Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 6940-76-7 | MDL No. : | MFCD00001096 |
Formula : | C3H6ClI | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SFOYQZYQTQDRIY-UHFFFAOYSA-N |
M.W : | 204.44 | Pubchem ID : | 81363 |
Synonyms : |
|
Num. heavy atoms : | 5 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 34.29 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.93 cm/s |
Log Po/w (iLOGP) : | 1.83 |
Log Po/w (XLOGP3) : | 2.28 |
Log Po/w (WLOGP) : | 2.05 |
Log Po/w (MLOGP) : | 2.6 |
Log Po/w (SILICOS-IT) : | 2.19 |
Consensus Log Po/w : | 2.19 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.41 |
Solubility : | 0.792 mg/ml ; 0.00387 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.92 |
Solubility : | 2.47 mg/ml ; 0.0121 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.67 |
Solubility : | 0.441 mg/ml ; 0.00216 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.24 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
88.0% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 42h; | [1-(3-Hydroxypropyl)imidazolidin-2-ylidene] malononitrile (0.370 g, 1.92 mmol) obtained in Step 1 of Example 8 was dissolved in DMF (4 mL) and the solution was sequentially added with potassium carbonate (0.532 g, 3.85 mmol) and 1-chloro-3-iodopropane (0.247 mL, 2.30 mmol). After stirring at room temperature for 26 hours, the mixture was added with potassium carbonate (0.185 g, 1.34 mmol) and 1-chloro-3-iodopropane (0.103 mL, 0.960 mmol), followed by stirring at room temperature for 16 hours. The mixture was added with saturated brine and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol (98:2 to 90:10)) to obtain (1-(3-chloropropyl)-3-(3-hydroxypropyl)imidazolidin-2-ylidene]malononitrile (0.454 g, 88.0 percent) as a white solid. 1H NMR (CDCl3, deltappm) : 1.87-1.99 (m, 2H), 2.12-2.24 (m, 2H), 3.61-3.76 (m, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | 1-(3-Chloropropyl)-5-nitro-1H-indole (38): To a flask (2 neck, 250 mL) containing sodium hydride (0.98 g, 24.5 mmol, 60percent in mineral oil) was added dry DMF (30 mL) while cooling in an ice bath. A solution of compound 1 (1.0 g, 617 mmol) in DMF (20 mL) was added to the ice-cold solution resulting in the formation of a wine coloured solution. This solution was stirred followed by the addition of 1-chloro-3-iodopropane (1.95 mL, 3 eq) neat. The mixture was removed from the ice bath and stirred for 2 hours and quenched with water (80 mL) and brine (20 mL). A yellow precipitate slowly formed which was collected by filtration and washed with water. The sample was air dried overnight. The sample was recrystallized from toluene to obtain compound 38 (1.0886 g, 74percent) as a solid. mp 74-76° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With NaH; potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; acetonitrile; | 6-Fluoro-7-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one (107LH93-2) A reaction flask was charged with 6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) in dry DMF (1 mL) under N2. NaH (60percent in oil, 0.038 g, 0.92 mmol) was added and stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.131 g, 0.84 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), NaI (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation exchange CC followed by flash CC (SiO2; EtOAc) to give the title compound (107LH93-2) (0.171 g, total yield 56percent). 1H NMR (CH3OD) delta 7.00 (d, J=6.4 Hz, 1H), 6.87 (d, J=9.2 Hz, 1H), 3.94 (brt, J=7.2 Hz, 2H), 3.39 (t, J=6.6 Hz, 2H), 3.35-3.26 (m, 1H), 2.85-2.70 (m, 4H), 2.58-2.51 (m, 2H), 2.39 (brt, 7.4 Hz, 2H), 2.24 (d, J=1.6 Hz, 3H), 2.21-2.12 (m, 2H), 1.92-1.75 (m, 4 H), 1.62-1.48 (m, 4H), 0.91 (t, J=7.4 Hz); 13C NMR (CH3OD) delta 171.0, 157.1 (d, J=241), 135.2 (d, J=3 Hz), 126.5 (d, J=8 Hz), 123.2 (d, J=18 Hz), 118.1 (d, J=5 Hz), 114.3 (d, J=24 Hz), 74.6, 69.5, 55.4, 51.0, 40.4, 31.5, 30.9, 24.7, 24.5, 23.2, 13.5 (br), 10.0. |
56% | A reaction flask was charged with 6-fluoro-7-methyl-3,4- dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) in dry DMF (1 mE) under N2. NaH (60percent in oil, 0.038 g, 0.92 mmol) was added and stirred at it for 30 mm. Then 3-chioro- 1-iodopropane (0.13 1 g, 0.84 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mE) followed by addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2C03 (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation exchange CC followed by flash CC (Si02 EtOAc) to give the title compound (107EH93-2) (0.171 g, total yield 56percent). ?H NMR (CH3OD) oe 7.00 (d, J=6.4 Hz, 1H), 6.87 (d, J=9.2 Hz, 1H), 3.94 (brt, J=7.2 Hz, 2H), 3.39 (t, J=6.6 Hz, 2H), 3.35-3.26 (m, 1H), 2.85-2.70 (m, 4H), 2.58-2.51 (m, 2H), 2.39 (brt, 7.4 Hz, 2H), 2.24 (d, J=1.6 Hz, 3H), 2.21-2.12 (m, 2H), 1.92-1.75 (m, 4 H), 1.62-1.48 (m, 4H), 0.91 (t, J=7.4 Hz); ?3C NMR (CH3OD) oe171.0, 157.1 (d, J=241), 135.2 (d, J=3 Hz), 126.5 (d, J=8 Hz), 123.2 (d, J=18 Hz), 118.1 (d, J=5 Hz), 114.3 (d, J=24 Hz), 74.6, 69.5, 55.4, 51.0, 40.4, 31.5, 30.9, 24.7, 24.5, 23.2, 13.5 (br), 10.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With caesium carbonate; In ethyl acetate; | 4-(3-Chloropropyl)-5,7-difluoro-4H-benzo[1,4]oxazin-3-one 5,7-Difluoro-4H-benzo[1,4]oxazin-3-one (0.24 g, 1.3 mmol), Cs2CO3 (1.08 g, 3.3 mmol), and 1-chloro-3-iodopropane (0.296 g, 1.45 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 30percent EtOAc) to give the title compound (0.17 g, 49percent). Rf=0.66 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 6.67-6.58 (m, 2H), 4.55 (s, 2H), 4.16-4.10 (m, 2H), 3.59-3.52 (m, 2H), 2.21-2.10 (m, 2H). |
49% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | A reaction flask or vial was charged 4H-benzo[1,4]ox- azin-3-one (1.0 equiv) dissolved in DMF (0.1 g/ml), Cs2CO3(1.5 equiv) and 1 -chloro-3-iodopropane (1.1 equiv). The reaction was stirred in rt for 60-70 h and evaporated to dryness. The reaction was redisolved in H20 and extractedwith EtOAc 3x1 50 ml. The combined organic phases weredried over Na2SO4 and concentrated to a crude that was useddirectly or purified by column chromatography (heptanes/ EtOAc).5,7-Difluoro-4H-benzo[ 1 ,4]oxazin-3-one (0.24 g, 1.3 mmol), Cs2CO3 (1.08 g, 3.3 mmol), and 1-chloro-3-iodo- propane (0.296 g, 1.45 mmol) were mixed according to GP2.Purified by column chromatography (Si02 heptanes/ EtOAc, gradient 0 to 30percent EtOAc) to give the title compound (0.17 g, 49percent). R1=0.66 (heptanes/EtOAc 1:1); ?H NMR (CDC13) oe 6.67-6.58 (m, 2H), 4.55 (s, 2H), 4.16-4.10 (m, 2H), 3.59-3.52 (m, 2H), 2.21-2.10 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With caesium carbonate; In water; acetonitrile; | 4-(3-Chloropropyl)-7-fluoro-4H-benzo[1.4]oxazin-3-one A reaction flask was charged with 6,7-difluoro-4H-benzo[1.4]oxazin-3-one (1.5 g, 8.1 mmol), 1-chloro-3-iodopropane (1.44 g, 8.1 mmol), and Cs2CO3 (4.0 g, 12.2 mmol) in MeCN (10 mL) and stirred at rt for 40 h. The reaction mixture was concentrated, water added, and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (1.88 g, 89percent). 1H NMR (CDCl3) d 6.99 (dd, J=8.0 Hz, J=5.6 Hz, 1H), 6.79-6.72 (m, 2H), 4.59 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H) 2.18-2.10 (m, 2H); 13C NMR (CDCl3) d 163.9, 159.1 (d, J=244.1 Hz), 146.4 (d, J=11.9 Hz), 124.9 (d, J=3.0 Hz), 115.4 (d, J=9.6 Hz), 109.5 (d, J=22.7 Hz), 105.4 (d, J=26.2 Hz), 67.7, 42.4, 39.2, 30.1. |
89% | With caesium carbonate; In acetonitrile; at 20℃; for 40h; | A reaction flask was charged with 6,7-difluoro-4H-benzo [1.4]oxazin-3-one (1.5 g, 8.1 mmol), 1-chioro-3-iodopro-pane (1.44 g, 8.1 mmol), and Cs2CO3 (4.0 g, 12.2 mmol) in MeCN (10 mE) and stirred at rt for 40 h. The reactionmixture was concentrated, water added, and the product extracted into EtOAc. The combined organic phases weredried over Na2SO4, filtered, and concentrated. The productwas purified by flash column chromatography (Si02 n-heptane/EtOAc 2:1) to give the title compound (1.88 g, 89percent).?H NMR (CDC13) oe 6.99 (dd, J=8.0 Hz, J=5.6 Hz, 1H), 6.79-6.72 (m, 2H), 4.59 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62(t, J=6.0 Hz, 2H) 2.18-2.10 (m, 2H); ?3C NMR (CDC13) oe163.9, 159.1 (d, J=244.1 Hz), 146.4 (d, J=11.9 Hz), 124.9 (d,J=3.0 Hz), 115.4 (d, J=9.6 Hz), 109.5 (d, J=22.7 Hz), 105.4 (d, J=26.2 Hz), 67.7, 42.4, 39.2, 30.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With caesium carbonate; In acetonitrile; | 4-(3-Chloropropyl)-6-fluoro-4H-benzo[1.4]oxazin-3-one A reaction flask was charged with 6-fluoro-4H-benzo[1.4]oxazin-3-one (1.67 g, 10 mmol), 1-chloro-3-iodopropane (2.04 g, 10 mmol), and Cs2CO3 (4.88 g, 15 mmol) in MeCN (10 mL) and stirred at rt for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (145LH20) (2.32 g, 95percent). 1H NMR (CDCl3) d 6.95-6.91 (m, 1H), 6.82-6.78 (m, 1H), 6.72-6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.19-2.11 (m, 2H); 13C NMR (CDCl3) d 164.6, 158.6 (d, J=240.7 Hz), 141.5 (d, J=2.3 Hz), 129.6 (d, J=10.5 Hz), 118.0 (d, J=9.3 Hz), 110.0 (d, J=23.1 Hz), 102.7 (d, J=28.8 Hz), 67.8, 42.3, 39.3, 30.0. |
95% | With caesium carbonate; In acetonitrile; at 20℃; for 72h; | A reaction flask was charged with 6-fluoro-4H-benzo[ 1.4]oxazin-3-one (1.67 g, 10 mmol), 1-chloro-3-iodopropane(2.04 g, 10 mmol), and Cs2CO3 (4.88 g, 15 mmol) in MeCN (10 mE) and stirred at it for 3 days. The reaction mixture wasquenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2504,filtered, and concentrated. The product was purified by flashcolunm chromatography (5i02 n-heptane/EtOAc 2:1) togive the title compound (145EH20) (2.32 g, 95percent). ?H NMR (CDC13) oe 6.95-6.91 (m, 1H), 6.82-6.78 (m, 1H), 6.72-6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2Hz, 2H), 2.19-2.11 (m, 2H); ?3C NMR (CDC13) oe 164.6,158.6 (d, J=240.7 Hz), 141.5 (d, J=2.3 Hz), 129.6 (d, J=10.5Hz), 118.0 (d, J=9.3 Hz), 110.0 (d, J=23.1 Hz), 102.7 (d, J=28.8 Hz), 67.8, 42.3, 39.3, 30.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Lithium diisopropylamide in THF (2.0 M; 12 mL, 24 mmol) was added to a mixture of 2-fluoro-3-iodopyridine (Alfa Aesar, 5.0 g, 22 mmol) in THF (50 mL) at ?78° C. The solution was stirred at ?78° C. for 1 h, then a solution of 1-chloro-3-iodo-propane, (5.0 g, 24 mmol) in 15 mL THF was added dropwise. The reaction mixture was stirred at ?78° C. for 30 min., then allowed to warm to room temperature. The reaction mixture was quenched with aq.NH4Cl and extracted with EtOAc. The combined organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 0 to 50percent EtOAc/hexanes, to give the sub-title compound (6.2 g, 92percent). LCMS calc. for C8H9ClFIN (M+H)+: m/z=299.9. Found: 300.1. | |
