5 g ( 0 . 0630 mole ) of ( e )- ethyl 3 -( 3 -( 5 - hydroxy - 2 - nitrophenyl )- 3 - oxoprop - 1 - enyl ) benzoate dissolved in 50 ml of dry dmf was added drop wise with stirring . after addition the ice - bath was removed and the reaction was allowed to stir at room temperature for 20 mins . methoxymethyl chloride , 6 . 05 g ( 0 . 0756 mol , 1 . 2 equiv .) in 15 ml of dry dmf was added drop wise at 0 ° c . followed by addition of 20 g of potassium carbonate to make ph 8 . reaction was allowed to stir at room temperature for 4 hrs . and then poured into 400 ml of ice water . mixture was then transferred to the 1000 ml separatory funnel and extracted with 100 ml of ethyl ether for three times . combined ether solution was then dried over magnesium sulfate , filtered and evaporated to get 23 . 1 g of crude product . recrystallization from ethyl acetate - hexane ( 2 %) resulted in 21 . 6 g ( 89 %) of pure product , m . p . 88 - 91 ° c . tlc ( 60 % n - hexane : 40 % etoac ) r f = 0 . 357 . ms : m / z 385 ( m −+ ), 356 ( m - c 2 h 5 − ) + , 340 [( m - 45 ), ( m - ch 2 — och 3 ) + or ( m - ch 3 ch 2 o − ) + ], 312 ( m - 73 ) ( m - cooc 2 h 5 ) + , 294 [( m - 91 ) ( 340 - no 2 ) + ], 236 ( m - 149 ) c 11 h 10 no 5 , 207 ( m - 178 ), 206 ( 236 - no ) + , 190 ( 236 - no 2 ) + , 176 c 11 h 12 o 2 ch 2 ═ ch — c 6 h 4 — cooc 2 h 5 , 163 ( base peak , + ch 2 — c 6 h 4 — cooc 2 h 5 , c 10 h 11 o 2 ), 149 c 9 h 9 o 2 , 133 [( 163 - ch 2 o ) + , 129 ( 157 - co ), 102 ( 176 - hcooc 2 h 5 ) + and / or ( 163 - och 2 och 3 ) + , 91 c 7 h 7 + , 77 c 6 h 5 + , 65 c 5 h 5 + , 59 ch 3 och 2 — o + , 45 ch 3 — + o ═ ch 2 . ir : 1719 cm − 1 ( aromatic ester , c ═ o ), 1648 cm − 1 ( α , β unsaturated ketone c ═ o ), 1518 and 1340 cm − 1 ( aromatic nitro ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 40 , t , 3h , j ac = 7 . 2 hz ; b : 3 . 51 , s , 3h ; c : 4 . 33 , q , 2h , j ca = 7 . 1 hz ; d : 5 . 29 , s , 2h ; e : 7 . 03 , d , 1h , j eh = 16 . 3 hz ; f : 7 . 05 , d , 1h , j = 2 . 6 hz ; g : 7 . 27 , dd , 1h , j mg = 9 . 3 hz ; h : 7 . 27 , d , 1h , j he = 16 . 4 hz ; i : 7 . 47 , t , 1h , j = 7 . 8 hz ; j : 7 . 70 , d , 1h , j ji = 7 . 8 hz ; k : 8 . 06 , d , 1h , j ki = 7 . 7 hz ; l : 8 . 14 , s , 1h ; m : 8 . 22 , d , 1h , j mg = 9 . 1 hz . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 14 . 50 , c 2 : 56 . 89 , c 3 : 61 . 54 , c 4 : 94 . 76 , c 5 : 115 . 86 , c 6 : 117 . 20 , c 7 : 127 . 26 , c 8 : 127 . 54 , c 9 : 129 . 29 , c 10 : 129 . 81 , c 11 : 131 . 55 , c 12 : 131 . 86 , c 13 : 132 . 43 , c 14 : 134 . 53 , c 15 : 138 . 97 , c 16 : 140 . 16 , c 17 : 144 . 65 , c 18 : 162 . 05 , c 19 : 166 . 01 , c 20 : 192 . 71 . anal . : calc . for c 20 h 19 no 7 : c , 62 . 33 ; h , 4 . 97 ; n , 3 . 63 . found : c , 62 . 11 ; h , 4 . 94 ; n , 3 . 64 . ( e )- ethyl 3 -( 3 -( 5 -( methoxymethoxy )- 2 - nitrophenyl )- 3 - oxoprop - 1 - enyl ) benzoate , 21 . 0 g ( 0 . 0545 mole ) was dissolved in 80 ml of dry ethanol and placed in the hydrogenation bomb . to the reaction solution , 100 mg of platinum oxide was added and the catalyst was activated after two cycles of vacuum - nitrogen . hydrogenation was done at 45 psi of hydrogen for 30 mins with stirring at room temperature . five drops of acetic acid were added followed by hydrogenation at 45 psi hydrogen for another 15 mins . at the end of reaction catalyst was carefully filtered over celite under nitrogen followed by evaporation of solvent on the rotary evaporation to get 19 . 0 g of thick oil . column chromatography ( 60 % hexane : 40 % etoac ) resulted in 16 . 1 g ( 82 . 7 %) of pure product . tlc ( 60 % n - hexane : 40 % etoac ) r f = 0 . 643 . ms : m / z 357 ( m + ), 327 ( m - 30 ) ( m - ch 2 o ) + , 325 ( m - 32 ) ( m - ch 3 oh ) + , 312 [( m - 45 ), ( m - oc 2 h 5 )+ or ( m - ch 2 och 3 ) + ], 266 ( m - 91 ), 176 [( m - 181 ), c 11 h 12 o 2 , ch 2 ═ chc 6 h 4 cooc 2 h 5 ), 162 c 10 h 10 o 2 , 150 ( c 9 h 10 o 2 , c 6 h 5 cooc 2 h 5 ), 136 ( c 8 h 8 o 2 , ch 3 och 2 oc 6 h 3 ), 119 c 7 h 5 no , 108 c 6 h 6 no , 92 c 6 h 4 o , 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 65 c 5 h 5 + , 52 c 4 h 4 , 45 ( base peak , ch 3 — + o ═ ch 2 ). ir : 3466 and 3350 cm − ( primary amine n — h ), 1716 cm − 1 ( aromatic ester , c ═ o ), 1650 cm − 1 ( ketone c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 39 , t , 3h , j ae = 7 . 1 hz ; b : 3 . 08 , t , 2h , j bc = 7 . 9 hz ; c : 3 . 08 , t , 2h , j bc b = 7 . 2 hz ; d : 3 . 48 , s , 3h ; e : 4 . 38 , q , 2h , j ea = 7 . 1 hz ; f : 5 . 06 , s , 2h ; g : 6 . 04 ( exchangeable with d 2 o ), s , 2h ; h : 6 . 61 , d , 1h , j hi = 8 . 9 hz ; i : 7 . 06 , dd , 1h , j jh = 8 . 9 hz ; j : 7 . 36 , t , j = 7 . 6 hz ; k : 7 . 4 , s , 1h ; l : 7 . 45 , d , 1h , j lj = 7 . 6 hz ; m : 7 . 89 , d , 1h , j mj = 7 . 7 hz ; n : 7 . 94 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 14 . 53 , c 2 : 30 . 50 , c 3 : 40 . 98 , c 4 : 56 . 08 , c 5 : 61 . 13 , c 6 : 96 . 04 , c 7 : 117 . 85 , c 8 : 118 . 04 , c 9 : 118 . 64 , c 10 : 125 . 46 , c 11 : 127 . 56 , c 12 : 128 . 68 , c 13 : 129 . 68 , c 14 : 130 . 92 , c 15 : 133 . 27 , c 16 : 141 . 93 , c 17 : 146 . 25 , c 18 : 147 . 65 , c 19 : 166 . 87 , c 20 : 200 . 78 . hydrazine hydrate ( 55 % hydrazine ), 40 ml ( 0 . 683 mole ; 2 . 8 equiv .) was placed in 500 ml of round bottom flask containing 150 ml of ethanol . to this 40 g ( 0 . 244 mole ) of 1 -( benzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) ethanone was added and the reaction mixture refluxed for 6 hours . gc - ms showed a single peak of m + 178 m / z for hydrazone ( m . p . 89 - 93 ° c .). ethanol was evaporated by rotary evaporation and 50 ml of ethylene glycol was added to the flask containing crude hydrazone . the solution was then transferred to 3 - neck flask with one neck fitted with condenser and other with nitrogen inlet . to this add 50 g of potassium hydroxide was added and the mixture was heated at 160 ° c . under nitrogen for 8 hours . after the completion of reaction it was allowed to cool and water was added to it . the resultant mixture was extracted with ether ( 3 × 150 ml ). the organic layer was then washed with 1n hcl ( 2 × 150 ml ) followed by water ( 2 × 50 ml ), dried over mgso 4 and evaporated to get 28 . 6 g of crude product . vacuum distillation of crude product 130 ° c . and 27 mmhg resulted in 23 . 2 g ( 63 . 4 %) of pure product ( kumar br 2006 ). ms : m / z 150 ( m + ), 135 ( base peak , m + - ch 3 ), 121 ( m + - c 2 h 5 ), 105 ( 135 - ch 2 ═ o ) + , 91 c 7 h 7 + , 79 c 5 h 3 o + , 77 c 6 h 5 + , 65 c 5 h 5 + , 63 c 5 h 3 + , 51 c 4 h 3 + . 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 19 , t , 3h , j ab = 7 . 6 hz ; b : 2 . 56 , q , 2h , j ba = 7 . 2 hz ; c : 5 . 89 , s , 2h ; d : 6 . 63 , d , 1h , j df = 7 . 5 hz ; e : 6 . 69 , s , 1h ; f : 6 . 72 , d , 1h , j fd = 7 . 8 hz . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 16 . 15 , c 2 : 28 . 24 , c 3 : 100 . 87 , c 4 : 108 . 27 , c 5 : 108 . 60 , c 6 : 120 . 58 , c 7 : 138 . 39 , c 8 : 145 . 59 , c 9 : 147 . 70 . 5 - ethylbenzo [ d ][ 1 , 3 ] dioxole , 22 g ( 0 . 146 mole ) was stirred with 50 ml of dichloromethane in a 500 ml round bottom flask . to this 33 . 73 g ( 0 . 292 mole ; 2 equiv .) of α , α - dichloromethyl methyl ether in 50 ml of dichloromethane was added dropwise at 0 ° c . with stirring . after 15 minutes 33 . 38 g ( 0 . 176 mole ; 1 . 2 equiv .) of titanium tetrachloride in 50 ml of dichloromethane was added dropwise at 0 ° c . after complete addition remove the ice bath and the reaction was stirred at room temperature for 1 hour . at the end reaction mixture was poured into 250 ml of ice - water and extracted with diethyl ether ( 3 × 75 ml ) and ethyl acetate ( 3 × 75 ml ). the combined organic extracts were washed with 100 ml of brine followed by aqueous sodium bicarbonate ( 3 × 100 ml ). after drying over mgso 4 , the organic extract was concentrated over rotary evaporation to get 25 . 9 g of crude product . column chromatography of the crude product ( 90 % hexane : 10 % etoac ) resulted in 22 . 6 g ( 86 . 6 %) of pure product . ms : m / z 178 ( base peak , m + ), 177 ( m - h ), 163 ( m + - ch 3 ), 161 ( m - ch 3 — h 2 ) + , 149 ( m - c 2 h 5 ) + or ( m - cho ) + , 135 ( m - ch 3 — co ) + , 131 ( 161 - ch 2 o ) + , 119 ( 149 - ch 2 o ) + , 105 c 6 h 5 co + , 91 c 7 h 7 + , 79 c 5 h 3 o + , 77 c 6 h 5 + , 65 c 5 h 5 + , 51 c 4 h 3 + . 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 26 , t , 3h , j ab = 7 . 6 hz ; b : 2 . 98 , q , 2h , j ba = 7 . 6 hz ; c : 6 . 02 , s , 2h ; d : 6 . 72 , s , 1h ; e : 7 . 30 , s , 1h ; f : 10 . 17 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 17 . 21 , c 2 : 25 . 38 , c 3 : 101 . 37 , c 4 : 108 . 5 , c 5 : 109 . 87 , c 6 : 128 . 0 , c 7 : 145 . 08 , c 8 : 145 . 74 , c 9 : 152 . 69 , c 10 : 189 . 52 . in a 500 ml round bottom flask 16 g ( 0 . 0448 mole ) of aminoketone , ethyl 3 -( 3 -( 2 - amino - 5 -( methoxymethoxy ) phenyl )- 3 - oxopropyl ) benzoate was dissolved in 150 ml of dichloroethane . to this 12 g ( 0 . 0672 mole ; 1 . 5 equiv .) of 6 - ethylbenzo [ d ][ 1 , 3 ] dioxole - 5 - carbaldehyde in 25 ml of dichloromethane was added . after stirring for 15 minutes 19 g of sodium triacetoxyborohydride ( 0 . 0896 mole ; 2 equiv .) was added and the reaction was stirred at room temperature for 5 hours . at the end reaction mixture was poured into 250 ml of ice - water and extracted with diethyl ether ( 3 × 100 ml ). after drying over mgso 4 , the organic extract was concentrated over rotary evaporation to get 19 . 3 g of oil . after triturating the oil with 4 ml of isopropyl alcohol it resulted in 17 . 5 g of solid crude product , m . p . 81 - 87 ° c . column chromatography of the crude product ( 70 % hexane : 30 % etoac ) resulted in 16 . 2 g ( 70 . 6 %) of pure product . m . p . 