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CAS No. : | 19481-82-4 | MDL No. : | MFCD00010383 |
Formula : | C3H4BrN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PYNYHMRMZOGVML-UHFFFAOYSA-N |
M.W : | 133.97 | Pubchem ID : | 140538 |
Synonyms : |
|
Num. heavy atoms : | 5 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 24.15 |
TPSA : | 23.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.29 cm/s |
Log Po/w (iLOGP) : | 1.28 |
Log Po/w (XLOGP3) : | 1.17 |
Log Po/w (WLOGP) : | 1.29 |
Log Po/w (MLOGP) : | 0.81 |
Log Po/w (SILICOS-IT) : | 0.74 |
Consensus Log Po/w : | 1.06 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.41 |
Solubility : | 5.24 mg/ml ; 0.0391 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.26 |
Solubility : | 7.28 mg/ml ; 0.0543 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.22 |
Solubility : | 8.05 mg/ml ; 0.0601 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.22 |
Signal Word: | Danger | Class: | 6.1,3 |
Precautionary Statements: | P210-P233-P240-P241-P242-P243-P261-P264-P270-P271-P280-P301+P310+P330-P303+P361+P353-P304+P340+P311-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501 | UN#: | 3275 |
Hazard Statements: | H226-H301+H311+H331-H315-H319-H335 | Packing Group: | Ⅱ |
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 |
---|---|---|
96% | With phosphorus pentoxide; silica gel Heating; | |
65% | With phosphorus pentaoxide for 1h; | |
60% | With phosphorus pentaoxide In 1,2-dimethoxyethane for 1h; Heating; |
With phosphorus pentaoxide at 250℃; | ||
With phosphorus pentoxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With iodine; zinc In tetrahydrofuran at 100℃; for 0.333333h; microwave irradiation; | |
(i) Zn, THF, (ii) /BRN= 528894/; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With iodine; zinc In tetrahydrofuran at 100℃; for 0.2h; microwave irradiation; | |
(i) Zn, THF, (ii) /BRN= 1773932/; Multistep reaction; | ||
With silver; zinc In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 2,4,4,6-Tetrabromo-2,5-cyclohexadien-1-one; triphenylphosphine In dichloromethane at 0℃; for 1h; | |
With pyridine; sulfurous dibromide; thionyl chloride 1) diethyl ether, 1 h: 2) diethyl ether, reflux, 12 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 2,2'-azobis(isobutyronitrile) In benzene at 80℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 2,2'-azobis(isobutyronitrile) In benzene at 80℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With indium In tetrahydrofuran at 20℃; for 3h; sonication; | |
34% | With indium In tetrahydrofuran at 60℃; for 1.53333h; | 9.1 Stage 9.1 2-Methyl-3-oxo-3-phenyl-propionitrile 2-Methyl-3-oxo-3-phenyl-propionitrile is prepared analogously to the procedure of Yoo et al., Tetrahedron Lett., Vol. 43, No. 27, pp. 4813-4815 (2002). 2-Bromo-propionitrile (0.965 mL, 11.05 mmol) and In-powder (975 mg, 8.5 mmol) are stirred under Ar in THF (15 mL) for 1 hour. After adding benzoylnitrile (735 mg, 5.6 mmol) during 2 minutes, the reaction mixture is stirred at 60° C. in a microwave ofen (Emrys optimizer, personal chemistry, Sweden) for 30 minutes. After filtration over Hyflo and washing with THF (5 mL), the reaction solution is concentrated under reduced pressure and partitioned between ether (150 mL) and phosphate buffer (pH=7, 150 mL). After separation of the organic phase, the aqueous phase is extracted with ether (150 mL). The combined organic phases are washed with brine (30 mL), dried (Na2SO4), concentrated under reduced pressure and flash chromatography (silica gel, 2×18 cm, hexane/AcOEt=3:1) to compound of Stage 9.1 as slightly yellowish oil (300 mg, 1.9 mmol; 34%); ES-MS: M-H=157.9; Rf(hexane/AcOEt=1:1)=0.60. 1H-NMR (400 MHz, DMSO-d6): 8.06 (d, 8.5 Hz, 2H), 7.74 (t, 8.5 Hz, 1H), 7.62 (t, 8.5 Hz, 2H), 5.17 (q, 8.5 Hz, 1H, CH), 1.52 (s, 3H, CH3). |
34% | Stage #1: 2-bromopropionitrile With indium In tetrahydrofuran for 1h; Stage #2: benzoyl cyanide In tetrahydrofuran at 60℃; for 0.5h; Microwave oven; | 9.1 Stage 9.1 2-Methyl-3-oxo-3-phenyl-propionitrile Stage 9.1 2-Methyl-3-oxo-3-phenyl-propionitrile 2-Methyl-3-oxo-3-phenyl-propionitrile is prepared analogously to the procedure of Yoo et al., Tetrahedron Lett., Vol. 43, No. 27, pp. 4813-4815 (2002). 2-Bromo-propionitrile (0.965 mL, 11.05 mmol) and In-powder (975 mg, 8.5 mmol) are stirred under Ar in THF (15 mL) for 1 hour. After adding benzoylnitrile (735 mg, 5.6 mmol) during 2 minutes, the reaction mixture is stirred at 60° C. in a microwave oven (Emrys optimizer, personal chemistry, Sweden) for 30 minutes. After filtration over Hyflo and washing with THF (5 mL), the reaction solution is concentrated under reduced pressure and partitioned between ether (150 mL) and phosphate buffer (pH=7, 150 mL). After separation of the organic phase, the aqueous phase is extracted with ether (150 mL). The combined organic phases are washed with brine 30 mL), dried Na2SO4), concentrated under reduced pressure and flash chromatography (silica gel, 2*18 cm, hexane/AcOEt=3:1) to compound of Stage 9.1 as slightly yellowish oil (300 mg, 1.9 mmol; 34%); ES-MS: M-H=157.9; Rf (hexane/AcOEt=1:1)=0.60. 1H-NMR (400 MHz, DMSO-d): 8.06 (d, 8.5 Hz, 2H), 7.74 (t, 8.5 Hz, 1H), 7.62 (t, 8.5 Hz, 2H), 5.17 (q, 8.5 Hz, 1H, CH), 1.52 (s, 3H, C1H3). |
34% | Stage #1: 2-bromopropionitrile With indium In tetrahydrofuran for 1h; Stage #2: benzoyl cyanide In tetrahydrofuran at 60℃; for 0.533333h; Microwave oven; | 9.1 2-Methyl-3-oxo-3-phenyl-propionitrile is prepared analogously to the procedure of Yoo et al., Tetrahedron Lett., Vol. 43, No. 27, pp. 4813-4815 (2002). 2-Bromo-propionitrile (0.965 mL, 11.05 mmol) and In-powder (975 mg, 8.5 mmol) are stirred under Ar in THF (15 mL) for 1 hour. After adding benzoylnitrile (735 mg, 5.6 mmol) during 2 minutes, the reaction mixture is stirred at 60°C in a microwave ofen (Emrys optimizer, personal chemistry, Sweden) for 30 minutes. After filtration over Hyflo and washing with THF (5 mL), the reaction solution is concentrated under reduced pressure and partitioned between ether (150 mL) and phosphate buffer (pH = 7, 150 mL). After separation of the organic phase, the aqueous phase is extracted with ether (150 mL). The combined organic phases are washed with brine (30 mL), dried (Na2SO4), concentrated under reduced pressure and flash chromatography (silica gel, 2 x 18 cm, hexane/AcOEt = 3: 1) to compound of Stage 9.1 as slightly yellowish oil (300 mg, 1.9 mmol ; 34%); ES-MS: M-H = 157.9 ; Rf (hexane/AcOEt = 1: 1) =0. 60. 'H-NMR (400 MHz, DMSO-d6) : 8.06 (d, 8.5 Hz, 2H), 7.74 (t, 8.5 Hz, 1H), 7.62 (t, 8.5 Hz, 2H), 5.17 (q, 8.5 Hz, 1H, CH), 1.52 (s, 3H, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With indium In tetrahydrofuran at 20℃; for 4h; sonication; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With indium In tetrahydrofuran at 20℃; for 2h; sonication; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With indium In tetrahydrofuran at 20℃; for 3h; sonication; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With indium In tetrahydrofuran at 20℃; for 3h; sonication; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [2,2]bipyridinyl In various solvent(s) at 55℃; for 1.8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [2,2]bipyridinyl In various solvent(s) at 55℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With [2,2]bipyridinyl; copper; copper(I) bromide In benzene at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: (2R,5S)-7-ethoxycarbonyl-2-phenyl-1-aza-3-oxa-lbicyclo<3.3.0>octan-8-one With sodium hydride In tetrahydrofuran at 0℃; Stage #2: 2-bromopropionitrile In tetrahydrofuran Heating; | |