70% | a) Freshly prepared LDA (8.97 mmol) was added to a solution of 2-fluoro-3- iodopyridine (2.00 g, 8.97 mmol) in THF (15 mL) cooled at -78 °C. After 1 h, 1 - chloro-3-iodopropane (0.96 mL, 8.97 mmol) was added to the anion solution, allowing to reach room temperature (overnight). The reaction volume was reduced to ca. 10 mL and the mixture was poured over EtAcO (60 mL) and washed with water (2 x 20 mL); the organic layer was dried over anhydrous Na2S04 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (2>4percent EtAcO/hexanes), affording 1 .88 g of 3-(3-chloropropyl)-2-fluoro-4- iodopyridine [Rf= 0.70 (5percent EtAcO/hexanes), colorless oil, 70percent yield].LC-MS ESI+ m/z: 300 (M+1 , 98percent) (Method 5).1 H-NMR (CDCI3, 250 MHz, ?): 7.70 (d, J= 5.2 Hz, 1 H, ArH); 7.61 (d, J= 5.2 Hz, 1 H, ArH); 3.62 (t, J= 6.5 Hz, 2H); 2.99-2.90 (m, 2H); 2.10-1 .97 (m, 2H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Step B: To a solution of 3,4-difluorobenzenesulfinic acid (2.5 g, 14.0 mmol) in dimethyl formamide (20 mL) was added 1-chloro-3-iodopropane (4.46 mL, 42.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.82 mL, 15.4 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was poured into water and extracted into diethyl ether. The combined organic layers were washed with water, brine, dried over MgS04, filtered and concentrated in vacuo. The material was purified over silica gel (4: 1 hexanes/EtOAc) to yield 4-(3-chloropropylsulfonyl)-1,2-difluorobenzene (2.8 g, 80percent). |
42% | With triethylamine; In DMF (N,N-dimethyl-formamide); at 65℃; for 3h; | (b) 4-(3-Chloro-propane-1-sulfonyl)-1,2-difluoro-benzene To 3,4-difluoro-benzenesulfinic acid (500 mg, 2.81 mmol) and triethylamine (0.43 ml, 3.10 mmol) in 10 ml DMF was added 1-chloro-3-iodopropane (1.43 g, 7.00 mmol) and the mixture heated at 65° C. for 3 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed over SiO2 (ethyl acetate/heptane 1:50) to afford the title compound (300 mg, 42percent) as an off-white crystalline solid. MS (ISP): 257.2 {37Cl}MH+, 255.1{35Cl}MH+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | 4-(3-chloropropyl)-tetrahydro-2H-pyran-4-carbonitrile. To a stirred solution of 1 M LiHMDS (25 mL, 25 mmol) in THF (10 mL) at -78° C. was added dropwise a solution of intermediate 4 (2.23 g, 20 mmol) in THF (15 mL) over 10 minutes. After 40 min, 1-chloro-3-iodopropane (2.7 mL, 25 mmol) was added at once, stirred at -78° C. for 1 h and 4 h room temperature. Then the reaction mixture was diluted with ether (100 mL), washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated to give yellow oil which was purified by flash column chromatography using 10-30percent EtOAc/Hexanes to afford the product intermediate 5 as a colorless liquid (3.737 g, 99percent). 1H NMR (500 MHz, CDCl3) delta: 3.97 (2H, dd, J=11.3, 3.7 Hz), 3.71 (2H, td, J=12.2, 1.8 Hz), 3.61 (2H, t, J=6.3 Hz), 2.05-1.98 (2H, m), 1.88 (2H, dd, J=13.4, 1.8 Hz), 1.77-1.74 (2H, m), 1.65-1.59 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; | To a solution of (2,6-dimethyl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2- yl) -methanone (111, 964 mg, 3.95 mmol) in DMF (7 mL) was added 1-chloro-3-iodo- propane (0.6 mL, 5.58 mmol) and Cs2CO3 (1.7 g, 5.21 mol) The mixture was stirred overnight at RT. Water was added to the mixture and the resulting solution was extracted with EtOAc. The organic layer was dried (Na2S04) and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with a DCM: MeOH: NH40H gradient (99: 0.7:0.07 to 96: 3.5:0.35 over 50 min. ) to afford 0.828 g (65percent) of 113: ms (LCMS) m/z 321 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With NaH; potassium carbonate; In N,N-dimethyl-formamide; acetonitrile; | 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (107LH93-1) A reaction flask was charged with 6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) in dry DMF (1 mL) under N2. NaH (60percent in oil, 0.038 g, 0.92 mmol) was added and stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.131 g, 0.84 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-butylpiperidine (0.085 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation exchange CC followed by flash CC (SiO2; EtOAc) to give the title compound (107LH93-1) (0.166 g, total yield 55percent). 1H NMR (CH3OD) delta 7.00 (d, J=6.4 Hz, 1H), 6.88 (d, J=9.2 Hz, 1H), 3.98-3.91 (m, 2H), 2.93-2.86 (m, 2H), 2.85-2.78 (m, 2H), 2.58-2.52 (m, 2H), 2.40-2.43 (m, 2H), 2.25 (d, J=2.0 Hz, 3H), 1.98-1.76 (m, 4H), 1.70-1.62 (m, 2H), 1.35-1.22 (m, 9 H), 0.88 (t, J=7.0 Hz, 3H); 13C NMR (CH3OD) 6 171.1, 157.2 (d, J=241 Hz), 135.1 (d, J=3 Hz), 126.5 (d, J=8 Hz), 123.2 (d, J=18 Hz), 118.1 (d, J=5 Hz), 114.3 (d, J=24 Hz), 55.8, 43.9, 40.4, 36.2, 35.7, 32.0, 31.5, 29.0, 24.6, 24.3, 22.8, 13.4 (br). |
55% | With NaH; potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; acetonitrile; | 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (107LH93-1) A reaction flask was charged with 6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) in dry DMF (1 mL) under N2. NaH (60percent in oil, 0.038 g, 0.92 mmol) was added and stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.131 g, 0.84 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-butylpiperidine (0.085 g, 0.6 mmol), NaI (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation exchange CC followed by flash CC (SiO2; EtOAc) to give the title compound (107LH93-1) (0.166 g, total yield 55percent). 1H NMR (CH3OD) delta 7.00 (d, J=6.4 Hz, 1H), 6.88 (d, J=9.2 Hz, 1H), 3.99-3.91 (m, 2H), 2.93-2.86 (m, 2H), 2.85-2.78 (m, 2H), 2.58-2.52 (m, 2H), 2.40-2.43 (m, 2H), 2.25 (d, J=2.0 Hz, 3H), 1.98-1.76 (m, 4H), 1.70-1.62 (m, 2H), 1.35-1.22 (m, 9 H), 0.88 (t, J=7.0 Hz, 3H); 13C NMR (CH3OD) 6 171.1, 157.2 (d, J=241 Hz), 135.1 (d, J=3 Hz), 126.5 (d, J=8 Hz), 123.2 (d, J=18 Hz), 118.1 (d, J=5 Hz), 114.3 (d, J=24 Hz), 55.8, 43.9, 40.4, 36.2, 35.7, 32.0, 31.5, 29.0, 24.6, 24.3, 22.8, 13.4 (br). |
55% | A reaction flask was charged with 6-fluoro-7-methyl-3,4- dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) in dryDMF (1 mE) under N2. NaH (60percent in oil, 0.038 g, 0.92 mmol) was added and stirred at it for 30 mm. Then 3-chioro- 1-iodopropane (0.13 1 g, 0.84 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. Thecombined organic layers were dried over Na2SO4, filtered,and concentrated. The crude material was dissolved inMeCN (2 mE) followed by addition of 4-butylpiperidine(0.085 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2C03(0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. Thereaction mixture was quenched with water and the productextracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation exchange CC followed by flash CC (Si02 EtOAc) to give the title compound (107EH93-1)(0.166 g, total yield 55percent). ?H NMR (CH3OD) oe 7.00 (d,J=6.4 Hz, 1H), 6.88 (d, J=9.2 Hz, 1H), 3.98-3.91 (m, 2H),2.93-2.86 (m, 2H), 2.85-2.78 (m, 2H), 2.58-2.52 (m, 2H),2.40-2.43 (m, 2H), 2.25 (d, J=2.0 Hz, 3H), 1.98-1.76 (m,4H), 1.70-1.62 (m, 2H), 1.35-1.22 (m, 9 H), 0.88 (t, J=7.0Hz, 3H); ?3C NMR (CH3OD) oe 171.1, 157.2 (d, J=241 Hz),135.1 (d, J=3 Hz), 126.5 (d, J=8 Hz), 123.2 (d, J=18 Hz),118.1 (d, J=5 Hz), 114.3 (d, J=24 Hz), 55.8, 43.9, 40.4, 36.2,35.7, 32.0, 31.5, 29.0, 24.6, 24.3, 22.8, 13.4 (br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.4% | 8-Methyl-i ,2,3,4-tetrahydroquinoline (125 mg, 0.85 mmol), 1 -chioro-3-iodopropane (82 jii, 0.77 mmol) and Cs2CO3 (415 mg, 1.27 mmol) in acetonitrile (2 mE) were shaken at 60C. for 7 days. KI (140 mg, 0.85 mmol), K2C03 (117 mg, 0.85 mmol) and 4-butylpiperidine (113 jtl, 0.68 mmol) were added and the reaction mixture was shaken60 C. for 2 days. Water (5 mE) was added and the product was extracted with ethyl acetate (2xiO mE). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent:20% methanol in ethyl acetate) to yield the title compound. Yield: 45.6 mg (20.4%). HPEC-MS: M+i=329.5 (UV/MS (%)=99/97). ?H NMR (400 MHz, CDC13): oe=0.89 (3H, t), 1.18-1.34 (9H, m), 1.70 (2H, broad d), 1.75-1.92 (4H, m),1.99 (2H, broad t), 2.22 (3H, s), 2.38 (2H, dd), 2.70-2.81(4H, m), 2.96 (2H, broad d), 3.04-3.10 (2H, m), 6.76 (iH, t),6.80 (iH, broad d), 6.91 (iH, broad d). ?3C NMR (CD3OD):13.2, 17.2, 18.0, 18.1, 22.8, 25.7, 27.7, 28.9, 31.9, 35.7,36.2, 52.7, 53.9, 56.3, 121.5, 127.1, 128.7, 128.9, 131.0, 148.0. | |
45.6 mg (20.4%) | With Ki; potassium carbonate; caesium carbonate; In methanol; water; ethyl acetate; acetonitrile; | 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-8-methyl-1,2,3,4-tetrahydro-quinoline (77-LH-1) <strong>[52601-70-4]8-Methyl-1,2,3,4-tetrahydroquinoline</strong> (125 mg, 0.85 mmol), 1-chloro-3-iodopropane (82 mul, 0.77 mmol) and Cs2CO3 (415 mg, 1.27 mmol) in acetonitrile (2 mL) were shaken at 60 C. for 7 days. KI (140 mg, 0.85 mmol), K2CO3 (117 mg, 0.85 mmol) and 4-butylpiperidine (113 mul, 0.68 mmol) were added and the reaction mixture was shaken at 60 C. for 2 days. Water (5 mL) was added and the product was extracted with ethyl acetate (2*10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: 20% methanol in ethyl acetate) to yield the title compound. Yield: 45.6 mg (20.4%). HPLC-MS: M+1+=329.5 (UV/MS(%)=99/97). 1H NMR (400 MHz, CDCl3): delta=0.89 (3H, t), 1.18-1.34 (9H, m), 1.70 (2H, broad d), 1.75-1.92 (4H, m), 1.99 (2H, broad t), 2.22 (3H, s), 2.38 (2H, dd), 2.70-2.81 (4H, m), 2.96 (2H, broad d), 3.04-3.10 (2H, m), 6.76 (1H, t), 6.80 (1H, broad d), 6.91 (1H, broad d). 13 C NMR (CD3OD): delta13.2, 17.2, 18.0, 18.1, 22.8, 25.7, 27.7, 28.9, 31.9, 35.7, 36.2, 52.7, 53.9, 56.3, 121.5, 127.1, 128.7, 128.9, 131.0, 148.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With NaH; potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; acetonitrile; | 1-[3-(4-Butyl-piperidin-1-yl)propyl]-6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH95-1) A reaction flask was charged with 6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.090 g, 0.50 mmol) in dry DMF (0.5 mL) under N2. NaH (60percent in oil, 0.023 g, 0.55 mmol) was added and stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.079 g, 0.50 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-butylpiperidine (0.085 g, 0.6 mmol), NaI (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation-exchange CC followed by flash CC (SiO2; EtOAc) to give the title compound (107LH95-1) (0.059 g, total yield 33percent). 1H NMR (CH3OD) delta 7.02 (dd, J=4.8, 9.2 Hz, IH), 6.98-6.92 (m, 1H), 3.95 (brt, J=7.4 Hz, 2H), 2.92-2.82 (m, 4H), 2.59-2.52 (m, 2H), 2.39-2.32 (m, 2H), 2.00 (d, J=1.6 Hz, 3H), 1.97-1.75 (m, 4H), 1.66 (brd, 10.8 Hz, 2H), 1.35-1.12 (m, 9H), 0.89 (t, J=6.4 Hz); 13C NMR (CH3OD) delta 170.9, 157.6 (d, J=240 Hz), 135.4 (d, J=3 Hz), 128.1 (d, J=4 Hz), 122.7 (d, J=18 Hz), 114.2 (d, J=8 Hz), 112.9, (d, J=25 Hz), 55.9, 53.9, 40.6, 36.2, 35.7, 31.9, 30.9, 28.9, 24.4, 22.8, 21.4 (br), 13.2, 9.7 (br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.3% | 6-Methoxy-3,4-dihydro-1H-quinolin-2-one (108 mg,0.61 mmol), 1-chloro-3-iodopropane (64 pi, 0.6 mmol) andCs2CO3 (290 mg, 0.9 mmol) in acetonitrile (2 mE) wereshaken at 60 C. for 14 h then the reaction was cooled toroom temperature. Water (5 mE) was added and the product was extracted with ethyl acetate (2x10 mE). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The syrup was dissolved in acetonitrile (4 mE). KI (83 mg, 3.6 mmol), K2C03 (100 mg, 0.6 mmol) and 4-bu- tylpiperidine (83 jtl, 0.5 mmol) were added and the reaction mixture was shaken at 60 C. for 16 h. Water (5 mE) was added and the product was extracted with ethyl acetate (2x10 mE). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: 20% methanol in ethyl acetate) to yield the title compound. Yield: 24.8 mg, 11.3%. HPEC-MS:M+1=359.5 (UV/MS(%)=90/78). ?H NMR (400 MHz, CDC13): oe=0.89 (3H, t), 1.12-1.34 (9H, m), 1.67 (2H, broad d), 1.85 (2H, quin.), 1.93 (2H, broad t), 2.39 (2H, t), 2.59 (2H, dd), 2.83 (2H, t), 2.90 (2H, broad d), 3.76 (3H, s), 3.94 (2H, t), 6.70 (1H, d), 6.74 (1H, dd), 7.01 (1H, d). ?3C NMR (CDC13): oe 14.3, 23.0,25.0,26.1,29.2,32.1,32.5 (2C), 35.9, 36.4, 40.8, 54.3 (2C), 55.8, 56.3, 112.2, 114.2, 116.2, 128.3,133.4, 155.4, 169.9 | |