93 - 94 ° c ., tlc ( 80 % hexane : 20 % etoac ) r f = 0 . 58 . ms : m / z 519 ( m + ), 490 ( m - c 2 h 5 ) + , 488 ( m - och 3 ) + , 474 ( m - oc 2 h 5 ) + or ( m - ch 3 och 2 ) + , 357 ( m - 162 ) + , 356 ( m - 163 or m - c 10 h 11 o 2 ) + , 327 ( 357 - cho ) + , 312 ( 357 - ch 3 och 2 ) + , 163 ( base peak , c 10 h 10 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 45 ch 3 — + o ═ ch 2 . ir : 3329 cm − 1 ( secondary amine n — h ), 1716 cm − 1 ( aromatic ester , c ═ o ), 1644 cm − 1 ( ketone c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 21 , t , 3h , j ac = 7 . 5 hz ; b : 1 . 39 , t , 3h , j bh = 7 . 1 hz ; c : 2 . 61 , q , 2h , j ca = 7 . 6 hz ; d : 3 . 07 , t , 2h , j de = 7 . 4 hz ; e : 3 . 28 , t , 2h , j ed = 8 . 0 hz ; f : 3 . 48 , s , 3h ; g : 4 . 39 , d , 2h , j = 5 . 2 hz ; h : 4 . 38 , q , 2h , j hb = 7 . 1 hz ; i : 5 . 06 , s , 2h ; j : 5 . 90 , s , 2h ; k : 6 . 59 , d , 2h , j kn = 9 . 2 hz ; l : 6 . 72 , s , 1h ; m : 6 . 78 , s , 1h ; n : 7 . 13 , dd , 1h , j kn = 9 . 1 hz ; o : 7 . 36 , t , 1h , j = 7 . 5 hz ; p : 7 . 44 , d , 1h , j po = 7 . 4 hz ; q : 7 . 47 , s , 1h ; r : 7 . 89 , d , 1h , j ro = 7 . 6 hz ; s : 7 . 94 , s , 1h ; t : 8 . 8 ( exchangeable with d 2 o ), s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 14 . 56 , c 2 : 15 . 53 , c 3 : 25 . 53 , c 4 : 30 . 67 , c 5 : 41 . 01 , c 6 : 44 . 82 , c 7 : 56 . 10 , c 8 : 61 . 153 , c 9 : 96 . 17 , c 10 : 101 . 01 , c 11 : 108 . 67 , c 12 : 109 . 17 , c 13 : 113 . 35 , c 14 : 117 . 29 , c 15 : 119 . 22 , c 16 : 126 . 01 , c 17 : 127 . 60 , c 18 : 128 . 71 , c 19 : 128 . 99 , c 20 : 129 . 69 , c 21 : 130 . 95 , c 22 : 133 . 27 , c 23 : 135 . 74 , c 24 : 141 . 95 , c 25 : 146 . 01 , c 26 : 146 . 55 , c 27 : 147 . 08 , c 28 : 147 . 19 , c 29 : 166 . 89 , c 30 : 200 . 89 . anal . : calc . for c 30 h 33 no 7 : c , 69 . 35 ; h , 6 . 40 ; n , 2 . 70 . found : c , 69 . 07 ; h , 6 . 46 ; n , 2 . 71 . in a solution of 16 g ( 0 . 031 mole ) of secondary amine in 60 ml of n , n - dimethyl formamide ( dried over molecular sieves overnight ), 3 . 1 g ( 0 . 04 mole ) of triethylamine was added dropwise at 0 ° c . the mixture was allowed to stir at room temperature for 15 minutes followed by addition of 5 . 44 g ( 0 . 04 moles ) of ethyl oxalyl chloride in 15 ml of dmf . the reaction was stirred for 4 hours and then poured into 200 ml of ice - water followed by extraction with 100 ml of ethyl acetate for three times . organic extract was dried over mgso 4 and evaporated to get 18 . 4 g of crude oil . column chromatography of the oil ( 60 % hexane : 40 % etoac ) resulted in 18 . 0 g ( 94 . 3 %) of pure product as colorless oil . ms : m / z 619 ( m + ), 602 ( m - 17 , m - oh ) + , 601 ( m - h 2 o ) + , 556 ( m - h 2 o — c 2 h 5 ) + , 546 ( m - 73 , m - cooc 2 h 5 ) + , 545 ( m - 74 , m - hcooc 2 h 5 ) + , 518 ( m - 101 , m - c ( o )— cooc 2 h 5 ) + , 438 ( m - 181 , m - h 2 o — ch 2 c 6 h 4 cooc 2 h 5 ), 364 ( 438 - cooc 2 h 5 ) + , 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 45 ch 3 — + o ═ ch 2 . ir : 2965 and 2934 cm − 1 ( alkyl ), 1739 cm − 1 ( oxalyl ester , c ═ o ) 1721 cm − 1 ( aromatic ester , c ═ o ), 1702 cm − 1 ( amide , c ═ o ), 1676 cm − 1 ( ketone c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 0 . 97 , t , 3h , j ad = 7 . 5 hz ; b : 1 . 02 , t , 3h , j bh = 7 . 2 hz ; c : 1 . 40 , t , 3h , j ci = 7 . 1 hz ; d : 2 . 28 , q , 2h , j da = 7 . 7 hz ; e : 3 . 05 - 3 . 15 , m , 4h ; f : 3 . 44 , s , 3h ; g : 4 . 02 , q , 2h , j gb = 7 . 0 hz ; h : 4 . 37 , q , 2h , j hc = 7 . 1 hz ; i : 4 . 47 , d , 1h , j = 14 . 5 hz , j : 5 . 14 , s , 2h ; k : 5 . 29 , d , 1h , j = 14 . 5 hz ; l : 5 . 87 , d , 2h ; m : 6 . 59 , s , 1h ; n : 6 . 65 , s , 1h ; o : 6 . 71 , d , 1h , j op = 8 . 7 ; p : 6 . 95 , dd , 1h , j po = 8 . 6 hz ; q : 7 . 18 , d , 1h , j = 2 . 6 hz ; r : 7 . 37 , t , 1h , j = 7 . 6 hz ; s : 7 . 45 , d , 1h , j sr = 7 . 5 hz ; t : 7 . 89 , d , 1h ; j = 7 . 6 hz ; u : 7 . 94 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 91 , c 2 : 14 . 53 , c 3 : 15 . 68 , c 4 : 25 . 35 , c 5 : 29 . 68 , c 6 : 42 . 79 , c 7 : 49 . 14 , c 8 : 56 . 42 , c 9 : 61 . 14 , c 10 : 61 . 78 , c 11 : 94 . 64 , c 12 : 101 . 09 , c 13 : 108 . 71 , c 14 : 110 . 97 , c 15 : 116 . 61 , c 16 : 118 . 77 , c 17 : 126 . 20 , c 18 : 127 . 65 , c 19 : 128 . 75 , c 20 : 129 . 60 , c 21 : 130 . 21 , c 22 : 130 . 96 , c 23 : 133 . 07 , c 24 : 133 . 33 , c 25 : 137 . 53 , c 26 : 139 . 30 , c 27 : 141 . 50 , c 28 : 145 . 83 , c 29 : 147 . 60 , c 30 : 157 . 34 , c 31 : 161 . 18 , c 32 : 162 . 32 , c 33 : 166 . 84 , c 34 : 200 . 24 . dissolve 18 . 2 g ( 0 . 0294 mole ) of ethyl 3 -( 3 -( 2 -( 2 - ethoxy - n -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 2 - oxoacetamido )- 5 -( methoxymethoxy ) phenyl )- 3 - oxopropyl ) benzoate in 100 ml of ethanol in a 500 ml round bottom flask . to this 5 . 37 g ( 0 . 0353 mole , 1 . 2 equiv .) of 1 , 8 - diazabicyclo [ 5 . 4 . 0 ] undec - 7 - ene dbu ) was added dropwise and stirred at room temperature for 2 hours . after removing the solvent on rotary evaporation , the residue was dissolved in 150 ml of ethyl acetate and washed with 100 ml of water for three times . organic extract was dried over mgso 4 and evaporated to get 17 . 2 g of crude product , m . p . 89 - 96 ° c . recrystallization from etoac - hexane ( 95 : 5 ) resulted in 16 . 3 g ( 92 %) of pure product . ms : m / z 601 ( m + ), 556 [( m - ch 2 — och 3 )+ or ( m - ch 3 ch 2 o ) + ], 528 [( m - 73 ) + , m - cooc 2 h 5 ) + ], 438 ( m - 163 , m - c 10 h 11 o 2 ) + , 410 [( 438 - co ) + or ( 438 - c 2 h 4 ) + ], 364 ( 438 - hcooc 2 h 5 ) + , 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 45 ch 3 — + o ═ ch 2 . ir : 2964 and 2933 cm − 1 ( alkyl ), 1730 cm − 1 ( α β unsaturated ester , c ═ o ), 1714 cm − 1 ( aromatic ester , c ═ o ), 1597 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 05 , t , 3h , j ad = 7 . 1 hz ; b : 1 . 27 , t , 3h , j bg = 7 . 5 hz ; c : 1 . 36 , t , 3h , j ch = 7 . 1 hz ; d : 2 . 64 , q , 2h , j da = 7 . 5 hz ; e : 3 . 46 , s , 3h ; f : 3 . 98 , s , 2h ; g : 4 . 24 , q , 2h , j gb = 7 . 1 hz ; h : 4 . 34 , q , 2h , j hc = 7 . 1 hz ; i : 5 . 19 , s , 2h ; j : 5 . 23 , s , 2h ; k : 5 . 86 , s , 2h ; l : 6 . 23 , d , 1h ; m : 6 . 74 , s , 1h ; n : 7 . 10 , d , 1h , j no = 9 . 3 hz ; o : 7 . 24 , dd , 1h , j on = 9 . 3 hz ; p : 7 . 31 , t , 1h , j = 7 . 7 hz ; q : 7 . 59 , d , 1h , j = 7 . 5 hz ; r : 7 . 84 , d , 1h , j = 7 . 7 hz ; s : 7 . 99 , s , 1h ; t : 8 . 03 , d , 1h ; j = 2 . 7 hz . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 68 , c 2 : 14 . 53 , c 3 : 14 . 77 , c 4 : 25 . 61 , c 5 : 32 . 46 , c 6 : 51 . 35 , c 7 : 56 . 42 , c 8 : 60 . 93 , c 9 : 62 . 94 , c 10 : 94 . 84 , c 11 : 101 . 25 , c 12 : 106 . 50 , c 13 : 109 . 07 , c 14 : 110 . 80 , c 15 : 117 . 94 , c 16 : 118 . 23 , c 17 : 124 . 01 , c 18 : 125 . 54 , c 19 : 127 . 44 , c 20 : 127 . 51 ; c 21 : 128 . 44 , c 22 : 129 . 86 , c 23 : 130 . 46 , c 24 : 133 . 59 , c 25 : 133 . 62 , c 26 : 135 . 46 , c 27 : 140 . 54 , c 28 : 144 . 41 , c 29 : 146 . 56 , c 30 : 147 . 48 , c 31 : 153 . 97 , c 32 : 163 . 93 , c 33 : 166 . 99 , c 34 : 176 . 73 . anal . : calc . for c 34 h 35 no 9 : c , 67 . 87 ; h , 5 . 86 ; n , 2 . 33 . found : c , 67 . 49 ; h , 5 . 98 ; n , 2 . 34 . ethyl 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 - hydroxy - 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate 1a , ( r , ═ h , r ′, r ″═ c 2 h 5 ) ethyl 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 -( methoxymethoxy )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate was dissolved in 350 ml of anhydrous ethanol ( dried over molecular sieves overnight ). anhydrous hydrochloric acid gas was bubbled in the reaction mixture at 0 ° c . and allowed to stir overnight at room temperature . at the end of reaction ( disappearance of starting material on tlc ) ethanol and excess hcl gas were evaporated on rotary evaporation to get crude product . recrystallization from ethanol - water ( 98 : 2 ) resulted in 12 . 45 g ( 82 . 5 %) of pure product . ms : m / z 557 ( m + ), 528 ( m - c 2 h 5 ) + , 527 ( m - ch 2 o + ), 512 ( m - c 2 h 5 o ) + , 484 ( m - cooc 2 h 5 ) + , 408 ( c 23 h 22 no 6 ), 394 [( m - 163 ) + , ( m - c 10 h 11 o 2 ) + ], 366 ( 394 - co ) + , 320 [( 394 - hcooc 2 h 5 ) + , c 19 h 14 no 4 ], 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 no ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3258 cm − 1 ( phenolic — oh ), 1727 cm − 1 ( α β unsaturated ester , c ═ o ), 1714 cm − 1 ( aromatic ester , c ═ o ), 1599 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 0 . 99 , t , 3h , j ad = 6 . 6 hz ; b : 1 . 19 , t , 3h , j bf = 6 . 9 hz ; c : 1 . 29 , t , 3h , j cf = 6 . 8 hz ; d : 2 . 67 , q , 2h , j da = 7 . 1 hz ; e : 3 . 84 , s , 2h ; f : 4 . 27 , q , 4h , j = 6 . 7 hz ; g : 5 . 30 , s , 2h ; h : 5 . 90 , s , 2h ; i : 5 . 93 , s , 1h ; j : 6 . 88 , s , 1h ; k : 7 . 18 , d , 1h , j kl = 7 . 1 hz ; l : 7 . 26 , d , 1h , j lk = 9 . 0 hz ; m : 7 . 39 , t , 1h , j = 7 . 4 hz ; n : 7 . 53 , d , 1h , j nm = 8 . 8 hz ; o : 7 . 55 , s , 1h ; p : 7 . 76 , d , 1h , j pm = 6 . 8 hz ; q : 7 . 86 , s , 1h ; r : 9 . 97 ( exchangeable with d 2 o ), s , 1h . 13 c - nmr ( dmso - d 6 , δ ppm ): c 1 : 13 . 17 , c 2 : 14 . 13 , c 3 : 14 . 46 , c 4 : 24 . 41 , c 5 : 31 . 58 , c 6 : 50 . 50 , c 7 : 60 . 61 , c 8 : 62 . 75 , c 9 : 100 . 89 , c 10 : 105 . 15 , c 11 : 108 . 27 , c 12 : 108 . 79 , c 13 : 115 . 48 , c 14 : 119 . 24 , c 15 : 122 . 85 , c 16 : 126 . 08 , c 17 : 126 . 69 , c 18 : 126 . 75 , c 19 : 128 . 34 , c 20 : 128 . 86 , c 21 : 129 . 66 , c 22 : 132 . 94 , c 23 : 133 . 19 , c 24 : 133 . 99 , c 25 : 140 . 82 , c 26 : 143 . 90 , c 27 : 145 . 47 , c 28 : 146 . 52 , c 29 : 154 . 31 , c 30 : 163 . 14 , c 31 : 165 . 77 , c 32 : 174 . 99 . anal . : calc . for c 32 h 31 no 8 : c , 68 . 93 ; h , 5 . 