Structure of 214470-68-5
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| CAS No. : | 214470-68-5 |
| Formula : | C14H12Cl2N2O2 |
| M.W : | 311.16 |
| SMILES Code : | N#CC1=C(Cl)C2=CC(OC)=C(OCCCCl)C=C2N=C1 |
| English Name : | 4-Chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile |
| MDL No. : | MFCD09833974 |
| InChI Key : | BEGHZKYNLSIHIA-UHFFFAOYSA-N |
| Pubchem ID : | 11220637 |
| Num. heavy atoms | 20 |
| Num. arom. heavy atoms | 10 |
| Fraction Csp3 | 0.29 |
| Num. rotatable bonds | 5 |
| Num. H-bond acceptors | 4.0 |
| Num. H-bond donors | 0.0 |
| Molar Refractivity | 78.86 |
| TPSA ? Topological Polar Surface Area: Calculated from |
55.14 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.83 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.43 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.78 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.83 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
4.32 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.24 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-3.97 |
| Solubility | 0.0333 mg/ml ; 0.000107 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-4.27 |
| Solubility | 0.0168 mg/ml ; 0.0000539 mol/l |
| Class? Solubility class: Log S scale |
Moderately soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-6.08 |
| Solubility | 0.000256 mg/ml ; 0.000000822 mol/l |
| Class? Solubility class: Log S scale |
Poorly soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.76 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.18 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In 2-ethoxy-ethanol Heating; | ||
| 48.5 % | With pyridine hydrochloride In 2-ethoxy-ethanol at 150℃; Inert atmosphere; | 4-(4-phenoxyanilino)-4-chloro-6-methoxy-7-[3-(4-methylpiperazin-l-yl) propoxy] quinoline-3-carbonitrile (01-012): 250 mg of 10 and 1.1 eq of 4-phenoxyaniline and pyridine hydrochloride was added to a vial with a magnetic stir bar. The vial was capped, purged with argon, and 10 mL of 2 -ethoxy ethanol added. The vial was heated at 150°C for 3h. The reaction was then cooled and purified by RP-HPLC. Product containing fractions were pooled and dried under reduced pressure to yield 6.4 mg (48.5%) of 11 and used in the next step. Compound 01-012 was obtained and purified by RP-HPLC, after reaction of compound 11 with methyl piperazine in presence of N,N-Diisopropyl ethylamine (DIEA) in tert-Butyl alcohol at 95 °C in 67% yield. MS (ES+) m/z 524.5 (M + H)+ |
| 48.5 % | With pyridine hydrochloride In 2-ethoxy-ethanol at 150℃; Inert atmosphere; | 4-(4-phenoxyanilino)-4-chloro-6-methoxy-7-[3-(4-methylpiperazin-l-yl) propoxy] quinoline-3-carbonitrile (01-012): 250 mg of 10 and 1.1 eq of 4-phenoxyaniline and pyridine hydrochloride was added to a vial with a magnetic stir bar. The vial was capped, purged with argon, and 10 mL of 2 -ethoxy ethanol added. The vial was heated at 150°C for 3h. The reaction was then cooled and purified by RP-HPLC. Product containing fractions were pooled and dried under reduced pressure to yield 6.4 mg (48.5%) of 11 and used in the next step. Compound 01-012 was obtained and purified by RP-HPLC, after reaction of compound 11 with methyl piperazine in presence of N,N-Diisopropyl ethylamine (DIEA) in tert-Butyl alcohol at 95 °C in 67% yield. MS (ES+) m/z 524.5 (M + H)+ |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 65% | With trichlorophosphate at 105 - 108℃; | 7-(3-Chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile (14) A reaction solution of 13 (0.50 g, 1.71 mmol) in POCl3 (1.7 mL) was heated to reflux for2.5 h. Volatile materials were removed under reduced pressure at about 70 . The residuewas dissolved with CH2Cl2 then added water. The resulting solution was stirred at 0 andadded solid K2CO3 carefully until the pH was 8-9. After stirring for 30 min at roomtemperature, the organic layer was collected. The organic layer was washed with H2O anddried over MgSO4. The MgSO4 was removed by filtration and the filtrate was concentratedunder reduced pressure to give the crude product as orange powder. The crude was dissolvedin CH2Cl2 and added hexane (CH2Cl2/Hex = 2/1) to precipitate 14 (0.34 g, 65%) as an orangesolid. Mp 156 ; 1H NMR (200 MHz DMSO-d6) δ 2.29 (p, J = 12.6 Hz, 6.2 Hz, 2 H), 3.83 (t,J = 6.5 Hz, 2 H), 4.00 (s, 3 H), 4.34 (t, J = 6.1 Hz, 2 H), 7.38 (s, 1 H), 7.53 (s, 1 H), 8.95 (s, 1H); 13C NMR (50 MHz DMSO-d6) δ 31.4, 41.9, 55.8, 65.5, 100.8, 104.5, 108.2, 119.9, 134.9,148.2, 152.9, 165.4, 165.5, 175.2; MS (ESI) m/z 311.0 (M + H) +. |