Stage #1: (2R,5S)-7-ethoxycarbonyl-2-phenyl-1-aza-3-oxa-lbicyclo<3.3.0>octan-8-one With sodium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: 2-bromopropionitrile In tetrahydrofuran for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With iodine; zinc In tetrahydrofuran at 100℃; for 0.333333h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With iodine; zinc In tetrahydrofuran at 100℃; for 0.333333h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With Ki; potassium carbonate In methanol; dichloromethane; acetonitrile | A Part A Part A A solution of 1-ethylpropylamine (1.97 g, 22.6 mmol) in acetonitrile (50 mL) was treated with K2CO3 (9.3 g, 67.7 mmol) 2-bromopropionitrile (3.0 g, 22.6 mmol) and KI (4.13 g, 24.9 mmol). The mixture was heated at 55° C. for 20 h. The mixture was cooled to room temperature and was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (2% MeOH in CH2Cl2) to afford 2-(1-ethylpropylamino)-propionitrile (1.04 g, 36% yield) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.5% | With potassium iodide; potassium carbonate In butanone | 1.a a. a. α-(2,6-dichlorophenoxy)-propionitrile 100 ml. Of dry ethylmethyl ketone are added to 32.6 g. of 2,6-dichlorophenol, 26 g. of anhydrous, finely powdered potassium carbonate and 0.5 g. of potassium iodide. A solution of 29.5 g. of α-bromopropionitrile in 20 ml. of absolute ethyl methyl ketone is added dropwise over 11/2 hrs. to the resulting vigorously stirred suspension as it boils under reflux. On completion of the addition, the reaction mixture is heated under reflux for another hour, after which it is separated on cooling from the insoluble components present in it by filtration under suction, the residue washed with ethylmethyl ketone and the filtrate concentrated by evaporation in vacuo. Ether is added to the oily residue, the ethereal solution extracted three times with 50 ml. of 10% sodium hydroxide in order to remove the excess 2,6-dichlorophenol, and then with 50 ml. of 5% sodium thiosulphate solution in order to remove the iodine. The product is then washed with water until it reacts neutrally and dried over anhydrous sodium sulphate. After the solvent has been removed, fractionation of the residual oil in a high vacuum gives 31 g. of α-(2,6-dichlorophenoxy)-propionitrile. Yield: 71.5% of the theoretical. White needles M.p. 28° - 29° |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: 1′-(6-chloro-1H-indole-3-carbonyl)spiro[isobenzofuran-3,4′-piperidine]-1-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide | 38 To a stirred solution of 100 mg (0.26 mmol) of 1'-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidine]-3-one (the preparation of which has been described in example 16) in 5 ml DMF was added 11.5 mg (0.28 mmol) NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 35 mg (0.26 mmol) of 2-bromo-propionitrile was added. The mixture was stirred overnight and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (EtOAc/Hx, 2:1; SiO2) afforded 54 mg (34%) of 2-{6-chloro-3-[(3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl) carbonyl]-1H-indol-1-yl}propanenitrile as a light yellow solid. ES-MS m/e (%): 434(M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: (6-chloro-1H-indol-3-yl)-spiro[1H-isobenzofuran-3,4′-piperidine]-1′-yl-methanone With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide | 73 To a stirred solution of 100 mg (0.26 mmol) of 1'-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidine] (the preparation of which has been described in example 69) in 5 ml DMF was added 11.5 mg (0.28 mmol) NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 35 mg (0.26 mmol) of 2-bromo-propionitrile was added. The mixture was stirred overnight and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (EtOAc/Hx, 1:1; SiO2) afforded 93 mg (91%) of 2-[6-chloro-3-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1-ylcarbonyl)-1H-indol-1-yl] propanenitrile as a light yellow solid. ES-MS m/e (%): 420(M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | b: 1-(Cyano-methyl-methyl)-1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> A mixture of K2CO3 (7.93 g, 57.0 mmol) and 1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> (5.0 g, 19.14 mmol) in DMF (30 mL) was stirred at room temperature for 0.5 h. Then 2-bromo-propionitrile (3.4 mL, 38.3 mmol) in DMF (10 mL) was added. The reaction was warmed to 80 C. and kept at this temperature for 6 h. Then the reaction was cooled down to the room temperature. Most of the DMF solvent was removed in vacuo and the crude residue was extracted several times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. The crude product was triturated with MeCN to give 3.9 g of 1-(cyano-methyl-methyl)-1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> as a white fluffy solid. The filtrate was concentrated and purification by silica gel chromatography provided 1.6 g of 1-(cyano-methyl-methyl)-1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong>, yield 91%. | |
91% | Step 1: Synthesis of diethyl l-(l-cyanoethyl)-1H-indole-2,6-dicarboxylateA mixture of K2C03 (7.9 g, 57.4 mmol) and diethyl lH-indole-2,6-dicarboxylate (Intermediate A, 5.0 g, 19.1 mmol) in DMF (30mL) is stirred at room temperature for 30 min. A solution of 2-bromo-propionitrile (3.4 mL, 38.3 mmol) in DMF (10 mL) is added. The reaction mixture is warmed to 80 C for 6 h and then cooled to room temperature and stirred for another 16 h. Solvent is removed and the residue is partitioned between EtOAc and water. The organic layer is separated, dried and concentrated to afford crude compound which is purified by flash column chromatography using EtOAc in hexanes followed by trituration with acetonitrile to afford the title compound (5.5 g, 91 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 65℃; for 14h; | 8.A Preparation of 2-(1-(2-nitrophenyl)ethylamino)acetonitrile (18): 2-Nitrobenzylamine (513 mg, 3.37 mmol) was added to an acetonitrile (40 mL) containing K2CO3 (932 mg, 6.74 mmol) and 2-bromopropanitrile (677 mg, 5.06 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 65° C. for 14 hours. The product (18) was used without purification or concentration in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate In acetonitrile at 80℃; for 12h; | 5 0.51 g (3.4 mmol) of the indoline III are dissolved in 10 ml_ of acetonithle. 0.59 ml_ (16.8 mmol) of the bromoderivative and 1.41 g (10 mmol) of potassium carbonate are added. It is heated at 8O0C for 12 h. It is allowed to cool and the solvent is eliminated under low pressure. 50 ml_ of water and 50 ml_ of DCM are added and the organic phase is extracted. The organic phase is dried over anhydrous magnesium sulphate and filtered. The residue thus obtained is purified by column chromatography using hexane/ethyl acetate as an eluant. 0.27 mg (Yield = 39%) of indoline Vl are obtained as a yellowish oil.HPLC-MS: Purity 99.9%, M+1 = 203 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: tellurium; methyllithium In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 2-bromopropionitrile for 2h; | 6 Example 6Preparation of 2-methyltellanylpropionitrile A 6.38 g quantity (50 mmoles) of metallic tellurium was suspended in 50 ml of THF, and 52.9 ml (55 mmoles) of methyllithium was slowly added dropwise to the suspension at room temperature (for 10 minutes). The reaction mixture was stirred until the metallic tellurium disappeared completely (for 20 minutes). To the reaction mixture was added 8.0 g (60 mmoles) of 2-bromopropionitrile at room temperature, followed by stirring for 2 hours. After the completion of reaction, the solvent was concentrated in a vacuum, followed by vacuum distillation to give 4.52 g (46% in yield) of yellow oil. IR, MS (HRMS), 1H-NMR and 13C-NMR analyses indicated that the product was 2-methyltellanylpropionitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: [2-(1H-inden-2-yl)ethyl]dimethylamine With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: 2-bromopropionitrile In tetrahydrofuran at 20℃; | 22 To a solution of [2-(1H-inden-2-yl)-ethyl]-dimethyl-amine 3a (2 g, 10.68 mmol) in anhydrous THF (40 mL) cooled to -78 °C, nBuLi (12.8 mmol, 8 mL, 1.6M) was added. After stirring at-78 °C for 1 hr, 2-bromoproprionitrile (10.68 mmol, 0.92 mL) in THF (10 mL) was added. The reaction was mixture warmed to reach room temperature while being stirred overnight. The mixture was concentrated in vacuo. Dichloromethane was added, and the mixture was