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Structure of 114365-04-7
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 114365-04-7 |
Formula : | C11H16N2 |
M.W : | 176.26 |
SMILES Code : | N1(CCCC1)C2=CC=C(C=C2)CN |
MDL No. : | MFCD04971090 |
InChI Key : | OCVQUKOCFUOCBM-UHFFFAOYSA-N |
Pubchem ID : | 7017834 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3259 |
Packing Group: | Ⅲ |
* 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 |
---|---|---|
86% | With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃; | Benzonitrile 181 (1.68 g, 9.76 mmol) dissolved in 10 ml of ether was added drop wise at 0C to LiAlH4 (2equiv., 742 mg) suspended in diethyl ether (40 ml). The mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and filtrated and the salts were washed with ether. The organic phase was separated, anhydrified and evaporated giving 1.48 g of a yellow oil. Yield = 86% 'HNMR (DMSO, 200 MHz) δ 1.60 (2H, bs), 1.93 (4H, m), 3.17 (4H, m), 3.57 (2H, s), 6.46 (2H, d, J = 8.6 Hz), 7.09 (2H, d, J = 8.4 Hz). |
86% | With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃; for 24h; | Preparation of (4-(pyrrolidin-1-yl)phenyl)methanamine 21 Benzonitrile 181 (1.68 g, 9.76 mmol) dissolved in 10 ml of ether was added drop wise at 0C to LiA1H4 (2equiv., 742 mg) suspended in diethyl ether (40 ml). The mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and filtrated and the salts were washed with ether. The organic phase was separated, anhydrified and evaporated giving 1.48 g of a yellow oil. Yield = 86% 1HNMR (DMSO, 200 MHz) δ 1.60 (2H, bs), 1.93 (4H, m), 3.17 (4H, m), 3.57 (2H, s), 6.46 (2H, d, J = 8.6 Hz), 7.09 (2H, d, J = 8.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; | EXAMPLE 82 N-[4-(pyrrolidin-1-yl)-phenylmethyl]-3-(biphenyl-2-carbonylamino)-benzoic acid amide Prepared analogously to Example 34 from 3-(biphenyl-2-carbonylamino)-benzoic acid, 4-(pyrrolidin-1-yl)-phenylmethylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide. Rf value:0.70 (silica gel; dichloromethane/ethanol=9:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 177 Ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate and 4-(1-pyrrolidinyl)benzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 178 Ethyl 3-(4-fluorophenyl)-2-hydroxyimino-3-oxopropionate and 4-(1-pyrrolidinyl)benzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 160 N-(3-methyl-5-isoquinolinyl)-N'-[4-(1-pyrrolidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 61B using 4-(1-pyrrolidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.54 (s, 1H), 8.27 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.67 (d, 1H, J=7.5 Hz), 7.49 (t, 1H, J=7.5 Hz), 7.16 (d, 2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.53 (d, 2H, J=9 Hz), 4.22 (d, 2H, J=6 Hz), 3.20 (m, 4H), 2.63 (s, 3H), 1.94 (m, 4H); MS (ESI) 361 (M+H)+. Anal. Calcd for C22H24N4O.0.2H2O: C, 72.58; H, 6.76; N, 15.39. Found: C, 72.33; H, 6.64; N, 15.22. | ||
EXAMPLE 160 N-(3-methyl-5-isoquinolinyl)-N'-[4-(1-pyrrolidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 61B using 4-(1-pyrrolidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.54 (s, 1H), 8.27 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.67 (d, 1H, J=7.5 Hz), 7.49 (t, 1H, J=7.5 Hz), 7.16 (d, 2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.53 (d, 2H, J=9 Hz), 4.22 (d, 2H, J=6 Hz), 3.20 (m, 4H), 2.63 (s, 3H), 1.94 (m, 4H); MS (ESI) 361 (M+H)+. Anal. Calcd for C22H24N4O.0.2H2O: C, 72.58; H, 6.76; N, 15.39. Found: C, 72.33; H, 6.64; N, 15.22. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 108 N-5-isoquinolinyl-N'-[4-(1-pyrrolidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 61B using 4-(1-pyrrolidinyl)benzylamine instead of 4-cyanobenzyl alcohol. NMR (DMSO-d6) δ 9.81 (s, 1H), 9.58 (s, 1H), 8.80 (d, 1H), 8.71 (m, 2H), 8.11 (d, 1H), 7.93 (t, 1H), 7.48 (bs, 1H), 7.20 (m, 2H), 6.65 (m, 2H), 4.43 (d, 2H), 3.13 (m, 4H), 1.97 (m, 4H); MS (ESI) (M+H)+347. | ||
