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CAS No. : | 4152-90-3 | MDL No. : | MFCD00040752 |
Formula : | C7H8ClN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BJFPYGGTDAYECS-UHFFFAOYSA-N |
M.W : | 141.60 | Pubchem ID : | 77802 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 39.13 |
TPSA : | 26.02 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.97 cm/s |
Log Po/w (iLOGP) : | 1.87 |
Log Po/w (XLOGP3) : | 1.68 |
Log Po/w (WLOGP) : | 1.65 |
Log Po/w (MLOGP) : | 2.14 |
Log Po/w (SILICOS-IT) : | 2.1 |
Consensus Log Po/w : | 1.89 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.2 |
Solubility : | 0.886 mg/ml ; 0.00626 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.84 |
Solubility : | 2.04 mg/ml ; 0.0144 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.03 |
Solubility : | 0.131 mg/ml ; 0.000927 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P501-P264-P280-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P405 | UN#: | 2735 |
Hazard Statements: | H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
98 %Chromat. | at 35℃; for 5 h; | General procedure: In a 25mL round bottom flask, CuNP/WS was added into amixed solution containing 5mL doubly distilled water and 1 mmol nitroarene or benzonitrile. Next, 4 mmol NaBH4 was added in 4 portions to the reaction mixture and stirredat room temperature for the appropriate amount of time. The progress of the reaction was monitored by TLC [usingethyl acetate/n-hexane as eluent: 1/5]. After completion of the reaction, the reaction mixture was filtered off and thecatalyst rinsed twice with dichloromethane. The organic extracts were washed with H2O, dried over MgSO4 and evaporated in vacuo to give corresponding amines. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.0 g (73% based on 3-chlorobenzyl chloride) | With hydrogenchloride; sodium hydroxide; tetrabutylammomium bromide; benzaldehyde In chlorobenzene | EXAMPLE 2 Into a 1 l four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 728 g of a 7percent aqueous ammonium solution (3.0 mols in terms of NH3) and, while maintaining the internal temperature of the flask at 70° to 75° C., 80.5 g (0.50 mol) of 3-chlorobenzyl chloride and 53 g (0.5 mol) of benzaldehyde and 0.1 g of tetrabutylammonium bromide were admixed thereinto, followed by a reaction for 4 hours. After completion of the reaction, the reaction mixture was left to stand for a short time, and a separated oil phase was collected. Separately, into a 1 l four-necked flask, 548 g of a 5percent hydrochloric acid (0.75 mol in terms of HCl) and 300 g of chlorobenzene were charged. The oil phase separated as mentioned above was added thereto, and stirred at 80° C. for 30 minutes. Then, a chlorobenzene phase was collected by separation, mixed with 150 g of fresh chlorobenzene and 69 g (0.83 mol) of a 48percent sodium hydroxide aqueous solution, and reacted. An oil phase formed after the reaction was collected by separation, washed and dried according to a conventional method, and distilled under a reduced pressure of 20 Torr to obtain 49.0 g (73percent based on 3-chlorobenzyl chloride) of 3-chlorobenzylamine as a fraction of 113° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.1 %Chromat. | Stage #1: With hydrogenchloride; hydroxyammonium sulfate In water; toluene at 20℃; for 0.5 h; Stage #2: With sodium hydroxide In water; toluene |
At room temperature, 2.07 parts by weight of 1,3,5-tris(3-chlorobenzyl)-1,3,5-hexahydrotriazine, 15 parts by weight of toluene, 5.04 parts by weight of a 24 wtpercent aqueous hydroxylamine sulfate solution and 1.40 parts by weight of 35 wtpercent hydrochloric acid were stirred for 30 minutes. The mixture was adjusted to pH 13.1 by an addition of 6.16 parts by weight of a 27 wtpercent aqueous sodium hydroxide solution, and then subjected to a phase separation treatment to obtain a toluene layer containing 3-chlorobenzylamine and an aqueous layer. The aqueous layer thus obtained was extracted twice with 10 parts by weight and 5 parts by weight of toluene, and the obtained toluene layers were combined with the previously obtained toluene layer to obtain 31.50 parts by weight of a toluene solution containing 3-chlorobenzylamine (content: 5.21 wtpercent; GC method). The yield of 3-chlorobenzylamine was 86.1percent (based on 1,3,5-tris(3-chlorobenzyl)-1,3,5-hexahydrotriazine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; N,N-dimethylethylenediamine; copper(l) chloride; In toluene; at 80℃; for 24h;Sealed tube; Schlenk technique; | General procedure: A mixture of benzylamine 1a (107.0 mg, 1.0 mmol), CuCl (5.0 mg, 0.05 mmol, 5 mol%), 2,2,6,6-tetramethyl-1-piperidyloxy (TEMPO, 7.8 mg, 0.05 mmol, 5 mol%), and N,N-dimethylethane-1,2-diamine (DMEDA, 4.4 mg, 0.05 mmol, 5 mol%) in toluene (0.5 mL) sealed in a Schlenk tube (100 mL) with an air balloon was stirred at 80 C for 24 h. The reaction was then monitored by TLC and/or GC-MS. After completion of the reaction, solvent was evaporated under vacuum. The residue was purified by scosh column chromatography on silica gel using petroleum ether and ethyl acetate (0-100/1) as the eluent, giving product 2a in 80% isolated yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1-methyl-1H-imidazole; oxygen; copper(ll) bromide; In dimethyl sulfoxide; at 100℃; for 24h; | General procedure: To a 100 mL eggplant type Schlenk flask were added CuBr2 (67.0 mg, 0.3 mmol), corresponding amine (3 mmol) and a solution of NMI (73.8 mg, 0.9 mmol) in DMSO (6 mL). The flask was evacuated and purged with oxygen for three times before the flask was attached to a balloon filled with oxygen. Then the flask was heated at 100 C for 24 h. After the flask was cooled down and the reaction mixture turned into green color, water (15 mL) and dichloromethane (15 mL) was added into the mixture. The water layer was extracted with dichloromethane (5 mL x 3) and the organic layers were combined. After removing the solvent, residue was purified by column chromatography (PE/EA = 100:1) to give the product. |
73.4% | With 5% active carbon-supported ruthenium; oxygen; In toluene; at 150℃; under 3750.38 Torr; for 4h;Autoclave; | General procedure: In a typical process, into a 25 ml autoclave equipped with a magnetic stirrer were added 5%Ru/AC (0.03 mmol, 3 mol%), benzylamine (1 mmol), 5 mL toluene at room temperature successively. After which the resulting reaction mixture was heated at 150 C for 4 h under 0.5 MPa of oxygen atmosphere. The final reaction conversion and selectivity towards the corresponding nitriles were determined by Gas Chromatograph. After reaction, the product was purified by column chromatography of the reaction mixture on neutral alumina using hexanes/dichloromethane (80:20) or hexanes/EtOAc (30:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In butan-1-ol; at 90℃; for 4h; | Example 2 6-(3-chlorobenzylamino)purine 4 mmol of 6-chloropurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity>97percent. Yield 94percent. Table 2 compound prepared by the method of example 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; In dichloromethane; at 0 - 20℃; | General procedure: To a stirring solution of benzylamine (4.29 g, 40 mmol), Et3N (4.45 g, 45 mmol) in CH2Cl2 (45 mL), was added acetyl chloride (3.53 g, 45 mmol) at 0 °C (ice/water bath). The reaction mixture was stirred at 0 °C for 10 minutes. Then, the reaction mixture was stirred at room temperature overnight. After the completion, the mixture was washed with NaHCO3 (3 times) and brine, and dried over MgSO4. Then, the organic layer was concentrated and recrystallized from PE-EtOAc (v/v=6/1), affording the N-benzylacetamide (1a) (5.13 g, yield 86percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In tetrahydrofuran; at 40℃; for 20h; | Compound (E) (12.5 g, 45.9 mmol) prepared in the step 4 was dissolved in tetrahydrofuran (400 mL), then triethylamine (19.2 ml, 3 equivalents) and 3-chlorobenzylamine (11.2 mL, 2 equivalents) were added and the mixture was stirred at 40°C for 20 hours. The salt separated out therefrom was removed by filtration and the solvent was evaporated. The residue was purified by a chromatography (chloroform:methanol = 100:1 --> 40:1) and a mixed solvent of hexane/ethyl acetate (3:1) was added to a concentrated residue of a fraction containing the objective substance so that the crystals were separated out. The suspension containing the crystals was stirred for 1 hour and the crystals separated out therefrom were filtered and driedin vacuo to prepare compound (F) (11.9 g, yield: 69percent). |