60 ; n , 2 . 51 . found : c , 68 . 73 ; h , 5 . 68 ; n , 2 . 64 . sodium hydride dispersion ( 60 % in mineral oil ), 50 - 60 mg equivalent to 30 - 36 mg of nah ( 1 . 2 - 1 . 6 equiv .) was weighed and placed in the three - neck flask under nitrogen . mineral oil was washed out with 5 ml of hexane for three times followed by addition of 5 ml of dry dimethyl formamide ( dried over molecular sieves overnight ). three - neck flask was then kept in the ice - water bath . when the temperature of the reaction had reached 0 ° c ., 0 . 4 - 0 . 45 g ( 0 . 7181 mmol ) of ethyl 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 - hydroxy - 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate dissolved in 10 ml of dry dmf was added dropwise with stirring . after addition the ice - bath was removed and the reaction was allowed to stir at room temperature for 20 mins . appropriate alkyl halide , ˜ 1 . 4 equiv . in 15 ml of dry dmf was added drop wise at 0 ° c . followed by addition of ˜ 0 . 8 g of potassium carbonate to make ph 8 . reaction was stirred at room temperature for 4 hours and then poured into 75 ml of ice water . mixture was then transferred to the 250 ml separatory funnel and extracted with 50 ml of ethyl ether for three times . combined ether solution was then dried over magnesium sulfate , filtered and evaporated to get crude product . column chromatography of the crude product resulted in pure product in 79 - 92 % yield . product 1a , 0 . 45 g ( 0 . 808 mmol ) was reacted with iodoethane , 0 . 164 g ( 1 . 051 mmol ) in presence of 0 . 045 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 36 g ( 79 %) of the pure product , 1b . m . p . 124 - 126 ° c ., tlc ( 60 % hexane : 40 % etoac ) r f = 0 . 434 . ms : m / z 585 ( m + ), 528 ( m - c 2 h 5 ) + , 527 ( m - ch 2 o —), 512 ( m - c 2 h 5 o ) + , 484 ( m — cooc 2 h 5 ) + , 408 ( c 23 h 22 no 6 ), 394 [( m - 163 ) + , ( m - c 10 h 11 o 2 ) +], 366 ( 394 - co ) + , 320 [( 394 - hcooc 2 h 5 ) + , c 19 h 14 no 4 ], 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 o ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3019 cm − 1 ( alkyl ), 1732 cm − 1 ( α β unsaturated ester , c ═ o ), 1709 cm − 1 ( aromatic ester , c ═ o ), 1597 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 05 , t , 3h , j ad = 6 . 5 hz ; b : 1 . 27 , t , 3h , j bf = 6 . 7 hz ; c : 1 . 36 , t , 3h , j cg = 6 . 8 hz ; a : 1 . 42 , t , 3h , j ab = 6 . 8 hz ; d : 2 . 65 , q , 2h , j da = 7 . 4 hz ; e : 3 . 99 , s , 2h ; b : 4 . 13 , q , 2h , j ba = 6 . 8 hz ; f : 4 . 24 , q , 2h , j fb = 6 . 9 hz ; h : 5 . 19 , s , 2h ; i : 5 . 86 , s , 2h ; j : 6 . 21 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 08 , d , 1h , j lm = 9 . 0 hz ; m : 7 . 15 , dd , 1h , j ml = 9 . 4 hz ; n : 7 . 31 , t , 1h , j = 7 . 7 hz ; o : 7 . 60 , d , 1h , j on = 7 . 3 hz ; p : 7 . 83 , s , 1h ; q : 7 . 84 , d , 1h , j qn = 8 . 8 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 19 , c 2 : 14 . 54 , c 3 : 14 . 76 , c i : 14 . 90 , c 4 : 25 . 61 , c 5 : 32 . 51 , c 6 : 51 . 33 , c 7 : 60 . 94 , c 8 : 62 . 91 , c ii : 64 . 15 , c 9 : 1 . 25 , c 10 : 106 . 5 , c 11 : 106 . 72 , c 12 : 109 . 05 , c 13 : 117 . 82 , c 14 : 118 . 23 , c 15 : 124 . 20 , c 16 : 125 . 62 , c 17 : 127 . 44 , c 18 : 127 . 50 , c 19 : 128 . 44 , c 20 : 129 . 44 , c 21 : 130 . 45 , c 22 : 133 . 59 , c 23 : 134 . 69 , c 24 : 140 . 62 , c 25 : 144 . 16 , c 26 : 146 . 54 , c 27 : 147 . 46 , c 28 : 155 . 99 , c 29 : 163 . 99 , c 30 : 167 . 01 , c 31 : 176 . 72 . ethyl 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 6 - propoxy - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1c ( r = n -( c 3 h 7 , r ′═ c 2 h 5 , r ″═ h ) product 13 , 3 . 5 g ( 6 . 283 mmol ) was reacted with 1 - iodopropane , 1 . 6 g ( 8 . 95 mmol ) in presence of 0 . 35 g of 60 % w / w sodium hydride and 4 . 5 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 36 g ( 87 . 7 %) of the pure product , 14c . m . p . 134 - 135 ° c ., tlc ( 50 % hexane : 50 % etoac ) r f = 0 . 653 . ms : m / z 599 ( m + ), 571 [( m - c 2 h 4 ) + or ( m - co ) + ], 570 ( m - c 2 h 5 ) + , 554 [( m - 45 ), ( m - c 2 h 5 o ) + , 526 [( m - 73 ), ( m — cooc 2 h 5 ) + ], 436 [( m - 163 ), ( m - c 10 h 11 o 2 ) + , 408 ( c 23 h 22 no 6 ), 362 ( 436 - hcooc 2 h 5 ) + , 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 no ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 2965 cm − 1 ( alkyl ), 1738 cm − 1 ( α β unsaturated ester , c ═ o ), 1714 cm − 1 ( aromatic ester , c ═ o ), 1597 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 02 , t , 3h , j ab = 7 . 1 hz ; a : 1 . 05 , t , 3h , j ad = 7 . 1 hz ; b : 1 . 27 , t , 3h , j bf = 6 . 8 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 1 hz ; b : 1 . 81 , sextet , 2h , j = 6 . 9 hz ; d : 2 . 64 , q , 2h , j da = 7 . 4 hz ; e : 3 . 99 , s , 2h ; c , 4 . 02 , t , 2h , j cb = 6 . 5 hz ; f : 4 . 24 , q , 2h , j fb = 7 . 1 hz ; g : 4 . 34 , q , 2h , j gc = 7 . 1 hz ; h : 5 . 20 , s , 2h ; i : 5 . 86 , s , 2h ; j : 6 . 21 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 08 , d , 1h , j lm = 9 . 2 hz ; m : 7 . 15 , dd , 1h , j ml = 9 . 3 hz ; n : 7 . 32 , t , 1h , j = 7 . 6 hz ; o : 7 . 60 , d , 1h , j qn = 7 . 3 hz ; p : 7 . 83 , s , 1h ; q : 7 . 84 , d , 1h , j qn = 7 . 5 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 10 . 65 , c 1 : 13 . 68 , c 2 : 14 . 53 , c 3 : 14 . 75 , c ii : 22 . 59 , c 4 : 25 . 60 , c 5 : 32 . 50 , c 6 : 51 . 32 , c 7 : 60 . 94 , c 8 : 62 . 90 , c iii : 70 . 19 , c 9 : 101 . 23 , c 10 : 106 . 48 , c 11 : 106 . 75 , c 12 : 109 . 03 , c 13 : 117 . 79 , c 14 : 118 . 19 , c 15 : 124 . 17 , c 16 : 125 . 61 , c 17 : 127 . 42 , c 18 : 127 . 48 , c 19 : 128 . 44 , c 20 : 129 . 87 , c 21 : 130 . 43 , c 22 : 133 . 59 , c 23 : 134 . 63 , c 24 : 140 . 61 , c 25 : 144 . 13 , c 26 : 146 . 52 , c 27 : 147 . 44 , c 28 : 155 . 99 , c 29 : 163 . 98 , c 30 : 167 . 01 , c 31 : 176 . 71 . ethyl 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 - isopropoxy - 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1d ( r = i - c 3 h 7 , r ′═ c 2 h 5 , r ″═ c 2 h 2 ) product 1a , 0 . 45 g ( 0 . 808 mmol ) was reacted with 2 - iodopropane , 0 . 164 g ( 1 . 051 mmol ) in presence of 0 . 045 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 36 g ( 74 . 4 %) of the pure product , 1d . m . p . 124 - 126 ° c ., tlc ( 60 % hexane : 40 % etoac ) r f = 0 . 626 . ms : m / z 599 ( m + ), 570 ( m - c 2 h 5 ) + , 554 [( m - 45 ), ( m - c 2 h 5 o ) + , 526 [( m - 73 ), ( m - cooc 2 h 5 ) + ], 436 [( m - 163 ), ( m - c 10 h 11 o 2 ) + ], 408 ( c 23 h 22 no 6 ), 362 ( 436 - hcooc 2 h 5 ) + , 320 [( 362 - c 3 h 6 ) + , ( c 19 h 14 no 4 )], 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 no ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3019 cm − 1 ( alkyl ), 1731 cm − 1 ( α β unsaturated ester , c ═ o ), 1713 cm − 1 ( aromatic ester , c ═ o ), 1598 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 05 , t , 3h , j ad = 7 . 1 hz ; b : 1 . 27 , t , 3h , j bf = 7 . 5 hz ; a : 1 . 34 , d , 6h , j ab = 6 . 0 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 2 hz ; d : 2 . 64 , q , 2h , j da = 7 . 5 hz ; e : 3 . 99 , s , 2h ; f : 4 . 24 , q , 2h , j fb = 7 . 5 hz ; g : 4 . 34 , q , 2h , j gc = 7 . 1 hz ; b : 4 . 70 , septet , 1h , j ba = 6 . 0 hz ; h : 5 . 19 , s , 2h ; i : 5 . 86 , s , 2h ; j : 6 . 23 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 07 , d , 1h , j lm = 9 . 3 hz ; m : 7 . 11 , dd , 1h , j ml = 9 . 3 hz ; n : 7 . 32 , t , 1h , j = 7 . 7 hz ; o : 7 . 60 , d , 1h , j on = 7 . 7 hz ; p : 7 . 83 , s , 1h ; q : 7 . 85 , d , 1h , j qn = 6 . 6 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 68 , c 2 : 14 . 54 , c 3 : 14 . 75 , c i : 22 . 10 , c 4 : 25 . 60 , c 5 : 32 . 52 , c 6 : 51 . 31 , c 7 : 60 . 94 , c 8 : 62 . 90 , c ii : 70 . 51 , c 9 : 101 . 24 , c 10 : 106 . 53 , c 11 : 107 . 98 , c 12 : 109 . 04 , c 13 : 117 . 74 , c 14 : 118 . 29 , c 15 : 125 . 06 , c 16 : 125 . 65 , c 17 : 127 . 46 , c 18 : 127 . 49 , c 19 : 128 . 44 , c 20 : 129 . 87 , c 21 : 130 . 46 , c 22 : 133 . 59 , c 23 : 134 . 54 , c 24 : 140 . 65 , c 25 : 144 . 15 , c 26 : 146 . 54 , c 27 : 147 . 45 , c 28 : 155 . 97 , c 29 : 164 . 0 , c 30 : 167 . 02 , c 31 : 176 . 69 . ethyl 6 -( allyloxy )- 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1e , ( r ═ h 2 c ═ ch —, r ′═ c 2 h 5 , r ″═ c 2 h 5 h ) product 1a , 0 . 40 g ( 0 . 718 mmol ) was reacted with allyliodide , 0 . 181 g ( 1 . 081 mmol ) in presence of 0 . 045 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 36 g ( 90 . 0 %) of the pure product , 1e . m . p . 128 - 131 ° c ., tlc ( 60 % hexane : 40 % etoac ) r f = 0 . 645 . ms : m / z 597 ( m + ), 568 ( m - c 2 h 5 ) + , 552 [( m - 45 ), ( m - c 2 h 5 o ′) + , 524 [( m - 73 ), ( m - cooc 2 h 5 ) + ], 434 [( m - 163 ), ( m - c 10 h 11 o 2 ) + ], 408 ( c 23 h 22 no 6 ), 388 ( 434 - c 2 h 5 oh ), 360 ( 434 - hcooc 2 h 5 ) + , 288 ( c 19 h 14 no 2 ), 248 ( c 16 h 10 o 2 ), 163 ( base peak , c 10 h 11 o 2 , + ch 2 c 6 h 4 cooc 2 h 5 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3018 cm − 1 ( alkyl ), 1735 cm − 1 ( α β unsaturated ester , c ═ o ), 1711 cm − 1 ( aromatic ester , c ═ o ), 1597 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 05 , t , 3h , j ad = 7 . 1 hz ; b : 1 . 27 , t , 3h , j bf = 7 . 5 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 2 hz ; d : 2 . 64 , q , 2h , j da = 7 . 5 hz ; e : 3 . 99 , s , 2h ; f : 4 . 24 , q , 2h , j fb = 7 . 5 hz ; g : 4 . 34 , q , 2h , j gc = 7 . 1 hz ; a : 4 . 62 , d , 2h , j ad = 3 . 8 hz ; h : 5 . 19 , s , 2h ; b : 5 . 29 , d , 1h , j bd = 17 . 3 hz ; c , 5 . 42 , d , 1h , j cd = 17 . 3 hz ; i : 5 . 86 , s , 2h ; d : 6 . 05 , octet , 1h , j = 5 . 3 hz ; j : 6 . 22 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 09 , d , 1h , j lm = 9 . 3 hz ; m : 7 . 19 , dd , 1h , j ml = 9 . 