With Ki; potassium carbonate; caesium carbonate; In methanol; water; ethyl acetate; acetonitrile; | 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methoxy-3,4-dihydro-1H-quinolin-2-one (77-LH-22A) 6-Methoxy-3,4-dihydro-1H-quinolin-2-one (108 mg, 0.61 mmol), 1-chloro-3-iodopropane (64 mul, 0.6 mmol) and Cs2CO3 (290 mg, 0.9 mmol) in acetonitrile (2 mL) were shaken at 60 C. for 14 h then the reaction was colled to room temperature. Water (5 mL) was added and the product was extracted with ethyl acetate (2*10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The syrup was dissolved in acetonitrile (4 mL). KI (83 mg, 3.6 mmol), K2CO3 (100 mg, 0.6 mmol) and 4-butylpiperidine (83 mul, 0.5 mmol) were added and the reaction mixture was shaken at 60 C. for 16 h. Water (5 mL) was added and the product was extracted with ethyl acetate (2*10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: 20% methanol in ethyl acetate) to yield the title compound. Yield: 24.8 mg, 11.3%. HPLC-MS: M+1+=359.5 (UV/MS(%)=90/78). 1H NMR (400 MHz, CDCl3): delta=0.89 (3H, t), 1.12-1.34 (9H, m), 1.67 (2H, broad d), 1.85 (2H, quin.), 1.93 (2H, broad t), 2.39 (2H, t), 2.59 (2H, dd), 2.83 (2H, t), 2.90 (2H, broad d), 3.76 (3H, s), 3.94 (2H, t), 6.70 (1H, d), 6.74 (1H, dd), 7.01 (1H, d). 13C NMR (CDCl3): delta14.3, 23.0, 25.0, 26.1, 29.2, 32.1, 32.5 (2C), 35.9, 36.4, 40.8, 54.3 (2C), 55.8, 56.3, 112.2, 114.2, 116.2 128.3, 133.4, 155.4, 169.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With NaH; potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; acetonitrile; | 6-Fluoro-5-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one (107LH95-2) A reaction flask was charged with 6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.090 g, 0.50 mmol) in dry DMF (0.5 mL) under N2. NaH (60percent in oil, 0.023 g, 0.55 mmol) was added and stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.079 g, 0.50 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-propoxypiperidine (0.086 g, 0.6 mrnol), NaI (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation-exchange CC followed by flash CC (SiO2; EtOAc) to give the title compound (107LH95-2) (0.074 g, total yield 41percent). 1H NMR (CH3OD) delta 7.03 (dd, J=4.8, 9.2 Hz, 1H), 6.99-6.92 (m, 1H), 3.98 (brt, J=7.4 Hz, 2H), 3.46-3.38 (m, 3H), 2.95-2.84 (m, 4H), 2.64-2.42 (m, 6H), 2.20 (d, J=2.0 Hz, 3H), 1.98-1.83 (m, 4H), 1.72-1.30 (m, 4H), 0.92 (t, J=7.4 Hz, 3H); 13C NMR (CH3OD) delta 171.1, 157.7 (d, J=240 Hz), 135.4 (d, J=3 Hz), 128.1 (d, J=4 Hz), 122.8 (d, J=18 Hz), 114.1, (d, J=9 Hz), 113.0 (d, J=25 Hz), 73.1, 69.7, 55.0, 50.3, 40.3, 30.8, 29.9, 23.9, 23.1, 22.7, 21.4, 9.8 (br). |
41% | With NaH; potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; acetonitrile; | 6-Fluoro-5-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one (107LH95-2) A reaction flask was charged with 6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.090 g, 0.50 mmol) in dry DMF (0.5 mL) under N2. NaH (60percent in oil, 0.023 g, 0.55 mmol) was added and stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.079 g, 0.50 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), NaI (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation-exchange CC followed by flash CC (SiO2; EtOAc) to give the title compound (107LH95-2) (0.074 g, total yield 41percent). 1H NMR (CH3OD) delta 7.03 (dd, J=4.8, 9.2 Hz, 1H), 6.99-6.92 (m, 1H), 3.98 (brt, J=7.4 Hz, 2H), 3.46-3.38 (m, 3H), 2.95-2.84 (m, 4H), 2.64-2.42 (m, 6H), 2.20 (d, J=2.0 Hz, 3H), 1.98-1.83 (m, 4H), 1.72-1.30 (m, 4H), 0.92 (t, J=7.4 Hz, 3H); 13C NMR (CH3OD) delta 171.1, 157.7 (d, J=240 Hz), 135.4 (d, J=3 Hz), 128.1 (d, J=4 Hz), 122.8 (d, J=18 Hz), 114.1, (d, J=9 Hz), 113.0 (d, J=25 Hz), 73.1, 69.7, 55.0, 50.3, 40.3, 30.8, 29.9, 23.9, 23.1, 22.7, 21.4, 9.8 (br). |
41% | A reaction flask was charged with 6-fluoro-5-methyl-3,4- dihydro-1H-quinolin-2-one (0.090 g, 0.50 mmol) in dry DMF (0.5 mE) under N2. NaH (60percent in oil, 0.023 g, 0.55 mmol) was added and stirred at it for 30 mm. Then 3-chloro- 1 -iodopropane (0.079 g, 0.50 mmol) was added followed by stirring at ri for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mE) followed by addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2C03 (0.138 g, 1.0 mmol) and shaken at 500 C. for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation-exchange CC followed by flash cc(Si02 EtOAc) to give the title compound (107EH95-2) (0.074 g, total yield 41percent). ?H NMR (CH3OD) oe 7.03 (dd, J=4.8, 9.2 Hz, 1H), 6.99-6.92 (m, 1H), 3.98 (bit, J=7.4 Hz, 2H), 3.46-3.38 (m, 3H), 2.95-2.84 (m, 4H), 2.64-2.42 (m, 6H), 2.20 (d, J=2.0 Hz, 3H), 1.98-1.83 (m, 4H), 1.72-1.30 (m, 4H), 0.92 (t, J=7.4 Hz, 3H); ?3C NMR (CH3OD) oe 171.1, 157.7 (d, J=240 Hz), 135.4 (d, J=3 Hz), 128.1 (d, J=4 Hz), 122.8 (d, J=18 Hz), 114.1, (d, J=9 Hz), 113.0 (d, J=25 Hz), 73.1, 69.7, 55.0, 50.3, 40.3, 30.8, 29.9, 23.9, 23.1, 22.7, 21.4, 9.8 (br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In water; ethyl acetate; acetonitrile; | 3.101 1-(3-Chloropropyl)-1H-indol-2,3-dione (85LM02). A 500 ml flask was charged with 1H-indol-2,3-dione (isatin) (3.62 g, 25 mmol), 1-chloro-3-iodopropan (2.8 ml, 27 mmol) and Cs2CO3 (18 g, 55 mmol) in MeCN (200 ml). The mixture was stirred 40 C. for 48 hours. Water (50 ml) and EtOAc (50 ml) were added and the phases were separated. The aqueous phase was re-extracted with EtOAc (50 ml). The combined org. layer were dried (Na2SO4) and evaporated to dryness. The crude product was purified by to column chromatography (SiO2; EtOAc/n-heptane 1:4) to give the title compound (85LM02) (4.2 g, 80%). 1H NMR (CDCl3) delta2.20 (qv, 2H), 3.60 (t, 2H), 3.90 (t, 2H), 7.00 (d, 1H), 7.15 (t, 1H), 7.55-7.65 (m, 2H); HPLC-MS (ammonium acetate) [M+H]+=224.2. |
80% | With caesium carbonate; In water; ethyl acetate; acetonitrile; | 3.101 1-(3-Chloropropyl)-1H-indol-2,3-dione (85LM02). A 500 ml flask was charged with 1H-indol-2,3-dione (isatin) (3.62 g, 25 mmol), 1-chloro-3-iodopropan (2.8 ml, 27 mmol) and Cs2CO3 (18 g, 55 mmol) in MeCN (200 ml). The mixture was stirred 40 C. for 48 hours. Water (50 ml) and EtOAc (50 ml) were added and the phases were separated. The aqueous phase was re-extracted with EtOAc (50 ml). The combined org. layer were dried (Na2SO4) and evaporated to dryness. The crude product was purified by to column chromatography (SiO2; EtOAc/n-heptane 1:4) to give the title compound (85LM02) (4.2 g, 80%). 1H NMR (CDCl3) delta 2.20 (qv, 2H), 3.60 (t, 2H), 3.90 (t, 2H), 7.00 (d, 1H), 7.15 (t, 1H), 7.55-7.65 (m, 2H); HPLC-MS (ammonium acetate) [M+H]+=224.2. |
80% | With caesium carbonate; In acetonitrile; at 40℃; for 48h; | 3.101 1-(3-Chloropropyl)-1H-indol-2,3-dione (85LM02). A 500 ml flask was charged with 1H-indol-2,3-dione (isatin) (3.62 g, 25 mmol), 1-chloro-3-iodopropan (2.8 ml, 27 mmol) and Cs2CO3 (18 g, 55 mmol) in MeCN (200 ml). The mixture was stirred 40 C. for 48 hours. Water (50 ml) and EtOAc (50 ml) were added and the phases were separated. The aqueous phase was re-extracted with EtOAc (50 ml). The combined org. layer were dried (Na2SO4) and evaporated to dryness. The crude product was purified by to column chromatography (SiO2; EtOAc/n-heptane 1:4) to give the title compound (85LM02) (4.2 g, 80%). 1H NMR (CDCl3) delta 2.20 (qv, 2H), 3.60 (t, 2H), 3.90 (t, 2H), 7.00 (d, 1H), 7.15 (t, 1H), 7.55-7.65 (m, 2H); HPLC-MS (ammonium acetate) [M+H]+=224.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With magnesium sulfate; In water; toluene; | a) Preparation of 5-Chloro-2-(3.4-dimethoxyphenyl)-2-isopropylpentanenitrile 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile (1.21 g, 5.52 mmol) was added to a suspension of sodium amide (0.59 g, 14.4 mmol) in toluene (12 ml). The mixture was then heated to reflux for 2 hours before the addition of 1-chloro-3-iodopropane (0.9 ml, 8.3 mmol). The mixture was cooled to room temperature over 80 minutes, and worked up by addition of water. The product was extracted with methyl-t-butyl ether (MTBE). After usual work-up, including drying the organic extract using MgSO4 and concentrating under reduced pressure the product was purified on column chromatography eluding with (ethyl acetate: light petroleum (b.p. 40 -60° C.) =1:2), to give 1.4g (82percent yield) of the required product. |
81% | 10.16g(50mmol) of 2-(3',4' -dimethoxyphenyl)-3-methylbutyronitrile was dissolved in 80ml of anhydrous toluene, and 3.90g(100mmol) of sodium amide was added in fractional amounts while being stirred. After being heated and refluxed at 120 ° C for 2 hours, the mixture was cooled down to 80°C and, with 15.33g(75mmol) of 1-chloro-3-iodopropane added thereto, further stirred at 80 ° C for 1 hour. After disappearance of the starting material was checked, a small amount of methanol was added to the mixture to decompose excess sodium amide, and the solvent was evaporated out under a vacuum. The residue was extracted with ethyl acetate and then washed with water until it became neutral. The organic layer was filtrated through 1PS filter paper, and then the solvent was evaporated out. The residue was purified by silica gel column chromatography, to give 12.03g(41mmol, 81percent) of 5-chloro-2-(3',4' -dimethoxyphenyl)-2-isopropylpentanenitrile. 1H-NMR (d, CDCl3):0.82 (3H, d, J=6.7Hz), 1.21 (3H, d, J=6.7Hz), 1.38-1.54 (1H, m), 1.80-1.98 (1H, m), 2.00-2.30 (3H, m), 3.45-3.54 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 6.82-6.96 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | EXAMPLE 14; Ethyl 4-(3-chloropropyl)-4-cyano-1-piperidinecarboxylate; To a solution of ethyl 4-cyano-1-piperidinecarboxylate (6.0 g) in tetrahydrofuran (120 ml) at -70°C, under nitrogen, was added a solution of lithium diisopropylamide (4.6 g) in tetrahydrofuran (21.5 ml), dropwise, with stirring. The reaction was allowed to warm to -10°C and after 30 min was recooled to -70°C. A solution of 1-chloro-3-iodopropane (7.4 g) in tetrahydrofuran (20 ml) was added to the mixture over 30 min. The reaction mixture was quenched with water and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentratedin vacuo and the residue was flash chromatographed (silica), eluting with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to afford 5.5 g (64percent) of product; Calculated for C12H19ClN2O2 ; 55.70percentC; 7.40percentH; 10.83percentN; Found; 55.88percentC; 7.67percentH; 10.80percentN | |