69% | With triethylamine; In tetrahydrofuran; at 40℃; for 20h; | Compound (E) (12.5 g, 45.9 mmol) prepared in the step 4 was dissolved in tetrahydrofuran (400 mL), then triethylamine (19.2 ml, 3 equivalents) and 3-chlorobenzylamine (11.2 mL, 2 equivalents) were added and the mixture was stirred at 40°C for 20 hours. The salt separated out therefrom was removed by filtration and the solvent was evaporated. The residue was purified by a chromatography (chloroform:methanol = 100:1 --> 40:1) and a mixed solvent of hexane/ethyl acetate (3:1) was added to a concentrated residue of a fraction containing the objective substance so that the crystals were separated out. The suspension containing the crystals was stirred for 1 hour and the crystals separated out therefrom were filtered and dried in vacuo to prepare compound (F) (11.9 g, yield: 69percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; diisopropyl-carbodiimide; In DMF (N,N-dimethyl-formamide); dichloromethane; | Fmoc-Orn (Boc) -OH (70.0 mg, 454.52 g/mol, 0.15 mmol, 1 eq), DIC (24.1 ILL, 126.20 g/mol, 0.806 G/CM3, 0.15 mmol, 1 eq) and HOBt (20.8 mg, 135.12 g/mol, 0.15 mmol, 1 eq) were dissolved in dry DMF/DCM (1/1, 5 ml). After 5 minutes 3-chlorobenzylamine (18.8 pLI, 141.60 g/mol, 1.159 G/CM3, 0.15 mmol, 1 eq, Acros) was added to the reaction mixture. According to TLC analysis, reaction was complete after overnight stirring. Solvent was then evaporated and the yellow residue was purified with flash chromatography. 5- (N-BOC-AMINO)-N - (3-CHLOROBENZYL)- (S)-2- (N"-FMOC-AMINO) pentanamide as white foam was obtained with quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h; | N-(3-Chlorobenzyl)-5-fluoro-2-nitrobenzenamine:; 2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-chlorobenzylarnine (2.6 g, 18.1 mmol) 0 and LambdazetaiV-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95 percent yield). 1H NMR (400 MHz, CDCl3): delta 8.55 (s, IH), 8.25 (dd, IH), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethanol; hexane; ethyl acetate; | Example 4 Preparation of Intermediate 4-[4-(3-Chloro-benzylamino)-pyrimidin-2-yl]-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-4a): A mixture of <strong>[479691-42-4]4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester</strong> I-2a (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (2*18 mL). The combined organic extracts were washed with H2O (2*10 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography using 40% EtOAc in hexane as an eluding solvent to afford the title compound I-4a (93 mg) as a colorless oil. 1H NMR (400 MHz, CD3OD) delta 7.69 (d, 1H); 7.32 (s, 1H); 7.28-7.19 (m, 3H); 5.88 (d, 1H); 4.49 (s, 2H); 3.64-3.61 (m, 4H); 3.37-3.29 (m, 4H); 1.45 (s, 9H). MS (ES+) Calc: 403.2, Found: 404.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In ethanol; at 20℃; | General procedure: In a simply obtainable screw cap bottle, a mixture of ethylcyanoacetate6 (1.2 mmol) and the suitable amine (1 mmol) in EtOH (10 mL)was stirred at RT for 4-8 h. After completion as indicated by TLC, thereaction liquid was refrigerated down to 4 C in an ice bath. In severalcases, the precipitation of amide usually took later than some minutesto hours [12]. Filtered off the formed solid, rinsed with ether numeroustimes to obtain pure 7(a-q) in corresponding yield. |
In ethanol;Reflux; | General procedure: To a solution of different amines (1 mmol) in ethanol (10 mL), ethylcyanoacetate (1.2 mmol) was added. The reaction mixture was stirred for 5-8 h under reflux. Progress of the reaction was monitoredby TLC. After completion of the reaction, the resulting mixture was cooled to 0-5 C in an ice bath and the solid separated was filtered off. | |
In ethanol; water; | (a) N-(3'-chlorobenzyl)-2-cyanoacetamide A solution of 38.5 g. (0.34 mole) of ethyl cyanoacetate and 48.1 g. (0.34 mole) of 3-chlorobenzylamine in 120 ml. of 95% ethanol is refluxed for 5 hours and then allowed to stand overnight at ambient temperature. Agitation causes crystallization. Filtration is followed by washing of the solid with a small amount of ether to give 28.7 g. of the desired product as small, white needles, m.p. 123-5 C. The filtrate is evaporated in vacuo and a solid is obtained by trituration of the oily residue with ether. The solid is isolated by filtration, slurried in 900 ml. of deionized water, reisolated by vacuum filtration and dried to give an additional 11.9 g. of product, m.p. 122-4 C. yield: 40.6 g., 57% nu3300 (NH), 2270 (CN) and 1660 cm.-1 (C=O); delta 8.87 (broad t, 1H, NH), 7.4 (broad s, 4H, phenyl protons), 4.37 (d, 2H, benzyl methylene); and 3.7 (s, 2H, CH2 CO). Anal. Calc'd for C10 H9 ClN2 O: C,57.57;H,4.35;N,13.43;Cl,16.99; Found: C,57.94;H,4.36;N,13.42;Cl,77.21. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 15h; | To a 125 mL round-bottomed flask equipped with N2 inlet were added 1.02 g (4.53 mmol) N-t-butylcarboxy-octahydro-cyclopenta[c]pyrrol-5-one)-amine (preared as described in Becker, Daniel P.; Flynn, Daniel L. Synthesis of N-BOC-3- azabicyclo[3.3.0]octan-7-one via reductive Pauson-Khand cyclization and subsequent conversion to a novel diazatricyclic ring system. Tetrahedron (1993), 49(23), 5047-54.), 554 uL (4.53 mmol) 3-chlorobenzylamine, 259 uL (4.53 mmol) acetic acid, 1.44 g (4.16 mmol) sodium triacetoxy borohydride, and 20 mL dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 15 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil The residue was chromatographed on silica gel using methanol/ethyl acetate as eluant to afford 1.59 g (100%) of an oil.13C-NMR (delta, CDCI3): 13.11 , 16.47, 25.97, 28.74, 39.30, 40.97, 52.48, 60.74, 79.31 , 108.55, 112.49, 126.43, 127.35, 128.41 , 129.89, 134.47, 142.66, 154.90. MS: 351/353 (parent+1 for MW = 350.5, C19H27N2O2CI). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A library of compounds in which R4 was various groups having the formula [CONHR »] was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows: [72] Aldehyde resin was mixed with a primary amine (R17-NH2) in [DICHLOROETHANE] (DCE), triethylorthoformate (TEOF), and DMF (containing [1%] acetic acid) in a 1: 1: 1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq. ) dissolved in DMF was added (Abdel-Magid, A. F. , et al., Tetrahedron Lett, 3 1: 5595-5598 (1990) ). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL), [MEOH] [(3 X 5] mL), DMF [(3 X 5] mL), [MEOH] [(3 X 5] mL), and [CH2CL2] [(3 X 5] mL). The resin was washed twice with 5 mL DMF containing [1%] Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq. ) and diisopropylcarbodiimide (DIC, 5 eq. ) in 2: 1 DMF : DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL) and [CH2C12] (3 x 5 mL). [73] The resin was shaken with a primary amine [(R2-NH2)] in DMF for 8 hrs, filtered, and washed with DMF (6 x 5 mL), [MEOH] [(3 X 5] mL), and CH2C12 (3 x 5 mL). The aryl nitro group was reduced by the addition of tin (II) chloride dihydrate (20 eq. , >2 M) and N-methyl morpholine (NMM, 20 eq. ) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3 x 5 mL), [MEOH] (3 x 5 mL), and [CH2CI2 (3 X 5] mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq. ) overnight, filtered, and washed with CH2Cl2 (3 x 5 mL), [MEOH] (3 x 5 mL), and CH2CI2 (3 x 5 mL). To produce a free amine, the resin was shaken for 30 min. in CHCl2 with the addition of sodium methoxide in methanol, filtered, and washed with CH2Cl2 [(4 X 5] mL). [[74]] In the final diversification step, the resin was heated at 500 C in DMF with a mono- substituted epoxide [[RLCH (-CH2O-)].] After shaking for 2 to 4 days the resin was filtered and washed with DMF (5 x 5 mL), [MEOH] [(3 X 5] mL), and CH2Cl2 (3 x 5 mL). T he resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA: [CH2C12] (2: 3) for 1 hour at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; | N-Boc-L-proline (2.0 g, 9.30 mmol), <strong>[4152-90-3]m-chlorobenzylamine</strong> (1.45 g, 10.2 mmol), HOAt (1.38 g, 10.2 mmol) and EDCI (1.78 g, 9.30 mmol) were dissolved in 30 mL anhydrous DCM. After 10 min DIEA (3.45 mL, 20 mmol) was added to the mixture and left for stirring for 16 h at room temperature. The product was obtained as white solid after purification with flash chromatography (3.0 g, 95percent). 500 MHz, 1H NMR (CDCl3-d1): delta 1.40 (s, 9H) 1.80-2.02 (m, 3H) 2.10-2.20 (s, 1H) 3.39-3.41 (m, 2H) 4.0-4.52 (m, 3H) 7.20 (s, 4H) 7.40 (s, 1H) m/z (LCMS, ESI): found 361.3 [M+Na]+; [C17H23ClN2O3 + Na]+requires 361.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: m-chlorobenzylamine In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 120℃; for 0.166667h;Microwave irradiation; Inert atmosphere; | A solution of 5-chloro-jV-cyclohexylpyrazolo[ 1 ,5-alpha]pyrimidine-3-carboxamide(28 mg, 0.09 rnM, 1.0 equiv), 3-chlorobenzylamine (28 mg, 0.18 rnM, 2.0 equiv), N5N- diisopropylethylamine (26 mg, 0.18 rnM, 2.0 equiv) and 2 rnL of ethanol were microwaved at 120 0C for 10 minutes. TLC (95:5 dichloromethane methanol) showed reaction complete. The reaction mixture was cooled, the crystalline product collected by filtration, washed with cold ethanol and air dried to yield 29.7 mg (77percent) of 5-(3-chlorobenzylamino)-7V- cyclohexylpyrazolo[l,5-alpha]pyrimidine-3-carboxamide. LCMS (ESI) m+H = 384.2; 1H NMR (400 MHz, OMSO-d) delta: 8.61 (overlapping d and t, 2 H), 8.06 (s, 1 H), 7.60 (d, 1 H), 7.4- 7.25 (m, 4 H), 6.49 (d, 1 H), 3.70 (m, 1 H), 1.75-1.5 (m, 5 H), 1.4-0.8 (m, 5 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | 3- [5,6-bis(methyloxy)-2-pyridinyll -N- [(3-chlorophenvDmethyll -2,4-dioxo-l ,2,3,4-tetrahvdro- 7-quinazolinecarboxamide; 24a) Methyl 2-amino-4-(3-chlorobenzylaminocarbonyl)benzoate; To a stirred suspension of 3-amino-4-(methoxycarbonyl)benzoic acid (1.0 g, 5.13 mmol, 1 eq.) in DMF (7 mL) was added HATU (2.1 g, 0.5.64 mmol, 1.1 eq.) and DIEA (0.98 mL, 0.11 mol, 1.1 eq.) and the mixture was stirred at rt for 5 minutes until all dissolved. The resulting solution was added to 3-chlorobenzylamine (0.69 mL, 5.64 mmol, 1.1 eq.) in DMF (3 mL) via syringe and stirred at rt for 30 minutes when LCMS showed that the reaction was complete. The solution was added dropwise to ice-water with stirring and the precipitate collected by vacuum filtration, washed with ice-water and dried under vacuum to yield the title product methyl 2-amino-4-(3 chlorobenzylaminocarbonyl)benzoate (24a) which was used without further purification. (Yield: 1.52g, 93percent); MS(ES+) m/e 319 (MH+); 1H NMR (400 MHz, OMSO-d6) delta ppm: 3.81 (s, 3 H) 4.44 (d, J 6.06 Hz, 2 H) 6.81 (s, 2 H) 6.97 (d, J 8.59 Hz, 1 H) 7.24 - 7.40 (m, 5 H) 7.77 (d, J 8.59 Hz, 1 H) 9.07 (t, J 6.06 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With oxygen; methylene blue; potassium carbonate; In acetonitrile; at 20℃; for 10h;Irradiation; Green chemistry; | General procedure: A solution of 4-tert-butylbenzylamine (1a, 0.3 mmol), K2CO3 (3.7 equiv), and MB (1.0 mol%) in dry MeCN (5 mL) in a Pyrex test tube, purged with an O2 balloon, was stirred and irradiated externally with four 22 W fluorescent lamps for 10 h. Products were purified by filtration through a pad of silica gel (3 mm thick) with Et2O, and the filtrate was concentrated. |
90% | With Cu/Al2O3; In para-xylene; at 140℃; for 48h;Inert atmosphere; | 1 mmol of an amine compound substrate having the structure shown in the following table was added to the reaction flask.The Cu/Al2O3 (7 mol%) obtained in Example 1 was prepared.P-xylene 5ml,Raise the temperature to 140 C under nitrogen protection conditions, sample detection,The detection method is a GC method in which twelve n-hexane is an internal standard.The reaction is over,The reaction solution was filtered, and the filter cake was washed with toluene (3×5 mL).Wash with K2CO3 aqueous solution (3×5 mL), and concentrate the filtrate.The target product was purified by column purification. The experimental results are as follows: |
77% | With copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In neat (no solvent); at 30℃; for 17h; | General procedure: The mixture of benzylamine 1a (5.0 mmol), CuI (0.0190 g, 0.1 mmol, 2 mol%), and TEMPO (0.0156 g, 0.1 mmol, 2 mol%) was directly stirred in open air at room temperature (ca. 30 oC) in a reaction tube. After completion of the reaction as monitored by GC-MS and/or TLC, the mixture was then directly purified, without any workup, through a Et3N-washed silica gel column using ethyl acetate and petroleum ether as the eluent, affording N-benzylidenebenzylamine 2a in 85% isolated yield. |
73% | With [Et3NH]2[Ru(2,6-pyridinedicarboxylate)Cl3]; In neat (no solvent); at 100℃; for 15h; | General procedure: In a typical process, into a 5 ml two-necked, round-bottom flask equipped with a magnetic stirrer was added [Et3NH]2[Ru(dipic)Cl3] (0.005 mmol 0.01 equiv.) and benzylamine (5 mmol 1 equiv.) at room temperature successively. After which the resulting reaction mixture was heated at 100 C for 10 h in an air atmosphere. The final reaction conversion and selectivity towards the corresponding imines were determined by 1H NMR. After completion of the reaction, the product was received by column chromatography of the reaction mixture on neutral alumina using hexanes/EtOAc (95:5) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dimethyl sulfoxide; at 20℃; | To a solution of 6-Bromo-2-chloro-quinoxaline (0.3 g, 1 eq., 1.23 mmol) in DMSO (9 mL), was added 3-chloro benzyl amine (0.87 g, 5 eq., 6.2 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, water (60 mL) was added and the reaction mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The organic layer was concentrated under vacuum to obtain the crude product.For final purification, column chromatography was used on neutral silica gel of 60-120 mesh size employing a gradient of 0-1% methanol in hexane to elute the title compound (0.39g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In dichloromethane; at 20℃; | General procedure: In a round bottom flask equipped with a stir bar, 1.2 mmol of the appropriate amine was added to 10 mL of anhydrous dichloromethane. To this solution, 1.0 mmol of the appropriate isocyanate followed by 3.6 mmol of triethylamine was added. The reaction was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The resulting residue was purified by flash chromatography using a petroleum ether to ethyl acetate gradient to elute the final compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dihydrogen peroxide; at 80℃; for 10h;Inert atmosphere; | General procedure: Benzylamine (0.214 g, 2.00 mmol), [VO(PS-BBMA]SO4 (80 mg, 0.08 mmol) and H2O2 (4 mmol) was heated at 80 C for 10 h in a round bottom flask under nitrogen atmosphere. The reaction was monitored by TLC, and after complete consumption of benzylamine, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate: hexane=1:8) to afford benzamide. The product was analyzed by 1H NMR spectroscopy. |