3 hz ; n : 7 . 32 , t , 1h , j = 7 . 6 hz ; o : 7 . 60 , d , 1h , j on = 7 . 3 hz ; p : 7 . 84 , s , 1h ; q : 7 . 85 , d , 1h , j qn = 6 . 6 hz ; r : 8 . 00 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 66 , c 2 : 14 . 52 , c 3 : 14 . 74 , c 4 : 25 . 58 , c 5 : 32 . 47 , c 6 : 51 . 34 , c 7 : 60 . 93 , c 8 : 62 . 91 , c i : 69 . 32 , c 9 : 101 . 23 , c 10 : 106 . 44 , c 11 : 107 . 12 , c 12 : 109 . 03 , c 13 : 117 . 84 , c 14 : 118 . 30 , c ii : 118 . 32 , c 15 : 124 . 18 , c 16 : 125 . 52 , c 17 : 127 . 34 , c 18 : 127 . 48 , c 19 : 128 . 42 , c 20 : 129 . 83 , c 21 : 130 . 41 , c iii : 132 . 86 , c 22 : 133 . 55 , c 23 : 133 . 59 , c 24 : 134 . 84 , c 25 : 140 . 54 , c 26 : 144 . 21 , c 27 : 146 . 51 , c 28 : 147 . 44 , c 29 : 155 . 55 , c 30 : 163 . 92 , c 31 : 166 . 98 , c 32 : 176 . 65 . 879 ethyl 6 - butoxy - 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1 g : ( r = n - c 4 h 9 , r ′═ c 2 h 5 , r ″═ c 2 h 5 ) product 1a , 0 . 40 g ( 0 . 718 mmol ) was reacted with 1 - iodobutane , 0 . 182 g ( 1 . 081 mmol ) in presence of 0 . 045 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 36 g ( 90 . 0 %) of the pure product , 1 g . m . p . 147 - 150 ° c ., tlc ( 60 % hexane : 40 % etoac ) r f = 0 . 632 . ms : m / z 613 ( m + ), 568 [( m - 45 ), ( m - c 2 h 5 o ) + ], 540 [( m - 73 ), ( m - cooc 2 h 5 ) + ], 450 [( m - 163 ), ( m - c 10 h 11 o 2 ) + ], 422 [( 450 - 28 ), ( m - co ) + , ( c 23 h 22 no 6 )], 376 ( 436 - hcooc 2 h 5 ) + , 320 [( 362 - c 3 h 6 ) + , ( c 19 h 14 no 4 )], 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 o ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3019 cm − 1 ( alkyl ), 1732 cm − 1 ( α β unsaturated ester , c ═ o ), 1711 cm − 1 ( aromatic ester , c ═ o ), 1597 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 0 . 96 , t , 3h , j ab = 7 . 4 hz ; a : 1 . 05 , t , 3h , j ad = 7 . 1 hz ; b : 1 . 27 , t , 3h , j bf = 7 . 5 hz ; b : 1 . 34 , sextet , 2h , j = 7 . 5 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 2 hz ; c , 1 . 34 , quintet , 2h , j = 7 . 7 hz ; d : 2 . 64 , q , 2h , j da = 7 . 5 hz ; e : 3 . 99 , s , 2h ; d : 4 . 06 , t , 2h , j dc = 6 . 0 hz ; f : 4 . 23 , q , 2h , j fb = 7 . 2 hz ; g : 4 . 34 , q , 2h , j gc = 7 . 1 hz ; h : 5 . 19 , s , 2h ; i : 5 . 86 , s , 2h ; j : 6 . 21 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 07 , d , 1h , j = 9 . 4 hz ; m : 7 . 11 , dd , 1h , j ml = 9 . 3 hz ; n : 7 . 32 , t , 1h , j = 7 . 7 hz ; o : 7 . 60 , d , 1h , j on = 7 . 7 hz ; p : 7 . 83 , s , 1h ; q : 7 . 84 , d , 1h , j qn = 6 . 3 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 68 , c i : 13 . 98 , c 2 : 14 . 54 , c 3 : 14 . 76 , c ii : 19 . 40 , c 4 : 25 . 61 , c iii : 31 . 32 , c 5 : 32 . 52 , c 6 : 51 . 33 , c 7 : 60 . 94 , c 8 : 62 . 90 , c iv : 68 . 42 , c 9 : 101 . 24 , c 10 : 106 . 51 , c 11 : 106 . 76 , c 12 : 109 . 04 , c 13 : 117 . 82 , c 14 : 118 . 19 , c 15 : 125 . 06 , c 16 : 125 . 64 , c 17 : 127 . 45 , c 18 : 127 . 49 , c 19 : 128 . 44 , c 20 : 129 . 88 , c 21 : 130 . 45 , c 22 : 133 . 59 , c 23 : 134 . 65 , c 24 : 140 . 64 , c 25 : 144 . 14 , c 26 : 146 . 55 , c 27 : 147 . 46 , c 28 : 155 . 21 , c 29 : 163 . 99 , c 30 : 167 . 01 , c 31 : 176 . 72 . ethyl 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 - isobutoxy - 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1 h : ( r = i - c 4 h 9 , r ′═ c 2 h 5 , r ″═ c 2 h 5 ) product 1a , 0 . 40 g ( 0 . 718 mmol ) was reacted with 2 - methyl - 1 - iodopropane , 0 . 182 g ( 1 . 081 mmol ) in presence of 0 . 045 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 33 g ( 81 . 3 %) of the pure product , 1 h . m . p . 129 - 132 ° c ., tlc ( 50 % hexane : 50 % etoac ) r f = 0 . 722 . ms : m / z 613 ( m + ), 568 [( m - 45 ), ( m - c 2 h 5 o ) + ], 540 [( m - 73 ), ( m - cooc 2 h 5 ) + ], 450 [( m - 163 ), ( m - c 10 h 11 o 2 ) + ], 422 [( 450 - 28 ), ( m - co ) + , ( c 23 h 22 no 6 )], 376 ( 436 - hcooc 2 h 5 ) + , 320 [( 362 - c 3 h 6 ) + , ( c 19 h 14 no 4 )], 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 no ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3019 and 2978 cm − 1 ( alkyl ), 1731 cm − 1 ( α β unsaturated ester , c ═ o ), 1717 cm − 1 ( aromatic ester , c ═ o ), 1596 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 0 . 95 , t , 3h , j ab = 7 . 4 hz ; a : 1 . 05 , t , 3h , j ad = 7 . 1 hz ; b : 1 . 27 , t , 3h , j bf = 7 . 4 hz ; b : 1 . 30 , d , 3h , j be = 6 . 1 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 2 hz ; c , 1 . 63 , octet , 1h , j = 6 . 8 hz ; d : 1 . 34 , octet , 1h , j = 7 . 1 hz ; d : 2 . 65 , q , 2h , j da = 7 . 4 hz ; e : 3 . 99 , s , 2h ; f : 4 . 24 , q , 2h , j fb = 7 . 1 hz ; g : 4 . 34 , q , 2h , j gc = 6 . 9 hz ; e : 4 . 46 , sextet , 1h , j = 6 . 0 hz ; h : 5 . 19 , s , 2h ; i : 5 . 86 , s , 2h ; j : 6 . 24 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 07 , d , 1h , j lm = 9 . 3 hz ; m : 7 . 11 , dd , 1h , j ml = 9 . 3 hz ; n : 7 . 32 , t , 1h , j = 7 . 7 hz ; o : 7 . 60 , d , 1h , j on = 7 . 4 hz ; p : 7 . 83 , s , 1h ; q : 7 . 84 , d , 1h , j qn = 6 . 5 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c i : 9 . 96 , c 1 : 13 . 69 , c 2 : 14 . 54 , c 3 : 14 . 76 , c ii : 19 . 28 , c 4 : 25 . 60 , c iii : 29 . 25 , c 5 : 32 . 53 , c 6 : 51 . 31 , c 7 : 60 . 94 , c 8 : 62 . 90 , c iv : 75 . 62 , c 9 : 101 . 24 , c 10 : 106 . 53 , c 11 : 107 . 94 , c 12 : 109 . 03 , c 13 : 117 . 69 , c 14 : 118 . 29 , c 15 : 125 . 05 , c 16 : 125 . 64 , c 17 : 127 . 44 , c 18 : 127 . 48 , c 19 : 128 . 44 , c 20 : 129 . 88 , c 21 : 130 . 43 , c 22 : 133 . 58 , c 23 : 134 . 48 , c 24 : 140 . 64 , c 25 : 144 . 13 , c 26 : 146 . 52 , c 27 : 147 . 43 , c 28 : 155 . 30 , c 29 : 164 . 00 , c 30 : 167 . 01 , c 31 : 176 . 69 . ethyl 6 - sec - butoxy - 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1i : ( r = sec - c 4 h 9 , r ′═ c 2 h 5 , r ″═ c 2 h 5 ) product 1a , 0 . 40 g ( 0 . 718 mmol ) was reacted with 2 - iodobutane , 0 . 182 g ( 1 . 081 mmol ) in presence of 0 . 045 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 37 g ( 92 . 5 %) of the pure product , 1i . m . p . 129 - 132 ° c ., tlc ( 60 % hexane : 40 % etoac ) r f = 0 . 600 . ms : m / z 613 ( m + ), 568 [( m - 45 ), ( m - c 2 h 5 o ) + ], 540 [( m - 73 ), ( m - cooc 2 h 5 ) + ], 450 [( m - 163 ), ( m - c 10 h 11 o 2 ) + ], 422 [( 450 - 28 ), ( m - co ) + , ( c 23 h 22 no 6 )], 376 ( 436 - hcooc 2 h 5 ) + , 320 [( 362 - c 3 h 6 ) + , ( c 19 h 14 no 4 )], 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 o ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3019 and 2966 cm − 1 ( alkyl ), 1733 cm − 1 ( α β unsaturated ester , c ═ o ), 1718 cm − 1 ( aromatic ester , c ═ o ), 1597 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 00 , d , 6h , j ab = 6 . 8 hz ; a : 1 . 05 , t , 3h , j ad = 7 . 1 hz ; b : 1 . 27 , t , 3h , j bf = 7 . 5 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 1 hz ; b : 2 . 11 , nonet , 1h , j = 6 . 7 hz ; d : 2 . 65 , q , 2h , j da = 7 . 5 hz ; c , 3 . 82 , d , 2h , j = 6 . 6 hz ; e : 3 . 99 , s , 2h ; f : 4 . 24 , q , 2h , j fb = 7 . 1 hz ; g : 4 . 34 , q , 2h , j gc = 7 . 1 hz ; h : 5 . 19 , s , 2h ; i : 5 . 85 , s , 2h ; j : 6 . 21 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 08 , d , 1h , j lm = 9 . 4 hz ; m : 7 . 11 , dd , 1h , j ml = 9 . 3 hz ; n : 7 . 31 , t , 1h , j = 7 . 7 hz ; o : 7 . 60 , d , 1h , j qn = 7 . 6 hz ; p : 7 . 82 , s , 1h ; q : 7 . 84 , d , 1h , j qn = 8 . 9 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 70 , c 2 : 14 . 55 , c 3 : 14 . 78 , c i : 19 . 41 , c 4 : 25 . 60 , c ii : 28 . 31 , c 5 : 32 . 53 , c 6 : 51 . 33 , c 7 : 60 . 96 , c 8 : 62 . 92 , c iii : 75 . 11 , c 9 : 101 . 25 , c 10 : 106 . 52 , c 11 : 106 . 82 , c 12 : 109 . 05 , c 13 : 117 . 83 , c 14 : 118 . 19 , c 15 : 124 . 19 , c 16 : 125 . 65 , c 17 : 127 . 45 , c 18 : 127 . 50 , c 19 : 128 . 45 , c 20 : 129 . 90 , c 21 : 130 . 45 , c 22 : 133 . 62 , c 23 : 134 . 63 , c 24 : 140 . 65 , c 25 : 144 . 14 , c 26 : 146 . 56 , c 27 : 147 . 47 , c 28 : 155 . 32 , c 29 : 164 . 01 , c 30 : 167 . 04 , c 31 : 176 . 74 . ethyl 6 -( cyclopropylmethoxy )- 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1j : ( r = cyclo - c 3 h 5 ch 2 , r ′═ c 2 h 5 , r ″═ c 2 h 5 ) product 1a , 0 . 40 g ( 0 . 718 mmol ) was reacted with 2 - iodobutane , 0 . 182 g ( 1 . 081 mmol ) in presence of 0 . 045 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 37 g ( 81 %) of the pure product , 1j . m . p . 129 - 132 ° c ., tlc ( 60 % hexane : 40 % etoac ) r f = 0 . 54 . ms : m / z 613 ( m + ), 568 [( m - 45 ), ( m - c 2 h 5 o ) + ], 540 [( m - 73 ), ( m - cooc 2 h 5 ) + ], 450 [( m - 163 ), ( m - c 10 h 11 o 2 ) + ], 422 [( 450 - 28 ), ( m - co ) + , ( c 23 h 22 no 6 )], 376 ( 436 - hcooc 2 h 5 ) + , 320 [( 362 - c 3 h 6 ) + , ( c 19 h 14 no 4 )], 248 ( c 16 h 22 no 2 ), 220 [( 248 - co ) + , c 15 h 10 no ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3019 and 2966 cm − 1 ( alkyl ), 1733 cm − 1 ( α β unsaturated ester , c ═ o ), 1718 cm − 1 ( aromatic ester , c ═ o ), 1597 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 0 . 33 , d , 2h , j ab = 4 . 4 hz ; b : 0 . 56 , d , 2h , j ba = 7 . 8 hz ; a : 1 . 05 , t , 3h , j ad = 7 . 1 hz ; c , 1 . 20 , t , 1h , j = 7 . 4 hz ; b : 1 . 27 , t , 3h , j bf = 7 . 5 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 1 hz ; b : 2 . 11 , nonet , 1h , j = 6 . 7 hz ; d : 2 . 65 , q , 2h , j da = 7 . 5 hz ; c , 3 . 82 , d , 2h , j = 6 . 6 hz ; e : 3 . 99 , s , 2h ; f : 4 . 24 , q , 2h , j fb = 7 . 1 hz ; g : 4 . 34 , q , 2h , j gc = 7 . 1 hz ; h : 5 . 19 , s , 2h ; i : 5 . 85 , s , 2h ; j : 6 . 21 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 08 , d , 1h , j lm = 9 . 4 hz ; m : 7 . 11 , dd , 1h , j ml = 9 . 3 hz ; n : 7 . 31 , t , 1h , j = 7 . 7 hz ; o : 7 . 60 , d , 1h , j on = 7 . 6 hz ; p : 7 . 82 , s , 1h ; q : 7 . 