washed with IN NaOH and water, dried over MgS04, filtered and concentrated in vacuo to afford 2.08g of 2-[2-(2-dimethylamino-ethyl)-3H- inden-l-yl]-propionitrile 22a which was used in the next step without further purification (83% yield). (MH+ = 241, tR = 3.675 (2)) To a solution of 2-[2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-propionitrile 22a (2 g, 8.33 mmol) in ethylacetate (70 mL), dithiophosphoric acid 0,0-diethylester (1.55 g, 8.33 mmol) in EtOAc (10 mL) was added. HCI was bubbled through the reaction mixture while stirring. After the internal temperature had stabilized, the reaction was sealed and stirred for 3 days. An additional portion of dithiophosphoric acid 0,0- diethylester (6.1 mmol, 1 mL) was added and HCI gas wwas bubbled through while being stirred overnight. The mixture was concentrated in vacuo, diluted with dichloromethane, washed with water, dried (MgS04), filtered and concentrated in vacuo. Silica gel column chromatography (gradient of dichloromethane/MeOH/NH40H 99/1/0.2 to dichloromethane/MeOH/NH40H 98/2/0.2) afforded 0.72 g of 2-[2-(2-dimethylamino- ethyl)-3H-inden-l-yl]-thiopropionamide 22b (31% yield). To a solution of 2-[2-(2-dimethylamino-ethyl)-3H-inden-l-yl]- thiopropionamide 22b (0.372 g, 1.36 mmol) in EtOH (10 mL), chloroacetone (0.22 mL, 2.72 mmol) was added. The mixture was stirred at 80 °C overnight. The reaction mixture was concentrated in vacuo and the residue was purified using silica gel column chromatography. (dichloromethane/MeOH/NH40H 98/2/0.02 as elutant) to afford 0.174 g of dimethyl-(2- (3-[ 1 -(4-methyl-thiazol-2-yl)-ethyl]- l H-inden-2-yl) -ethyl)-amine 22-1 in 41 % yield. (MH+ = 313) Separation by chiral HPLC (Chiralpak-AD-H, profile 6) afforded the R and S enantiomers 22-2 and 22-3. The following compounds were made according to this procedure: No R3 R2b Method MH+ tR (method 2) 22-1 H-CH3 312.48 313 4.363 22-2 H -(R)-CH3 312.48 313 4.929 profile 6 22-3 H -(S)-CH3 312.48 313 4.875 profile 6 22-4 OCH3 -CH3 342.50 342.9 4.478 22-5 Cl -(R)-CH3 346.92 346.8 5.345 profile 6 |
Stage #1: [2-(1H-inden-2-yl)ethyl]dimethylamine With n-butyllithium In tetrahydrofuran at -78℃; Stage #2: 2-bromopropionitrile In tetrahydrofuran at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 5-fluoro-2-hydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide Inert atmosphere; | |
Stage #1: 5-fluoro-2-hydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 4-fluoro-2-hydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 3-methoxy-2-hydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide Inert atmosphere; | |
Stage #1: 3-methoxy-2-hydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With magnesium sulfate; potassium hydroxide In dimethyl sulfoxide for 14h; | 16 Example 16Synthesis of 2-(4-(4-(4-(4-((2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-difluorophenyl)-1,3-dioxolan-4-yl)methylthio)phenyl)piperazin-1-yl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)propanenitrile (Formula I(D)-Rd)2-bromopropanenitrile (1.2 mol) was added to a suspension of KOH powder (1.3 mol) and 4-(4-(4-(4-((2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-difluorophenyl)-1,3-dioxolan-4-yl)methylthio)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one which was prepared from the Example 12 (1.0 mol) in 250 mL DMSO/MgSO4. The reaction mixture was stirred for 14 hrs, then was diluted with water. After extraction with CHCl3 and dried over MgSO4, solvent was evaporated under vacuo. The crude product was initially purified by flash chromatography with CHCl3/CH3OH (98/2) as the eluent and further purified by recrystallization in toluene (47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With magnesium sulfate; potassium hydroxide In dimethyl sulfoxide for 14h; | 23 Example 23Synthesis of 2-(4-(4-(4-(4-((2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-difluorophenyl)-1,3-dioxolan-4-ylthio)methyl)phenyl)piperazin-1-yl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)propanenitrile (Formula II(D)-Rd)2-bromopropanenitrile (1.2 mol) was added to a suspension of KOH powder (1.3 mol) and 4-(4-(4-(4-((2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-difluorophenyl)-1,3-dioxolan-4-ylthio)methyl)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one which was prepared from the Example 12 (1.0 mol) in 250 mL DMSO/MgSO4. The reaction mixture was stirred for 14 hrs, then was diluted with water. After extraction with CHCl3 and dried over MgSO4, solvent was evaporated under vacuo. The crude product was initially purified by flash chromatography with CHCl3/CH3OH (98/2) as the eluent, and further purified by recrystallization in toluene (47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With magnesium sulfate; potassium hydroxide In dimethyl sulfoxide for 14h; | 30 Example 30Synthesis of 2-(4-(4-(4-(4-((5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methylthio)phenyl)piperazin-1-yl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)propanenitrile (Formula I (T)-Rd)2-bromopropanenitrile (1.2 mol) was added to a suspension of KOH powder (1.3 mol) and 4-(4-(4-(4-((5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methylthio)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one which was prepared from the Example 12 (1.0 mol) in 250 mL DMSO/MgSO4. The reaction mixture was stirred for 14 hrs, then was diluted with water. After extraction with CHCl3 and dried over MgSO4, solvent was evaporated under vacuo. The crude product was initially purified by flash chromatography with CHCl3/CH3OH (98/2) as the eluent. The product was further purified by recrystallization in toluene (47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With magnesium sulfate; potassium hydroxide In dimethyl sulfoxide for 14h; | 37 Example 37Synthesis of 2-(4-(4-(4-(4-((5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-ylthio)methyl)phenyl)piperazin-1-yl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)propanenitrile (Formula II (T)-Rd)2-bromopropanenitrile (1.2 mol) was added to a suspension of KOH powder (1.3 mol) and 4-(4-(4-(4-((5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-ylthio)methyl)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one which was prepared from the Example 12 (1.0 mol) in 250 mL DMSO/MgSO4. The reaction mixture was stirred for 14 hrs, then was diluted with water. After extraction with CHCl3 and dried over MgSO4, solvent was evaporated under vacuo. The crude product was initially purified by flash chromatography with CHCl3/CH3OH (98/2) as the eluent. The product was further purified by recrystallization in toluene (47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide at 80℃; | J.1 Step 1: Synthesis of diethyl l-(l-cyanoethyl)-lH-pyrrolo[2,3-b]pyridine-2,6- dicarboxylateTo a solution of diethyl lH-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 1.55 g, 5.91 mmol) in DMF (15 mL) is added potassium carbonate (2.45 g, 17.7 mmol), and the mixture is stirred at room temperature for 20 min. 2-bromopropionitrile (1.05 mL, 11.8 mmol) is added, the mixture is warmed to 80 °C, and is stirred overnight. After being cooled to room temperature, the mixture is poured onto H20, and the aqueous layer is extracted with EtOAc (3 x 100 mL). The combined organic extracts are dried (MgS04), filtered, and concentrated. The crude material is purified via flash column chromatography using a gradient elution of 10-50% ethyl acetate/hexanes to afford the title compound as a bright yellow solid (809 mg, 43%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In N,N-dimethyl-formamide at 20 - 50℃; | 54.1 In a 50ml round bottom flask was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1 H- pyrido[2,3-b][1 ,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50mg, 0.106 mmol) in DMF (Volume: 4 ml) to give a brown solution, sodium hydride (10.18 mg, 0.254 mmol) and 2- bromopropanenitrile (17.05 mg, 0.127 mmol) were added. The reaction mixture was stirred at 50 degree for 1 h then room temperature overnight. The reaction mixture was partitioned between DCM (20ml) and water (20ml). The organic phase was separated and concentrated. The residue was purified by column (biotage, 25g) eluted with ethyl acetate/cyclohexane (0-50%) to give product (19mg). LCMS (Method A): RT = 7.14 min, M+H+ = 525.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 20℃; | 54.3 54.3 4-[2-Cvano-methyl-methoxy)-4-fluoro-phenylamino1-5-methyl-thieno[2,3-The product from 54.2 (30 mg), 2-bromopropionitrile (13 mg), cesiumcarbonate (40 mg) inDMF (1 ml) were stirred at rt overnight. The mixture was filtrated and the solid was washed with DMF. Water was added to the filtrate. The solid was isolated by filtration. The combined solids were freeze-dried. Yield: 14 mgESI mass spectrum: m/z = 372 (M+H)+ Retention time HPLC: 1 .92 minHPLC method: 004_CC_ZQ6 | |