75% | With tert.-butylhydroperoxide; caesium carbonate; In water; acetonitrile; for 4h;Reflux; | General procedure: To a solution of 4-methoxybenzyl amine (1.0 mmol) and cesium carbonate (1.0 mmol) in 3 mL of CH3CN was added a solution of 70% aqueous TBHP (3.0 mmol) and the mixture was refluxed for 4 h. The mixture was then dried to vacuum and extracted three times with ethyl acetate followed by washing with brine,and dried over anhydrous Na2SO4. Evaporation of the solvent under vacuum afforded the crude product, which was furthur purified by column chromatography using hexane/ethyl acetate mixture and then analyzed by spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 4h; | Example 12: 5-((trans)-2-aminocyclopropyl)-N-(3-chlorobenzyI)pyridin-2-amine hydrochloride; Step 1 :;A solution of tert-butyl (trans)-2-(6-bromopyridin-3-yi)cyclopropylcarbamate (Intermediate E, 350 mg, 1 . 1 18 mmol), 3-chlorobenzylamine (237 mg, 1.677 mmol), Sodium tert-butoxide (161 mg, 1.677 mmol) in 1 ,4-dioxane (7 mL) was degassed for 30 min, tris(dibenzylidene acetone) dipalladium (0) (51 mg, 0.055 mmol), 4,5-Bis(diphenyl phosphino)-9,0-dimethyl xanthene (193 mg, 0.335 mmol) was added and heated for 4 h at 80 °C. After completion, the solvent was removed, the residue was poured into ice cold water (10 mL) and extracted with EtOAc (2 X 20 mL). The combined extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04, filtered and evaporated. The crude residue was purified by flash chromatography to give tert-butyl (trans)-2-(6-(3- chlorobenzylamino) pyridin-3-yl) cyclopropyl carbamate (100 mg, yield: 24 percent) as white solid. |
24% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 80℃; for 4h;Inert atmosphere; | A solution of tert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (Intermediate E, 350 mg, 1.118 mmol), 3-chlorobenzylamine (237 mg, 1.677 mmol), Sodium tert-butoxide (161 mg, 1.677 mmol) in 1,4-dioxane (7 mL) was degassed for 30 min, tris(dibenzylidene acetone)dipalladium(0) (51 mg, 0.055 mmol), 4,5-Bis(diphenyl phosphino)-9,0-dimethyl xanthene (193 mg, 0.335 mmol) was added and heated for 4 h at 80° C. After completion, the solvent was removed, the residue was poured into ice cold water (10 mL) and extracted with EtOAc (2*20 mL). The combined extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography to give tert-butyl (trans)-2-(6-(3-chlorobenzylamino) pyridin-3-yl)cyclopropyl carbamate (100 mg, yield: 24percent) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,4-dioxane; at 120℃; for 6h;sealed tube; Inert atmosphere; | Example 47; { 3-[6-(3-Chloro-benzylamino)-pyridin-2-yl]- lH-pyrazolo[3,4-d]pyrimidin-6-yl}-(2- morpholin-4-yl-ethyl)-amine; Step A; [3-[6-(3-Chloro-benzylamino)-pyridin-2-yl]- l-(2-trimethylsilanyl-ethoxymethyl)- 1H- pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine; A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)- l-(2-trimethylsilanyl- ethoxymethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (200 mg, 0.37 mmol), 3-chlorobenzylamine (74 mg, 0.52 mmol), Pd2(dba)3 (21 mg, 10percent mmol), DavePhos (29 mg, 20percent mmol), i-BuONa (50 mg, 0.52 mmol) and dioxane (10 mL). The mixture was stirred at 120 °C under an atmosphere of N2 for 6 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane : MeOH, 100: 1) to give [3-[6-(3-chloro-benzylamino)-pyridin-2-yl]- l-(2-trimethylsilanyl-ethoxymethyl)- lH-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield HO mg, 50percent). |
50% | With sodium t-butanolate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 120℃; for 6h;Sealed vial; Inert atmosphere; | Step A[3-[6-(3-Chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amineA sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (200 mg, 0.37 mmol), 3-chlorobenzylamine (74 mg, 0.52 mmol), Pd2(dba)3 (21 mg, 10percent mmol), DavePhos (29 mg, 20percent mmol), t-BuONa (50 mg, 0.52 mmol) and dioxane (10 mL).The mixture was stirred at 120° C. under an atmosphere of N2 for 6 hours.After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure.The residue was purified by column chromatography (silica gel, dichloromethane:MeOH, 100:1) to give [3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 110 mg, 50percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium t-butanolate; tert-butyl XPhos;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; In toluene; at 100℃; for 15h;Inert atmosphere; Sealed vial; | 5-[3-(3-Chloro-benzylamino)-phenyl]-5-methyl-5,6-dihydro-2H-[l,4]oxazin-3-ylamine a) (RS)- (3-Chloro-benzyl)-[3-(5-methoxy-3-methyl-3,6-dihydro-2H-[l,4]oxazin-3-yl)- phenyl] -amineA dried pressure tube was charged consecutively under a nitrogen atmosphere with a solution of (RS)-3-(3-bromo-phenyl)-5-methoxy-3-methyl-3,6-dihydro-2H [l,4]oxazine (150 mg, 0.5 mmol) in toluene (5 ml), sodium tert-butylate (157 mg, 1.6 mmol), 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl (ie/t-butyl-x-phos) (23 mg, 0.1 mmol), tris(dibenzylideneacetone)- dipalladium chloroform complex (17 mg), and 3-chlorobenzylamine (154 mg, 1.1 mmol). The sealed pressure tube was heated at 100 C for 15 hours. After cooling, the reaction mixture was evaporated to dryness and directly purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate = 100/0 to 50/50 as the eluent. 85 mg (47%) of (RS)- (3-chloro-benzyl)-[3-(5-methoxy-3-methyl-3,6-dihydro-2H-[l,4]oxazin-3-yl)-phenyl]-amine were obtained as a yellow oil. Mass (calculated) C19H21CIN2O2 [344.844]; (found) [M+H]+ = 345. |
47% | With sodium t-butanolate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; tert-butyl XPhos; In toluene; at 100℃; for 15h;Inert atmosphere; Sealed tube; | a) (RS)-(3-Chloro-benzyl)-[3-(5-methoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amine A dried pressure tube was charged consecutively under a nitrogen atmosphere with a solution of (RS)-3-(3-bromo-phenyl)-5-methoxy-3-methyl-3,6-dihydro-2H [1,4]oxazine (150 mg, 0.5 mmol) in toluene (5 ml), sodium tert-butylate (157 mg, 1.6 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-butyl-x-phos) (23 mg, 0.1 mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (17 mg), and 3-chlorobenzylamine (154 mg, 1.1 mmol). The sealed pressure tube was heated at 100 C. for 15 hours. After cooling, the reaction mixture was evaporated to dryness and directly purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 50/50 as the eluent. 85 mg (47%) of (RS)-(3-chloro-benzyl)-[3-(5-methoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amine were obtained as a yellow oil. Mass (calculated) C19H21ClN2O2 [344.844]; (found) [M+H]+=345. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere; | To a stirred solution of <strong>[2840-28-0]3-amino-4-chloro-benzoic acid</strong> (0.200 g, 1.16 mmol) in DMF (10 mL) was added HBTU (0.487 g, 1.27 mmol), DIPEA (0.58 mL, 3.50 mmol) and 3-chlorobenzylamine (0.14 mL, 1.00 mmol) and the resulting mixture was stirred for 4 hours at room temperature under nitrogen (monitored by silica TLC; ethyl acetate-hexanes, 1:1). Solvent was distilled off under reduced pressure, obtained crude material was diluted with ice-water (10 mL) and was extracted with dichloromethane (3*25 mL). Collected organic parts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-amino-4-chloro-N-(3-chloro-benzyl)-benzamide as off white solid, which was used in the next step reaction without further purification. (Yield 0.300 g, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere; | To a stirred solution of <strong>[231958-04-6]3-tert-butoxycarbonylamino-4-methyl-benzoic acid</strong> (0.160 g, 0.64 mmol) in dichloromethane (5 mL) were added 1-hydroxybenzotriazole (0.172 g, 1.27 mmol) (Aldrich), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.244 g, 1.27 mmol) (Aldrich), triethyl amine (0.17 mL, 1.91 mmol) (Aldrich) and 3-chloro-benzylamine (0.07 mL, 1.00 mmol) (Aldrich) sequentially at room temperature under nitrogen and the resulting mixture was stirred for 1 hour (monitored by silica TLC; ethyl acetate-hexanes, 1:1). Solvent was distilled off under reduced pressure; obtained crude material was diluted with ice-water (10 mL) and was extracted with dichloromethane (3*25 mL). Collected organic parts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude [5-(3-chloro-benzyl-carbamoyl)-2-methyl-phenyl]carbamic acid tert-butyl ester as off white solid, which was used for the next step reaction without further purification. (Yield 0.223 g, 93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h; | To a 250 mL round bottom flask equipped with a stir bar was added 4-chloro-3-[(2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonyl)-amino]-benzoic acid (4.8 g, 12.3 mmol), DMF (50 mL), triethylamine (8.3 mL, 60.0 mmol), 3-chlorobenyzl amine (2.2 mL, 18.0 mmol) and then HATU (6.84 g, 18.0 mmol). The reaction was allowed to stir at room temperature for 12 hours, after which it was diluted with ethyl acetate, filtered and then successively rinsed with water and ethyl acetate. The collected solid was dried in an vacuum oven (70° C.) overnight to provide 2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid [2-chloro-5-(3-chloro-benzylcarbamoyl)-phenyl]amide. (Yield 5.5 g, 87percent).HR-MS (ES+) m/z Calculated for C23H18Cl2N5O3S ([M+H]+): 514.0502. Found: 514.0503. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In ethanol; for 0.5h; | 2-((3-chlorobenzyl)amino)naphthalene- 1,4-dione (2r). To a solution of 2-bromo-l,4-napthoquinone (283 mg, 1.2 mmol) in abs EtOH (40 mL) was added an excess of 3-chlorobenzylamine (293 uL, 2.4 mmol). Reaction was stirred for 30 min after which the precipitated solid was filtered to yield 199 mg bright orange powder (56% yield). MS m/z calcd (M+) 298.06, found 298.1. 1H NMR (400 MHz, DMSO-d6) Shift 8.23 (t, J = 6.53 Hz, 1H), 7.95 - 8.05 (m, 1H), 7.87 - 7.94 (m, 1H), 7.79 - 7.87 (m, 1H), 7.70 - 7.79 (m, 1H), 7.45 (s, 1H), 7.25 - 7.42 (m, 3H), 5.60 (s, 1H), 4.47 (d, J = 6.53 Hz, 2H). C13-HSQC (400 MHz, DMSO-d6) Shift (ppm) 40.08, 44.86, 100.96, 125.82, 126.28, 126.48, 127.51, 127.51, 130.72, 132.58, 135.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With [Ru-NHC]; In toluene; at 110℃; for 8h;Inert atmosphere; Schlenk technique; Sealed tube; | General procedure: A mixture of amide (5mmol), amine (5mmol), [Ru?NHC] complex (0.5molpercent) and toluene (5mL) was stirred in a sealed tube under nitrogen atmosphere at 110°C for 8h. After cooling down to room temperature, the reaction solvent was removed under vacuum. After removal of the solvent, the crude reaction mixture was dissolved in CH2Cl2 and purified by column chromatography on silica gel (200?400mesh) eluting with heptane:ethanol [25:1] to give corresponding amides as a white solid. The yields are mentioned in Tables 3?5. The product was confirmed by NMR spectroscopy. Reported isolated yields are an average of two runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With [Ru-NHC]; In toluene; at 110℃; for 8h;Inert atmosphere; Schlenk technique; Sealed tube; | General procedure: A mixture of amide (5mmol), amine (5mmol), [Ru?NHC] complex (0.5molpercent) and toluene (5mL) was stirred in a sealed tube under nitrogen atmosphere at 110°C for 8h. After cooling down to room temperature, the reaction solvent was removed under vacuum. After removal of the solvent, the crude reaction mixture was dissolved in CH2Cl2 and purified by column chromatography on silica gel (200?400mesh) eluting with heptane:ethanol [25:1] to give corresponding amides as a white solid. The yields are mentioned in Tables 3?5. The product was confirmed by NMR spectroscopy. Reported isolated yields are an average of two runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1,4-diaza-bicyclo[2.2.2]octane; 1,10-Phenanthroline; copper(II) acetate monohydrate; sulfur; In dimethyl sulfoxide; at 100℃; | General procedure: A mixture of 2-iodoaniline 1 (1 mmol), benzylamine 2 (1.2 mmol), sulfur powder (6 mmol), DABCO (2 mmol), Cu(OAc)2·H2O (0.02 mmol), and 1,10-phenanthroline (0.02 mmol) was stirred in DMSO (5mL) at 100 °C. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, water (20 mL) was added, and then the aqueous solution was extracted with ethyl acetate (3×15 mL). The organic layers were combined, dried over anhydrous MgSO4, the filtrate was concentrated under vacuum and then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate (10:1 to 14:1) on silica gel to provide the desired product. |
79% | With 1,4-diaza-bicyclo[2.2.2]octane; 1,10-Phenanthroline; copper(II) acetate monohydrate; sulfur; In dimethyl sulfoxide; at 100℃; | General procedure: A mixture of 2-iodoaniline 1 (1 mmol), benzylamine 2 (1.2 mmol), sulfur powder (6 mmol), DABCO (2 mmol), Cu(OAc)2.H2O (0.02 mmol), and 1,10-phenanthroline (0.02 mmol) was stirredin DMSO (5 mL) at 100 °C. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, water (20 mL) was added, and then the aqueous solution was extracted with ethyl acetate (3 15 mL). The organic layers were combined, dried over anhydrous MgSO4, the filtrate was concentrated under vacuum and then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate (10:1 to 14:1) on silicagel to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.3% | Stage #1: m-chlorobenzylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h; | 13 Example 13 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-chlorobenzyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS11) Example 13 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-chlorobenzyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS11) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 3-chlorobenzylamine (0.28g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.38g, 63.3%), i.e. the compound of Number MS11. m.p.: 103-105°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 5H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.76- 3.66(s, 4H); ESI-MS m/z: 599[M+H]+. |
63.3% | Stage #1: m-chlorobenzylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h; | 13 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-chlorobenzyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS11) Example 13 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-chlorobenzyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS11) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 3-chlorobenzylamine (0.28 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.38 g, 63.3%), i.e. the compound of Number MS11. m.p.: 103-105° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 5H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.76-3.66 (s, 4H); ESI-MS m/z: 599[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; | In a 250 mL round-bottomed flask, 3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (2 g, 8.22 mmol), (3-chlorophenyl)methanamine (1.28 g, 9.04 mmol) and HATU (3.44 g, 9.04mmol) were combined with DMF (20 mL). DIPEA (1.44 mL, 8.22 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with water. The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude material was triturated with DCM to give the desired compound which was filtered and dried under air. [3-(3-Chloro-benzylcarbamoyl)-cyclohexyll-carbamic acid tert-butyl ester was obtained (2.8 g, 93percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In butan-1-ol; at 90℃; for 4h; | Example 4 2-hydroxy-6-(3-chlorobenzylamino)purine 3 mmol of 2-hydroxy-6-chloropurine from example 3 were dissolved in 20 mL of butanol and then 4 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity>97percent. Yield 