5.5 g (64%) | With lithium diisopropyl amide; In tetrahydrofuran; | EXAMPLE 14 Ethyl 4-(3-chloropropyl)-4-cyano-1-piperidinecarboxylate To a solution of ethyl 4-cyano-1-piperidinecarboxylate (6.0 g) in tetrahydrofuran (120 ml) at -70° C., under nitrogen, was added a solution of lithium diisopropylamide (4.6 g) in tetrahydrofuran (21.5 ml), dropwise, with stirring. The reaction was allowed to warm to -10° C. and after 30 min was recooled to -70° C. A solution of 1-chloro-3-iodopropane (7.4 g) in tetrahydrofuran (20 ml) was added to the mixture over 30 min. The reaction mixture was quenched with water and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was flash chromatographed (silica), eluding with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to afford 5.5 g (64percent) of product. Analysis: Calculated for C12 H19 ClN2 O2: 55.70percentC 7.40percentH 10.83percentN Found: 55.88percentC 7.67percentH 10.80percentN |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; N,N-dimethyl-formamide; | (1) A solution of ethyl aminoisobutyrate hydrochloride (10 g) in DMF (50 mL) was cooled to 0 C. To the solution were added potassium carbonate (18 g) and 1-chloro-3-iodopropane (12 g), and the mixture was stirred overnight at 0 C. to room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 12.5 g of crude ethyl 2-(3-chloropropylamino)isobutyrate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | A solution of morpholine (2 mL, 23.0 mmol) in /V,A/-dimethylformamide (15 mL) was treated with potassium carbonate (4.75g, 34.4 mmol) and1-chloro-3-iodopropane (3.7 mL, 34.4 mmol). After 16h, the reaction mixture was partitioned between EtOAc and H20. The aqueous layer was washed with EtOAc(15x). The combined organic layers were dried (Na2S04) and concentrated. 1H NMR indicated a very large amount of DMF still remaining, so the product was taken up in EtOAc and washed with H20. The organic layer was washed with brine, dried (Na2S04) and concentrated. The resulting pale yellow oil was taken up in Et20 and treated with 4N HCI in dioxane to precipitate the product, affording 1.45g (32%) of the hydrochloride salt of 4-(3-chloropropyl)morpholine as a white solid. 1H NMR (D20): 8 3.94 (br m, 2H), 3.70 (brm, 2H), 3.53 (m, 2H), 3.15 (brm, 2H), 3.19 (m, 2H), 3.10 (brm, 2H), 2.08 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In acetone; at 50℃; for 16h; | A mixture of (+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine (10.6 g, 68.7 mmol, prepared according to the literature procedure described by Janetka, J.W. et al., J. Org. Chem., 2003, 68, 3976-3980), 1 -chloro-3-iodo-propane (16.9 g, 82.8 mmol, 1.2 eq), and K2CO3 (24.6 g, 178 mmol, 2.6 eq) in acetone (230 mL) was heated at 5O0C for 16 hours. The mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated in vacuo. Chromatography on silica gel using a gradient of 2M NHs/MeOH in CH2CI2 (0-2percent) gave 14.05 g (89percent) of (2S,5fi)-1 -allyl^^S-chloro-propyO^.delta- dimethyl-piperazine as a light yellow oil.To a solution of (2S,5/^-1-allyl-4-(3-chloro-propyl)-2,5-dimethyl-piperazine (14.05 g, 61 mmol) in anhydrous THF (78 mL) under argon was added thiosalicylic acid (10.33 g, 67 mmol, 1.1 eq) followed by the addition of a solution of tris(dibenzylidenacetone)-dipalladium (Pd2(dba)3, 2.8 g, 3.1 mmol, 5 molpercent) and1 ,4-bis(diphenylphosphino)butane (DPPB, 1.33 g, 3.1 mmol, 5 molpercent) in anhydrous THF (26 mL, pre-mixed for 15 minutes). After stirring at room temperature for 2 hours, the mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was partitioned between 1 N aqueous HCI (70 mL) and Et2O (70 mL). The aqueous layer was separated and extracted with Et2O (50 mL x 2), and treated with NaOH (solid) to bring its pH to 13. The aqueous phase was extracted with CHCI3 (50 mL x 4). The combined organic phase was dried (Na2SO4) and concentrated in vacuo EPO <DP n="37"/>to give 11.6 g (100percent) of (2S,5/:?)-4-(3-chloro-propyl)-2I5-ciimethyl-piperazine as a light yellow oil.To a solution of (2S,5R)-4-(3-chloro-propyl)-2,5-dimethyl-piperazine (11.6 g, 61 mmol) in CH2CI2 (240 ml_) at O0C was added Boc2O (14.9 g, 67 mmol, 1.1 eq) and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was chromatographed on silica gel by eluting with 30percent EtOAc/hexane to give 12.8 g (72percent) of (2S,5fl)-4-(3-chloro-propyl)- 2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a light yellow oil. 1H NMR (300 MHz, CDCI3): delta 4.22 (m, 1 H), 3.64 (m, 3H), 3.23 (dd, J = 11.4, 3.9 Hz, 1 H), 2.55 (m, 1 H), 2.42 (m, 1 H), 2.22 (d, J = 11.4 Hz, 1 H), 1.87 (t, J = 6.3 Hz, 2H), 1.46 (s, 9H)7 1.21 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate; In acetone; at 50℃; for 3h; | To a solution of <strong>[198989-07-0]2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester</strong> (0.10 g, 0.50 mmol) in acetone (2 mL) was added 1 -chloro-3-iodo-propane (0.10 g, 0.50 mmol, 1 eq) and K2CO3 (0.084 g, 0.60 mmol, 1.2 eq). The mixture was heated at 50 0C for 3 h and then cooled to r.t. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. Chromatography on silica gel by eluting with 5% EPO <DP n="38"/>MthetaOH/CH2CI2 gave 0.095 g (69%) of 5-(3-chloro-propyl)-2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a yellowish oil. 1H NMR (300 MHz, CDCI3): delta 4.20 (m, 1 H), 3.58 (m, 2H), 3.46 (m, 2H), 3.12 (m, 1 H), 2.86 (m, 1 H), 2.62 (m, 3H), 1.82 (m, 3H), 1.66 (m, 1 H), 1.41 (s, 9H). By analogy to Preparative Example 8, substituted and/or unsubstituted 1-(3- chloro-propyl)-pyrrolidine and 1 -(3-chloro-propyl)-piperidine groups can be prepared with pyrrolidine and piperidine respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | EXAMPLE 2; 4-Hydroxy-4-methyl-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide, trifluoroacetate salt (I-16); Step 1-; A mixture of aniline (1 mL, 11.1 mmol), 1-chloro-3-iodo-propane (1.31 mL, 12.2 mmol) and Cs2CO3 (10.8 g, 33.3 mmol) in DMF (15 mL) was stirred at RT overnight. It was diluted with water and extracted with hexane. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified via SiO2 chromatography eluting with hexane/EtOAc, (95/5) to afford 2.52 g (67percent) of 19a (Ar=Ph) as an oil: M+H=170. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With caesium carbonate; In acetonitrile; at 100℃; for 0.416667h;Microwave reactor; | Typical procedure 1 (See Scheme 1) (TPl): 1 -f 1 -O-chloropropyiyiH-indol-3-yli-ethanone[0212] 3-Acetylindole (795 mg, 5 mmol), cesium carbonate (3.25 g, 10 mmol) and l-chloro-3-iodopropane (3.06 g, 15 mmol) were weighed into a MW vial and dry MeCN (15 mL) was added. The vial was capped and heated in the MW at 100 0C for 25 min. The reaction was filtrated and concentrated onto celite and purified by flash chromatography 0-30 percent EtOAc in heptane. Yield: 971 mg (83percent).(0213] 1H NMR (400 MHz, CDCl3) delta 8.40-8.37 (m, IH), 7.75 (s, IH), 7.37-7.28 (m, 3H)5 4.36 (t, J = 6.0 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H)5 2.51 (S5 3H), 2.30 (pentet, J= 6.0 Hz5 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With caesium carbonate; In acetonitrile; at 50℃; for 24h; | Typical procedure 2 (See Scheme 1) (TP2): l-(3-chloropropyl)-7-isopropoxy-lH-indole[0214] 7-isopropoxy-lH-indole_(736 mg, 4.2 mmol), cesium carbonate (2.73 g, 8.4 mmol) and l-chloro-3-iodopropane (2.57 g, 12.6 mmol) were weighed into a vial and dry <n="77"/>MeCN (20 mL) was added. The vial was sealed and heated on a shaker at 50 0C for 24 h. The reaction was filtrated and concentrated onto celite and purified by flash chromatography 0-20 percent EtOAc in heptane. Yield: 750 mg (71percent).[0215] 1H NMR (400 MHz, CDCl3) delta: 7.2 (d, J = 7.8 Hz, 1 H), 7.04 (d, J = 3.1 Hz, 1 H), 6.99 (t, J= 7.8 Hz, 1 H)5 6.62 (d, J= 7.8 Hz, 1 H)5 6.43 (d, J= 3.1 Hz, 1 H), 4.80 - 4.73 (m, 1 H), 4.58 - 4.49 (m, 2H), 3.49 - 3.46 (m, 2H), 2.37 - 2.35 (m, 2H), 1.45 (d, J = 5.8 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.3 - 75% | Example 4 1-(3-chloropropyl)-<strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> <strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> (1.50 g, 7.81 mmol) was dissolved in anhydrous DMF (30 mL) in an argon purged round bottom flask. The reaction was stirred in an ice-water bath and 60% sodium hydride in mineral oil (1.25 g, 31.25 mmol) was added in one portion. The reaction became dark red-orange. This solution was transferred using a cannulating needle to a solution of 1-chloro-3-iodopropane (2.52 mL, 23.47 mmol) in DMF (20 mL). The reaction was stirred at room temperature for 5 hours. The reaction was quenched with brine (25 mL), transferred to a separatory funnel and partitioned with ethyl acetate (30 mL). The aqueous was extracted twice more with ethyl acetate (2*20 mL). The combined organic layers were washed with brine, dried with sodium sulphate, decanted and concentrated to afford a yellow solid. Purification by flash column chromatography afforded a yellow solid (Ethyl acetate:hexanes, 30:70-100:0); Yield: 1.58 g (75%). 