With caesium carbonate In N,N-dimethyl-formamide at 20℃; | 54.3 The product from 54.2 (30 mg), 2-bromopropionitrile (13 mg), cesium carbonate (40 mg) in DMF (1 ml) were stirred at rt overnight. The mixture was filtrated and the solid was washed with DMF. Water was added to the filtrate. The solid was isolated by filtration. The combined solids were freeze-dried.Yield: 14 mgESI mass spectrum: m/z=372 (M+H)+ Retention time HPLC: 1.92 minHPLC method: 004_CC_ZQ6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(4-Fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (3-dimethylamino-propyl)-amide With caesium carbonate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide at 20℃; | 63.3 63.3 4-[2-Cvano-methyl-methoxy)-4-fluoro- phenylamino1-5-methyl-thieno[2,3- dlpyrimidine-6-carboxylic acid (2-dimethylamino-propy)-amide To the product from 63.2 (157 mg) in DMF (4 ml) was added cesium carbonate (165 mg). After 5 min. 2-Bromopropionitrile (37 μΙ) was added and the mixture was stirred at rt overnight. Then the mixture was concentrated and diluted with DCM and water. The organic layer was seperated, dried and concentrated.Yield: 130 mgESI mass spectrum: m/z = 457 (M+H)+ | |
Stage #1: 4-(4-Fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (3-dimethylamino-propyl)-amide With caesium carbonate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide at 20℃; | 63.3 To the product from 63.2 (157 mg) in DMF (4 ml) was added cesium carbonate (165 mg). After 5 min. 2-Bromopropionitrile (37 μl) was added and the mixture was stirred at rt overnight. Then the mixture was concentrated and diluted with DCM and water. The organic layer was seperated, dried and concentrated.Yield: 130 mgESI mass spectrum: m/z=457 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In N,N-dimethyl-formamide at 10 - 20℃; | 48 Example 48.N-((S)- 1 -(3 -(3 -Chloro-4-cyanophenyl)- 1 H-pyrazol- 1 -yl)propan-2-yl)- 1 -( 1 - cyanoethyl)-2-methyl- 1 H-imidazole-4-carboxamide Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and (S)-N-(l-(3-(3-chloro-4- cyano-phenyl)- 1 H-pyrazol- 1 -yl)propan-2-yl)-2-methyl- 1 H-imidazole-4-carboxamide (0.542 mmol, 200 mg) were dissolved in DMF (2 ml). The mixture was cooled to -10 °C with an ice bath and 2-bromopropanenitrile (0.813 mmol, 109 mg) was slowly added. The mixture was allowed to warm to RT and it was stirred for 2 h. Solvent was evaporated, DCM was added and the mixture was washed twice with water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and trituration from diethyl ether. 63 mg of the title compound was obtained. -NMR (400 MHz, DMSO- 6): δ 1.04-1.12 (m, 3H), 1.77 (d, 3H), 2.42 (s, 3H), 4.23-4.49 (m, 3H), 5.72 (q, 1H), 6.92-6.97 (m, 1H), 7.79-7.85 (m, 2H), 7.95-8.01 (m, 2H), 8.08-8.11 (m, 1H), 8.15 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; Nickel (II) acetylacetonate; diisobutylaluminium hydride In toluene at 100℃; for 10h; Cooling with ice; | |
91% | With 10-phenyl-10H-phenothiazine; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane at 20℃; for 24h; Inert atmosphere; Irradiation; | |
54% | With 4-methoxypyridine; tris(2,2'-bipyridyl)ruthenium dichloride; sodium hydrogencarbonate; triethylamine In N,N-dimethyl-formamide for 36h; Schlenk technique; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 2,4-dichlorophenol With potassium carbonate In N,N-dimethyl-formamide for 0.25h; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide at 50℃; for 55h; | 2 5-[1-(2,4-dichlorophenoxy )ethyl ]-3-( 4-fluorophenyl)-1,2,4-oxadiazole (MBX-2667) To a solution of2,4-dichlorophenol (1.0 g, 6.1mmol) in DMF (10 mL) was added K2C03(0.93 g, 6.75 mmol, 1.1 eq). After 15 min of stirring, 2-bromopropanenitrile (0.58 mL, 6.75 mmol, 1.1 eq), then the reaction was heated to 50 oc for 55 h. The reaction mixture was thencooled to room temperature and diluted with water ( 40 mL). The resulting precipitate wasfiltered, rinsed with water, and dried under vacuum for 20 h to provide 1.3 g (95% yield) offwhitepowder: 1H-NMR [300 MHz, CDCb]: d 7.42 (d, IH), 7.25 (dd, IH + CHCb), 7.10 (d,1H), 4.84 (q, 1H), 1.83 (d, 3H). |
84% | With caesium carbonate In acetonitrile for 20h; Reflux; | |
84% | With caesium carbonate In acetonitrile for 20h; Reflux; | General Procedure A (Nucleophilic displacement) General procedure: A mixture of 2,4-disubstitutedphenol (1.1 equiv), 2-bromopropionitrile (1.0 equiv) and Cs2CO3 (1.5 equiv) inacetonitrile was refluxed for 20 h. After cooling to room temperature, the reaction mixture was quenched with H2O. Theaqueous phase was extracted with DCM, the combined organic phases were washed with brine, dried over Na2SO4,filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (hexane/AcOEt) to obtain the pure product. The reaction as described in scheme 4 above may be carried out according tothe general procedure A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.1% | With sodium methylate In methanol; ethanol; n-heptane; water; dihydrogen peroxide | 3 Step 3: Step 3: tert-Butyl ((2R)-2-(5-bromo-2-fluorophenyl)-1-((1-cyanoethyl)sulfonyl)propan-2-yl)carbamate To a solution of (R)-S-(2-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl) amino)propyl)ethanethioate (5.13 g, 12.63 mmol) in ethanol (84 mL) was added sodium methoxide (0.5 M solution in methanol, 25.3 mL, 12.63 mmol). The mixture was stirred at RT for 10 minutes, and then (+/-)-2-bromopropionitrile (1.310 ml, 15.15 mmol) was added. The reaction was stirred at RT for 20 minutes, concentrated, and partitioned between water and 1:1 ethyl acetate/heptane. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine and concentrated. The residue was dissolved in MeOH (63.2 mL) and cooled in an ice-water bath. To this solution was added a solution of ammonium molybdate (3.12 g, 2.53 mmol) in 30% hydrogen peroxide in water (19.35 mL, 632 mmol). The mixture was stirred at RT for 16 hours, quenched with saturated aqueous sodium bicarbonate, and extracted with DCM. The combined organic layers were washed with water and brine and concentrated. The crude material was purified by silica-gel chromatography, eluting with 20-100% ethyl acetate in heptane, to provide the title intermediate (3.92 g, 8.72 mmol, 69.1% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With tert.-butylhydroperoxide; triethylamine; cobalt acetylacetonate In water at 100℃; for 24h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1,10-Phenanthroline; sodium carbonate; copper(l) chloride In N,N-dimethyl-formamide at 100℃; for 24h; Schlenk technique; Inert atmosphere; | |
73% | With pentamethylcyclopentadienyl bis(triphenylphosphine)ruthenium(II) chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 100℃; for 24h; Inert atmosphere; | |