93percent. Table 3 compound prepared by the method of example 4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In butan-1-ol; at 90℃; for 4h; | Example 7 2-(3-chlorobenzylamino)-6-aminopurine 4 mmol of 2-chloro-6-aminopurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity>95percent. Yield 92percent. Table 5 compound prepared by the method of example 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In butan-1-ol; at 90.0℃; for 4.0h; | Example 8 2-(3-chlorobenzylamino)-6-hydroxypurine 4 mmol of 2-chloro-6-hydroxypurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90 C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity>91%. Yield 88%. Table 6 compound prepared by the method of example 8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In butan-1-ol; at 90℃; for 4h; | Example 1 2-amino-6-(3-chlorobenzylamino)purine 4 mmol of 2-amino-6-chloropurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity>98percent. Yield 95percent. Table 1 compound prepared by the method of example 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In butan-1-ol; at 90℃; for 4h; | Example 6 2-methy-6-(3-chlorobenzylamino)purine 3 mmol of 2-methyl-6-chloropurine from example 5 were dissolved in 20 mL of butanol and then 4 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90 C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity>98%. Yield 93%. Table 4 compound prepared by the method of example 6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 24h;Glovebox; | To a mixture of SAL (500 mg, 0.66 mmol) in dichloromethane (15 mL) the following compounds were added: DCC (206 mg, 1.0 mmol), HOBt (45 mg, 0.33 mmol) and corresponding monosubstituted benzyl amine (2.0 mmol). The mixture was first stirred at a temperature below 0 °C for 6 h and then for further 18 h at room temperature. The solvent was subsequently evaporated under reduced pressure to dryness. The residue was suspended in hexane and filtered off. The filtrate was evaporated under reduced pressure and the residue was purified chromatographically on silica gel (Fluka type 60) to give mono-substituted benzyl amides of SAL (yield from 67percent to 84percent, see Table 1) as a white solid state. The 1H, 13C as well as 2D NMR spectra of selected Br-o amide of SAL are included in the Supplementary material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h; | General procedure: To solutions of <strong>[120-36-5]2-(2,4-dichlorophenoxy)propanoic acid</strong> (100 mg,0.43 mmol) in DMF (2 mL) were added 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU; 200 mg,0.53 mmol), the corresponding benzylamines (0.50 mmol), anddiisopropylethylamine (100 lL, 0.57 mmol). The resulting mixtureswere stirred at room temperature for 16 h, then poured intowater (20 mL). The aqueous mixtures were then stirred at roomtemperature until solids precipitate. The solids were filtered,rinsed with water, and dried to provide solids that were recrystallizedfrom CH2Cl2/hexane to provide the products 34a-y. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acide 2,4,6-trihydroxybenzoique; oxygen; In para-xylene; at 140℃; under 750.075 Torr; for 24h;Green chemistry; | General procedure: To a two-necked flask, benzylamine derivatives 1 (4.0 mmol), o-aminothiophenol (8a) (3.0 mmol), 4,6-dihydroxysalicylic acid (10 mol%), and distilled p-xylene (2.0 mL) were added, and then the reaction vessel was connected to an O2 balloon at room temperature. The mixture was stirred in 140 C under O2 atmosphere for 24 h. The resulting mixture was transferred into a round-bottom flask using ethyl acetate (EtOAc) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/EtOAc) to give product 9. |
72% | With 2,8-dibromo-10-(4-bromophenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-dipyrrolo[1,2-c:2?,1?-f ][1,3,2]diazaborinin-4-ium-5-uide; In acetonitrile; at 50℃; under 1500.15 Torr; for 5h;Irradiation; Green chemistry; | General procedure: Amine (1 mmol), 2-aminothiophenol (2 mmol), BODIPY photosensitizer (0.01 mmol, 1.0 mol%), and acetonitrile (5 mL) were added to a dry 10-mL flask. The flask was pressurized with air (2 bar) and then heated to 50 C. The solution was then irradiated using a 35-W xenon lamp through a cutoff filter (0.72M NaNO2 aqueous solution, which is transparent for light >385nm, because lamps could emit a small amount of ultraviolet light). After the reaction was completed, the solvent was evaporated under reduced pressure. The crude product was further purified using column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | General procedure: 10495] In an oven-dried vial, G8 (1 equiv.) and benzotriazol-1 -yloxytripyrrolidinophosphonium hexafluorophosphate (1.2 equiv.) were dissolved in dichloromethane (0.1 M). Diisopropylethylamine (1 equiv.) was added, and the reaction was stirred at room temperature for 1-2 hours. Afier complete complexation by TLC, amine (1-3 equiv.) and additional diisopropylethylamine (1-3 equiv.) were added, and the reaction was allowed to stir at room temperature for 12-16 hours. The reaction was concentrated and purified by flash silica chromatography (hexanes/ethyl acetate) to provide the amide. (Note: G16a can be isolated and purified prior to the addition of amine.) Yield: 130.0 mg, 91percent.10502] ?H NMR (CD3OD, 500 MHz): oe 7.35 (t, J=1 .8 Hz,1H), 7.33-7.22 (m, 4H), 5.78 (dt, J=5.5, 2.0 Hz, 1H), 5.05 (t,J=2.5 Hz, 1H), 4.91 (t, J=1.9 Hz, 1H), 4.70 (t, J=5.3 Hz, 1H),4.38 (d, J=15.0 Hz, 1H), 4.34 (d, J=15.0 Hz, 1H), 4.19 (d,J=5.3 Hz, 1H), 3.38-3.33 (m, 1H), 2.68 (d, J=6.0 Hz, 1H),2.49 (dt, J=16.3, 3.0 Hz, 1H), 2.38 (d, J=6.0 Hz, 1H), 2.16(ddt, J=16.0, 2.0, 1.0 Hz, 1H), 2.02-1.88 (m, 1H), 1.76-1.62(m, 2H), 1.51-1.46 (m, 1H) 1.46 (dd, J=11.0, 3.0 Hz, 1H),1.36 (dd, J=1 1.0,2.5Hz, 1H), 1.15 (s, 3H). HRMS(ESI): mlzcalc. for C25H29NO5Cl[M+H]: 470.1734. found: 470.1740.10500] G1 6b: Prepared from 3-chlorobenzylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With triethylamine; In tetrahydrofuran; at 70℃; for 15.0h; | General procedure: Compounds 1-6 were prepared according to conventional organic synthesis methods. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was dissolved in THF (20 mL) in a round bottom flask and after that treated with two equivalents of the corresponding benzylamine and an equimolar amount of triethylamine. The reaction was conducted with continuous stirring and heating (70 C) under reflux in an oil bath for 15 h. Compounds 7-15 were synthesised using a microwave reactor with a focused field. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was put into a thick-walled tube together with the corresponding benzylamine (2.54 mmol), pyridine (1.27 mmol), methanol (approx. 5 mL) and a magnetic stir bar and then sealed with a special cap. The reaction parameters were set according to the previously published paper as follows-140 C, 30 min, 200 W [29]. Reaction progress was checked by TLC (hexane:ethyl acetate-1:1). Regardless of the synthesis method used,all reaction mixtures were adsorbed on silica and subjected to preparative flash chromatography (hexane and ethyl acetate, gradient elution, detection wavelengths 260 nm and 280 nm). Products were recrystallized from ethanol or ethanol and water if necessary. All final substances were chemically characterized (1H-NMR, 13C-NMR, IR, melting point and elemental analysis). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In N,N-dimethyl-formamide; for 4.0h;Reflux; | General procedure: Compound 4 (1.84 g, 0.01 mol) was mixed with (1.06 g, 0.01 mol) of trimethylamine and (0.01 mol)of the appropriate aromatic amine in 5 mL of dimethylformamide (DMF). The mixture was refluxedfor 4 h, cooled, and poured on crushed ice. The crystals were collected and crystallized from ethylalcohol. The melting points for all synthesized compounds were above 300 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With pyridine; In methanol; at 150℃; for 0.5h;Microwave irradiation; | General procedure: Compounds 5a?7a, 9a?11a, and 13a were synthetized using a microwave reactor with a focusedfield. Corresponding N-benzyl-3-chloropyrazine-2-carboxamide (0.6 mmol) was dissolved in methanol(3 mL) and appropriate benzylamine (1.8 mmol, 3 equiv.), along with pyridine (40 mg, 0.6 mmol,1 equiv.) as a base, were added. Our previous observations revealed that triethylamine (TEA) as a basecannot be used for microwave reactions. During the procedure, TEA is partially decomposed (probablyto diethylamine and similar species, which may act as undesired nucleophiles in the dehalogenationreaction). The use of pyridine as the base combined with benzylamines was experimentally verifiedin previous projects [18]. Conditions for synthesis were 150°C, 30 min, and 100 W. The progressof the reactions was monitored by TLC in system hexane/ethyl acetate 1:1. The reaction mixturewas adsorbed on silica by removing the solvents in vacuo and the product was purified by flashchromatography using gradient elution with ethyl acetate (0?100percent) in hexane. Products 7a and 10awere recrystallized from EtOH/H2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In tetrahydrofuran; at 18 - 25℃; for 1h; | To a mixture of <strong>[102393-82-8]6-bromo-2,4-dichloroquinazoline</strong> (278 mg, 1.0 mmol) and (3- chlorophenyl)methanamine (142 mg, 1.0 mmol) in THF (2 ml) was added Et3N (0.209 ml, 1.5 mmol). The mixture was stirred at RT for 1 h. The mixture was poured into EtOAc/H20 (5 mLI5 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer wasdried (Na2504) and filtered. After removal of solvent, the product was triturated with hexane and dried to give 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (360 mg, 0.94 mmol, 94 % yield) as a white solid. MS (M+H)= 384. |
94% | With triethylamine; In tetrahydrofuran; at 20℃; for 1h; | To a mixture of <strong>[102393-82-8]6-bromo-2,4-dichloroquinazoline</strong> (278 mg, 1.0 mmol) and (3-chlorophenyl)methanamine (142 mg, 1.0 mmol) in THF (2 ml) was added Et3N (0.209 ml, 1.5 mmol). The mixture was stirred at rt for 1 h. The mixture was poured into EtOAc/H2O (5 mL/5 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was dried (Na2SO4) and filtered. After removal of solvent, the product was triturated with hexane and dried to give 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (360 mg, 0.94 mmol, 94 % yield) as a white solid. LC-MS (Method 1): tR = 3.69 min, m/z (M+H)+ = 384. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In tetrahydrofuran; at 18 - 25℃; for 3h; | To a mixture of 6-bromo-4-chloroquinazoline (243 mg, 1.0 mmol) and (3- chlorophenyl)methanamine (142 mg, 1.0 mmol) in THF (2 ml) was added Et3N (0.21 ml, 1.5 mmol). The mixture was stirred at RT for 3 h. The mixture was poured into EtOAc/H20 (5 mLI5 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer wasdried (Na2504) and filtered. After removal of solvent, the product was triturated with hexane and dried to give 6-bromo-N-(3-chlorobenzyl)quinazolin-4-amine (342 mg, 0.98 mmol, 98 percent yield) as a white solid. MS (M+H)= 350. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.5% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 150℃; for 1h;Microwave irradiation; Sealed tube; | In a microwave tube was placed <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (242 mg, 1 mmol), (3- chlorophenyl)methanamine (283 mg, 2.0 mmol), DMSO (1 ml), and Hunig?s Base (0.349 ml, 2.0 mmol). The tube was sealed and heated at 150 00 for 1 h under microwave irradiation. The mixture was poured into EtOAc/H20 (30 mL/30 mL). The organic layer was washed with H20 (30 mL), dried (Na2504), and filtered. After removal of solvent, the product was triturated with 2% CH2CI2/hexane and then dried to give 6-bromo-N-(3-chlorobenzyl)quinolin-4-amine (238 mg,0.685 mmol, 68.5 % yield). MS (M+H)= 349. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | To a suspension of ethyl 6-brorno-4-hydroxyquinazoline-2-carboxylate (0.891 g, 3 rnrnol) and brornotri(pyrrolidin-1-yl)phosphoniurn hexafluorophosphate (2.10 g, 4.50 rnrnol) in 1,4-dioxane (12 rnl) was added Et3N (1.254 rnl, 9.0 rnrnol). The rnixture was stirred at rt for 3 h and then (3-chlorophenyl)rnethanarnine (0.85 g, 6.0 rnrnol) was added. The rnixture was stirred at rt for another 5 h. The rnixture was poured into hexane/H20 (10 rnL/10 rnL). The solid was filtered and triturated with 3percent EtOAc/hexane and then dried to give ethyl 6-brorno-4-((3- chlorobenzyl)arnino)quinazoline-2-carboxylate (1.2 g, 2.85 rnrnol, 95 percent yield). The rnaterial wasused without further purification. MS (M+H)= 421. | |
To a suspension of ethyl 6-bromo-4-hydroxyquinazoline-2-carboxylate (0.89 g, 3 mmol) and bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (2.10 g, 4.50 mmol) in 1,4-dioxane (12 ml) was added Et3N (1.25 ml, 9.0 mmol). The mixture was stirred at rt for 3 h and then (3-chlorophenyl)methanamine (0.85 g, 6.0 mmol) was added. The mixture was stirred at rt for another 5 h. The mixture was poured into hexane/H2O (10 mL/10 mL). The solid was filtered and triturated with 3percent EtOAc/hexane and then dried to give ethyl 6-bromo-4-((3-chlorobenzyl)amino)quinazoline-2-carboxylate (1.2 g, 2.85 mmol, 95 percent yield). The material was used without further purification. LC-MS (Method 1): tR = 3.45 min, m/z (M+H)+ = 421. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95%Chromat. | With palladium diacetate; 2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole; In water; at 100℃; for 4h;Inert atmosphere; | General procedure: [0041] Equation 7A mixture of aryl chlorides (10 mmol, 1.0 equiv, listed in Table 5), phenylboronic acid (1.829 g, 15 mmol, 1.5 equiv), Pd(OAc)2 (as listed in Table 5), PtB (as listed in Table 5) and 0 (25 mL, 1384 mmol) in a 3-neck round-bottom flask was stirred under reflux at 100 C in a N2 atmosphere for the time listed in Table 5. The initial and final pH values of the aqueous phase was measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 C, as reported in Table 5. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 C; the time to reach this temperature was approximately 15-20 minutes. The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then was thoroughly extracted with organic solvent (chloroform for aliphatic amine-containing substrates and ethyl acetate for aminopyridine substrates). The combined organic phase was dried over anhydrous MgSC , filtered, and then concentrated in vacuo. The crude product was analyzed by GC and FontWeight="Bold" FontSize="10" Eta NMR, as provided in Table 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In ethanol; at 80℃; for 18h; | A solution of 8-chloro-3-((3aR,4S,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-[1,2,4]triazolo[4, 3-a]pyrazine (500 mg, 1.60 mmol), (3-chlorophenyl)methanamine (0.39 mL, 3.2 mmol) and TEA (0.68 mL, 4.8 mmol) in EtOH (8.0 mL) was stirred at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with DCM and washed with water and brine. The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by MPLC on SiO2 (2-5percent MeOH in DCM) to give N-(3-chlorobenzyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-[1,2,4]triazolo[4,3-a]pyrazin-8-amine (2.40 g, 90percent) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): delta 7.41 (m, 2H), 7.27 (m, 3H), 7.24 (d, J=4.8 Hz, 1H), 5.75 (d, J=5.2 Hz, 1H), 5.31 (t, J=4.0 Hz, 1H), 4.62 (s, 1H), 2.95 (m, 2H), 1.59 (s, 3H), 1.42 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; In 2-methyl-propan-1-ol; at 170℃; for 4h;Microwave irradiation; | STEP7 Preparation of N-(3-chlorobenzyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazin-8-amine