EXAMPLE 108 N-5-isoquinolinyl-N'-[4-(1-pyrrolidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 61B using 4-(1-pyrrolidinyl)benzylamine instead of 4-cyanobenzyl alcohol. NMR (DMSO-d6) δ 9.81 (s, 1H), 9.58 (s, 1H), 8.80 (d, 1H), 8.71 (m, 2H), 8.11 (d, 1H), 7.93 (t, 1H), 7.48 (bs, 1H), 7.20 (m, 2H), 6.65 (m, 2H), 4.43 (d, 2H), 3.13 (m, 4H), 1.97 (m, 4H); MS (ESI) (M+H)+347. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 18 N-(4-pyrrolidin-1-ylbenzyl)-4-[(trifluoromethyl)thio]benzamide The product was prepared from 4-trifluoromethylthiobenzoic acid (133 mg) and <strong>[114365-04-7](4-(pyrrolidin-1-yl)phenyl)methanamine</strong> (127 mg) according to Method B: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.84 - 1.99 (m, 4 H), 3.12 - 3.23 (m, 4 H), 4.35 (d, J=6.1 Hz, 2 H), 6.49 (m, J=8.8 Hz, 2 H), 7.13 (m, J=8.8 Hz, 2 H), 7.81 (m, J=8.1 Hz, 2 H), 7.93 - 8.00 (m, 2 H), 9.06 (t, J=5.9 Hz, 1 H); MS (DCI/NH3) m/z 381.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃;Inert atmosphere; | To a solution of 4-(l-pirrolidino)-benzaldehyde (833 mg, 4.75 mmol) in EtOH (25 ml) hydroxylamine hydrochloride (396.4 mg, 5.70 mmol) and sodium acetate (467.8 mg, 5.70 mmol) were added. The mixture was heated to reflux and stirred for 1.0 hour. The mixture was diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated to dryness. The residue was then dissolved in anhydrous THF (20.0 ml) under N2. LiAlH4 (1.0 M in THF) (5.7 ml) was slowly added to the solution. The mixture was stirred at r.t. for 24 h. Then it was carefully poured into MeOH (60 ml), the solvent was removed and the residue was suspended in MeOH and filtered. The filtrate was concentrated under reduced pressure yielding 4-(l-Pirrolidino)-benzylamine which was coupled to 2-Methyl-l,8-naphthyridine following the general amide coupling procedure. Purification was done by flash chromatography (CH2Cl2ZMeOH 95:5) to give the title substance in 29% yield.1H NMR (CDCl3) δ 9.08 (m, IH), 8.11 (m, 2H), 7.46 (m, IH), 7.27 (d, 2H), 6.60 (d, 2H), 6.24 (bs, IH), 4.58 (d, 2H), 3.30 (m, 4H), 2.92 (s, 3H), 2.03 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trifluoroacetic acid; In dichloromethane; at 20℃; for 2h; | General procedure: To a stirred solution of carbamate (1 equiv.) in dry DCM TFA (10 equiv.) was added. The reaction mixture was stirred at room temperature for 2h. The mixture was quenched with a saturated aqueous solution of sodium bicarbonate and the product was extracted with DCM. The organic layers were dried over Na2S04, filtered and concentrated under vacuum to provide the expected compound which was used without further purificationThe following compounds are examples illustrating this procedure:.; 3-pyrrolidin-1 -ylphenyl)methanamine was prepared from te/t-butyl N-[(3- pyrrolidin-1 -ylphenyl)methyl]carbamate (203 mg, 0.74 mmol). Yield: 130 mg (100%) of the title compound as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 0 - 80℃; | (4-(pyrrolidin-l-yl)phenyl)methanamine 21 (774 mg, 4.4 mmol) was dissolved in 40ml of AcOEt and at 0C triphosgene (1.3 g, lequiv.) was added to the solution. The mixture was warmed at 80C for 4 hours then evaporated and the residue was dissolved in 20 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound la (660 mg, 4.4 mmol) and the mixture was warmed at 80C for 8 hours. (TLC AcOEt 9.5 / MeOH 0.5). The solvent was evaporated and the crude was dissolved in AcOEt (50 ml) and washed with water (1 X 30 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 250 mg of a white solid. Yield = 16% 'HNMR (DMSO, 200 MHz) δ 1.92 (4H, m), 3.17 (4H,m), 4.17 (2H, d, J = 5.6 Hz), 6.58 (4H, m), 6.84 (2H, m), 7.12 (2H, d, J = 8.6 Hz), 8.16 (1H, bs), 9.93 (1H, bs), 10.58 (1H, bs); [M+1] 352.3 (C19H21N5O2 requires 351.