52% | With nickel(II) bromide dimethoxyethane In N,N-dimethyl-formamide at 25℃; for 48h; Inert atmosphere; Irradiation; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 50% 2: 39% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | Synthesis of 2-(5-bromo-3-morpholino-2-oxopyridin-1(2H)-yl)propanenitrile and 2-((5-bromo-3-morpholinopyridin-2-yl)oxy)propanenitrile General procedure: To a solution of the starting pyridone or pyrazinone (1.0 equiv.) in DMF (0.1-0.2 M) was added the electrophile (1.0-1.5 equiv.) followed by potassium carbonate or cesium carbonate (1.0-2.0 equiv.). The solution was stirred at room temperature (or alternatively heated up to 80° C.) for 2-24 hours. Upon cooling to room temperature, the solution was partitioned between water and ethyl acetate, the organic phase was washed with water, then brine, dried over sodium sulfate, filtered and concentrated under vacuo. The crude material was a mixture of N-alkyl and O-alkyl products. The material could be used for the next step without further purification as a mixture of isomers or it could be purified via silica gel column chromatography eluting with 0-100% ethyl acetate in heptanes. Method 1 was followed using 5-bromo-3-morpholinopyridin-2(1H)-one (1.0 equiv.), 2-bromopropanenitrile (1.2 equiv.) and potassium carbonate (1.0 equiv.) at 80° C. and the isomers were purified via silica gel column chromatography (0-50% ethyl acetate and heptanes). Isolated 2-(5-bromo-3-morpholino-2-oxopyridin-1(2H)-yl)propanenitrile in 50% yield. LCMS (m/z) (M+H)=312/314, Rt=0.63 min. And 2-((5-bromo-3-morpholinopyridin-2-yl)oxy)propanenitrile in 39% yield. LCMS (m/z) (M+H)=312/314, Rt=0.84 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In N,N-dimethyl-formamide at 40℃; for 16h; | 1.1 (+/-)-2-(Methylsulfonyl)propanenitrile To a suspension of sodium methanesulfinate (8.44 g, 83 mmol) in DMF (127 mL) was added 2-bromopropionitrile (5.5 mL, 63.6 mmol). The reaction was stirred at 40° C. After 16 hours, the reaction mixture was diluted with water (1 L) and extracted with ethyl acetate. The combined organic layers were washed with water and brine and concentrated to provide the title compound (8.5 g, quantitative yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With caesium carbonate In acetonitrile at 60℃; for 2h; | 7.008 30.0 mg (0.08 mmol) Intermediate V.2, 70.0 mg (0.21 mmol) Cs2CO3 and 0.01 mL (12.0 mmol) 2-bromo-propionitrile in 1 mL ACN are stirred 60° C. for 2 h. The mixture is diluted with water and extracted with DCM. The organic layer is separated, dried and evaporated. The residue is purified by HPLC. Yield: 15.4 mg (45%), ESI-MS: m/z=440 (M+H)+; Rt(HPLC): 0.50 min (HPLC-K). |
With caesium carbonate In acetonitrile at 60℃; for 2h; | 7.008 30.0 mg (0.08 mmol) Intermediate V.2, 70.0 mg (0.21 mmol) Cs2003 and 0.01 mL(12.0 mmol) 2-bromo-propionitrile in 1 mL ACN are stirred 60°C for 2 h. The mixture is diluted with water and extracted with DCM. The organic layer is separated, dried andevaporated. The residue is purified by HPLC.Yield: 15.4 mg (45%), ESI-MS: m/z = 440 (M+H) R(HPLC): 0.50 mm (HPLC-K) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; sodium iodide In N,N-dimethyl acetamide at 20℃; for 48h; | 7.005 0.2 g (0.56 mmol) Intermediate V.1, 0.2 g (1.67 mmol) K2CO3 and 0.1 g (0.83 mmol) 2-bromo-propionitrile and a catalytic amount of sodium iodide in dimethylacetamide are stirred at RT for 2 days. The mixture is diluted with brine and extracted with EtOAc. The organic layers are dried and evaporated. The residue is purified by FC. Yield: 0.2 g (70%), ESI-MS: m/z=414 (M+H)+; Rt(HPLC): 0.65 min (HPLC-B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
105 mg | With potassium carbonate; In acetonitrile; at 80℃; | A mixture of <strong>[1914-02-9]3,3-dimethylindoline</strong> (103 mg, 0.700 mmol), potassium carbonate (288 mg, 2.084 mmol), and 2-bromopropanenitrile (303 mu^, 3.506 mmol) in 2 mL CH3CN was stirred at 80C (oil bath) over night. The mixture was purified by preparative HPLC. Fractions containing product were partly concentrated and residue was extracted with 1 M NaHC03and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give 2-(3,3-dimethylindolin-l-yl)propanenitrile (105 mg). LCMS m/z = 201.2 [M+l]+; NMR (400 MHz, CDC13) delta ppm 1.26 (s, 3H), 1.40 (s, 3H), 1.63 (d, J = 7.3 Hz, 3H), 3.05 (d, J = 8.2 Hz, 1H), 3.25 (d, J = 8.2 Hz, 1H), 4.57 (q, J = 7.3 Hz, 1 H), 6.57 (d, J = 7.9 Hz, 1H), 6.83-6.87 (m, 1H), 7.06 (dd, J1=7.4 Hz, J2= 0.8 Hz, 1H), 7.12-7.16 (m, 1H). |
105 mg | With potassium carbonate; In acetonitrile; at 80℃; | A mixture of <strong>[1914-02-9]3,3-dimethylindoline</strong> (5s, 103 mg, 0.700 mmol), potassium carbonate (288 mg,2.084 mmol), and 2-bromopropanenitrile (303 muL, 3.506 mmol) in 2 mL CH3CN was stirred at 80C overnight. The mixture was concentrated and purified by preparative HPLC. Fractions containing productwere partly concentrated and residue was extracted with 1 M NaHCO3 and CH2Cl2. Organic phases weredried over MgSO4, filtered, and concentrated to give 2-(3,3-dimethylindolin-1-yl)propanenitrile (105mg). LCMS m/z = 201.2 [M+1]+; 1H NMR (400 MHz, CDCl3) delta ppm 1.26 (s, 3H), 1.40 (s, 3H), 1.63 (d, J = 7.3Hz, 3H), 3.05 (d, 1H, J = 8.2 Hz), 3.25 (d, 1H, J = 8.2 Hz), 4.57 (q, 1 H, J = 7.3 Hz), 6.57 (d, 1H, J = 7.9 Hz),6.83-6.87 (m, 1H), 7.06 (dd, 1H, J1 =7.4 Hz, J2 = 0.8 Hz), 7.12-7.16 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In acetonitrile; at 80℃; | A mixture of <strong>[155135-61-8]methyl indoline-4-carboxylate</strong> (114 mg, 0.643 mmol), potassium carbonate (270 mg, 1.954 mmol), and 2-bromopropanenitrile (277 μ, 3.267 mmol) in 2 ml CH3CN was stirred at 80C (oil bath) overnight. Mixture was purified by HPLC (CH3CN/H20 gradient + 0.1 % TFA). Fractions containing product were partly concentrated and residue was extracted with 1 M NaHC03and CH2C12. Organic phases were dried over MgS04, filtered, and concentrated to give methyl 1-(1- cyanoethyl)indoline-4-carboxylate (106 mg, 72 %). LCMS m/z = 331.4 [M+l]+. NMR (400 MHz, CDC13) δ 1.65 (d, 7 = 7.2 Hz, 3H), 3.19-3.31 (m, 2H), 3.52-3.67 (m, 2H), 3.88 (s, 3H), 4.57 (q, 7 = 7.2 Hz, 1H), 6.72 (d, 7 = 7.8 Hz, 1H), 7.19-7.23 (m, 1H), 7.36 (dd, J}= 7.8 Hz, 72= 0.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | Stage #1: 3-(4-bromobenzyl)-7-fluoroquinazoline-2,4(1H,3H)-dione With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromopropionitrile In N,N-dimethyl-formamide at 120℃; Heating; | 30 Example 30: 2-(3-(4-Bromobenzyl)-7-fluoro-2,4-dioxo-3,4-dihydroquinazolin-l(2H)- yl)-propanenitrile Sodium hydride (68.7 mg; 1.72 mmol; 60 %) and 2 ml of dry DMF were charged in a reaction flask under nitrogen. 3-(4-Bromobenzyl)-7-fluoroquinazoline-2,4( 1 H,3H)-dione (200 mg; 0.573 mmol) prepared in Example 26 was added at 0 °C and the mixture was stirred at rt for 30 min. 2-Bromopropanenitrile (0.149 ml; 1.72 mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was heated at 50 °C for 2 h and then at 70 °C for 2.5 h. The mixture was cooled to 0 °C, water and EtOH were added, and the precipitation was filtered and washed with water. The crude product was crystallized from EtOH and purified with CombiFlash (normal phase silica) to yield 40 mg of 2-(3-(4- bromobenzyl)-7-fluoro-2,4-dioxo-3 ,4-dihydroquinazolin- l(2H)-yl)propanenitrile. 'H-NMR (400 MHz, CDC13): δ 1.83 (d, 3H), 5.18 (dd, 2H), 6.33 (q, IH), 7.01-7.10 (m, IH), 7.22 (dd, IH), 7.35-7.48 (m, 4H), 8.31 (dd, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: (4-thiomethoxyphenyl)boronic acid With tert.-butylnitrite In acetonitrile at 40℃; Inert atmosphere; Stage #2: 2-bromopropionitrile With N,N,N',N'',N'''-pentamethyldiethylenetriamine; copper In acetonitrile at 23℃; Inert atmosphere; Stage #3: With N,N,N,N,N,N-hexamethylphosphoric triamide; samarium diiodide at 23℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 2-Methoxyphenylboronic acid With tert.-butylnitrite In acetonitrile at 40℃; Inert atmosphere; Stage #2: 2-bromopropionitrile With N,N,N',N'',N'''-pentamethyldiethylenetriamine; copper In acetonitrile at 23℃; Inert atmosphere; Stage #3: With N,N,N,N,N,N-hexamethylphosphoric triamide; samarium diiodide at 23℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 4-methoxyphenylboronic acid With tert.-butylnitrite In acetonitrile at 40℃; Inert atmosphere; Stage #2: 2-bromopropionitrile With N,N,N',N'',N'''-pentamethyldiethylenetriamine; copper In acetonitrile at 23℃; Inert atmosphere; Stage #3: With N,N,N,N,N,N-hexamethylphosphoric triamide; samarium diiodide at 23℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: 4-phenoxyphenylboronic acid With tert.