A mixture of 8-chloro-3-((3aR,4S,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazine (500 mg, 1.60 mmol), (3-chlorophenyl)methanamine (0.236 mL, 1.92 mmol) and DIPEA (0.700 mL, 4.01 mmol) in i-BuOH (8.0 mL) was subjected to microwave irradiation at 170° C. for 4 h. (The reaction was repeated 4 times in same scale). The combined reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water and brine. The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH-SiO2 (Hexanes:EtOAc=1:1) to give N-(3-chlorobenzyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazin-8-amine (2.40 g, 90percent) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): delta 7.44 (d, J=4.8 Hz, 1H), 7.39-7.40 (m, 2H), 7.26-7.25 (m, 4H), 6.32-6.24 (m, 1H), 5.10-5.05 (m, 2H), 4.78 (d, J=6.4 Hz, 2H), 4.55 (s, 1H), 3.05-3.04 (m, 2H), 1.60 (s, 3H), 1.38 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; for 12h;Reflux; | Compound I E (2 mmd), and (3chlorophenyflmethanamine (42 mmd) was dissolved in dioxane (5 mL). The mixture was refiuxed for 12 hours. Analysis of thereaction mixture by LCMS confirmed that the reaction was completed. The solventwas removed, and the residue was suspended with toluene for 12 hours. The suspension was ffltered and the ffltered cake was dried under vacuum to afford compound IF. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In acetonitrile; at 20℃;Green chemistry; | General procedure: To a solution of benzylamine (0.6 mmol), indole (1.0 mmol) and CuI (0.1 mmol ) in CH3CN (1 mL) was added TEMPO (0.15 mmol) under atmosphere and the mixture was stirred at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:4) to yield the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In acetonitrile; at 20℃;Green chemistry; | General procedure: To a solution of benzylamine (0.6 mmol), indole (1.0 mmol) and CuI (0.1 mmol ) in CH3CN (1 mL) was added TEMPO (0.15 mmol) under atmosphere and the mixture was stirred at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:4) to yield the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 equivalents) was added to a solution of compound 1 (1 equivalent) and N-ethyldiisopropylamine (3 equivalents) in CH2Cl2 (5 ml) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Then, in a typical experiment, primary amine (1.1 equivalents) was added and stirred for 1?6 h, diluted with CH2Cl2 (50 ml), washed with brine (3×50 ml), dried over Na2SO4, filtered and evaporated in vacuo. Chromatography on silica gel using petroleum ether : ethyl acetate as the eluent gave 5a-5m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In ethanol; at 20 - 40℃; for 5h; | General procedure: To a stirred solution of compound 2 (3 g, 9.2 mmol) in EtOH(50 mL) was added Et3N (2.6 mL, 18.4 mmol) and 3-fluorobenzylamine (2.1 mL, 18.4 mmol) at room temperature. Themixture was stirred for 5 h at 40 °C and concentrated. The residuewas purified by column chromatography over silica gel (DCM:MeOH: NH3H2O 200: 10: 0.1) to yield compound 3a (3.13 g, 82percent)as a colorless oil; [a]20D167.77 (c 0.78, MeOH); 1H NMR(500 MHz, CDCl3) delta 8.39 (s, 1H, purin-H), 7.79 (s, 1H, purin-H),7.35e7.30 (m, 1H, Ar-H), 7.17 (d, J 7.5 Hz, 1H, Ar-H), 7.11 (d,J 9 Hz, 1H, Ar-H), 6.59 (brs, 1H, NH), 5.89 (s, 1H, tetrahydrofuro-H),5.24 (t, J 5.1 Hz, 1H, tetrahydrofuro-H), 5.14 (d, J 5.5 Hz, 1H,tetrahydrofuro-H), 4.89 (brs, 2H, benzyl-CH2), 4.58 (s, 1H,tetrahydrofuro-H), 4.00 (d, J 12.6 Hz, 1H, CH2OH-CH), 3.84 (d,J 12.6 Hz, 1H, CH2OH-CH), 1.68 (s, 3H, CH3), 1.42 (s, 3H, CH3); 13CNMR (400 MHz, CDCl3) delta 162.5 (d, J 242.6 Hz, Ar-C), 154.8 (purin-C), 152.8 (purin-C), 147.5 (purin-C), 140.7 (purin-C), 139.8 (Ar-C),130.2 (d, J 8.1 Hz, Ar-C), 123.12 (d, J 2.5 Hz, Ar-H), 121.2 (purin-C), 114.5 (d, J 21.8 Hz, Ar-C), 114.0 (Ar-C), 94.4 (tetrahydrofuro-C),86.1 (tetrahydrofuro-C), 83.1 (tetrahydrofuro-C), 81.7 (tetrahydrofuro-C), 63.4 (CH2-C), 43.8 (benzyl-CH2-C), 27.6 (CH3), 25.2(CH3); LRMS (ESI): m/z 438 [M Na] |
82% | With triethylamine; In ethanol; at 40℃; for 5h; | To compound 2 (3 g, 9.2 mmol) at room temperatureEthanol (50mL)Et3N (2.6 mL, 18.4 mmol) was added to the solution.And 3-chlorobenzylamine (2.1 mL, 18.4 mmol),The resulting mixture was stirred at 40 ° C for 5 h;Concentrated and the residue is purified by silica gel column(by volume ratio, DCM: MeOH: NH3·H2O=200:10:0.1),Obtaining colorless oily compound 3(3.13g, 82percent), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; | General procedure: To a mixture of 5a (435mg, 1mmol), HATU (760mg, 2mmol), HOAt (272mg, 2mmol), substituted amine (1.2mmol) and DCM (10mL) at 0°C was added DIPEA (0.52mL, 3mmol), and the reaction mixture was then slowly warm to room temperature and stirred overnight. The reaction was quenched by water and the mixture was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4 and then subjected to flash chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; | To a mixture of 5d (227mg, 0.5mmol), HATU (380mg, 1mmol), HOAt (136mg, 1mmol), (3-chlorophenyl)methanamine (85mg, 0.6mmol) and DCM (5mL) at 0°C was added DIPEA (0.26mL, 1.5mmol), and the reaction mixture was then slowly warm to room temperature and stirred overnight. The reaction was quenched by water and the mixture was extracted by ethyl acetate, washed with water and brine, dried over Na2SO4 and then subjected to flash chromatograph to give compound 6x as off-white solid. Yield: 91percent; mp 231.5?233.4°C; 1H NMR (400MHz, DMSO-d6) delta 9.79 (s, 1H), 9.15 (t, J=5.9Hz, 1H), 7.90 (dd, J=14.1, 8.1Hz, 3H), 7.69 (dd, J=17.9, 9.8Hz, 4H), 7.59?7.46 (m, 4H), 7.44?7.21 (m, 6H), 7.04 (d, J=15.8Hz, 1H), 4.47 (d, J=5.9Hz, 1H), 3.15 (s, 3H); 13C NMR (100MHz, DMSO-d6) delta 166.3, 164.4, 142.9, 142.4, 140.3, 140.0, 139.0, 138.1, 135.8, 135.5, 133.6, 133.5, 131.1, 130.9, 130.8, 128.6, 128.4, 127.7, 127.4, 127.0, 126.6, 126.6, 126.1, 125.5, 124.1, 44.0, 42.9, ESI-MS m/z 577.1 [M+H]+; HRMS m/z calcd for C30H25ClN2O4S2 [M+H]+ 599.0837, found 599.0841. HPLC purity: 95.1percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | In ethanol; for 24h;Reflux; Sealed tube; | General procedure: To a Radley reaction carousel tube, add 1 equivalent 1, 1.1 equivalents of the amine, a stir bar, and 5 mL 95% ethanol. Reflux while stirring for 24 hours. After cooling to room temperature the resulting precipitate was collected by vacuum filtration, washing with 10 mL deionized water and 5 mL chloroform. |
Tags: 4152-90-3 synthesis path| 4152-90-3 SDS| 4152-90-3 COA| 4152-90-3 purity| 4152-90-3 application| 4152-90-3 NMR| 4152-90-3 COA| 4152-90-3 structure
[ 10541-69-2 ]
(2,5-Dichlorophenyl)methanamine
Similarity: 0.94
[ 10541-69-2 ]
(2,5-Dichlorophenyl)methanamine
Similarity: 0.94
[ 10541-69-2 ]
(2,5-Dichlorophenyl)methanamine
Similarity: 0.94
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H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
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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 |
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Health hazards | |
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H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
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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 |
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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 |
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H332 | Harmful if inhaled |
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H335 | May cause respiratory irritation |
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H351 | Suspected of causing cancer |
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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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