| With trichlorophosphate Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With pyridine hydrochloride In 1,2-dimethoxyethane at 85℃; for 24h; | 7-(3-Chloropropoxy)-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile (15b) To a solution of 14 (1.45 g, 4.68 mmol) was added 2,4-dichloro-5-methoxyaniline (0.98g, 5.15 mmol) in dimethoxyethane (7 mL) in the presence of pyridine hydrochloride (3.30 g,28.56 mmol). The reaction mixture was heated to reflux for 24 h. The resulting solution wascooled to room temperature then poured into water. The resulting precipitate was filtered andwashed with EtOAc to give 15b (2.13 g, 98%) as brown solid. Mp 188-190 ; 1H NMR(200 MHz DMSO-d6) δ 2.27 (p, J = 12.5 Hz, 12.3 Hz, 7.0 Hz, 2 H ), 3.83 (t, J = 7.3 Hz, 2 H),3.87 (s, 3 H), 3.95 (s, 3 H), 4.28 (t, J = 6.0 Hz, 2 H), 7.34 (s, 2 H), 7.73 (s, 1 H), 7.83 (s, 1 H),8.41 (s, 1 H), 9.66 (s, 1 H); 13C (50 MHz DMSO-d6) δ 31.5, 41.9, 56.3, 56.8, 65.3, 86.3,102.0, 109.2, 112.8, 113.4, 117.0, 120.2, 123.0, 130.0, 149.3, 149.5(2C), 150.7, 152.5,154.0(2C); MS (ESI) m/z 466.1(M + H) +. |
| 77% | With pyridine hydrochloride In 2-methoxy-ethanol at 120℃; Reflux; | |
| 77% | With pyridine hydrochloride In 2-methoxy-ethanol at 120℃; for 3h; | 7-(3-Chloropropoxy)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxyquinoline-3-carbonitrile (31) A mixture of compound 25 (31.2 g, 0.10 mol), 2,4-dichloro-5-methoxyaniline (30, 21.1 g, 0.11 mol), and pyridine hydrochloride (12.8 g, 0.11 mol) in 2-methoxyethanol (150 g) was heated to 120 °C for 3 h. The suspension was cooled to r.t. and poured into water (600 g) while stirring. The resulting solid was filtered, washed with water (2 × 40 g), and dried at 50 °C to give product 31 (35.9 g, 77%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ = 2.28 (m, J = 6.0 Hz, 2 H), 3.82 (t,J = 6.0 Hz, 2 H), 3.87 (s, 3 H), 3.97 (s, 3 H), 4.30 (t, J = 6.0 Hz, 2 H), 7.35(s, 1 H), 7.37 (s, 1 H), 7.75 (s, 1 H), 7.85 (s, 1 H), 8.43 (s, 1 H), 9.63 (s, 1H).13C NMR (100 MHz, DMSO-d6): δ = 31.9, 42.1, 56.7, 57.3, 65.8, 86.9,102.4, 110.0, 113.1, 114.0, 117.4, 120.9, 123.6, 130.3, 136.7, 146.2,149.8, 149.9, 151.3, 152.9, 154.5.MS (ESI): m/z = 468.0 [M + H]+. |
| 67% | With pyridine hydrochloride In 2-ethoxy-ethanol at 140℃; for 2h; Sealed tube; Inert atmosphere; | 2 4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxyquinoline-3-cyanide A solution of 2,4-dichloro-5-methoxyaniline (1.9 g, 10 mmol), pyridine hydrochloride (1.2 g, 10 mmol) and4-chloro-7-(3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (3.1 g, 10 mmol)Placed in sealed tube,Anhydrous 2-ethoxyethanol (30 mL) was added,The mixture was heated at 140 ° C for 2 hours.After completion of the reaction,After the reaction solution was cooled to room temperature,Diluted with water (500 mL)Dichloromethane extraction (250 mL X2),The organic phases were combined,Respectively, with water,Washed with a saturated saline solution,Dried over anhydrous sodium sulfate,filter,Concentrated under reduced pressure,Purified by column chromatography7-(3-chloro-propoxy) _4_ (2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile(Gray solid, 3.0 g),Yield 67%. |
| 60.2% | With pyridine hydrochloride In 2-ethoxy-ethanol for 2.5h; Reflux; | |
| 46% | With pyridine hydrochloride In 2-ethoxy-ethanol for 2.5h; Heating; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92.4% | With trichlorophosphate In toluene for 2h; Reflux; | |
| 83% | With trichlorophosphate for 2h; Reflux; | |