-butylnitrite In acetonitrile at 40℃; Inert atmosphere; Stage #2: 2-bromopropionitrile With N,N,N',N'',N'''-pentamethyldiethylenetriamine; copper In acetonitrile at 23℃; Inert atmosphere; Stage #3: With N,N,N,N,N,N-hexamethylphosphoric triamide; samarium diiodide at 23℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; at 40℃; | To a 2 L reaction flask, 200 g of 3-methyl-4-methoxy-salicylaldehyde and 1 L of DMF were added and stirred and dissolved.200 g of 2-methyl bromoacetonitrile and 100 g of sodium carbonate were added slowly to the reaction flask and the reaction was continued after heating to 40 C. After completion of the reaction by TLC monitoring, the reaction solution was poured into 4 L of methyl acetate and washed three times with water, each time with 4 L of water. Dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to give 260 g of crude product of intermediate I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With [2,2]bipyridinyl; water; palladium diacetate at 70℃; for 24h; Schlenk technique; Sealed tube; | General Procedure XII - Synthesis of Primary Amide Products in Water General procedure: To an oven dried Schlenk carousel tube containing the appropriate nitrile (1 mmol) was added palladium acetate (11 mg, 5 mol%), 2,2'-bipyridine (7.8 mg, 5 mol%) and water (2 mL, 0.5 M). The tube was then sealed and the reaction mixture heated at 70 °C for 24 hours. After being allowed to cool to room temperature, the reaction mixture was diluted with methanol (5 mL) and the solvent removed in vacuo on a rotary evaporator whilst azeotroping with toluene. Where the reaction had gone to quantitative conversion or the starting nitrile was volatile, the crude reaction mixture was passed through a short plug of silica to remove the catalyst (eluting with DCM/MeOH, 95:5). Otherwise, the primary amide products were purified by column chromatography (eluting with DCM/MeOH, 95:5, unless otherwise stated). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.8% | With trichlorosilane; zinc In tetrahydrofuran at -10℃; for 14h; Inert atmosphere; | 9 Example 9 Zinc powder (4 g, 61.5 mmol) was dissolved in anhydrous THF (100 mL),Replace with nitrogen three times and add silicon trichloride (0.1 g, 0.926 mmol)Stir at room temperature for 30 min, then cool to -10 °C, add slowly2-bromo-propionitrile (4.09 g, 30.8 mmol) and1-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone(3.43g, 15.4mmol)The resulting solution was stirred at -10°C for 14 hours until the starting material disappeared.Then add 50 mL of saturated ammonium chloride solution and filter. The resulting mixture is 60 mL.Extract with ethyl acetate and wash three times with saturated sodium chloride solution.The organic phase was dried over anhydrous sodium sulfate, spin-dried and passed through a silica gel column (PE:EA=1:1)Obtained racemic (2S,3R) and (2R,3S) 3.46 g according to formula (I) (R2=F)White solid (yield: 80.8%, d.e. approximately 98%).The resulting white solid was dissolved in 10 ml of toluene, 20 ml of methyl tert-butyl ether andIn a mixed solvent of 5 mL of methanol, D-10-camphorsulfonic acid (2.89 g, 12.45 mmol) was added.Heat the reaction to 60 °C, react for 1h, slowly cool and cool, filter,Obtain a white solid, then add water, stir with sodium bicarbonate, extract with dichloromethane,The organic phase is concentrated to obtain the (2S,3R) diastereoisomer according to formula (I) (R2=F)1.2 g (Yield: 34.7%, e.e. >99%, d.e. >99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | Indium powder (15.4 g, 133.8 mmol) was dissolved in dry THF (150 mL).Replace with nitrogen three times, then cool to 0C and slowly add(S)-2-Bromo-propionitrile (8,90,66.9 mmol) stirring for 30 min,Then slowly adding <strong>[1157938-97-0]1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone</strong> dissolved in(9.95 g, 44.6 mmol) of dry THF (15 mL) was stirred at -10C for 10 hours,Until the disappearance of raw materials, filtration, the filtrate was added 200mL of n-hexane stirring for 40min,Cool, filter, wash with water, and dry to obtain (2S, 3R) andA mixture of (2R, 3S) 11.1 g, (yield 89.5%, d.e. > 99.2%).The resulting white solid was dissolved in 20 ml of toluene, 40 ml of methyl tert-butyl ether andIn a mixed solvent of 10 mL methanol,Add D-10-camphorsulfonic acid (7.09 g, 30.56 mmol) to heat the reaction to 60C,After reacting for 1 h, slowly cooling and cooling, filtering to obtain a white solid, then adding water,Stir with sodium bicarbonate and extract with dichloromethane.The organic phase was concentrated to obtain 9.4 g of the (2S,3R) diastereoisomer according to Formula (I).(Yield: 84.7%, e.e. > 99.1%, d.e. > 99.2%).The results of the LC-MS and H-NMR measurements of the resulting compound were the same as those described in Example 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In N,N-dimethyl-formamide at 80℃; for 2h; | 141.1 Step 1: (+-)-2-(4-nitropyrazol-1-yl)propanenitrile A mixture of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol), 2-bromopropionitrile (1185 mg, 8.85 mmol) and potassium carbonate (610 mg, 4.42 mmol) in N,N-dimethylformamide (15 mL) was stirred at 80° C. for 2 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography eluting with PE/EA (5/1) to give (+-)-2-(4-nitropyrazol-1-yl)propanenitrile (720 mg, 4.334 mmol, 98% yield) as a yellow solid. LCMS (ESI): [M+H]+=167.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Methyl isobutyrate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 2-bromopropionitrile In tetrahydrofuran at -78 - 25℃; for 10h; Inert atmosphere; | Methyl 3-cyano-2,2-dimethylbutanoate: To a solution of LDA (2 M, 3 50 mL) in (0689) THF (15 mL) was added dropwise methyl 2-methylpropanoate (0.65 g, 6.36 mmol) at -78 °C under N2. The mixture was stirred for 1 h, and then 2-bromopropanenitrile (1.02 g, 7.64 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 10 h. The reaction mixture was quenched with aq. HC1 (3 mL, IN) at 0 °C, and then diluted with H20 (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organics were washed with brine (30 mL), dried over Na2S04, filtered and concentrated under reduced pressure to provide the title compound (0.84 g, 85%>) as a yellow oil, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine In acetonitrile at 20 - 30℃; | 16.1 Step 1: Preparation of 2-(3-((6-fluoroquinolin-4-yl)oxy)-8-azabicyclo[3.2.1]octane-8-yl)propanenitrile in room temperature,To 4-((8-azabicyclo[3.2.1]oct-3-yl)oxy)-6-fluoroquinoline dihydrochloride (345 mg,1.0mmol) TEA (505 mg, 5.0 mmol) was added to a 5 mL MeCN solution.The temperature of the control system is below 30 °C.Additional 2-bromopropionitrile (147 mg, 1.1 mmol) was added.The reaction mixture was stirred at room temperature overnight.TLC showed the reaction was completed.The reaction system was poured into 20 mL of water.Extract with EA (10 mL x 3).The organic phase was washed twice with saturated brine.The anhydrous Na2SO4 was sufficiently dried and concentrated under reduced pressure.The residue was chromatographed on silica gel (PE: EA = 1:1)Purification afforded 220 mg (yield: 68%) of title compound.It is a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 0.75h; | 2.59.3.iii Step Hi: 2-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-3-pyridyl]oxy]propanenitrUe To a suspension of 6-[/vv[(4-mcthoxyphcnyl)mcthyl] amino] -4-chloro-pyridin-3-ol (500 mg, 1.24 mmol, 1.0 eq.) and CS2CO3 (612 mg, 1.86 mmol, 1.5 eq.) in dry DMF (7 mL) is added 2- bromopropionitrile (133 pL, 1.5 mmol, 1.2 eq.). The resulting mixture is stirred at 75 °C for 45 min and after being cooled down to RT is poured into an EtOAc (70 mL)/water (45 mL)/brine (45 mL) mixture. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with 50 mL of brine, dried over Na2S04, filtered and concentrated. The residue is purified by flash chromatography on silica gel (eluting with 0 to 25% EtOAc in cyclohexane) to afford the expected product. (2002) LCMS: MW (calcd): 437.9; m/z MW (obsd): 438.2 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 18h; | 72.1 [00751] Step 1 : Preparation of 2-(3-(5-cyclopropylisoxazol-3-yl)-4-((2,4-dimethoxybenzyl)amino)-7-fluoro-1H-pyrazolo[4,3-c]pyridin-1-yl)propanenitrile . A mixture of 3-(5-cyclopropylisoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrazolo[4,3-c]pyridin-4- amine (Example 9, Step 3; 25 mg, 0.0611 mmol), 2-bromopropanenitrile (16.4 mg, 0.122 mmol), and CS2CO3 (39.8 mg, 0.122 mmol) in DMF (305 pL) was stirred at 80°C for 18 h. After cooling to RT, the reaction was partitioned between H2O and EtOAc (1 mL ea.). The aqueous phase was extracted with EtOAc (2 x 1 mL), and the pooled organic extracts were dried over Na2S04, filtered, and concentrated. The crude material was purified by reverse-phase chromatography (5 to 70% ACN in water) to yield the title product as white solid (21 mg, 76%). MS (apci) m/z = 463.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; potassium iodide; In chloroform;Reflux; | 424 mg (1.0 mmol) of <strong>[15291-77-7]ginkgolide B</strong> was dissolved in 30 mL of chloroform, and 266 mg (2.0 mmol) of 1-bromopropiononitrile, 332 mg (2.0 mmol) of KI, and 1 mL of triethylamine were sequentially added.Heat to reflux to end the reaction. After treatment, the mother liquor was concentrated, and the residue was subjected to column chromatography to obtain 340 mg of a yellow solid with a yield of 71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: (R)-S-(2-(5-Bromo-2-fluorophenyl)-2-((tert-butoxy carbonyl)amino)propyl) ethanethioate With sodium methylate In methanol; ethanol at 20℃; for 0.166667h; Stage #2: 2-bromopropionitrile In methanol; ethanol for 1h; | 7.2 Step 2: Synthesis of Compound 7-3 To a solution of Compound 7-2 (1.21 g, 2.97 mmol) in EtOH (18 mL) was added NaOMe (1 N in MeOH; 2.97 mL, 2.97 mmol) at room temperature. After being stirred for 10 minutes, 2-bromopropionitrile (0.31 mL, 3.56 mmol) was added. After being stirred for 1 hour, the mixture was diluted with H 2O and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO 4, filtered, and evaporated. The residue was purified by column chromatography (silica gel; hexane/EtOAc, gradient: 0-30% EtOAc) to give Compound 7-3 (1.33 g, 100% yield) as a colorless oil. 1H NMR (400 MHz, CDCl 3) (mixture of diastereomers) δ 1.38 (9H, br s), 1.56 (3H, s), 1.76 (3H, d, J = 3.6 Hz), 3.30-3.35 (1H, m), 3.48-3.56 (1H, m), 3.73-3.81 (1H, m), 5.09 (1H, br s), 6.94 (1H, dd, J = 11.6, 8.4 Hz), 7.35-7.44 (2H, m). MS-ESI (m/z): 417 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; sodium iodide In acetonitrile at 90℃; for 16h; Sealed tube; | 3 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino) propanenitrile (3a) A mixture of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1e) (0.2 g, 609.40 umol, 1 eq), K2CO3 (168.44 mg, 1.22 mmo), NaI (182.69 mg, 1.22 mmol) and 2-bromopropanenitrile (816.44 mg, 6.09 mmol) in CH3CN (5 mL) was added to a seal tube and heated to 90° C. for 16 hours. LCMS showed desired MS and STM of 1e, the mixture was filtered and washed with ethyl acetate (10 mL*2). The combined filtrates was washed with brine (20 mL), and the organic phase was concentrated to give 3a (0.25 g, crude), the crude product was used for the next step directly. MS mass calculated for [M+1]+ (C17H18Cl2N4O2) requires m/z 381.1, LCMS found m/z 381.0. | |
0.25 g | With potassium carbonate; sodium iodide In acetonitrile at 90℃; for 16h; Sealed tube; | 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino) propanenitrile (6a) A mixture of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (4a) (0.2 g, 609.4 umol, 1 eq), K2CO3 (168.44 mg, 1.22 mmol), NaI (182.69 mg, 1.22 mmol) and 2-bromopropanenitrile (816.44 mg, 6.09 mmol) in CH3CN (5 mL) was placed into a sealed tube and heated at 90 °C for 16 hours. The mixture was filtered and washed with ethyl acetate (2x 10 mL). The combined organic layer was washed with brine (20 mL), and the organic phase was concentrated to give 6a (0.25 g, crude) as brown oil, the crude product was used for the next step directly. MS mass calculated for [M+1]+ (C17H18Cl2N4O2) requires m/z 381.1, LCMS found m/z 381.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 2-bromopropionitrile With zinc In acetonitrile for 0.25h; Inert atmosphere; Stage #2: ethyl (4-methoxyphenylimino)acetate In acetonitrile at 30℃; for 12h; Inert atmosphere; | 4.3. Procedure A: Zn-mediated addition of 2-bromoacetonitrile (2a) or 2-bromopropanenitrile (2b) to α-imino esters (1) General procedure: Zinc powder (1 mmol), 2-bromoacetonitrile 2a (0.75 mmol) or 2-bromopropanenitrile 2b (0.75 mmol) and MeCN (2 mL) were stirred vigorously under a nitrogen atmosphere for 15 min. To this mixture, α-imino ester 1 (0.25 mmol) was added and the mixture was allowed to stir for 12 h at 30 °C. After this period, the reaction mixture was quenched with water (5 mL) and transferred to a separating funnel and extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SO4 and then the solvent was evaporated under vacuum. Purification of the resulting crude reaction mixture by column chromatography on silica gel (eluent EtOAc/Hexanes) gave the corresponding product 3 (See Tables 1 and 2 and Scheme 5 for individual entries). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 44% 2: 47% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 16h; | 216 Preparation 216 Ethyl 2-(l-cyanoethyl)pyrazole-3-carboxylate (Prep. 216A) and ethyl 1-(1- cyanoethyl)pyrazole-3-carboxylate (Prep. 216B) To a solution of ethyl lH-pyrazole-5-carboxylate (600 mg, 4.28 mmol) in DMF (10 mL) was added CS2CO3 (2.32 g, 7.12 mmol) and 2-bromopropanenitrile (617 pL, 956 mg, 7.14 mmol). The reaction mixture was stirred at 60°C for 16 hours, cooled to room temperature and then diluted with water. The mixture was extracted with EtOAc (x 2) and the combined organic phases were washed with brine, dried with Na2S04, filtered and concentrated in vacuo. Purification by flash chromatography (silica, eluting with heptane to 50% EtOAc in heptane) gave ethyl 2-(l-cyanoethyl)pyrazole-3-carboxylate (Prep. 216A) (TLC: rf = 0.7 in 1 : 1 EtOAc: heptane) (367 mg, 44%) as a crystalline solid and ethyl 1-(1- cyanoethyl)pyrazole-3-carboxylate (Prep. 216B) (TLC: rf = 0.5 in 1 : 1 EtOAc: heptane) (387 mg, 47%). Prep. 216A: 1H NMR (400 MHz, Chloroform-d) d 7.63 (s, 1H), 6.90 (s, 1H), 6.46 (q, J = 7.0 Hz, 1H), 4.38 (d, J = 7.0 Hz, 1H), 1.91 (d, J = 7.0 Hz, 3H), 1.40 (t, J = 7.2 Hz, 2H); LCMS (METHOD 3) (ES) : m/z 194.2 [M + H]+, RT = 0.63 min. Prep. 216B: 1H NMR (400 MHz, Chloroform-d) d 7.68 (s, 1H), 6.91 (s, 1H), 5.44 (q, J = 7.0 Hz, 1H), 4.42 (d, J = 7.2 Hz, 2H), 1.95 (d, J = 7.3 Hz, 3H), 1.41 (t, J = 7.1 Hz, 2H); LCMS (METHOD 3) (ES) : m/z 194.2 [M + H]+, RT = 0.52 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-bromopropionitrile With copper(I) bromide; zinc In acetonitrile at 20℃; for 1h; Molecular sieve; Stage #2: C20H16N4O2 In acetonitrile at 60℃; for 3h; | Synthesis of 5-imino-1,2-oxazoles 4a-l (general method) General procedure: 1-Bromonitrile 3a,b (1.0 mmol) andmolecular sieves (4 Å, 50 mg) were added to a suspension of zinc (4.0 mmol) and CuBr (1.5 mmol) inMeCN (3.0 mL) and the mixture was stirred for 1 h at room temperature followed by addition ofC-benzotriazolated nitrones 2a-h (1.0 mmol) dissolved in MeCN (1 mL). The reaction mixture washeated to 60 oC for 3 h and cooled to room temperature. The mixture was filtered, concentrated underreduced pressure and the residue subjected to column chromatography on silica gel using EtOAc-hexane,9:1 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 2-bromopropionitrile With copper(I) bromide; zinc In acetonitrile at 20℃; for 1h; Molecular sieve; Stage #2: C20H15ClN4O2 In acetonitrile at 60℃; for 3h; | Synthesis of 5-imino-1,2-oxazoles 4a-l (general method) General procedure: 1-Bromonitrile 3a,b (1.0 mmol) andmolecular sieves (4 Å, 50 mg) were added to a suspension of zinc (4.0 mmol) and CuBr (1.5 mmol) inMeCN (3.0 mL) and the mixture was stirred for 1 h at room temperature followed by addition ofC-benzotriazolated nitrones 2a-h (1.0 