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 0 - 80℃; for 4h; | Preparation of 1-(4-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea <strong>[114365-04-7](4-(pyrrolidin-1-yl)phenyl)methanamine</strong> 21 (774 mg, 4.4 mmol) was dissolved in 40ml of AcOEt and at 0C triphosgene (1.3 g, lequiv.) was added to the solution. The mixture was warmed at 80C for 4 hours then evaporated and the residue was dissolved in 20 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1a (660 mg, 4.4 mmol) and the mixture was warmed at 80C for 8 hours. (TLC AcOEt 9.5 / MeOH 0.5). The solvent was evaporated and the crude was dissolved in AcOEt (50 ml) and washed with water (1 X 30 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 250 mg of a white solid. Yield = 16% 1HNMR (DMSO, 200 MHz) δ 1.92 (4H, m), 3.17 (4H,m), 4.17 (2H, d, J = 5.6 Hz), 6.58 (4H, m), 6.84 (2H, m), 7.12 (2H, d, J = 8.6 Hz), 8.16 (1H, bs), 9.93 (1H, bs), 10.58 (1H, bs); [M+1] 352.3 (C19H21N5O2 requires 351.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 53 2-Methyl-N-(4-(pyrrolidin-1-yl)benzyl)-1,8-naphthyridine-3-carboxamide To a solution of 4-(1-pirrolidino)-benzaldehyde (833 mg, 4.75 mmol) in EtOH (25 ml) hydroxylamine hydrochloride (396.4 mg, 5.70 mmol) and sodium acetate (467.8 mg, 5.70 mmol) were added. The mixture was heated to reflux and stirred for 1.0 hour. The mixture was diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated to dryness. The residue was then dissolved in anhydrous THF (20.0 ml) under N2. LiAlH4 (1.0 M in THF) (5.7 ml) was slowly added to the solution. The mixture was stirred at r.t. for 24 h. Then it was carefully poured into MeOH (60 ml), the solvent was removed and the residue was suspended in MeOH and filtered. The filtrate was concentrated under reduced pressure yielding 4-(1-Pirrolidino)-benzylamine which was coupled to 2-Methyl-1,8-naphthyridine following the general amide coupling procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0℃; for 1h; | To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (200 mg, 0.9697 mmol) and al2 (205.11 mg, 1.1637 mmol) in DCM (20 mL) was added HATU (553.09 g, 1.4546 mmol) followed by DIPEA (376.02 mg, 2.9092 mmol) at 0 C, then stirring was continued further for 1 h at 0 C. The reaction mixture was concentrated under reduced pressure, and then diluted by adding water (10.0 mL) and then the reaction mixture was extracted with EtOAc (2x25 mL), the combined extracts were dried over anhydrous Na2SC>4, filtered, concentrated under reduced pressure to obtain the crude residue (220 mg) as a viscous liquid. The crude material was purified by Combi-Flash column chromatography (100-200 silica gel), eluting 0-40% EtOAc in hexanes to afford 23 (75.4 mg, 0.2012 mmol, 20% yield) as a solid. LCMS: 365.1 (M+H), Rt = 2.206 min, Column: X-Bridge BEH C- 18(3.0X50mm, 2.5pm); Mobile Phase: A: 0.025% FA in Water, B: ACN; (0302) T/B%:0.01/2, 0.2/2, 2/98, 3/98, 3.2/2, 4/2; Flow rate: 1.2ml/min (Gradient); Column Oven temperature: 50 C. HPLC: Rt= 6.138 min, 97.26%; Column: XSELECT CSH C18 (150 X 4.6mm, 3.5p); Mobile Phase-A:0.05%TFA: ACETONITRILE (95:05); Mobile Phase- B: ACETONITRILE :0.05%TFA(95:05); Program:T/B%: 0.01/10,12/90,16/90; Flow : 1.0 mL/min; Diluent -de) d 9.23 (t, 1H), 7.84 (d, 1H), 7.79 (d, 1H), 7.11 (d, 2H), 6.49 (d, 2H), 4.33 (d, 2H), 3.37 (s, 3H), 3.18 (t, 4H), 1.98 - 1.89 (m, 4H). |
20% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0℃; for 1h; | To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (200 mg, 0.9697 mmol) and al2 (205.11 mg, 1.1637 mmol) in DCM (20 mL) was added HATU (553.09 g, 1.4546 mmol) followed by DIPEA (376.02 mg, 2.9092 mmol) at 0 C, then stirring was continued further for 1 h at 0 C. The reaction mixture was concentrated under reduced pressure, and then diluted by adding water (10.0 mL) and then the reaction mixture was extracted with EtOAc (2x25 mL), the combined extracts were dried over anhydrous Na2SC>4, filtered, concentrated under reduced pressure to obtain the crude residue (220 mg) as a viscous liquid. The crude material was purified by Combi-Flash column chromatography (100-200 silica gel), eluting 0-40% EtOAc in hexanes to afford 23 (75.4 mg, 0.2012 mmol, 20% yield) as a solid. LCMS: 365.1 (M+H), Rt = 2.206 min, Column: X-Bridge BEH C- 18(3.0X50mm, 2.5pm); Mobile Phase: A: 0.025% FA in Water, B: ACN; (0302) T/B%:0.01/2, 0.2/2, 2/98, 3/98, 3.2/2, 4/2; Flow rate: 1.2ml/min (Gradient); Column Oven temperature: 50 C. HPLC: Rt= 6.138 min, 97.26%; Column: XSELECT CSH C18 (150 X 4.6mm, 3.5p); Mobile Phase-A:0.05%TFA: ACETONITRILE (95:05); Mobile Phase- B: ACETONITRILE :0.05%TFA(95:05); Program:T/B%: 0.01/10,12/90,16/90; Flow : 1.0 mL/min; Diluent -de) d 9.23 (t, 1H), 7.84 (d, 1H), 7.79 (d, 1H), 7.11 (d, 2H), 6.49 (d, 2H), 4.33 (d, 2H), 3.37 (s, 3H), 3.18 (t, 4H), 1.98 - 1.89 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | To a stirred solution of a3 (200 mg, 0.9040 mmol) in DMF (10 mL), was added HATU (443 mg, 1.1651 mmol) and DIPEA (323 mg, 2.499 mmol) followed by corresponding amine (244 mg, 1.3843 mmol) at 0 C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layers were dried over NaiSCE and concentrated under reduced pressure. The crude material was purified by flash column chromatography using EtOAc in heptane = 0% to 35% to 90% as an eluent to afford 30 (27.6 mg, 0.0802 mmol, 9%). LCMS: 380.2 (M+H), Rt = 3.389 min, ColummX-Bridge BEH C- 18(3.0X50mm,2.5pm); Mobile Phase: A:2.5mM Ammonium Bicarbonate, B:ACN; (Gradient) T/B%:0.01/10, 3/90, 5/90, 5.5/10, 6/10; Flow rate:0.8ml/min. HPLC: Rt = 9.58 min, 97.12%; Mobile Phase A : 5mM Ammonium Bi Carbonate; Mobile Phase B : Acetonitrile; Program :T/B% :0.01/20, 12/90, 16/90; Flow : l.OmL/min; Diluent :: WATER: ACN. 'll NMR (400 MHz, DMSO-d6) 9.16 (t, 1H), 7.79 (d, 2H), 7.56 (d, 1H), 7.11 (d, 2H), 6.49 (d, 2H), 4.32 (d, 2H), 3.14 (t, 4H), 1.93 (t, 4H), 3 H Merged in solvent peak. |
9% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | To a stirred solution of a3 (200 mg, 0.9040 mmol) in DMF (10 mL), was added HATU (443 mg, 1.1651 mmol) and DIPEA (323 mg, 2.499 mmol) followed by corresponding amine (244 mg, 1.3843 mmol) at 0 C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layers were dried over NaiSCE and concentrated under reduced pressure. The crude material was purified by flash column chromatography using EtOAc in heptane = 0% to 35% to 90% as an eluent to afford 30 (27.6 mg, 0.0802 mmol, 9%). LCMS: 380.2 (M+H), Rt = 3.389 min, ColummX-Bridge BEH C- 18(3.0X50mm,2.5pm); Mobile Phase: A:2.5mM Ammonium Bicarbonate, B:ACN; (Gradient) T/B%:0.01/10, 3/90, 5/90, 5.5/10, 6/10; Flow rate:0.8ml/min. HPLC: Rt = 9.58 min, 97.12%; Mobile Phase A : 5mM Ammonium Bi Carbonate; Mobile Phase B : Acetonitrile; Program :T/B% :0.01/20, 12/90, 16/90; Flow : l.OmL/min; Diluent :: WATER: ACN. 'll NMR (400 MHz, DMSO-d6) 9.16 (t, 1H), 7.79 (d, 2H), 7.56 (d, 1H), 7.11 (d, 2H), 6.49 (d, 2H), 4.32 (d, 2H), 3.14 (t, 4H), 1.93 (t, 4H), 3 H Merged in solvent peak. |
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