1H NMR (DMSO) delta: 8.16 (s, 1H), 8.13 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 4.09-4.04 (m, 2H), 3.71 (t, J=6.3 Hz, 2H), 3.01 (t, J=7.5 Hz, 2H), 2.66-2.61 (m, 2H), 2.04-1.99 (m, 2H). MS (ESI): 291.0 and 293.0 (M+1). Example 59 1-(3-Chloropropyl)-<strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> To a stirred solution of <strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> (5 g, 26.0 mmol) in DMF (100 ml), cooled to 0 C. was added sodium hydride (3.12 g, 78 mmol). The mixture was stirred until bubbling had ceased, then 1-chloro-3-iodopropane (8.23 ml, 78 mmol) was added. The reaction was kept in an ice bath and allowed to warm to room temperature slowly, then stirred overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3*). The combined organics were then washed with a 1:1 mixture of brine and water (3*), then brine (1*). The organic phase was dried, filtered and concentrated then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired 1-(3-chloropropyl)-<strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> (5.22 g, 19.43 mmol, 74.7% yield). Example 69 1-(3-Chloropropyl)-<strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> To a stirred solution of <strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> (2 g, 10.41 mmol) at 0 C. under argon was added sodium hydride, 60% (0.624 g, 15.61 mmol). The mixture was stirred at 0 C. until bubbling ceased, approximately 30 min. To this mixture was then added 1-chloro-3-iodopropane (3.29 ml, 31.2 mmol). The mixture was then allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (2*). The combined organics were then washed with a 1:1 mixture of water and brine (3*) then brine (1*). The organic phase was then dried, filtered and concentrated on to silica gel, then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired 1-(3-chloropropyl)-<strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> (2.05 g, 7.63 mmol, 73.3% yield) as a yellow solid. 1H NMR (DMSO-d6) delta 8.15 (m, 1H), 8.13 (dd, J=9, 2.7 Hz, 1H), 7.36 (d, J=9 Hz, 1H), 4.07 (t, J=7.4 Hz, 2H), 3.71 (t, J=6.5 Hz, 2H), 3.02 (t, J=7.4 Hz, 2H), 2.63 (t, J=7.4 Hz, 2H), 1.99 (quint, J=7.2 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Methyl 4-(2-(3-chloropropyl)-1,3-dithian-2-yl)benzoate To a dry vial was added the methyl 4-(1,3-dithian-2-yl)benzoate (KSC-335-053) (0.256 g, 1.01 mmol) and this was evacuated with argon 3 times. The dry THF (7 mL) was added and the reaction was cooled to -78° C. at and the NaHMDS (1.258 mL, 1.258 mmol) was added. After 30 minutes the 1-chloro-3-iodopropane (0.531 mL, 5.03 mmol) was added. The reaction was then allowed to warm to rt overnight. The mixture was quenched with the addition of saturated NH4Cl (10 mL) at and diluted with EtOAc (15 mL) and shaken. The EtOAc layer was collected, dried with MgSO4, filtered and adsorbed to silica and purified by MPLC (20 min, -25percent EtOAc:Hex) to produce pure methyl 4-(2-(3-chloropropyl)-1,3-dithian-2-yl)benzoate (0.102 g, 0.308 mmol, 31percent yield).). 1H NMR (400 MHz, CDCl3): delta 8.07-8.03 (m, 2H), 8.01-7.98 (m, 2H), 3.93 (s, 3H), 3.41 (t, J=6.4 Hz, 2H), 2.74-2.62 (m, 4H), 2.19-2.13 (m, 2H), 1.99-1.92 (m, 2H), 1.78-1.70 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydroxide;tetrabutylammomium bromide; In dichloromethane; at 20℃; for 20h;Reflux; | 4-(3-Chloropropyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine: A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (1.0 g, 5.10 mmol) and 1-chloro-3-iodopropane (1.075 mL, 10.19 mmol) in CH2Cl2 (10 mL) was treated with 50percent NaOH solution (10 mL), followed by tetrabutylammonium bromide (0.082 g, 0.255 mmol) at room temperature. The resulting mixture was stirred overnight (16 hours) at room temperature and then refluxed for 4 hours. The reaction was brought to room temperature and diluted with water (50 mL), and the product was extracted into CH2Cl2 (3.x.25 mL). The combined CH2Cl2 layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (1:4 to 2:3 EtOAc:hexanes) to obtain the title compound (0.65 g, 47percent) as a solid. 1H NMR (CDCl3) delta 7.96 (d, 1H, J=2.7 Hz), 7.88 (dd, 1H, J=2.7, 9.3 Hz), 6.64 (d, 1H, J=9.3 Hz), 3.84-3.80 (m, 2H), 3.65-3.60 (m, 4H), 3.05-3.02 (m, 2H), 2.16-2.08 (m, 2H); ESI-MS (m/z, percent): 273 (MH+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of tert-butyl 4-(4-chloro-l-ethoxycarbonylbutan-1-yl)piperidine-1-carboxylate 1.76 g of the title compound was obtained from ter<strong>[135716-09-5]t-butyl 4-ethoxycarbonylmethyl-piperidine-1-carboxylate</strong> (CAS No. 142851-03-4, 1.95 g) and 1-chloro-3-iodopropane (1.16 ml) according to the method in Example 113. The property value of the compound is as' follows. ESI-MS; m/z 370 [M++Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of ethyl 5-chloro-2-(tetrahydropyran-4-yl)-valerate 672 mg of the title compound was obtained from ethyl (tetrahydropyran-4-yl)acetate (CAS No. 103260-44-2, 650 mg) and 1-chloro-3-iodopropane (0.61 ml) according to the method in Example 113. The property value of the compound is as follows. ESI-MS; m/z 249 [M++H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | NaHMDS (1.0 M in THF, 100 mL, 100 mmol) was added to a stirred solution of 2-(4-fluorophenyl)acetic acid (7.71 g, 50.0 mmol) in THF (100 mL) at 0 0C. The resulting mixture was aged for 20 min at 0 0C and neat l-chloro-3- iodopropane (5.27 mL, 50.0 mmol) was added. The mixture was allowed to warm to rt. After 16 hr, the reaction was quenched with water (3 raL). The crude mixture was concentrated in vacuo. Aqueous NaOH (1 M, 150 mL) was added to the residue and the resulting mixture was extracted with Et2O (2x100 mL). The basic layer was acidified with aqueous HCl (1 M, 200 mL) and the resulting solution was extracted with Et2O (2x100 mL). The combined organic layers from the acidic extraction were washed with mixture of brine/lN HCl/sodium sulfite, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (0-10percent EtOAc/hexane, linear gradient). The pure fractions were combined and concentrated to afford 5-chloro-2-(4-fluorophenyl)pentanoic acid (7.59 g, 29.6 mmol, 59 percent yield) as a light brown solid. 1H NMR (500 MHz, chloroform-d) delta ppm 7.30 (dd, J=8.55, 5.19 Hz, 2 H) 7.04 (t, J=8.70 Hz, 2 H) 3.58 (t, J-7.78 Hz5 1 H) 3.53 (t, J-5.80 Hz, 2 H) 2.21 (dddd, J-13.35, 10.45, 7.78, 5.34 Hz, 1 H) 1.90 - 2.01 (m, 1 H) 1.65 - 1.84 (m, 2 H). | |
59% | To a solution of 2-(4-fluorophenyl)acetic acid (1.54 g, 10 mmol) in anhydrous THF (20 mL) under nitrogen and cooled to 0 °C was added NaHMDS (l .OM, 20 mL, 20 mmol) dropwise. After 20 minutes at 0 °C l-chloro-3-iodopropane (1.05 mL, 10 mmol) was added and the reaction was allowed to warm to 25 °C. After 16 hours, water (4 mL) was added to the reaction dropwise, which was then concentrated under reduced pressure. The residue was diluted with aqueous NaOH solution (1.0 M) and extracted with Et20. The aqueous phase was acidified with dilute aqueous HC1 solution to pH 5 then extracted with Et20. The organic phase was washed with sodium sulfite solution and brine, dried (MgS0 ) and concentrated under reduced pressure. The residue was purified by chromatography (silica, petroleum ether/EtOAc) to afford the title compound as a solid (1.36 g, 5.91 mmol, 59percent yield) LC-MS 229 (M- H)-. NMR (400 MHz, DMSO-d6): delta 12.38 (s, 1 H); 7.27 (t, J = 6.72 Hz, 2 H); 7.09 (t, J = 8.62 Hz, 2 H); 3.59-3.48 (m, 3 H); 2.03-1.91 (m, 1 H); 1.76-1.43 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.8% | With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium hexamethyldisilazane; In tetrahydrofuran; at -15 - 0℃; | Example 2; [0060]Synthesis of (4SV3-((2S)-5-chloro-2-r2-(trifluormethvpiphenyllpentanovU-4-phenyl-L3- oxazolin-2-one [Formula 36][0061]LHMDS (1 M solution in THF, 94.3 mL, 94.3 mmol) was added dropwise to a solution of the compound of Example 1 (27.5 g, 78.7 mmol) in THF (275 mL) at -15°C. 1- Chloro-3-iodopropane (33 mL, 315 mmol) and DMPU (94.8 mL, 787 mmol) were added dropwise thereto at -15°C. The mixture was stirred at -150C for 23 hours and at 00C for 15 hours, followed by addition of a 5percent sodium chloride solution (275 mL) and MTBE (275 mL). The organic layer was washed with a 5percent sodium chloride solution (275 mL) and concentrated under reduced pressure. The residue was extracted with a mixture of MTBE (140 mL) and heptane (140 mL) and with water. The organic layer was concentrated under reduced pressure and then azeotropically distilled with MTBE (55 mL) twice. Ethanol (83 mL) was added to the residue, followed by heating to 500C. After confirming the formation of a homogeneous solution, a small amount of seed crystals were added. After one hour at room temperature, filtration was performed. The crystals were washed with cold ethanol (15 mL) and dried under reduced pressure to obtain 17.5 g of the title compound (content: 92percent, 94.6percent de) in a yield of 51.3percent.Ethanol (48 mL) was added to the resulting title compound (content: 92percent, 16 g, 34.6 mmol), and the compound was completely dissolved by heating to 500C. The solution was gradually cooled to room temperature. The generated crystals were washed with cold ethanol (15 mL) and dried under reduced pressure to obtain 14.9 g of the title compound (content: 96.3percent, 100percent de) in a yield of 97.8percent.1H-NMR (400 MHz, CDCl3): delta 1.64-1.72 (m, IH), 1.74-1.84 (m, IH), 1.98-2.09 (m, IH), 2.12- 2.23 (m, IH), 3.44-3.53 (m, 2H), 4.31 (dd, J = 3.2, 8.8 Hz, IH), 4.68 (dd, J = 8.8, 8.8 Hz, IH), 5.36 (dd, J = 3.2, 8.8 Hz, IH), 5.54 (dd, J = 4.8, 9.2 Hz, IH), 7.28-7.34 (m, 2H), 7.35-7.46 (m, 4H), 7.52-7.59 (m, 1 H), 7.60-7.68 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Sodium hydride (1.96 g, 49.337 mmol, 60percent suspension in mineral oil) was treated with DMF (60 mL), followed by 6-nitroindole (6) (2.0 g, 12.334 mmol) in DMF (20 mL) over a period of 5 min at 0° C. After stirring for 15 min, the solution was treated with 1-chloro-3-iodopropane (3.9 mL, 37.002 mmol), the reaction was brought to room temperature and stirred for 3 h. The reaction was quenched with saturated brine (80 mL), water (80 mL) and cooled to 0° C. The solid was filtered off, washed with water (50-75 mL) and dried to obtain the crude product. The crude product was recrystallised from hot toluene (10 mL)/hexanes (5 mL) to obtain compound 148 (2.637 g, 90percent) as solid. mp 85-87° C.; 1H-NMR (CDCl3) delta 2.28-2.36 (m, 2H), 3.46 (t, 2H, J=5.7 Hz), 4.45 (t, 2H, J=6.6 Hz), 6.62 (d, 1H, J=2.7 Hz), 7.43 (d, 1H, J=3.0 Hz), 7.66 (d, 1H, J=8.7 Hz), 8.02 (dd, 1H, J=1.8, 7.9 Hz), 8.36 (d, 1H, J=0.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Intermediate 54-(3~chloropropyl)-<strong>[4295-99-2]tetrahydro-2H-pyran-4-carbonitrile</strong>. To a stirred solution of 1 M LiHMDS (25 mL, 25 mmol) in THF (10 mL) at -78 0C was added dropwise a solution of intermediate 4 (2.23 g, 20 mmol) in THF (15 mL) over 10 minutes. After 40 min, l-chloro-3-iodopropane (2.7 mL, 25 mmol) was added at once, stirred at -78 C for 1 h and 4 h room temperature. Then the reaction mixture was diluted with ether (100 mL), washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated to give yellow oil which was purified by flash column chromatography using 10-30% EtOAc/Hexanes to afford the product intermediate 5 as a colorless liquid (3.737 g, 99%). 1H NMR (500 MHz, CDCl3) delta: 3.97 (2H, dd, J = 11.3, 3.7 Hz), 3.71 (2H, td, J = 12.2, 1.8 Hz), 3.61 (2H, t, J = 6.3 Hz), 2.05-1.98 (2H, m), 1.88 (2H, dd, J = 13.4, 1.8 Hz), 1.77-1.74 (2H, m), 1.65-1.59 (2H, m). | |