| 83% | With trichlorophosphate for 2h; Reflux; | 4-Chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile (25) A suspension of compound 13 (60.0 g, 0.20 mol) and POCl3 (240 g, 1.56 mol) was stirred and heated to reflux for 2 h to give a homogeneous solution. POCl3 (~120 g) was removed under vacuum and the residue was poured into ice-water (600 g) and the resulting mixture was stirred at r.t. for 2 h. The resulting solid was filtered, washed with water (2 × 100 g), and dried at 50 °C to give product 25 (51.7 g, 83%) as a faint yellow solid. 1H NMR (400 MHz, DMSO-d6): δ = 2.29 (m, J = 6.0 Hz, 2 H), 3.83 (t,J = 6.0 Hz, 2 H), 3.98 (s, 3 H), 4.33 (t, J = 6.0 Hz, 2 H), 7.29 (s, 1 H), 7.46(s, 1 H), 8.90 (s, 1 H).13C NMR (100 MHz, DMSO-d6): δ = 31.8, 42.2, 56.6, 66.3, 102.1, 104.9,109.4, 116.0, 120.3, 143.1, 146.9, 148.7, 152.1, 154.7.MS (ESI): m/z = 311.0 [M - H]-. |
| 69% | With N,N-dimethyl-formamide; trichlorophosphate at 110℃; for 1h; | |
| 69% | With N,N-dimethyl-formamide; trichlorophosphate at 110℃; for 1h; | 10.6 Step 6. 4-Chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile A stirred solution of 7-(3-chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile (1.90 g, 6.49 mmol) in POCl3 (10 mL) with a few drops DMF (~20) was heated to 110° C. for 1 hour. After cooling to room temperature, the solution was then concentrated and azetroped with toluene. The residue was poured over ice/H2O and neutralized with saturated NaHCO3. The precipitate was collected via vacuum filtration, washed with excess H2O and Et2O. The product was purified with Biotage Flash 40 (20 to 40% EtOAc:petroleum ether gradient) to afford the product (1.39 g, 69%); 1H NMR (DMSO-d6) δ 2.21-2.29 (m, 2H), 3.78 (t, J=6.4 Hz, 2H), 3.98 (s, 3H), 4.32 (t, J=6.0 Hz, 2H), 7.42 (s, 1H), 7.54 (s, 1H), 8.95 (s, 1H); mass spectrum [(+) ESI], m/z 311/313 (M+H)+. |
| With trichlorophosphate for 1.5h; Heating / reflux; Neat liquid(s); Alkaline conditions; | Example 54; 7-(3-Chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile A mixture of 3.5 g (12 mmol) of 7-(3-chloro-propoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile and 28 ml of phosphorous oxychloride was refluxed for 1.5 hr. Excess reagent was removed at reduced pressure. The residue was mixed with ice cold dilute sodium hydroxide and ethyl acetate. The mixture was extracted with a combination of ethyl acetate and tetrahydrofuran. The combined extracts were washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and filter through a short column of silica gel. Solvents were removed giving 3.2 g of the title compound as a pink solid that is used with additional purification. | |
| With trichlorophosphate for 1.5h; Heating / reflux; | 74 A mixture of 3.5 g (12 mmol) of 7-(3-chloro-propoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile and 28 ml of phosphorous oxychloride was refluxed for 1.5 hr. Excess reagent was removed at reduced pressure. The residue was mixed with ice cold dilute sodium hydroxide and ethyl acetate. The mixture was extracted with a combination of ethyl acetate and tetrahydrofuran. The combined extracts were washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and filter through a short column of silica gel. Solvents were removed giving 3.2 g of the title compound as a pink solid that is used with additional purification. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium hexamethyldisilazane In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 0.583333h; | 1 Example 14-(2-chloro-5-methoxypyrazin-3-ylamino)-7-(3-chIoropropoxy)-3-cyano-6-methoxyquinoline Sodium hexamethyldisilazane (1M solution in THF; 0.76 ml) was added dropwise to amixture of 3-amino-2-chloro-5-methoxypyrazine (0.062 g), 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline (Bioorg. Med. Chem. Letters. 2000,10,2826; 0.096 g) and DMF(1.5 ml) that had been cooled to 0°C. The mixture was stirred at 0°C for 5 minutes and atambient temperature for 30 minutes. Acetic acid (0.023 ml) was added and the resultantmixture was evaporated. The residue was partitioned between methylene chloride and a10% aqueous sodium bicarbonate solution. The organic solution was dried over magnesiumsulphate and evaporated. The residue was triturated under diethyl ether and the resultant solidwas isolated. There was thus obtained the title compound as a solid (0.103 g); Mass Spectrum:M+lT434and436. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In N,N-dimethyl-formamide | ||
| With 18-crown-6 ether; tetra-(n-butyl)ammonium iodide at 20℃; for 16h; | 2; 7 The chloropropoxyquinoline intermediate (Mass Spectrum m/e 311.2 (M+H)+) was prepared by reacting the corresponding hydroxy quinoline with 1-bromo-3- chloropropane at room temperature for 16hr in the presence of nBu4NI/18-crown-6 | |
| Stage #1: 4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile With potassium <i>tert</i>-butylate In DMF (N,N-dimethyl-formamide) at 20℃; for 0.25h; Stage #2: 1,3-chlorobromopropane In DMF (N,N-dimethyl-formamide) at 20℃; for 16h; | 9 The 4-chloro-7- (3-chloropropoxy)-3-cyano-6-metlioxyquinoline used as a starting material was prepared as follows :- A mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g), potassium tert-butoxide (0.1 g) and DMF (8 ml) was stirred at ambient temperature for 15 minutes. [L-BROMO-3-CHOROPROPANE] (0.134 g) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The resultant mixture was evaporated and the residue was partitioned between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer was dried using magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and hexane. There was thus obtained the required starting material (0. [131] g); NMR Spectrum : [(DMSOD6)] 2.3 (m, 2H), 3.8 (m, [2H),] 4.0 (s, 3H), 4.35 (m, 2H), 7.42 (s, 1H), 7.68 (s, 1H), 8. 95 (s, [1H)] ; Mass Spectrum : [M+H+] 311. |
| With dibenzo-18-crown-6; potassium carbonate at 20 - 60℃; | A (A) in the presence of dibenzo-18-crown-6-ether and potassium carbonate,4-chloro-6-methoxy-7-hydroxy-3-quinolinecarbonitrile (starting material 1) and1-Bromo-3-chloropropane undergoes alkylation in an aprotic polar solvent,4-Chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile (Formula II) is obtained,The molar ratio of 4-chloro-6-methoxy-7-hydroxy-3-quinolinecarbonitrile to 1-bromo-3-chloropropane is 1:10 to 1:1.The reaction temperature is 20 ° C - 60 ° C,The aprotic polar solvent is selected from the group consisting of 1-methyl-2-pyrrolidone,Dimethylacetamide and dimethylformamide; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 45% | With pyridine hydrochloride In 2-ethoxy-ethanol at 120℃; | |
| 45% | With pyridine hydrochloride In 2-ethoxy-ethanol at 120℃; | 10.7 Step 7. 4-[3-Chloro-4-(1-ethyl-4,5-dimethyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile To a stirred solution of 4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile (0.298 g, 0.958 mmol) in ethoxyethanol (6 mL) was added 3-chloro-4-(1-ethyl-4,5-dimethyl-1H-imidazol-2-ylsulfanyl)-phenylamine (0.270 g, 0.958 mmol) and pyridine HCl (0.122 g, 1.05 mmol). The mixture was heated to 120° C., maintaining the temperature overnight. The solution was cooled to room temperature, then quenched with saturated NaHCO3 solution (10 mL), stirred at room temperature for 30 minutes and the precipitate was collected via vacuum filtration. The solid was absorbed on silica and purified by flash chromatography (0 to 3% MeOH:CHCl3 gradient) to afford the product (0.240 g, 0.431 mmol, 45%) as a solid; mass spectrum [(+) ESI], m/z 557 (M+H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77% | Stage #1: 4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: 1-iodo-3-chloro-propane In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 1 4-chloro-7-(3-chloropropoxy)-6-methoxy-quinoline-3-carbonitrile Anhydrous potassium carbonate (10.6 g, 6 eq) was added to a solution of 4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile (3 g,12.7 mmol) in DMF (30 mL)After stirring for half an hour,1-Chloro-3-iodopropane (13 g, 63.9 mmol) was added to the suspension and stirred at room temperature overnight.The reaction solution was diluted with water (500 mL)Dichloromethane extraction (250 mL X2),The organic phases were combined,Respectively, with water,Washed with a saturated saline solution,Dried over anhydrous sodium sulfate,filter,Concentrated under reduced pressure,Silica gel column chromatography gave 4-chloro-7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 3.1 g)Yield 77%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86 g | With trichlorophosphate In toluene at 25 - 85℃; for 5h; | 4 Example-4: Preparation of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3- carbonitrile Phosphorous oxychloride (131.1 gm) was slowly added to a mixture of 7-(3-chloropropoxy)-6-methoxy-4-oxo-3,4-dihydroquinoline-3-carbonitrile (100 gm) and toluene (500 ml) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 5 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Cooled the reaction mixture to 25-30°C, water was added and stirred for 1 hr at the same temperature. Filtered the solid and washed with water. Aqueous sodium bicarbonate solution was slowly added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the compound, washed with water and then dried the material. Isopropyl alcohol (500 ml) was added to the obtained compound at 25- 30°C. Heated the reaction mixture to 55-60°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and then dried the material to provide the title compound. Yield: 86.0 gm; M.R: 165-172°C. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | With pyridine hydrochloride In 1,2-dimethoxyethane at 85℃; for 24h; | 7-(3-Chloropropoxy)-4-((2-chloro-5-methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile (15a) To a solution of 14 (2.15 g, 6.94 mmol) was added 2-chloro-5-methoxyaniline (1.0 mL,7.63 mmol) and pyridine hydrochloride (4.88 g, 42.30 mmol) in dimethoxyethane (11 mL).The reaction mixture was heated to reflux for 24 h. The resulting solution was cooled to roomtemperature then poured into water. The resulting precipitate was filtered and washed withEtOAc to give 15a (3.1 g, 93%) as light yellow solid. Mp 154-156 ; 1H NMR (200 MHz DMSO-d6) δ 2.27 (p, J = 12.6 Hz, 12.3 Hz, 7.0 Hz, 2 H ), 3.78 (s, 3 H), 3.83 (t, J = 6.5 Hz, 2H), 3.94 (s, 3 H), 4.29 (t, J = 6.0 Hz, 2 H), 6.98 (dd, J = 8.9 Hz, 2.9 Hz, 1 H), 7.07 (d, J = 2.9Hz, 1 H), 7.35 (s, 1 H), 7.48 (d, J = 8.9 Hz, 1 H), 7.83 (s, 1 H), 8.40 (s, 1 H), 9.57 (s, 1 H);13C (50 MHz, DMSO-d6) δ 31.6, 42.0, 55.8, 56.3, 65.3, 86.5, 102.0, 109.5, 112.7, 114.6,114.9, 116.9, 123.0, 130.3, 137.0, 145.6, 149.3, 149.6, 151.0, 152.5, 158.7; MS (ESI) m/z432.1 (M + H) +. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 43% | With pyridine hydrochloride In 2-ethoxy-ethanol at 80℃; for 16h; | 18 4-Chloro-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile (18) Chloro-4-iodoaniline (4.01 g, 12.9 mmol), pyridine hydrochloride (4.48 g, 38.8 mmol) and 4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile (3.30 g, 13.0 mmol) were dissolved in dry 2-ethoxyethanol (42.5 mL) and stirred at 80 °C for 16 h. The reaction mixture was combined with H2O (100 mL) and extracted with EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2x100 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. Remaining DMF was blown off with N2. The crude was purified by column chromatography (10% acetone/toluene) to afford the product as a brown solid (2.95 g, 5.59 mmol, 43% yield).1H NMR (300 MHz, DMSO) δ 9.52 (s, 1H), 8.43 (s, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.81 (s, 1H), 7.76 (dd, J = 8.4, 2.0 Hz, 1H), 7.36 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.29 (t, J = 6.0 Hz, 2H), 3.94 (s, 3H), 3.82 (t, J = 6.4 Hz, 2H), 2.26 (p, J = 6.2 Hz, 2H).13C NMR (75 MHz, DMSO) δ 152.56, 150.73, 149.41, 145.80, 137.51, 136.91, 136.67, 132.28, 130.73, 116.83, 112.90, 109.53, 101.90, 92.38, 86.94, 65.31, 56.25, 41.89, 31.46 (one quaternary carbon was not observed). LCMS (Fleet, 10% → 90%): tR= 5.58 min; m/z: 528.25 [M+H]+, HRMS calculated for C20H16Cl2IN3O2+H+: 527.97370, found 527.97351 [M+H]+. |

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