mmol) dissolved in MeCN (1 mL). The reaction mixture washeated to 60 oC for 3 h and cooled to room temperature. The mixture was filtered, concentrated underreduced pressure and the residue subjected to column chromatography on silica gel using EtOAc-hexane,9:1 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 2-bromopropionitrile With copper(I) bromide; zinc In acetonitrile at 20℃; for 1h; Molecular sieve; Stage #2: C21H18N4O3 In acetonitrile at 60℃; for 3h; | Synthesis of 5-imino-1,2-oxazoles 4a-l (general method) General procedure: 1-Bromonitrile 3a,b (1.0 mmol) andmolecular sieves (4 Å, 50 mg) were added to a suspension of zinc (4.0 mmol) and CuBr (1.5 mmol) inMeCN (3.0 mL) and the mixture was stirred for 1 h at room temperature followed by addition ofC-benzotriazolated nitrones 2a-h (1.0 mmol) dissolved in MeCN (1 mL). The reaction mixture washeated to 60 oC for 3 h and cooled to room temperature. The mixture was filtered, concentrated underreduced pressure and the residue subjected to column chromatography on silica gel using EtOAc-hexane,9:1 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 2-bromopropionitrile With copper(I) bromide; zinc In acetonitrile at 20℃; for 1h; Molecular sieve; Stage #2: N-[(1H-benzotriazol-1-yl)-(4-methylphenyl)methylene]-4-methylbenzenamine oxide In acetonitrile at 60℃; for 3h; | Synthesis of 5-imino-1,2-oxazoles 4a-l (general method) General procedure: 1-Bromonitrile 3a,b (1.0 mmol) andmolecular sieves (4 Å, 50 mg) were added to a suspension of zinc (4.0 mmol) and CuBr (1.5 mmol) inMeCN (3.0 mL) and the mixture was stirred for 1 h at room temperature followed by addition ofC-benzotriazolated nitrones 2a-h (1.0 mmol) dissolved in MeCN (1 mL). The reaction mixture washeated to 60 oC for 3 h and cooled to room temperature. The mixture was filtered, concentrated underreduced pressure and the residue subjected to column chromatography on silica gel using EtOAc-hexane,9:1 as eluent. 4-Methyl-2,3-di(p-tolyl)isoxazol-5(2H)-imine (4a): Yield 237 mg (85%), colorless crystals, mp 192-194oC; IR (KBr): ν 1660 cm-1 (C=N). 1H NMR δ 2.02 (s, 3H), 2.22 (s, 3H), 2.30 (s, 3H), 6.93 (d, J = 8.1 Hz,2H), 7.23 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H); 13C NMR δ 20.7, 21.3,21.4, 118.3, 128.1, 128.7, 129.1, 129.3, 132.0, 132.6, 137.4, 139.8, 147.4, 165.1; MS m/z: 278. Anal.Calcd. for C18H18N2O: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.52; H, 6.40; N, 10.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 2-bromopropionitrile With copper(I) bromide; zinc In acetonitrile at 20℃; for 1h; Molecular sieve; Stage #2: C19H14N4O In acetonitrile at 60℃; for 3h; | Synthesis of 5-imino-1,2-oxazoles 4a-l (general method) General procedure: 1-Bromonitrile 3a,b (1.0 mmol) andmolecular sieves (4 Å, 50 mg) were added to a suspension of zinc (4.0 mmol) and CuBr (1.5 mmol) inMeCN (3.0 mL) and the mixture was stirred for 1 h at room temperature followed by addition ofC-benzotriazolated nitrones 2a-h (1.0 mmol) dissolved in MeCN (1 mL). The reaction mixture washeated to 60 oC for 3 h and cooled to room temperature. The mixture was filtered, concentrated underreduced pressure and the residue subjected to column chromatography on silica gel using EtOAc-hexane,9:1 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 2-bromopropionitrile With copper(I) bromide; zinc In acetonitrile at 20℃; for 1h; Molecular sieve; Stage #2: C17H12N4O2 In acetonitrile at 60℃; for 3h; | Synthesis of 5-imino-1,2-oxazoles 4a-l (general method) General procedure: 1-Bromonitrile 3a,b (1.0 mmol) andmolecular sieves (4 Å, 50 mg) were added to a suspension of zinc (4.0 mmol) and CuBr (1.5 mmol) inMeCN (3.0 mL) and the mixture was stirred for 1 h at room temperature followed by addition ofC-benzotriazolated nitrones 2a-h (1.0 mmol) dissolved in MeCN (1 mL). The reaction mixture washeated to 60 oC for 3 h and cooled to room temperature. The mixture was filtered, concentrated underreduced pressure and the residue subjected to column chromatography on silica gel using EtOAc-hexane,9:1 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 2-bromopropionitrile With copper(I) bromide; zinc In acetonitrile at 20℃; for 1h; Molecular sieve; Stage #2: C17H12N4OS In acetonitrile at 60℃; for 3h; | Synthesis of 5-imino-1,2-oxazoles 4a-l (general method) General procedure: 1-Bromonitrile 3a,b (1.0 mmol) andmolecular sieves (4 Å, 50 mg) were added to a suspension of zinc (4.0 mmol) and CuBr (1.5 mmol) inMeCN (3.0 mL) and the mixture was stirred for 1 h at room temperature followed by addition ofC-benzotriazolated nitrones 2a-h (1.0 mmol) dissolved in MeCN (1 mL). The reaction mixture washeated to 60 oC for 3 h and cooled to room temperature. The mixture was filtered, concentrated underreduced pressure and the residue subjected to column chromatography on silica gel using EtOAc-hexane,9:1 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 2-bromopropionitrile With copper(I) bromide; zinc In acetonitrile at 20℃; for 1h; Molecular sieve; Stage #2: C18H13N5O In acetonitrile at 60℃; for 3h; | Synthesis of 5-imino-1,2-oxazoles 4a-l (general method) General procedure: 1-Bromonitrile 3a,b (1.0 mmol) andmolecular sieves (4 Å, 50 mg) were added to a suspension of zinc (4.0 mmol) and CuBr (1.5 mmol) inMeCN (3.0 mL) and the mixture was stirred for 1 h at room temperature followed by addition ofC-benzotriazolated nitrones 2a-h (1.0 mmol) dissolved in MeCN (1 mL). The reaction mixture washeated to 60 oC for 3 h and cooled to room temperature. The mixture was filtered, concentrated underreduced pressure and the residue subjected to column chromatography on silica gel using EtOAc-hexane,9:1 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-bromo-1 H-imidazole With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333h; Stage #2: 2-bromopropionitrile In tetrahydrofuran; mineral oil at 50℃; for 4h; Sealed tube; | Route 16 A 100 mL round bottom flask with stir bar was charged with 4-bromo-1H-imidazole (1.00 g, 6.80 mmol, 1.00 equiv.) and THF (15 mL, 0.45 M). NaH (60 wt% in mineral oil, 408.4 mg, 10.21 mmol, 1.50 equiv.) was slowly added at 0°C, and the reaction mixture was allowed to stir at 0°C for 20 min. 2-bromopropanenitrile (1 .50 g, 11.11 mmol, 1 .63 equiv.) was added at 0°C, and the vial was capped and placed in an 50°C bath. The reaction mixture was allowed to stir at 50°C for 4 h. The reaction mixture was cooled to room temperature. The reaction mixture was quenched by the addition of H2O (5 mL). The resulting solution was concentrated in vacuo. The resulting crude material was purified via silica gel chromatography to yield the desired product. The desired isomer was confirmed by NOESY spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | Stage #1: 2-bromopropionitrile With magnesium; iodomethane In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: 2,5‐dimethoxybenzaldehyde In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; | 1.1; 4.1; 3.1 (1) Synthesis of 3-(2,5-dimethoxyphenyl)-3-hydroxy-2-methylpropionitrile: To the 250mL three-necked flask, add magnesium chips (1.93g, 79.52mmol),100 mL of dry tetrahydrofuran,To this was added 2-bromopropionitrile (10.10 g, 75.90 mmol)and 3 drops of methyl iodide (about 0.033 mmol), kept refluxing for 1 h under nitrogen protection,The temperature was cooled to room temperature, and 60 mL of dry tetrahydrofuran solution in which 2,5-dimethoxybenzaldehyde (12.00 g, 72.29 mmol) was dissolved was added dropwise, and after reacting at room temperature for 1 h,Add ammonium chloride solution for hydrolysis, extract with ethyl acetate, concentrate under reduced pressure,The target product 3-(2,5-dimethoxyphenyl)-3-hydroxy-2-methylpropionitrile 14.75g was obtained,Yield 92.3%; |
Tags: 19481-82-4 synthesis path| 19481-82-4 SDS| 19481-82-4 COA| 19481-82-4 purity| 19481-82-4 application| 19481-82-4 NMR| 19481-82-4 COA| 19481-82-4 structure
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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.
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