99% | 4-(3-Chloropropyl)-<strong>[4295-99-2]tetrahydro-2H-pyran-4-carbonitrile</strong>. To a stirred solution of 1 M LiHMDS (25 mL, 25 mmol) in THF (10 mL) at -78 C. was added dropwise a solution of <strong>[4295-99-2]tetrahydro-2H-pyran-4-carbonitrile</strong> (2.23 g, 20 mmol) in THF (15 mL) over 10 minutes. After 40 min, 1-chloro-3-iodopropane (2.7 mL, 25 mmol) was added at once, stirred at -78 C. for 1 h and 4 h room temperature. Then the reaction mixture was diluted with ether (100 mL), washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated to give yellow oil which was purified by flash column chromatography using 10-30% EtOAc/Hexanes to afford the title compound as a colorless liquid (3.74 g, 99%). 1H NMR (500 MHz, CDCl3) delta: 3.97 (2H, dd, J=11.3, 3.7 Hz), 3.71 (2H, td, J=12.2, 1.8 Hz), 3.61 (2H, t, J=6.3 Hz), 2.05-1.98 (2H, m), 1.88 (2H, dd, J=13.4, 1.8 Hz), 1.77-1.74 (2H, m), 1.65-1.59 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Step 2: To a cooled (-78 °C) solution of compound 402 (2.3 g, 8.4 mmol) in Et20 (25.5 ml.) was added drop-wise phenyl lithium (1 .8 M in dibutyl ether, 5.2 ml_, 9.3 mmol) keeping the internal temperature less than -65 °C. A white precipitate formed and the mixture became thick. The mixture was warmed to 0 °C and stirred for 30 minutes, and cooled back down to -78 °C and a solution of 1 -chloro-3-iodopropane (2.7 ml_, 25.3 mmol) in THF (5.0 ml.) was added. The reaction was warmed to room temperature and stirred overnight. The solution was diluted with EtOAc, washed sequentially with saturated NH4CI and brine, dried over MgS04, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel which was eluted with heptanes/EtOAc (0-20percent) and gave compound 403 as a clear gum (2.3 g, 78percent yield). 1H NMR (400 MHz, DMSO-d6) delta 3.67 (t, J = 6.3 Hz, 2 H), 3.03 - 2.97 (m, 2 H), 2.95 (s, 6 H), 2.20 (s, 3 H), 2.07 - 1.93 (m, 2 H). | |
Step 2: 4-Bromo-5-(3-chloro-propyl)-3-methyl-pyrazole-1 -sulfonic acid dimethylamideBrTo a solution of 4-bromo-3-methyl-pyrazole-1 -sulfonic acid dimethylamide (6.7 g, 25 mmol) in diethyl ether (75 ml.) was added dropwise at -780C under N2 phenyl lithium (1.8 M, 14.6 ml_, 26.3 mmol) in dibutyl ether. After warming to O0C for 15 m, the reaction mixture was re-cooled to -780C and a solution of 3-chloro-iodopropane (15.3 g, 75 mmol) in 20 ml. THF was added dropwise. The reaction was warmed to room temperature and stirred for 3 h before quenching with a saturated aqueous solution of NH4CI. The quenched reaction mixture was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified over normal phase silica starting with 5percent EtOAc in heptane for 10 m and then increasing to 50percent EtOAc in heptane for 20 m to give the desired product as a clear oil (3.85 g, 1 1.2 mmol) MS m/z 346.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A) Methyl 5-chloro-2-(2-fluorophenyl)-2-(6-methyl-3-nitropyridin-2-yl) pentanoate (XII) To 11.6 g of sodium hydride at 60% in oil in suspension in 100 ml of DMF is added at -10 C., dropwise, the mixture of 20 g of <strong>[56057-19-3]<strong>[56057-19-3]2-chloro-6-methyl-3-nitropyridin</strong>e</strong> and 21.5 g of methyl 2-fluorophenyl acetate in solution in 100 ml of DMF. The reaction mixture is stirred for 1 h 30 min, allowing the temperature to rise to RT; and then 19.1 ml of 1-chloro-3-iodopropane are added. The mixture is stirred at RT for 18 h. The mixture is poured over 600 ml of a 10% aqueous NH4Cl solution and the mixture is extracted with 300 ml of AcOEt. The organic phase is washed with brine, dried over MgSO4, filtered and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with a heptane/dichloromethane mixture to give the expected compound in the form of an orange-coloured oil. MH+=381; tr=9.15 min (M4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | NaH (60 percent dispersion in mineral oil; 2.0 g, 49 mmol) was added to a solution of methyl-2-chlorophenylacetate (8.3 g, 45 mmol) in DMF (120 ml) at 0°C. The r.m. was stirred at 0 °C for 10 min and for 30 min at r.t. The r.m. was then cooled again to 0 °C and l-chloro-3-iodopropane (5.1 ml, 48.1 mmol) was added dropwise under stirring. The r.m. was stirred at r.t. for 20 h. H20 was then carefully added followed by Et20, and the layers were separated. The organic layer was washed with H20 and brine, was dried (MgSC^), and was then evaporated under reduced pressure to yield intermediate 22 (8.75 g, 75 percent) which was used as such in the next reaction step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In acetonitrile; at 80℃; for 3h; | To a 2-L round-bottom flask was added methyl 4-hydroxy-3-methoxybenzoate (100 g, 548.93 mmol, 1.00 eq.), 1-chloro-3-iodopropane (224 g, 1.10 mol, 2.0 eq.), K2C03 (22.7 g, 3.00 eq.) followed by MeCN (1 L). The resulting mixture was allowed to stir at 80 °C for 3 h. The mixture wascooled to rt, the solids were filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure to afford methyl 4-(3-chloropropoxy)-3-methoxybenzoate as a white solid (12890percent). |
With potassium carbonate; In acetonitrile; at 80℃; for 3h; | To a 2-L round-bottom flask was added methyl 4-hydroxy-3-methoxybenzoate (100 g, 548.93mmol, 1.00 eq.), i-chloro-3-iodopropane (224 g, 1.10 mol, 2.0 eq.), K2C03 (22.7 ,3. 00 eq.)followed by CH3CN (1 L). The resulting mixture was allowed to stir at 80 C for 3 h. The reaction mixture was cooled to 11, the solids were filtered off and washed with EtOAc. The filtrate wasconcentrated under reduced pressure to afford the desired crude product of methyl 4-(3 chloropropoxy)-3-inethoxybenzoate as a white solid (128 g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | 152 mg (0.53 mmol) of 4-(4-chlorophenyl)-7-methoxyphthalazin-1(2H)-one (1c) was dissolved in 10 ml of N,N-dimethylformamide, and 25 mg (0.64 mmol) of sodium hydride were added at 0oC. After being stirred for 30 min, 0.08 ml (0.80 mmol) 3-iodo-1-chloropropane was then added to reaction mixture. After being stirred for 1 h, the reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml X 2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (ethyl acetate : n-hexane = 1 : 3) to obtain 193 mg (yield 99percent) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | 335 mg (1.30 mmol) of 4-(3,4-difluorophenyl)phthalazin-1(2H)-one (8n) was dissolved in 10 ml of N,N-dimethylformamide, and 62 mg (1.56 mmol) of sodium hydride were added at 0oC. After being stirred for 30 min, 0.21 ml (1.95 mmol) 3-iodo-1-chloropropane was then added to reaction mixture. After being stirred for 1 h, the reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml X 2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (ethyl acetate : n-hexane = 1 : 3) to obtain 400 mg (yield 92percent) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | A solution of [2-(trifluoromethyl)phenyl]acetic acid (3.06 g, 15.0 mmol) in toluene (30 mL) was heated to 80°C, 1,1-di-tert-butoxy-N,N-dimethylmethaneamine (14.4 g, 60.0 mmol) was added and the mixture was stirred at 80°C for 2 hr. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The obtained extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100 - 30/70) to give tert-butyl [2-(trifluoromethyl)phenyl]acetate (3.16 g, 81percent). To a solution of tert-butyl [2-(trifluoromethyl)phenyl]acetate (3.10 g, 11.9 mmol) in DMF (36 mL) was added sodium hydride (60percent oil, 524 mg, 13.1 mmol), and the mixture was stirred at room temperature for 30 min. 1-Chloro-3-iodopropane (1.34 mL, 12.5 mmol) was added, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100 - 30/70) to give tert-butyl 5-chloro-2-[2-(trifluoromethyl)phenyl]pentanoate (3.63 g, 91percent). A solution of tert-butyl 5-chloro-2-[2-(trifluoromethyl)phenyl]pentanoate (3.56 g, 9.83 mmol) in TFA (10 mL) was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was extracted with 1 M aqueous sodium hydroxide solution. The extract was acidified with 6 M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (2.74 g, 99percent). 1H NMR (CDCl3) delta: 1.55 - 1.75 (1 H, m), 1.76 - 2.04 (2 H, m), 2.16 - 2.34 (1 H, m), 3.50 (2 H, t, J=6.3 Hz), 4.06 (1 H, t, J=7.3 Hz), 7.31 - 7.45 (1 H, m), 7.46 - 7.62 (2 H, m), 7.67 (1 H, d, J=7.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | General procedure: A mixture of 5,6-dimethoxy-1-oxo-indan-2-carboxylic acid ethyl ester 14 (235 mg, 0.88 mmol) and NaH (79.5 mg, 2.65 mmol, 80percent dispersion in mineral oil) in DMF (8 mL) was stirred at room temperature for 30 min, after which 1-chloro-3-iodo propane (0.185 mL, 1.76 mmol) was added. The reaction mixture was stirred at room temperature for 20 h and quenched by adding water (15 mL) and aqueous HCl (1 mL, 1.0 N). The mixture was extracted with dichloromethane (3 * 20 mL), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, EtOAc/PE, 1/4) to generate the title compound (200 mg, 66percent) as pale yellow oil. 1H NMR (300 MHz, CDCl3): delta 7.09 (s, 1H), 6.85 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.55 (d, J = 17.0 Hz, 1H), 3.44 (t, J = 6.5 Hz, 2H), 2.91 (d, J = 17.0 Hz, 1H), 2.14 (m, 1H), 1.95 (m, 1H), 1.67 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): delta 200.5, 171.0, 156.0, 149.7, 148.3, 127.6, 107.0, 104.7, 61.4, 60.1, 56.2, 55.9, 44.7, 36.5, 32.0, 27.8, 13.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Step A: To a solution of methyl 3-(3-fhioro-4-(l-(l-(3-isopropyl-l,2,4- thiadiazol-5-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)phenylthio)propanoate (Example 44, Step A; 1.4 g, 2.7 mmol) in THF (50 mL) was added potassium 2-methylpropan-2-olate (8.0 mL, 8.0 mmol) and the reaction was stirred for 5 minutes at ambient temperature, followed by the addition of water (10 mL) and l-chloro-3-iodopropane (0.86 mL, 8.0 mmol). The reaction was stirred at ambient temperature for 2 hours. The reaction was poured into water and extracted into EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The crude material was purified over silica gel (30percent EtOAc/CH2Cl2) to yield 3-(4-(3-chloropropylthio)-2-fluorophenoxy)-l-(l-(3-isopropyl- l,2,4-thiadiazol-5-yl)piperidin-4-yl)pyrrolidin-2-one (1.2 g, 86percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: 3.5 Typical procedure for the preparation of 1-bromo-2-(1-isocyanoalkyl)benzenes 3e?i and l: To a stirred solution of LDA (2.0 mmol), generated from i-Pr2NH and n-BuLi by the standard method, in THF (5 mL) at ?78 °C was added a solution of 3a (0.29 g, 1.4 mmol) in THF (2 mL) dropwise. After 20min, MeI (0.29 g, 2.0 mmol) was added and stirring was continued an additional 20 min before satd aq NH4Cl and water (10 mL each) was added. The mixture was warmed to room temperature and extracted with AcOEt (3×10 mL). The combined extract was washed with brine (1 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on silica gel to afford 3e (2.7 g, 87 percent); a pale-yellow liquid; Rf 0.43 (AcOEt/hexane 1:5); IR (neat) 2133cm?1; 1H NMR (500MHz) delta 2.01 (s, 6H), 7.19 (dd, J=8.0, 7.4Hz, 1H), 7.36 (dd, J=8.0, 7.4Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.71 (d, J=8.0Hz, 1H); 13C NMR delta 29.63, 61.88 (t, J=6.0Hz), 120.29, 127.38, 127.83, 129.58, 135.99, 138.89, 156.72 (t, J=4.8Hz). HRMS calcd for C10H11BrN: M+H, 224.0075. Found: m/z 224.0065. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In tetrahydrofuran; | Embodiment 6 Preparation of 1-ethoxycarbonyl-4-(3-chloropropyl)-3-pyrrolidone <strong>[1027-35-6]1-benzyl-4-ethoxycarbonyl-3-pyrrolidone</strong> (2.5 g, 10.1 mmol) is dissolved in 25 ml tetrahydrofuran and then cooled by ice water bath, triethylamine (2 g, 20.2 mmol) is added and stirring is performed for 30 minutes, 1-chloro-3-iodopropane (4.12 g, 20.2 mmol) is dripped, this dripping is finished 30 minutes later, afterwards, the temperature is raised to room temperature for the purpose of continuous reaction for 18 hours. Extraction is carried out by methylene dichloride (10 ml*3 times) at the end of reaction, organic phase is combined and dried by anhydrous sodium sulfate, and the solvent is dried by concentration under reduced pressure to obtain oily product, which is then purified by column chromatography to obtain oily product (6-1) (2.12 g, 6.57 mmol, yield 65percent). 1H NMR (500 MHz, CDCl3) delta7.34-7.27 (m, 5H), 4.17 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 3.48-3.51 (m, 2H), 3.40 (d, J=9.6 Hz, 1H), 3.19 (d, J=17.2 Hz, 1H), 2.99 (d, J=17.2 Hz, 1H), 2.73 (d, J=9.6 Hz, 1H), 2.04-2.02 (m, 1H), 1.92-1.89 (m, 2H), 1.71-1.69 (m, 1H), 1.24 (t, J=7.1 Hz, 3H). MS-ESI: m/z: 324 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | To a suspension of NaH (1.10 g, 60 percent in mineral oil, 27.5 mmol) in THF (40 mL) at 0 was added a solution of triethyl phosphonoacetate (6.05 g, 5.3 mL, 27.0 mmol) in THF (20 mL) during a period of 5 min. The mixture was kept at 0 for 60 min. Then a solution of 1-chloro-3-iodopropane (2.04 g, 1.05 mL, 10.0 mmol) in THF (20 mL) was added dropwise over a period of 5 min. Then the mixture was kept at room temperature for an additional 24 h. The reaction was quenched by addition of saturated NH4Cl (15 mL), then THF was removed by vacuum distillation. The aqueous phase was extracted with EtOAc (30 mL*3), and washed with brine (40 mL). The combined organic layers were dried over NaSO4 and concentrated. The residue was purified by flash chromatography to give the substitued phosphonoacetate 6 (rotamers in a 1:1 ratio) as a slight yellow oil (2.54 g, 84percent yield from the 1-chloro-3-iodopropane 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | <strong>[1027-35-6]1-benzyl-4-ethoxycarbonyl-3-pyrrolidone</strong> (2.5g, 10.1mmol) is dissolved in 25ml tetrahydrofuran and then cooled by ice water bath, triethylamine (2g, 20.2mmol) is added and stirring is performed for 30 minutes, 1-chloro-3-iodopropane (4.12g, 20.2mmol) is dripped, this dripping is finished 30 minutes later, afterwards, the temperature is raised to room temperature for the purpose of continuous reaction for 18 hours. Extraction is carried out by methylene dichloride (10ml × 3 times) at the end of reaction, organic phase is combined and dried by anhydrous sodium sulfate, and the solvent is dried by concentration under reduced pressure to obtain oily product, which is then purified by column chromatography to obtain oily product (6-1) (2.12g, 6.57mmol, yield 65percent). 1H NMR (500 MHz, CDCl3) delta7.34-7.27 (m, 5H), 4,17 (q, J = 7.1Hz, 2H), 3.71(s, 2H), 3.48-3.51(m, 2H), 3.40 (d, J = 9.6Hz ,1H), 3.19 (d, J = 17.2Hz,1H), 2.99 (d, J =17.2Hz,1H), 2.73 (d, J = 9.6Hz, 1H),2.04-2.02(m, 1H),1.92-1.89(m,2H),1.71-1.69(m, 1H),1.24(t, J = 7.1Hz, 3H). MS-ESI: m/z:324(M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In acetonitrile; at 80℃; for 3h; | Step 11 -(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl) cyclobutanecarbonitrile10219] 1 -(4-(Hydroxyl)-5-methoxy-2-nitrophenyl)cy- clobutanecarbonitrile (0.5 g, 2 mmol) in MeCN (10 mE) wastreated with potassium carbonate (0.306 g, 2.2 mmol) and 1 -chloro-3-iodopropane (0.425 mE, 4 mmol) and stirred at80° C. for 3 hours. The reaction mixture was concentrated, extracted with dichloromethane and washed with brine. The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-24percent EtOAc/hexane) afforded 0.63 g (96percent) of 1 -(4-(3-chloropro- poxy)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile.MS (ESI) mlz 325 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | To a solution of 5j (250 mg, 1.01 mmol) in DMF (10 mL) were added sodium hydride (48 mg, 1.21 mmol) and 3-iodo-1-chloropropane (0.17 mL, 1.52 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h, diluted with water (50 mL), and extracted with ethylacetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/n-hexane, 1/3) to afford 6j (309 mg, 95 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 9h; | To a mixture of 1-chloro-3-iodopropane (6.133 g, 0.03 mol) and NaH (3 g, 0.075 mol) in THF (25 ml) at 0C, phenothiazine (5 g, 0.025 mol) in THF (25 ml) was added. The mixture was stirred at room temperature for 9 h. After work-up, 10-(3-chloropropyl)-10H-phenothiazine was obtained in 37% yield. |
8.3 g | Step 1 - Preparation of 10-(3-chloropropyl)-l OH-phenothiazine To a flask containing phenothiazine (5.45 g, 27.3 mmol) and DMF (140 mL) at 0C was added sodium hydride (60% in mineral oil, 2.19 g, 54.7 mmol). After stirring for 1 hour this mixture was added to a solution of l-chloro-3-iodopropane (8.65 mL, 82.0 mmol) in DMF (10 mL) over the course of 10 minutes and stirred overnight at room temperature. The reaction mixture was transferred to a separatory funnel, diluted with saturated sodium bicarbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0-2% ethyl acetate/hexanes to afford 8.3 grams of material that was of sufficient purity to be used in the next step. LCMS: ESI+ m/z of 276 and 278 (M+H for C135 and C137). NMR (400 MHz, CDC13) delta (ppm) = 2.24-2.30 (m, 2H), 3.68-3.71 (m, 2H), 4.10-4.13 (m, 2H), 6.92-6.99 (m, 4H), 7.18-7.22 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Synthesis of compound 7c To a suspension of NaH (22 mg, 0.85 mmol) in DMF (2.0 mL) was added S1 (305 mg, 0.78 mmol)in DMF (1.5 mL). After 10 min at room temperature, S4a (0.20 mL, 1.53 mmol) was added to thismixture, and the reaction mixture was stirred at room temperature for 6 h, diluted with ether,washed with water and dried over Na2SO4. Purification by FCC (PE/EtOAc, 8 : 1) gave thechloride S5a (344 mg, 94percent) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 7.81 (d, J = 1.8 Hz,1H), 7.80 (d, J = 7.9 Hz, 1H), 7.24 (dd, J = 1.8, 7.9 Hz, 1H), 3.74 (s, 6H), 3.54 (t, J = 6 Hz, 2H),3.23 (s, 2H), 1.98-1.94 (m, 2H), 1.80-1.73 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 170.6, 151.7,143.4, 142.6, 130.6, 125.3, 86.3, 58.4, 52.7, 44.4, 37.9, 30.3, 27.6. | |
84% | To a suspension of NaH (22 mg, 0.85 mmol) in DMF (2.0 mL) was added S1 (305 mg, 0.78 mmol) in DMF (1.5 mL). After 10 min at room temperature, S4a (0.20 mL, 1.53 mmol) was added to this mixture, and the reaction mixture was stirred at room temperature for 6 h, diluted with ether,washed with water and dried over Na2SO4. Purification by FCC (PE/EtOAc, 8 : 1) gave the chloride S5a (344 mg, 94percent) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.4 g | To a cooled (-78 C.) solution of <strong>[34941-92-9]4-chloro-2-fluoro-pyridine</strong> (2.0 g, 15 mmol) in THF (15 mL) is added LDA solution (9.1 mL, 18 mmol, 2.0 M in THF). After the mixture is allowed to stir at -78 C. for 90 min, 1-chloro-3-iodo-propane (4.9 mL, 46 mmol) is added and the mixture is allowed to slowly warm to room temperature for 16 hrs. Then reaction is quenched with saturated NH4Cl and the mixture is extracted with DCM (3×). The combined organic layers are washed with brine, dried over Na2SO4 and concentrated to give the crude product. Purification by flash column chromatography affords 2.4 g of 4-chloro-3-(3-chloro-propyl)-2-fluoro-pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | A solution of LDA in THF/heptane/ethylbenzene (2.0 M, 137 mL, 274 mmol) was added slowly over 90 min to a stirring solution of N,N'-diisopropyl-2,3-butanediimine (20.0 g, 119 mmol) in distilled THF (180 mL) under N2, maintained at -78 °C and stirred for an additional 5 h. A solution of 1-chloro-3-iodopropane (57.4 g, 280 mmol) in distilled THF (20 mL) was added over 15 min and the mixture was stirred at -78 °C under N2. After 15 h, aqueous HCl (1M, 600 mL) was added and the mixture was allowed to stir at room temperature (RT) for 5 h. THF was removed under reduced pressure, and CH2Cl2 (160mL x 3) was used to extract the product from the remaining aqueous layer. The organic layers were combined and washed with HCl (1M, 60mL), H2O (120 mL) and sat. NaHCO3 (120mL), and the organic layer was then dried over MgSO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to yield a crude orange oil. The oil was purified by distillation (133?137 °C/0.08 mmHg) to give 6 (22.5 g, 94.1 mmol, 79percent) as a yellow oil. 1H NMR (500 MHz,CDCl3): 3.55 (t, J = 6.3, 4H), 2.79 (t, J = 7.1, 4H), 1.85?1.70 (m, 8H). 13C NMR (125MHz, CDCl3): 198.9, 44.4, 35.1, 31.7, 20.2. ESI-MS: m/z 241 ([M + H]+, calcd for C10H1735Cl37ClO2 , 241.17554). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | To a solution of 2-(methylthio)propanenitrile (10.0 g, 98.8 mmol) in tetrahydrofuran (99 ml) wasadded 1.0 M solution lithium bis(trimethylsilyl)amide in tetrahydrofuran / ethylbenzene (109 ml,109 mmol) at -15 to -10 °C. After 1 h, 1-chloro-3-iodopropane (22.2 g, 11.5 ml, 109 mmol) was added in a quick fashion. The cooling bath was removed after the addition and stirring was continued for 2 h. The reaction mixture was partitioned between tert-butyl methyl ether (100 ml) and aqueous saturated ammonium chloride solution (50 ml). The layers were separated. Theorganic layer was washed with one 100-ml portion of aqueous saturated ammonium chloride solution and one 100-ml portion of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (12.4 g, 71percent) as light yellow oil. MS mle: 177 ([M]j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | General procedure: 1-Boc-piperazine (2 g, 10.74 mmol, 1.0 equiv) was combined with K2CO3 (5 equiv) in DMF (10 mL), followed by 1-Chloro-3-iodoproprane (1.0 equiv) and the mixture was stirred at 50 °C for 1 h. The reaction progress was monitored by LC-MS and upon completion of the reaction 4-cyanophenol (1.2 equiv) and sodium iodide (0.1 equiv) was added and the reaction allowed to stir at 70 °C for 2 h. The mixture was poured onto water and extracted with EtOAc, washed with brine and dried over Na2SO4. The volatiles were removed under reduced pressure and the crude mixture purified on silica gel (60 ? 90 °C PE : EtOAc = 3:1) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | 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 |