84 , d , 1h , j qn = 8 . 9 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c i : 3 . 12 , c ii : 10 . 00 , c 1 : 13 . 70 ; c 2 : 14 . 55 , c 3 : 14 . 78 , c 4 : 25 . 60 , c 5 : 32 . 53 , c 6 : 51 . 33 , c 7 : 60 . 96 , c 8 : 62 . 92 , c iii : 72 . 40 , c iii : 72 . 40 , c 9 : 101 . 25 , c 10 : 106 . 52 , c 11 : 106 . 82 , c 12 : 109 . 05 , c 13 : 117 . 83 , c 14 : 118 . 19 , c 15 : 124 . 19 , c 16 : 125 . 65 , c 17 : 127 . 45 , c 18 : 127 . 50 , c 19 : 128 . 45 , c 20 : 129 . 90 , c 21 : 130 . 45 , c 22 : 133 . 62 , c 23 : 134 . 63 , c 24 : 140 . 65 , c 25 : 144 . 14 , c 26 : 146 . 56 , c 27 : 147 . 47 , c 28 : 155 . 32 , c 29 : 164 . 01 , c 30 : 167 . 04 , c 31 : 176 . 74 . ethyl 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 6 -( pentyloxy )- 1 , 4 - dihydroquinoline - 2 - carboxylate , 1k : ( r = n - c 5 h 11 , r ′═ c 2 h 5 , r ″═ c 2 h 5 ) product 1k , 0 . 40 g ( 0 . 718 mmol ) was reacted with 1 - iodopentane , 0 . 214 g ( 1 . 081 mmol ) in presence of 0 . 055 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 38 g ( 84 . 4 %) of the pure product , 1k . m . p . 98 - 99 ° c ., tlc ( 70 % hexane : 30 % etoac ) r f = 0 . 555 . ms : m / z 627 ( m + ), 582 [( m - 45 ), ( m - c 2 h 5 o ) + ], 554 [( m - 73 ), ( m - cooc 2 h 5 ) + ], 464 [( m - 163 ), ( m - c 10 h 11 o 2 ) + ], 436 [( 464 - 28 ), ( m - co ) + ], 390 ( 464 - hcooc 2 h 5 ) + 320 -[( 362 - c 5 h 10 ) + c 19 h 14 no 4 )], 376 ( 436 - hcooc 2 h 5 ) + , 320 [( 362 - c 3 h 6 ) + , ( c 19 h 14 no 4 )], 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 no ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3019 cm − 1 ( alkyl ), 1732 cm − 1 ( α β unsaturated ester , c ═ o ), 1713 cm − 1 ( aromatic ester , c ═ o ), 1597 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 0 . 91 , t , 3h , j ab = 6 . 0 hz ; a : 1 . 05 , t , 3h , j ad = 6 . 0 hz ; b : 1 . 27 , t , 3h , j bf = 6 . 2 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 2 hz ; b : 1 . 38 , m , 4h , j = 5 . 5 hz ; c , 1 . 79 , quintet , 2h , j = 6 . 7 hz ; d : 2 . 64 , q , 2h , j da = 6 . 7 hz ; e : 3 . 99 , s , 2h ; d : 4 . 05 , t , 2h , j dc = 5 . 5 hz ; f : 4 . 23 , q , 2h , j fb = 6 . 1 hz ; g : 4 . 34 , q , 2h , j gc = 6 . 0 hz ; h : 5 . 19 , s , 2h ; i : 5 . 86 , s , 2h ; j : 6 . 21 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 07 , d , 1h , j lm = 8 . 8 hz ; m : 7 . 15 , dd , 1h , j ml = 8 . 5 hz ; n : 7 . 31 , t , 1h , j = 6 . 9 hz ; o : 7 . 60 , d , 1h , j on = 6 . 6 hz ; p : 7 . 83 , s , 1h ; q : 7 . 84 , d , 1h , j qn = 6 . 3 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 68 , c i : 14 . 19 , c 2 : 14 . 53 , c 3 : 14 . 75 , c ii : 22 . 59 , c 4 : 25 . 60 , c iii : 28 . 32 , c iv : 28 . 96 , c 5 : 32 . 51 , c 6 : 51 . 32 , c 7 : 60 . 94 , c 8 : 62 . 91 , c v : 68 . 69 , c 9 : 101 . 24 , c 10 : 106 . 49 , c 11 : 106 . 71 , c 12 : 109 . 03 , c 13 : 117 . 80 , c 14 : 118 . 20 , c 15 : 124 . 19 , c 16 : 125 . 61 , c 17 : 127 . 43 , c 18 : 127 . 49 , c 19 : 128 . 44 , c 20 : 129 . 87 , c 21 : 130 . 43 , c 22 : 133 . 59 , c 23 : 134 . 63 , c 24 : 140 . 62 , c 25 : 144 . 12 , c 26 : 146 . 52 , c 27 : 147 . 44 , c 28 : 155 . 20 , c 29 : 163 . 61 , c 30 : 167 . 01 , c 31 : 176 . 72 . ethyl 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 -( 3 - hydroxypropoxy )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1l : ( r ═ ho — c 3 h 6 —, r ′═ c 2 h 5 , r ″═ c 2 h 5 ) product 1a , 0 . 40 g ( 0 . 718 mmol ) was reacted with 1 - iodopropan - 3 - ol , 0 . 20 g ( 1 . 081 mmol ) in presence of 0 . 045 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 60 % hexane : 40 % etoac ) of the crude product resulted in 0 . 36 g ( 81 . 8 %) of the pure product , 1l . m . p . 129 - 132 ° c ., tlc ( 60 % hexane : 40 % etoac ) r f = 0 . 546 . ms : m / z 615 ( m + ), 597 [( m - 18 ), (— h 2 o ) + ], 587 [( m - c 2 h 4 ) + or ( m - co ) + ], 586 ( m - c 2 h 5 ) + , 570 [( m - 45 ), ( m - c 2 h 5 o ) + , 532 [( m - 73 ), ( m - cooc 2 h 5 ) + ], 452 [( m - 163 ), ( m - c 10 h 11 o 2 ) + , 408 ( c 23 h 22 no 6 ), 378 ( 452 - hcooc 2 h 5 ) + , 248 ( c 16 h 10 no 2 ), 220 [( 248 - co ) + , c 15 h 10 no ], 163 ( base peak , + ch 2 c 6 h 4 cooc 2 h 5 , c 10 h 11 o 2 ), 133 [( 163 - ch 2 o ) + , c 9 h 9 o ], 105 [( 133 - co ) or 133 - c 2 h 4 ) + , c 7 h 5 o ], 91 c 7 h 7 + , 79 c 6 h 7 + , 77 c 6 h 5 + , 55 c 4 h 7 + . ir : 3019 cm − 1 ( alkyl ), 1733 cm − 1 ( α β unsaturated ester , c ═ o ), 1713 cm − 1 ( aromatic ester , c ═ o ), 1598 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 05 , t , 3h , j ad = 6 . 9 hz ; b : 1 . 27 , t , 3h , j bf = 7 . 1 hz ; c : 1 . 36 , t , 3h , j cg = 6 . 9 hz ; a : 1 . 94 , bs , 1h ; b : 2 . 06 , quintet , 2h , j = 6 . 1 hz ; d : 2 . 64 , q , 2h , j da = 7 . 4 hz ; c , 3 . 84 , t , 2h , j = 6 . 5 hz ; e : 3 . 99 , s , 2h ; d : 4 . 22 , t , 2h , j db = 5 . 0 hz ; f : 4 . 24 , q , 2h , j fb = 7 . 0 hz ; g : 4 . 34 , q , 2h , j gc = 7 . 0 hz ; h : 5 . 20 , s , 2h ; i : 5 . 86 , s , 2h ; j : 6 . 20 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 08 , d , 1h , j lm = 9 . 2 hz ; m : 7 . 14 , d , 1h , j ml = 9 . 3 hz ; n : 7 . 31 , t , 1h , j = 7 . 6 hz ; o : 7 . 59 , d , 1h , j on = 7 . 5 hz ; p : 7 . 83 , d , 1h , j pn = 8 . 0 hz ; q : 7 . 84 , s , 1h ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 69 , c 2 : 14 . 54 , c 3 : 14 . 77 , c 4 : 25 . 61 , c i : 32 . 08 , c 5 : 32 . 48 , c 6 : 51 . 35 , c 7 : 60 . 46 , c ii : 60 . 96 , c 8 : 62 . 90 , c iii : 66 . 32 , c 9 : 101 . 26 , c 10 : 106 . 46 , c 11 : 107 . 00 , c 12 : 109 . 06 , c 13 : 117 . 90 , c 14 : 118 . 32 , c 15 : 124 . 02 , c 16 : 125 . 55 , c 17 : 127 . 40 , c 18 : 127 . 51 , c 19 : 128 . 45 , c 20 : 129 . 87 , c 21 : 130 . 45 , c 22 : 133 . 58 , c 23 : 133 . 62 , c 24 : 134 . 84 , c 25 : 140 . 57 , c 26 : 144 . 26 , c 27 : 146 . 55 , c 28 : 147 . 48 , c 29 : 155 . 82 , c 30 : 163 . 94 , c 31 : 167 . 01 , c 32 : 176 . 70 . ethyl 6 -( 2 - ethoxy - 2 - oxoethoxy )- 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoine - 2 - carboxylate 1m : ( r ═ c 2 h 5 oc ( o ) ch 2 , r ′═ c 2 h 5 , r ″═ c 2 h 5 ) product 1a , 0 . 40 g ( 0 . 718 mmol ) was reacted with bromoethylacetate , 0 . 18 g ( 1 . 077 mmol ) in presence of 0 . 055 g of 60 % w / w sodium hydride and 0 . 8 g of potassium carbonate for 4 hours . column chromatography ( 50 % hexane : 50 % etoac ) of the crude product resulted in 0 . 32 g ( 70 . 0 %) of the pure product , 1m . m . p . 129 - 132 ° c ., tlc ( 50 % hexane : 50 % etoac ) r f = 0 . 660 . ir : 3019 cm − 1 ( alkyl ), 1733 cm − 1 ( α β unsaturated ester , c ═ o ), 1713 cm − 1 ( aromatic ester , c ═ o ), 1598 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( cdcl 3 , δ ppm ): a : 1 . 05 , t , 3h , j ad = 7 . 0 hz ; b : 1 . 27 , t , 3h , j bf = 7 . 4 hz ; a : 1 . 30 , t , 3h , j ab = 7 . 3 hz ; c : 1 . 36 , t , 3h , j cg = 7 . 1 hz ; d : 2 . 64 , q , 2h , j da = 7 . 4 hz ; e : 3 . 99 , s , 2h ; f : 4 . 24 , q , 2h , j fb = 7 . 2 hz ; b : 4 . 26 , q , 2h , j ba = 7 . 1 hz ; g : 4 . 34 , q , 2h , j gc = 7 . 1 hz ; c , 4 . 71 , s , 2h ; h : 5 . 20 , s , 2h ; i : 5 . 87 , s , 2h ; j : 6 . 20 , s , 1h ; k : 6 . 74 , s , 1h ; l : 7 . 12 , d , 1h , j lm = 9 . 4 hz ; m : 7 . 14 , d , 1h , j ml = 7 . 7 hz ; n : 7 . 32 , t , 1h , j = 7 . 7 hz ; o : 7 . 58 , d , 1h , j on = 7 . 5 hz ; p : 7 . 78 , s , 1h ; q : 7 . 84 , d , 1h , j qn = 7 . 5 hz ; r : 7 . 99 , s , 1h . 13 c - nmr ( cdcl 3 , δ ppm ): c 1 : 13 . 67 , c i : 14 . 33 , c 2 : 14 . 54 , c 3 : 14 . 75 , c 4 : 25 . 60 , c 5 : 32 . 47 , c 6 : 51 . 40 , c 7 : 60 . 94 , c ii : 61 . 67 , c 8 : 62 . 90 , c iii : 65 . 54 , c 9 : 101 . 26 , c 10 : 106 . 45 , c 11 : 107 . 04 , c 12 : 109 . 07 , c 13 : 118 . 06 , c 14 : 118 . 61 , c 15 : 124 . 23 , c 16 : 125 . 41 , c 17 : 127 . 22 , c 18 : 127 . 53 , c 19 : 128 . 45 , c 20 : 129 . 83 , c 21 : 130 . 47 , c 22 : 133 . 51 , c 23 : 133 . 60 , c 24 : 135 . 40 , c 25 : 140 . 45 , c 26 : 144 . 40 , c 27 : 146 . 56 , c 28 : 147 . 51 , c 29 : 154 . 80 , c 30 : 163 . 85 , c 31 : 166 . 97 , c iv : 168 . 53 , c 32 : 176 . 70 . in a solution of adequate 1 , 3 , 6 - trisubstituted - 2 - ethylcarboxylate - quinol - 4 - ones ( 1a - m ) in an aqueous ethanol ( 85 %), add six equivalents of 6n koh and reflux overnight . reaction was monitored by tlc and on completion solvent was evaporated on rotary evaporation . the residue was dissolved in minimum amount of water and solution acidified with equal amount of 1 . 0 n hcl to get precipitate . precipitate filtered under vacuum , washed thoroughly with water and allowed to dry . recrystallization from methanol - water resulted in analytically pure compounds with sharp melting point . recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 36 g ( 80 . 0 %) of pure product . ir : 3506 cm − 1 ( carboxylic acid — oh ), 3258 cm − 1 ( phenolic — oh ), 1693 cm − 1 ( α β unsaturated acid , c ═ o ), 1693 cm − 1 ( aromatic acid , c ═ o ), 1587 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 1 . 19 , t , 3h , j ab = 7 . 6 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 3 hz ; c : 3 . 86 , s , 2h ; d : 5 . 37 , s , 2h ; e : 5 . 89 , s , 1h ; f : 5 . 93 , s , 1h ; g : 6 . 86 , s , 1h ; h : 7 . 14 , dd , 1h , j hi = 9 . 3 hz ; i : 7 . 21 , d , 1h , j ih = 9 . 1 hz ; j : 7 . 35 , t , 1h , j = 7 . 7 hz ; k : 7 . 52 , d , 1h , j kj = 6 . 3 hz ; l : 7 . 53 , s , 1h ; m : 7 . 72 , d , 1h , j mj = 7 . 6 hz ; n : 7 . 87 , s , 1h ; a : 9 . 91 ( exchangeable with d 2 o ), s , 1h ; o : 12 . 83 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c 1 : 14 . 63 , c 2 : 24 . 55 , c 3 : 32 . 02 , c 4 : 50 . 32 , c 5 : 100 . 89 , c 6 : 105 . 21 , c 7 : 108 . 27 , c 8 : 108 . 89 , c 9 : 114 . 23 , c 10 : 119 . 20 , c 11 : 122 . 59 , c 12 : 126 . 28 , c 13 : 126 . 72 , c 14 : 126 . 80 , c 15 : 128 . 09 , c 16 : 129 . 34 , c 17 : 130 . 46 , c 18 : 132 . 81 , c 19 : 132 . 86 , c 20 : 133 . 96 , c 21 : 140 . 88 , c 22 : 145 . 50 , c 23 : 145 . 99 , c 24 : 146 . 49 , c 25 : 154 . 12 , c 26 : 164 . 98 , c 27 : 167 . 45 , c 28 : 175 . 06 . anal . : calc . for c 28 h 23 no 8 . ½h 2 o : c , 65 . 88 ; h , 4 . 70 ; n , 2 . 74 . found : c , 65 . 79 ; h , 4 . 66 ; n , 2 . 89 . recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 22 g ( 81 . 0 %) of pure product . ir : 3426 cm − 1 ( carboxylic acid — oh ), 1682 cm − 1 ( α β unsaturated acid , c ═ o ), 1682 cm − 1 ( aromatic acid , c ═ o ), 1589 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 1 . 20 , t , 3h , j ab = 7 . 3 hz ; a : 1 . 34 , t , 3h , j ab = 6 . 7 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 4 hz ; c : 3 . 88 , s , 2h ; b : 4 . 09 , q , 2h , j ba = 6 . 8 hz ; d : 5 . 41 , s , 2h ; e : 5 . 89 , s , 1h ; f : 5 . 91 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 14 , d , 2h ; i : 7 . 36 , t , 1h , j = 7 . 7 hz ; j : 7 . 54 , d , 1h , j ji = 7 . 5 hz ; k : 7 . 60 , s , 1h ; l : 7 . 72 , d , 1h , j lj = 7 . 4 hz ; m : 7 . 89 , s , 1h ; n : 12 . 84 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c i : 14 . 53 , c 1 : 14 . 61 , c 2 : 24 . 55 , c 3 : 32 . 06 , c 4 : 50 . 39 , c ii : 63 . 44 , c 5 : 100 . 89 , c 6 : 105 . 15 , c 7 : 105 . 82 , c 8 : 108 . 92 , c 9 : 114 . 85 , c 10 : 119 . 38 , c 11 : 122 . 98 , c 12 : 126 . 16 , c 13 : 126 . 39 , c 14 : 126 . 83 , c 15 : 128 . 09 , c 16 : 129 . 30 , c 17 : 130 . 46 , c 18 : 132 . 91 , c 19 : 133 . 80 , c 20 : 133 . 99 , c 21 : 140 . 73 , c 22 : 145 . 51 , c 23 : 146 . 06 , c 24 : 146 . 52 , c 25 : 154 . 12 , c 26 : 164 . 89 , c 27 : 167 . 44 , c 28 : 175 . 01 . 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 6 - propoxy - 1 , 4 - dihydroquinoline - 2 - carboxylic acid , 1p : ( r = n - c 3 h 7 , r ′═ c 2 h 5 , r ″═ h ): recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 14 g ( 70 . 0 %) of pure product . ir : 3426 cm − 1 ( carboxylic acid — oh ), 1685 cm − 1 ( α β unsaturated acid , c ═ o ), 1685 cm − 1 ( aromatic acid , c ═ o ), 1589 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 0 . 97 , t , 3h , j ab = 7 . 4 hz ; a : 1 . 20 , t , 3h , j ab = 7 . 5 hz ; b : 1 . 74 , sextet , 2h , j = 6 . 9 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 4 hz ; c : 3 . 88 , s , 2h ; c , 3 . 99 , t , 2h , j cb = 6 . 4 hz ; d : 5 . 41 , s , 2h ; e : 5 . 89 , s , 1h ; f : 5 . 91 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 28 , d , 2h ; i : 7 . 36 , t , 1h , j = 7 . 6 hz ; j : 7 . 54 , d , 1h , j ji = 7 . 5 hz ; k : 7 . 60 , s , 1h ; l : 7 . 73 , d , 1h , j lj = 7 . 6 hz ; m : 7 . 89 , s , 1h ; n : 12 . 86 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c i : 10 . 34 , c 1 : 14 . 62 , c ii : 21 . 90 , c 2 : 24 . 56 , c 3 : 32 . 07 , c 4 : 50 . 41 , c ii : 69 . 32 , c 5 : 100 . 90 , c 6 : 105 . 17 , c 7 : 105 . 89 , c 8 : 108 . 92 , c 9 : 114 . 83 , c 10 : 119 . 38 , c 11 : 122 . 98 , c 12 : 126 . 18 , c 13 : 126 . 40 , c 14 : 126 . 83 , c 15 : 128 . 09 , c 16 : 129 . 32 , c 17 : 130 . 46 , c 18 : 132 . 92 , c 19 : 133 . 80 , c 20 : 133 . 99 , c 21 : 140 . 75 , c 22 : 145 . 52 , c 23 : 146 . 15 , c 24 : 146 . 52 , c 25 : 155 . 27 , c 26 : 164 . 09 , c 27 : 167 . 45 , c 28 : 175 . 02 . anal . : calc . for c 31 h 29 no 8 . ½h 2 o : c , 67 . 39 ; h , 5 . 52 ; n , 2 . 53 . found : c , 67 . 24 ; h , 5 . 34 ; n , 2 . 49 . 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 - isopropoxy - 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylic acid , 1q : ( r = i - c 3 h 7 , r ′═ c 2 h 5 , r ″═ h ): recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 19 g ( 79 . 0 %) of pure product . ir : 3409 cm − 1 ( carboxylic acid — oh ), 1687 cm − 1 ( α β unsaturated acid , c ═ o ), 1687 cm − 1 ( aromatic acid , c ═ o ), 1589 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 1 . 20 , t , 3h , j ab = 6 . 8 hz ; a : 1 . 74 , d , 6h , j = 5 . 1 hz ; b : 2 . 69 , q , 2h , j ba = 6 . 8 hz ; c : 3 . 88 , s , 2h ; b : 3 . 99 , septet , 1h , j ba = 6 . 1 hz ; d : 5 . 41 , s , 2h ; e : 5 . 90 , s , 1h ; f : 5 . 94 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 27 , d , 2h ; i : 7 . 37 , t , 1h , j = 7 . 2 hz ; j : 7 . 54 , d , 1h , j ji = 7 . 2 hz ; k : 7 . 60 , s , 1h ; l : 7 . 73 , d , 1h , j lj = 6 . 7 hz ; m : 7 . 90 , s , 1h ; n : 12 . 84 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , 8 ppm ): c 1 : 14 . 62 , c i : 21 . 65 , c 2 : 24 . 56 , c 3 : 32 . 09 , c 4 : 50 . 40 , c ii : 69 . 80 , c 5 : 100 . 90 , c 6 : 105 . 18 , c 7 : 107 . 12 , c 8 : 108 . 92 , c 9 : 114 . 77 , c 10 : 119 . 46 , c 11 : 123 . 72 , c 12 : 126 . 17 , c 13 : 126 . 42 , c 14 : 126 . 83 , c 15 : 128 . 09 , c 16 : 129 . 34 , c 17 : 130 . 46 , c 18 : 132 . 92 , c 19 : 133 . 65 , c 20 : 133 . 97 , c 21 : 140 . 74 , c 22 : 145 . 52 , c 23 : 146 . 13 , c 24 : 146 . 53 , c 25 : 154 . 03 , c 26 : 164 . 91 , c 27 : 167 . 44 , c 28 : 175 . 00 . anal . : calc . for c 31 h 29 no 8 . ½h 2 o : c , 67 . 39 ; h , 5 . 52 ; n , 2 . 53 . found : c , 67 . 35 ; h , 5 . 21 ; n , 2 . 52 . 6 -( allyloxy )- 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylic acid , 1r : ( r ═ h 2 c ═ ch —, r ′═ c 2 h 5 , r ″═ h ): recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 21 g ( 80 . 1 %) of pure product . ir : 3281 cm − 1 ( carboxylic acid — oh ), 1693 cm − 1 ( a 1 unsaturated acid , c ═ o ), 1693 cm − 1 ( aromatic acid , c ═ o ), 1590 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , 8 ppm ): a : 1 . 20 , t , 3h , j ab = 7 . 5 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 4 hz ; c : 3 . 88 , s , 2h ; a : 4 . 62 , d , 2h , j ad = 4 . 7 hz ; b : 5 . 26 , d , 1h , j bd = 10 . 3 hz ; c , 5 . 39 , d , 1h , j cd = 13 . 3 hz ; d : 5 . 41 , s , 2h ; e : 5 . 90 , s , 1h ; f : 5 . 94 , s , 1h ; d : 6 . 05 , octet , 1h , j = 5 . 5 ; g : 6 . 87 , s , 1h ; h : 7 . 31 , d , 2h ; i : 7 . 37 , t , 1h , j = 7 . 8 hz ; j : 7 . 54 , d , 1h , j ji = 7 . 4 hz ; k : 7 . 62 , d , 1h ; l : 7 . 73 , d , 1h , j lj = 7 . 5 hz ; m : 7 . 89 , s , 1h ; n : 12 . 86 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , 8 ppm ): c 1 : 14 . 63 , c 2 : 24 . 56 , c 3 : 32 . 09 , c 4 : 50 . 43 , c 1 : 68 . 49 , c 5 : 100 . 91 , c 6 : 105 . 18 , c 7 : 106 . 47 , c 8 : 108 . 93 , c 9 : 114 . 87 , c ii : 117 . 63 , c 10 : 119 . 42 , c 11 : 122 . 99 , c 12 : 126 . 17 , c 13 : 126 . 36 , c 14 : 126 . 84 , c 15 : 128 . 09 , c 16 : 129 . 33 , c 17 : 130 . 46 , c 18 : 132 . 93 , c 19 : 133 . 36 , c 20 : 133 . 95 , c iii : 134 . 00 , c 21 : 140 . 74 , c 22 : 145 . 52 , c 23 : 146 . 22 , c 24 : 146 . 53 , c 25 : 154 . 75 , c 26 : 164 . 90 , c 27 : 167 . 45 , c 28 : 175 . 01 . anal . : calc . for c 31 h 27 no 8 . ½h 2 o : c , 67 . 63 ; h , 5 . 09 ; n , 2 . 54 . found : c , 67 . 68 ; h , 5 . 01 ; n , 2 . 54 . 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 -( methoxymethoxy )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylic acid , is ( r ═ h 3 c — o — ch 2 —, r ′═ c 2 h 5 , r ″═ h ) recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 21 g ( 66 . 7 %) of pure product . m . p .= 176 - 177 ° c ., tlc ( 70 % etoac : 30 % methanol ) r f = 0 . 610 . ir : 3443 cm − 1 ( carboxylic acid — oh ), 1698 cm − 1 ( α , β unsaturated acid , c ═ o ), 1698 cm − 1 ( aromatic acid , c ═ o ), 1587 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 1 . 21 , t , 3h , j ab = 7 . 3 hz ; b : 2 . 71 , q , 2h , j ba = 7 . 3 hz ; c , 3 . 38 , s , 3h ; c : 3 . 89 , s , 2h ; e : 5 . 26 , s , 2h ; d : 5 . 42 , s , 2h ; e : 5 . 90 , s , 2h ; f : 5 . 96 , s , 1h ; g : 6 . 88 , s , 1h ; h : 7 . 32 , t , 1h , j = 9 . 3 hz ; i : 7 . 37 , d , 2h ; j : 7 . 54 , d , 1h , j ji = 6 . 9 hz ; k : 7 . 74 , d , 1h , j lj = 7 . 5 hz ; l : 7 . 79 , s , 1h ; m : 7 . 90 , s , 1h ; n : 12 . 82 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c 1 : 14 . 58 , c 2 : 24 . 54 , c 3 : 32 . 02 , c 4 : 50 . 42 , c i : 55 . 63 , c iii : 94 . 07 , c 5 : 100 . 88 , c 6 : 105 . 16 , c 7 : 108 . 89 , c 8 : 109 . 08 , c 9 : 114 . 98 , c 10 : 119 . 31 , c 11 : 123 . 51 , c 12 : 126 . 08 , c 13 : 126 . 29 , c 14 : 126 . 82 , c 15 : 128 . 06 , c 16 : 129 . 26 , c 17 : 130 . 47 , c 18 : 132 . 86 , c 19 : 134 . 00 , c 20 : 134 . 52 , c 21 : 140 . 66 , c 22 : 145 . 52 , c 23 : 146 . 29 , c 24 : 146 . 54 , c 25 : 153 . 22 , c 26 : 164 . 80 , c 27 : 167 . 41 , c 28 : 175 . 09 . anal . : calc . for c 30 h 27 no 8 . h 2 o : c , 63 . 94 ; h , 5 . 19 ; n , 2 . 49 . found : c , 63 . 87 ; h , 5 . 12 ; n , 2 . 62 . 6 - butoxy - 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylic acid , 1t , ( r = n - c 4 h 9 , r ′═ c 2 h 5 , r ″═ h ) recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 21 g ( 77 . 7 %) of pure product . ir : 3568 cm − 1 ( carboxylic acid — oh ), 1686 cm − 1 ( α β unsaturated acid , c ═ o ), 1686 cm − 1 ( aromatic acid , c ═ o ), 1589 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 0 . 93 , t , 3h , j ab = 7 . 4 hz ; a : 1 . 21 , t , 3h , j ab = 7 . 5 hz ; b : 1 . 43 , sextet , 2h , j = 7 . 5 hz ; c , 1 . 72 , quintet , 2h , j = 6 . 9 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 5 hz ; c : 3 . 89 , s , 2h ; d : 4 . 05 , t , 2h , j dc = 6 . 5 hz ; d : 5 . 42 , s , 2h ; e : 5 . 89 , s , 1h ; f : 5 . 93 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 28 , d , 2h ; i : 7 . 36 , t , 1h , j = 7 . 7 hz ; j : 7 . 54 , d , 1h , j ji = 7 . 7 hz ; k : 7 . 62 , s , 1h ; l : 7 . 73 , d , 1h , j lj = 7 . 7 hz ; m : 7 . 91 , s , 1h ; n : 12 . 84 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c i : 13 . 58 , c 1 : 14 . 55 , c ii : 18 . 64 , c 2 : 24 . 51 , c iii : 30 . 55 , c 3 : 32 . 02 , c 4 : 50 . 37 , c iv : 67 . 52 , c 5 : 100 . 85 , c 6 : 105 . 14 , c 7 : 105 . 92 , c 8 : 108 . 87 , c 9 : 114 . 85 , c 10 : 119 . 31 , c 11 : 122 . 93 , c 12 : 126 . 13 , c 13 : 126 . 37 , c 14 : 126 . 78 , c 15 : 128 . 03 , c 16 : 129 . 28 , c 17 : 130 . 45 , c 18 : 132 . 85 , c 19 : 133 . 79 , c 20 : 133 . 96 , c 21 : 140 . 70 , c 22 : 145 . 49 , c 23 : 146 . 02 , c 24 : 146 . 50 , c 25 : 155 . 25 , c 26 : 164 . 83 , c 27 : 167 . 39 , c 28 : 175 . 99 . anal . : calc . for c 32 h 31 no 8 . h 2 o : c , 66 . 77 ; h , 5 . 78 ; n , 2 . 43 . found : c , 67 . 14 ; h , 5 . 77 ; n , 2 . 48 . 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 - isobutoxy - 4 - oxo - 1 , 4 - dihydroquinolin - 2 - carboxylic , 1u ( r = i - c 4 h 9 , r ′═ c 2 h 5 , r ″═ h ) recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 22 g ( 81 . 4 %) of pure product . ir : 3456 cm − 1 ( carboxylic acid — oh ), 1699 cm − 1 ( α β unsaturated acid , c ═ o ), 1699 cm − 1 ( aromatic acid , c ═ o ), 1584 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 0 . 98 , d , 6h , j ab = 6 . 7 hz ; a : 1 . 20 , t , 3h , j ab = 7 . 4 hz ; b : 2 . 03 , nonet , 1h , j = 6 . 5 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 4 hz ; c , 3 . 82 , d , 2h , j = 6 . 4 hz ; c : 3 . 89 , s , 2h ; d : 5 . 41 , s , 2h ; e : 5 . 89 , s , 1h ; f : 5 . 91 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 31 , d , 2h ; i : 7 . 36 , t , 1h , j = 7 . 7 hz ; j : 7 . 54 , d , 1h , j ji = 7 . 6 hz ; k : 7 . 62 , s , 1h ; l : 7 . 73 , d , 1h , j lj = 7 . 6 hz ; m : 7 . 91 , s , 1h ; n : 12 . 84 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c 1 : 14 . 63 , c i : 18 . 98 , c 2 : 24 . 56 , c ii : 27 . 59 , c 3 : 32 . 07 , c 4 : 50 . 41 , c iii : 74 . 06 , c 5 : 100 . 91 , c 6 : 105 . 16 , c 7 : 105 . 94 , c 8 : 108 . 93 , c 9 : 114 . 86 , c 10 : 119 . 39 , c 11 : 123 . 01 , c 12 : 126 . 18 , c 13 : 126 . 39 , c 14 : 126 . 84 , c 15 : 128 . 09 , c 16 : 129 . 33 , c 17 : 130 . 47 , c 18 : 132 . 93 , c 19 : 133 . 81 , c 20 : 133 . 99 , c 21 : 140 . 75 , c 22 : 145 . 52 , c 23 : 146 . 11 , c 24 : 146 . 53 , c 25 : 155 . 36 , c 26 : 164 . 91 , c 27 : 167 . 46 , c 28 : 175 . 03 . anal . : calc . for c 32 h 31 no 8 . h 2 o : c , 66 . 77 ; h , 5 . 78 ; n , 2 . 43 . found : c , 66 . 73 ; h , 5 . 77 ; n , 2 . 49 . ethyl 6 - sec - butoxy - 3 -( 3 -( ethoxycarbonyl ) benzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylate , 1v ( r = sec - c 4 h 9 , r ′═ c 2 h 5 , r ″═ h ) recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 16 g ( 67 . 4 %) of pure product . ir : 3456 cm − 1 ( carboxylic acid — oh ), 1699 cm − 1 ( α , β unsaturated acid , c ═ o ), 1699 cm − 1 ( aromatic acid , c ═ o ), 1588 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 0 . 91 , t , 3h , j ab = 7 . 1 hz ; a : 1 . 20 , t , 3h , j ab = 7 . 2 hz ; b : 1 . 25 , d , 3h , j = 5 . 3 hz ; c , 1 . 61 , octet , 1h , j = 6 . 5 hz ; d : 1 . 66 , octet , 1h , j = 6 . 4 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 1 hz ; c : 3 . 87 , s , 2h ; e : 4 . 44 , sextet , 1h , j = 5 . 7 hz ; d : 5 . 40 , s , 2h ; e : 5 . 89 , s , 2h ; f : 5 . 95 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 27 , d , 2h ; i : 7 . 36 , t , 1h , j = 7 . 5 hz ; j : 7 . 54 , d , 1h , j ji = 6 . 9 hz ; k : 7 . 59 , s , 1h ; l : 7 . 73 , d , 1h , j lj = 6 . 9 hz ; m : 7 . 90 , s , 1h ; n : 12 . 83 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c i : 9 . 50 , c 1 : 14 . 61 , c ii : 18 . 86 , c 2 : 24 . 55 , c iii : 28 . 43 , c 3 : 32 . 10 , c 4 : 50 . 40 , c iv : 74 . 76 , c 5 : 100 . 89 , c 6 : 105 . 18 , c 7 : 107 . 15 , c 8 : 108 . 91 , c 9 : 114 . 75 , c 10 : 119 . 47 , c 11 : 123 . 70 , c 12 : 126 . 16 , c 13 : 126 . 41 , c 14 : 126 . 82 , c 15 : 128 . 08 , c 16 : 129 . 33 , c 17 : 130 . 45 , c 18 : 132 . 91 , c 19 : 133 . 64 , c 20 : 133 . 96 , c 21 : 140 . 74 , c 22 : 145 . 51 , c 23 : 146 . 14 , c 24 : 146 . 52 , c 25 : 154 . 36 , c 26 : 164 . 89 , c 27 : 167 . 43 , c 28 : 174 . 98 . anal . : calc . for c 32 h 31 no 8 : c , 68 . 73 ; h , 5 . 60 ; n , 2 . 51 . found : c , 68 . 34 ; h , 5 . 70 ; n , 2 . 50 . 3 -( 3 - carboxybenzyl )- 6 -( cyclopropylmethoxy )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylic acid , 1w ( r = cyclo - c 3 h 5 — ch 2 —, r ′═ c 2 h 5 , r ″═ h ) recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 16 g ( 67 . 4 %) of pure product . ir : 3446 cm − 1 ( carboxylic acid — oh ), 1692 cm − 1 ( α , β unsaturated acid , c ═ o ), 1692 cm − 1 ( aromatic acid , c ═ o ), 1589 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 0 . 33 , d , 2h , j ab = 4 . 4 hz ; a : 0 . 56 , d , 2h , j ba = 7 . 8 hz ; a : 1 . 20 , t , 3h , j ab = 7 . 4 hz ; c , 1 . 20 , t , 1h , j = 7 . 4 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 1 hz ; c : 3 . 87 , s , 2h ; d : 3 . 89 , d , 2h , j = 6 . 4 hz ; d : 5 . 41 , s , 2h ; e : 5 . 89 , s , 2h ; f : 5 . 95 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 30 , d , 2h ; i : 7 . 36 , t , 1h , j = 7 . 5 hz ; j : 7 . 53 , d , 1h , j ji = 7 . 5 hz ; k : 7 . 58 , s , 1h ; l : 7 . 73 , d , 1h , j lj = 7 . 6 hz ; m : 7 . 89 , s , 1h ; n : 12 . 84 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c i : 3 . 12 , c ii : 10 . 00 , c 1 : 14 . 61 , c 2 : 24 . 55 , c 3 : 32 . 04 , c 4 : 50 . 38 , c iii : 72 . 40 , c 5 : 100 . 89 , c 6 : 105 . 14 , c 7 : 105 . 84 , c 8 : 108 . 92 , c 9 : 114 . 85 , c 10 : 119 . 36 , c 11 : 123 . 08 , c 12 : 126 . 16 , c 13 : 126 . 37 , c 14 : 126 . 83 , c 15 : 128 . 08 , c 16 : 129 . 30 , c 17 : 130 . 45 , c 18 : 132 . 91 , c 19 : 133 . 77 , c 20 : 133 . 99 , c 21 : 140 . 73 , c 22 : 145 . 50 , c 23 : 146 . 03 , c 24 : 146 . 52 , c 25 : 154 . 23 , c 26 : 164 . 88 , c 27 : 167 . 44 , c 28 : 174 . 99 . anal . : calc . for c 32 h 29 no 8 . ½h 2 o : c , 68 . 08 ; h , 5 . 31 ; n , 2 . 48 . found : c , 68 . 18 ; h , 5 . 31 ; n , 2 . 46 . 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 4 - oxo - 6 -( pentyloxy )- 1 , 4 - dihydroquinoline - 2 - carboxylic acid , 1x ( r = n - c 5 h 11 , r ′═ c 2 h 5 , r ″═ h ) recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 21 g ( 66 . 7 %) of pure product . ir : 3568 cm − 1 ( carboxylic acid — oh ), 1684 cm − 1 ( α , β unsaturated acid , c ═ o ), 1684 cm − 1 ( aromatic acid , c ═ o ), 1589 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 0 . 89 , t , 3h , j ab = 4 . 7 hz ; a : 1 . 20 , t , 3h , j ab = 7 . 4 hz ; b : 1 . 33 - 1 . 37 , m , 4h , j = 7 . 7 hz ; c , 1 . 73 , quintet , 2h , j = 6 . 9 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 3 hz ; c : 3 . 88 , s , 2h ; d : 4 . 03 , t , 2h , j dc = 5 . 9 hz ; d : 5 . 41 , s , 2h ; e : 5 . 89 , s , 2h ; f : 5 . 91 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 29 , d , 2h ; i : 7 . 37 , t , 1h , j = 8 . 4 hz ; j : 7 . 54 , d , 1h , j ji = 7 . 6 hz ; k : 7 . 62 , s , 1h ; l : 7 . 73 , d , 1h , j lj = 6 . 5 hz ; m : 7 . 89 , s , 1h ; n : 12 . 83 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c i : 13 . 86 , c 1 : 14 . 59 , c ii : 21 . 82 , c 2 : 24 . 53 , c ii : 27 . 63 , c iii : 28 . 21 , c 3 : 32 . 02 , c 4 : 50 . 37 , c iv : 67 . 52 , c 5 : 100 . 88 , c 6 : 105 . 16 , c 7 : 106 . 09 , c 8 : 108 . 89 , c 9 : 114 . 81 , c 10 : 119 . 34 , c 11 : 122 . 95 , c 12 : 126 . 17 , c 13 : 126 . 37 , c 14 : 126 . 79 , c 15 : 128 . 05 , c 16 : 129 . 30 , c 17 : 130 . 59 , c 18 : 132 . 89 , c 19 : 133 . 97 , c 20 : 134 . 87 , c 21 : 140 . 74 , c 22 : 145 . 49 , c 23 : 146 . 50 , c 24 : 146 . 71 , c 25 : 155 . 25 , c 26 : 164 . 86 , c 27 : 167 . 42 , c 28 : 174 . 99 . anal . : calc . for c 33 h 33 no 8 . ½h 2 o : c , 68 . 27 ; h , 5 . 68 ; n , 2 . 41 . found : c , 68 . 04 ; h , 5 . 77 ; n , 2 . 48 . 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 -( 3 - hydroxypropoxy )- 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylic acid , 1y ( r ═ ho — h 2 c — ch 2 — ch 2 —, r ′═ c 2 h 5 , r ″═ h ) recrystallization from methanol - water ( 98 : 2 ) resulted in 0 . 14 g ( 74 . 0 %) of pure product . ir : 3392 cm − 1 ( carboxylic acid — oh ), 1690 cm − 1 ( α , β unsaturated acid , c ═ o ), 1690 cm − 1 ( aromatic acid , c ═ o ), 1586 cm − 1 ( quinol - 4 - one , c ═ o ). 1 h - nmr ( dmso - d 6 , δ ppm ): a : 1 . 20 , t , 3h , j ab = 7 . 5 hz ; a : 1 . 88 , quintet , 2h , j = 6 . 1 hz ; b : 2 . 69 , q , 2h , j ba = 7 . 4 hz ; b : 3 . 55 , t , 2h , j ba = 7 . 4 hz ; c : 3 . 88 , s , 2h ; c , 4 . 11 , t , 2h , j ca = 6 . 1 hz ; d : 5 . 41 , s , 2h ; e : 5 . 89 , s , 2h ; f : 5 . 91 , s , 1h ; g : 6 . 87 , s , 1h ; h : 7 . 29 , d , 2h ; i : 7 . 36 , t , 1h , j = 7 . 5 hz ; j : 7 . 54 , d , 1h , j ji = 7 . 6 hz ; k : 7 . 60 , s , 1h ; l : 7 . 73 , d , 1h , j lj = 7 . 6 hz ; m : 7 . 89 , s , 1h ; n : 12 . 84 ( exchangeable with d 2 o ), bs , 2h . 13 c - nmr ( dmso - d 6 , δ ppm ): c 1 : 14 . 59 , c 2 : 24 . 53 , c 3 & amp ; i : 31 . 97 , c 4 : 50 . 39 , c ii : 57 . 24 , c iii : 65 . 03 , c 5 : 100 . 88 , c 6 : 105 . 14 , c 7 : 105 . 90 , c 8 : 108 . 90 , c 9 : 114 . 85 , c 10 : 119 . 36 , c 11 : 122 . 98 , c 12 : 126 . 14 , c 13 : 126 . 37 , c 14 : 126 . 82 , c 15 : 128 . 08 , c 16 : 129 . 28 , c 17 : 130 . 46 , c 18 : 132 . 88 , c 19 : 133 . 79 , c 20 : 133 . 98 , c 21 : 140 . 71 , c 22 : 145 . 49 , c 23 : 146 . 02 , c 24 : 146 . 51 , c 25 : 155 . 28 , c 26 : 164 . 85 , c 27 : 167 . 42 , c 28 : 175 . 01 . anal . : calc . for c 31 h 29 no 9 . ½h 2 o : c , 65 . 49 ; h , 5 . 10 ; n , 2 . 46 . found : c , 65 . 24 ; h , 5 . 27 ; n , 2 . 59 . in vitro binding assay . varying concentrations of hjp272 , ranging from 10 3 to 10 8 pm , were incubated with 10 ug of bioxtal et - a or et - b receptor and 224 pm [ 125 i ] tyr13 - et - 1 in 50 mm nah 2 po 4 , 150 mm nacl , 5 mm edta , and 0 . 1 % bovine serum albumin . for total binding , radio labeled et - 1 and receptor were incubated without the receptor antagonist . for non - specific binding , 300 nm cold et - 1 was substituted for the antagonist . assay mixtures were incubated at 30 to 32 ° c . for two hours and the assays were stopped by the addition of cold buffer . assay mixtures were then quickly filtered through gf / c whatman filters and washed with cold assay buffer in a millipore sampling manifold . filters were collected and counts per minute of the bound radio labeled et - 1 were read by a packard cobra gamma counter ( perkin elmer ). percent specific binding was calculated for all data points . assays containing et - a receptor were run in triplicate and assays containing the et - b receptor were run in duplicate . animal models of preterm birth . the animal care and utilization committee of the college of pharmacy and allied health professions , st . john &# 39 ; s university approved all experimental protocols , and the research was conducted according to the requirements of nih guide for the care and use of laboratory animals ( revised 1996 ). c57b1 / 6 mice from taconic laboratory were used for all experiments . animals were housed in plastic cages in a temperature - controlled animal facility with alternating 12 : 12 hour light - dark cycles , with ad libitum access to food and water . nineteen timed pregnant c57b1 / 6 e15 . 5 mice were injected with lps in 0 . 5 ml pbs at a concentration of 50 mg / kg . these mice were randomly assigned to two groups . group a mice ( n = 8 ) received 50 mg / kg hjp272 dissolved in pbs and group b mice ( n = 11 ) received pbs only . all treatments were administered by ip injection 10 hours after lps injection . mice were continually monitored and the time of delivery of all pups , as well as the number of pups delivered , was recorded . all mice were autopsied at the end of the experiment to confirm pregnancy and to determine the number of pups retained in utero . animal models of smoking related acute lung injury . the animal care and utilization committee of the college of pharmacy and allied health professions , st . john &# 39 ; s university approved all experimental protocols , and the research was conducted according to the requirements of nih guide for the care and use of laboratory animals ( revised 1996 ). female syrian hamsters , weighing approximately 100 g each , were divided into two groups as follows : group 1 was treated ip with : 1 ) 500 μg of hjp272 in 0 . 5 ml na 2 co 3 and 2 ) 5 μg et - 1 in 0 . 25 ml pbs 60 minutes later , followed immediately by exposure to cigarette smoke for two hours . this regimen was continued for three days . group 2 was treated ip with : 1 ) 0 . 5 ml na 2 co 3 and 2 ) μg et - 1 in 0 . 25 ml pbs 60 minutes later , followed immediately by exposure to cigarette smoke for three consecutive days as per group 1 . the animals were placed in a 70 × 48 × 38 cm chamber and passively exposed to cigarette smoke produced by a te - 10 smoking machine ( teague enterprises , davis , calif .) that simultaneously burned two filtered research - grade cigarettes ( type 2r4f , university of kentucky ). smoke from both the filtered and burning ends of the cigarette was collected , and then mixed together with air in a separate chamber , thus simulating second - hand smoke exposure . each cigarette was puffed once per minute for two seconds at a flow rate of 1 . 05 lpm , yielding 35 ml of smoke . this cycle was repeated nine times before ejecting the cigarette and loading a new one . proper flow rate was maintained by a vacuum pump that established negative pressure at the exhaust port . total smoke particulates averaged 87 mg per cubic meter . all animals were sacrificed 24 hours after completing the smoke exposure regimen to maximize the neutrophil population in the lung , and the percentage of balf neutrophils was measured ( van der vaart et al . 2004 ) in vitro binding assay . the competitive binding assay with radio labeled ligand shows binding of hjp272 to the endothelin a receptor with an ic 50 of 70 . 1 nm ( fig2 ). furthermore , the compound is a selective antagonist , with the ratio of ic 50 for the endothelin a receptor to ic 50 for the endothelin b receptor of 219 . 2 . animal models of preterm birth . treatment with hjp272 of formula 1a controlled preterm labor and delivery in our mouse model of infection - associated preterm labor very effectively ( olgun et al . 2008 ). among mice treated at e15 . 5 with a high dose ( 50 mg / kg ) of lps , six out of eight mice treated with hjp272 delivered prematurely as compared to 11 out of 11 of the control mice treated with only pbs . ( fig3 ). the percent of prematurely delivered pups in the group of mice treated with the et a - ra was 30 . 0 ( 13 out of 44 ) and the percent of prematurely delivered pups in the control group treated with pbs only was 39 . 7 ( 25 out of 63 ) ( fig4 ). the average delivery time of the six hjp272 - treated mice that delivered , however was t15 . 0 +/− 1 . 8 hours , while the average delivery time of the control mice treated with only pbs was t10 . 9 +/− 0 . 61 hours . this shift in time of delivery , in the setting of the high dose of lps , was statistically significant ( p & lt ; 0 . 0001 ). animal models of smoking related acute lung injury . treatment with et - 1 prior to exposure to cigarette smoke significantly increased the percentage of balf neutrophils in hamsters ( bhavsar et al . 2008b ). as shown in fig5 , hamsters receiving et - 1 had 46 % neutrophils compared to 18 % and 1 % for controls treated only with cigarette smoke or et - 1 and room air , respectively . furthermore , pretreatment with the et a - ra reversed this effect ( fig5 ). in this work , we have shown that 3 -( 3 - carboxybenzyl )- 1 -(( 6 - ethylbenzo [ d ][ 1 , 3 ] dioxol - 5 - yl ) methyl )- 6 - hydroxy - 4 - oxo - 1 , 4 - dihydroquinoline - 2 - carboxylic acid ( hjp272 ), a novel 1 , 3 , 6 - trisubstituted - 2 - carboxy - quinol - 4 - one and et a - ra , is very effective in controlling both preterm delivery and acute lung inflammation in animal models . while endothelin has now been implicated in a very broad spectrum of disease processes , ranging from cancer to cardiovascular disease , its role in the pathogenesis of reproductive disorders , such as premature delivery , has not been thoroughly investigated . the enthusiasm for endothelin as a therapeutic target in reproductive disorders is dampened by our understanding , from work with both et - 1 and ece - 1 knockout mice ( yanagisawa et al . 1998 ), that blockade of et - 1 action early in gestation leads to severe craniofacial anomalies and death in the perinatal period . none of the pups in the work presented here demonstrated such abnormalities , probably because exposure to the et - 1 blocking agent was transient and relatively late in gestation , well after embryogenesis and organogenesis had been completed . the results of the testing of animal models of cigarette smoking related acute lung injury are consistent with selective recruitment of neutrophils by et - 1 , and suggest that this mediator may play an important role in modulating the pulmonary inflammatory response . the level of et - 1 synthesis could determine whether the inflammatory cell population is predominantly composed of neutrophils or monocytes . such variation in the nature of the inflammatory response could have important implications for the type and extent of lung damage resulting from exposure to different pulmonary toxins . while the mechanism responsible for the specific effect of et - 1 on neutrophils remains unclear , it may involve upregulation of icam - 1 , which facilitates their adhesion to vascular endothelium ( zhang et al . 2006 ). alternatively , et - 1 could increase neutrophil expression of cxcr2 , a cell - surface receptor that binds interleukin - 8 , a potent activator of these cells ( divietro et al . 2001 ; reutershan et al . 2006 ). either of these processes could be enhanced by the fact that et - 1 can change the f - actin content of neutrophils , thereby promoting their sequestration in pulmonary microvessels ( sato et al . 2000 ). in the current studies , treatment with the et a - ra reversed the effect of et - 1 on neutrophil recruitment to the lung . this finding may reflect an impaired ability of these cells to adhere to pulmonary vascular endothelium . further support for this concept is found in studies of inflammatory bowel disease , where treatment with the nonselective endothelin receptor antagonist , bosentan , resulted in markedly reduced attachment of neutrophils to colonic submucosal venules ( anthoni et al . 2006 ). with regard to the cellular composition of inflammatory reactions , there is increasing evidence that et - 1 confers a selective advantage on neutrophils , allowing them to populate the lung at the expense of other inflammatory cells . such a process might have important implications for the treatment of inflammatory lung disorders , including copd . reducing et - 1 activity with endothelin receptor antagonists could potentially decrease neutrophil - derived enzymes and oxidants in the lung , thereby slowing the progression of lung injury . the data presented in the current work demonstrate the potential use of the et a - ra for two extremely important clinical problems , namely preterm birth and acute lung injury . no satisfactory therapy currently exists for these disorders . furthermore , because et - 1 is implicated in such a broad range of pathological processes , the synthetic et a - ras may have clinical value in any one of a number of disorders , including ones that have extremely broad impact , such as cardiovascular disease and neoplasia . anthoni a m , revert f , moya a et al . 2000 . intravenous b q - 123 and phosphoramidon reduce ventricular ectopic beats and myocardial infarct size in dogs submitted to coronary occlusion and reperfusion . gen pharmacol 35 : 143 - 147 . bhavsar t m , cerreta j m , liu m , reznik s e and cantor j o . 2008 . phosphoramidon , an endothelin - converting enzyme inhibitor , attenuates lipopolysaccharide - induced acute lung injury . exper lung res 34 : 141 - 154 . 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