---|---|---|
72% | With caesium carbonate; In acetonitrile; at 20℃; | A 4 or 7 mE vial was charged with 4H-benzo[1,4]oxazin- 3-one (1.0 equiv), Cs2CO3 (1.5 equiv) and 3-chloro-1- iodopropane (1.1 equiv) in 3 mE dry MeCN and shaken atfor 66-72 h. The reaction mixture was diluted with 10 mEH20 and extracted into CH2C12 or EtOAc (3x30 mE). The combined organic layers were dried over Mg504 or filtered through a PTFF Whatman filter and concentrated. Theresidue was purified by CC (Heptane/EtOAc) or used without further purification in the next step; 6-l3romo-8-fluoro-4H-benzo[1 ,4]oxazin-3-one (95MF44)(0.091 g, 0.37 mmol), Cs2CO3 (0.180 g, 0.55 mmol) and3-chloro-1-iodopropane (0.083 g, 0.41 mmol) were mixedaccording to GP5. CC (Si02Heptane/EtOAc 9:1-4) gave thetitle compound (95MF50(2084)) (0.086 g, 72percent). ?H NMR(CDC13) oe 7.02-6.96 (m, 1H), 6.85 (d, J=5.2 Hz, 1H), 4.65(s, 2H), 4.04-4.11 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.10-2.18(m, 2H); ?3C NMR (CDC13) oe 163.8, 151.7 (d, J=250.9 Hz),133.1 (d, J=14.6 Hz), 131.5 (d, J=3.8 Hz), 115.1 (d, J=21.5Hz), 114.2 (d, J=10.0 Hz), 113.4 (d, J=3.4 Hz), 67.6, 42.2,39.5, 30.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With caesium carbonate; In acetonitrile; at 20℃; for 72h; | A 100 mE flask was charged with 4H-benzo[1,4]oxazin-3-one (1.0 equiv), Cs2CO3 (1.5 equiv) and 3-chloro-1-iodopropane (1.1 equiv) in 50 mE dry MeCN and stirred atfor 72 h. The reaction mixture was evaporated to drynessand diluted with 100 mE H20 and extracted into EtOAc(3x100 mE). The combined organic layers were dried overMgSO4, filtrated, evaporated to dryness and purified by CC(Heptane/EtOAc); 6,8-Dichloro-7-methyl-4H-benzo[ 1 ,4]oxazin-3-one(81MF2225a) (2.33 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (Si02 Heptane/EtOAc 10:1-5) gave the title compound (81MF2225b) (2.44 g, 79percent). ?H NMR (CDC13) oe 7.02 (s, 1H), 4.67 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2, 2H), 2.43 (s, 3H), 2.18-2.10 (m, 2H); ?3C NMR (CDC13) oe 163.7, 140.5, 130.3, 128.3, 127.6, 124.1, 113.5, 67.9, 42.2, 39.3, 30.0, 17.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | 2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3 (3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mE) under nitrogen atmosphere and stirred at rt for 30 mi 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mE) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mE) was added and the reaction mixture was extracted with ethyl acetate (3x1 50 mE). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4: 1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2percent. R1=0.24 [Heptane:EtOAC(4:1)], ?H NMR (CDC13):o 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), ?3C NMR (CDC13): 0 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49,145.47, 164.58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.2% | 2H-1,4-benzothiazine-3(4H)-one (1.0 g, 6.05 mmol) and Cs2CO3 (2.96 g, 9.08 mmol) were dissolved in dry acetonitrile (20 mE) under nitrogen atmosphere and stirred at it for30 mi 3-chioro-1-iodopropane (1.37 g, 6.66 mmol) dis60 solved in acetonitrile (4 mE) was added via a syringe. Thereaction mixture was stirred at it for 18 hours and concentrated in vacuo. Water (150 mE) was added and the reaction mixture was extracted with ethyl acetate (3x1 50 mE). Thecombined organic phases were dried (Mg504) and concen65 trated in vacou to give 1.45 g of crude. The crude productwas subjected to CC[eluent:Heptane:EtOAC(4: 1)] to give the pure title compound as a slightly yellow oil. Yield 1.37g, 90.2percent. R=0.24 [Heptane:EtOAC(4:1)], ?H NMR(CDC13): oe 2.14 (m, 2H), 3.38 (s, 2H), 3.36 (t, 2H), 4.17 (t,2H), 7.03 (t, 1H), 7.18 (d, 1H), 7.26 (t, 1H), 7.37 (d, 1H). ?3CNMR (CDC13): oe 30.61,31.81,42.48,42.66, 117.87, 123.78,124.29, 127.52, 127.52, 128.78, 139.40, 165.51 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With caesium carbonate; In acetonitrile; at 20℃; for 40h; | A reaction flask was charged with 6,7-difluoro-4H-benzo [1 .4]oxazin-3-one (9.0 g, 54 mmol), 1 -chloro-3-iodopropane(12.06 g, 59 mmol), and Cs2CO3 (26.39 g, 81 mmol) inMeCN (150 mE) and stirred at it for 40 h. The reactionmixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (Si02 n-heptane/EtOAc 4:1) to give the title compound (11.35 g, 86percent). ?H NMR (CDC13) oe 6.93-6.82 (m, 2H), 4.57 (s, 2H), 4.05-4.01(m, 2H), 3.62 (t, J=6.1 Hz, 2H), 2.17-2.10 (m, 2H); HPECMS (ammonium acetate) [M+H]=407.29 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | a) Methyl-5-chloro-2-(2-chloro-4-fluorophenyl)pentanoate In a 250 ml three-necked flask, <strong>[214262-88-1]methyl 2-(2-chloro-4-fluorophenyl)acetate</strong> (3.98 g, 19.6 mmol) was combined with dimethylformamide (70 ml) to give a colorless solution. At 0C sodium hydride (943 mg, 21.6 mmol) was added slowly in small portions. Stirring was continued for 10 minutes at 0C and then for 30 minutes at room temperature. The reaction mixture was then cooled again to 0C and l-chloro-3-iodopropane (4.30 g, 2.26 ml, 21.0 mmol) was added dropwise under stirring (temperature < 5C). Stirring was continued at 0C for 1 hour and then at room temperature overnight. The reaction mixture was slowly poured into 100 ml water and extracted with ethyl acetate (4 x 150 ml). The organic layers were combined and washed with saturated brine (2 x 100 ml). The organic layers were dried over magnesium sulfate, concentrated in vacuo and purified by chromatography (silica gel, 40 g, ethyl acetate/heptane = 0: 100 to 50:50) to yield the title compound as colorless liquid (4.63 g, 84%). MS: m/z = 279.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.5% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | (0917) <strong>[16292-95-8]3-Methoxy-4-nitrophenol</strong> (2.5 g, 14.79 mmol) was dissolved in N,N-dimethylformamide (30 mL), and 3-iodo-1-chloropropane (3.62 g, 17.74 mmol) and potassium carbonate (3.1 g, 22.30 mmol) were added. The reaction was carried out at room temperature overnight. After the reaction, water (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to get the title compound (2.3 g, yield: 63.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | A solution of methyl N-Boc-2-piperidinecarboxylate (21.9 g, 0.09 mol) in 60 ml of THF was added dropwise to a solution of LDA (0.1 mol, 2.0 mol / L in THF), the temperature was maintained at -70 ° C during the dropwise addition, and the temperature was maintained at -70 ° C After mixing for 2 h, 1-chloro-3-iodopropane (34.8 g, 0.17 mol) in THF was added at -70 ° C and the system was allowed to warm to room temperature. overnight. The system was quenched with saturated NH4Cl solution (200 ml) and extracted with ethyl acetate (200 ml x 3). The organic phase was saturated with salt Washed with water, dried over anhydrous sodium sulfate and evaporated to obtain crude product (24.7 g). The product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 16 / 1) was pure (18.7 g, 65percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | A solution of N-BOC-L-proline methyl ester (20 g, 0.09 mol) in 60 ml of THF was added dropwise to the LDA solution (0.1 mol, 2.0 mol / L in THF), maintaining the temperature- 70 ° C, dropwise to keep the temperature at -70 ° C for 2 hAfter adding 1-chloro-3-iodopropane (34.8 g, 0.17 mol) in THF at -70 ° C, the system was allowed to warm to room temperature and reacted night. The system was quenched with saturated NH4Cl solution (200 ml) and extracted with ethyl acetate (200 ml x 3). The organic phase was washed with saturated brine Washed with anhydrous sodium sulfate, and desalted 27 g of crude product. The product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 12/1) (19.2 g, 70percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In acetonitrile; at 80℃; for 4h; | Into a 100-mL round-bottom flask was placed ACN (100 mL), <strong>[450-93-1]4-fluoro-2-methoxyphenol</strong> (5 g, 35.18 mmol, 1.00 equiv.), 1-chloro-3-iodopropane (14.4 g, 70.44 mmol, 2.00 equiv), and potassium carbonate (14.6 g, 105.64 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 80 C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 7.7 g (100%) of the title compound as a yellow oil. Analytical Data: LC-MS: (ES, m/z): RT = 1.365 mi m/z = 219 [M+1]. |
98% | With potassium carbonate; In acetonitrile; at 85℃; for 14h; | Into a 50-mL round-bottom flask, was placed 4-fluoro-2-methoxy phenol (1 g, 7.04 mmol, 1 equiv), l-chloro-3-iodopropane (2.87 g, 14.04 mmol, 2.00 equiv), potassium carbonate (2.92 g, 21.13 mmol, 3.00 equiv), ACN (15 mL). The resulting solution was stirred for 14 h at 85 C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.5 g (98%) of as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In acetonitrile; at 85℃; for 3h; | Into a 500mL roundbottom flask, was placed a mixture of 2methoxy-5nitrophenoi (10,0 g,59.17 mmoi, 1.00 eq.), CH3CN (200 mL), ichior&-3-iodopropane (18.11 g, 88.76 mmol, 1.50 eq.)and potassium carbonate (16.33 g, 118.34 mnmnol, 2.00 eq.). The resulting mixture was allowed to stirat 85 C for 3 h and cooled to room temperature. The solids were filtered off and the filtrate was concentrated under vacuum. The residue was purified by a silica gel column eluted with ethyl acetate/petroleum ether (1/2) to provide 2-(3--chloropropoxy)--Imethoxy4nitrobenzene as an offwhite solid (7.86 g, 54%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.27 g | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5h;Inert atmosphere; | To a solution of 2,6-dichloro- 4-iodo-phenol (1) (1.0 g, 3.46 mmol) in DMF (20 mL) was added l-chloro-3-iodo-propane (2) (708 mg, 3.46 mmol) and CS2CO3 (2.26 g, 6.92 mmol) under N2 atmosphere at 20 C. The reaction was stirred at 60 C for 5 hours. TLC showed the reaction was completed. The solution was poured into H2O (20 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over NaiSOr. filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to give 1,3- dichloro-2-(3-chloropropoxy)-5-iodobenzene (80.0 %, 1.27 g, yield: 80.3 %) as brown oil. NMR(400MHz, CHCb-d) d 7.63 (s, 2H), 4.15 (t, .7=5.7 Hz, 2H), 3.85 (t, 7=6.4 Hz, 2H), 2.28 (t..7=6. 1 Hz. 2H). |
Tags: 6940-76-7 synthesis path| 6940-76-7 SDS| 6940-76-7 COA| 6940-76-7 purity| 6940-76-7 application| 6940-76-7 NMR| 6940-76-7 COA| 6940-76-7 structure
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :