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CAS No. : | 612-13-5 | MDL No. : | MFCD00019745 |
Formula : | C8H6ClN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZSHNOXOGXHXLAV-UHFFFAOYSA-N |
M.W : | 151.59 | Pubchem ID : | 69152 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.92 |
TPSA : | 23.79 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) : | -5.64 cm/s |
Log Po/w (iLOGP) : | 1.83 |
Log Po/w (XLOGP3) : | 2.23 |
Log Po/w (WLOGP) : | 2.15 |
Log Po/w (MLOGP) : | 2.1 |
Log Po/w (SILICOS-IT) : | 2.77 |
Consensus Log Po/w : | 2.21 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.56 |
Solubility : | 0.415 mg/ml ; 0.00274 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.36 |
Solubility : | 0.654 mg/ml ; 0.00432 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.49 |
Solubility : | 0.0495 mg/ml ; 0.000327 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.55 |
Signal Word: | Danger | Class: | 8,6.1 |
Precautionary Statements: | P501-P260-P270-P264-P280-P303+P361+P353-P301+P330+P331-P363-P301+P310+P330-P304+P340+P310-P305+P351+P338+P310-P405 | UN#: | 2923 |
Hazard Statements: | H301-H314 | 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 |
---|---|---|
85.62% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 60℃; for 1 h; | A solution of 5.66 g of 2-cyanobenzyl chloride (R1 is H and R2 is Cl), 6.00 g of 3-methyl-6-chlorouracil and 5.30 g of N, N-diisopropylethylamine in 78 ml of DMSO , The reaction mixture was stirred for 1 h at 60 ° C. The reaction was cooled to room temperature, 80 ml of ice water was slowly added dropwise, and the mixture was stirred for 1 hour under ice-cooling. The crude compound 9.08 was filtered off with a yield of 88.14percent. The crude compound III was beaten with 72.6 ml of ether at 15 ° C, filtered, washed and dried to give pure 8.82 g of compound III with a purity of 97.14percent. The total yield of compound III was 85.62percent and the purity was 99.10percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sulfuric acid; water; at 80 - 90℃; for 1h; | To H2SO4 (70 mL) heated to 80-85 C, finely ground <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> (15.1 g, 0.1 mol) was added by portions. The reaction mixture was stirred at 90 C for 1 h, cooled to room temperature and poured into cold water (300 mL). The precipitated product was collected by filtration, washed with cold water, and dried in air. Yield 13.2 g (78%), colorless crystals, m.p.194-196 C (EtOH). Found (%): C, 56.88; H, 4.62; N, 8.14; Cl, 20.74. C8H8ClNO. Calculated (%): C, 56.65; H, 4.75; N, 8.26; Cl, 20.90. IR, nu/cm-1: 3381, 3189, 3037, 2924, 1680, 1647, 1618, 1577, 1446, 1392, 1082, 740. 1H NMR, delta: 4.90 (s, 2 H, CH2Cl); 7.27 (br.s, 1 H, NH); 7.39 (t, 1 H, H (5)Bza, J = 6.6 Hz); 7.42-7.50 (m, 2 H, H (3,4)Bza);7.51 (br.s, 1 H, NH); 7.58 (d, 1 H, H (6)Bza, J = 7.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In para-xylene; at 140℃; for 12h;Inert atmosphere; Green chemistry; | Under atmospheric pressure, 498.6 g of triethyl phosphite and 1000 ml of p-xylene were charged into a closed reactor equipped with a reflux condenser, heated to 140 C, and 151.6 g of an <strong>[612-13-5]o-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> solution (The molar ratio of triethyl phosphite and <strong>[612-13-5]o-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> is 3: 1), the feeding time is 2h, after the reaction is kept for 10h after completion of the reaction, the excess triethyl phosphite and the reaction solvent are recovered by distillation and reused; The resulting reaction mixture was cooled to 25-30 C, dissolved in 500 ml of N, N-dimethylformamide (DMF), dissolved in equimolar amounts for 3 hours under stirring, and 67 g of terephthalic aldehyde and 180 g of 30% Sodium methoxide methanol solution, the temperature dropped to 35 C after the end of the incubation reaction 3h, then cooled to 30 C, adjust the PH value to 7, cooled to 10 ~ 15 C, centrifuged, the resulting crude product was refined methanol , Finely centrifuged, and the crude product was centrifuged and dried to obtain 1,4-bis (o-cyanostyryl) benzene. The yield was 92% and the purity was 98%. The mother liquor was distilled to remove DMF and methanol [DMF back to the condensation process, methanol to refined crude], to give two phosphate Ethyl ester, yield 91%, purity 96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.5% | In N-methyl-acetamide; methanol; water; | EXAMPLE 2 30.4 g (0.2 mole) of <strong>[612-13-5]o-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> are dissolved in 70 g of dimethylformamide, and 24 g (0.6 mole) of sodium hydroxide powder are added at the same time as nitrogen is passed in. The mixture is stirred at 20 C. for about 6-10 hours until all the organically bound chlorine has reacted, 70 g of methanol are added dropwise, and the precipitate is filtered off with suction at 0 C. and is washed with methanol and then with water until no chlorine ions are detectable in the water from the wash. Drying gives 17.8 g of stilbene-2,2'-dicarbonitrile in the form of white crystals. Yield: 77.5%, Melting point: 187-189 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 48h; | General procedure for preparation of compounds with formula Io, wherein R3 (R3 ? hydrogen) is as defined above:2-(3,5-Dichloro-pyridin-4-yl)-l-(3-ethoxy-2-hydroxy-4-methoxy-phenyl)- ethanone from example 263 (12 mg, 0.034 mmol) was dissolved in dry DMSO (0.25 ml_). Aqueous K2CO3 (0.025 ml. of a 2M) was added followed by 1.5 eq. of an alkyl bromide or iodide dissolved in 0.025 ml. DMSO. The reaction mixture was left at rt for 48 hours. The pure compounds were obtained by standard preperative HPLC purification.Using this procedure the following compounds were obtained:Example 267 (compound 267)2-{2-Allyloxy-6-[2-(3,5-dichloro-pyridin-4-yl)-acetyl]-3-methoxy- phenoxymethyl}-benzonitrileLC/MS (METHOD B): (m/z) 383.2 (MH+); RT = 4.72 min; purity (UV) = 100% Alkyl halide: 2-Chloromethyl-benzonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 55℃; for 0.666667h; | General procedure: To a stirred solution of 7a-c or 16 (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong>9 (11) (0.6 g, 4 mmol) in DMF (4 ml) was added dry K2CO3 (1.1 g, 8 mmol). The mixture was stirred at 50-55 for 40 min, poured into H2O (30 ml), and extracted with CHCl3 (15 ml × 3). The extract was washed with H2O (20 ml × 2) and dried over Na2SO4. The solvent was evaporated in vacuo and the product crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 55℃; for 0.666667h; | General procedure: To a stirred solution of 7a-c or 16 (4 mmol) and 2-(chloromethyl)benzonitrile9 (11) (0.6 g, 4 mmol) in DMF (4 ml) was added dry K2CO3 (1.1 g, 8 mmol). The mixture was stirred at 50-55 for 40 min, poured into H2O (30 ml), and extracted with CHCl3 (15 ml × 3). The extract was washed with H2O (20 ml × 2) and dried over Na2SO4. The solvent was evaporated in vacuo and the product crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 55℃; for 0.666667h; | General procedure: To a stirred solution of 7a-c or 16 (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong>9 (11) (0.6 g, 4 mmol) in DMF (4 ml) was added dry K2CO3 (1.1 g, 8 mmol). The mixture was stirred at 50-55 for 40 min, poured into H2O (30 ml), and extracted with CHCl3 (15 ml × 3). The extract was washed with H2O (20 ml × 2) and dried over Na2SO4. The solvent was evaporated in vacuo and the product crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 55℃; for 0.666667h; | General procedure: To a stirred solution of 7a-c or 16 (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong>9 (11) (0.6 g, 4 mmol) in DMF (4 ml) was added dry K2CO3 (1.1 g, 8 mmol). The mixture was stirred at 50-55 for 40 min, poured into H2O (30 ml), and extracted with CHCl3 (15 ml × 3). The extract was washed with H2O (20 ml × 2) and dried over Na2SO4. The solvent was evaporated in vacuo and the product crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.3% | With sodium hydroxide; In N,N-dimethyl-formamide; | General procedure: Compound 7a was synthesized referencing to the literatures [18] and [29]. To be pointed out, the crude products of 7b, 7i, 7k, 7l, 7n-p required to wash with the solution of ethyl acetate/petroleum ether (v/v = 1:5) again; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 60℃; for 10h; | General procedure: To a mixture of <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> (10 mmol) and alkyl mercaptoacetate (10 mmol) in CH3CN (80 mmol) K2CO3 (10 mmol) was added. The mixture was stirred at 60C for 10h, then cooled to room temperature, and the precipitate was filtered off, washed with CH3CN (5 ml). The solvent was removed under reduced pressure. The compounds 1a,b was obtained in 96-98% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 60℃; for 10h; | General procedure: To a mixture of <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> (10 mmol) and alkyl mercaptoacetate (10 mmol) in CH3CN (80 mmol) K2CO3 (10 mmol) was added. The mixture was stirred at 60C for 10h, then cooled to room temperature, and the precipitate was filtered off, washed with CH3CN (5 ml). The solvent was removed under reduced pressure. The compounds 1a,b was obtained in 96-98% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile;Reflux; | (2) vanillin (5.0 mmol), potassium carbonate (20.0 mmol) and 4-methylbenzyl chloride (6.0 mmol),30mL of acetonitrile is used as a solvent, added to a 100mL three-necked bottle, and refluxed for 3-5h.The progress of the reaction was followed by TLC. After the reaction was completed, the reaction was stopped and washed with ice water.The solid intermediate 2-((4-formyl-2-methoxyphenoxy)methyl)benzonitrile was then collected by filtration; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; copper(ll) sulfate pentahydrate; sodium L-ascorbate; In acetone; at 20℃; for 2.5h; | General procedure: To a solution of substituted benzyl chloride (3.3mmol) in acetone (9mL) with stirring at r.t. for 30 min. Then NaN3 (0.24g, 3.6mmol), compound 9 (1.12g, 3mmol), saturated CuSO4 solution (10mL) and catalytic amount of sodium ascorbate were added. The mixture was stirred at room temperature for 2h. The mixture was poured into ice-water (200mL) with severe stirring. The solution was extracted with EtOAc and the EtOAc layer was washed with brine, dried with MgSO4 and concentrated to afford target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | General procedure: 1-(4-Chlorobenzyl)-2-(pyrrolidin-1-ylmethyl)-1H-benzimidazole dihydrochloride (1). Under an atmosphere of nitrogen, compound 36 (250 mg, 1.24 mmol, 1 equiv) was dissolved in freshly distilled warm tetrahydrofuran (THF) (2.5 mL), then cooled to 0 C. To this solution was added 60% NaH in oil (100 mg, 60 mg pure, 2.48 mmol, 2 equiv) and the mixture stirred at 0 C for 5 min. 4-Chlorobenzyl bromide (255 mg, 1.24 mmol, 1 equiv) was added followed by the addition of tetra-n-butylammonium bromide (23 mg, 0.07 mmol, 6 mol %). The mixture was stirred at rt overnight, then diluted with a solution of water (2 drops) in THF (5 mL). The solution was filtered through Celite, and the Celite was washed with THF (50 mL) and then EtOAc (50 mL). The filtrate was concentrated and the remaining residue purified by flash column chromatography on silica gel (EtOAc) to give the free base (195 mg) as an oil (Rf = 0.46, EtOAc). To a solution of the free base in MeOH (2 mL) was added a solution of 37% aqueous HCl (158 mg, 1.60 mmol, 2.7 equiv) in MeOH (2 mL). The mixture was concentrated, Et2O (5 mL) was added, and the mixture concentrated again. High-vacuum drying gave the product (242 mg, 0.61 mmol, 49%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | General procedure: To a solution of the 3a-d (2 mmol) in dry DMF (10 mL) wasadded sodium hydride (60% dispersion in mineral oil, 96 mg,2.4 mmol) at 0 C. After stirring for 15 min, the alkyl halide(2.4 mmol) was added at 0 C. The resulting mixture was stirredat 75 C for 12 h. Thereafter, the solvent was evaporated off in vacuo. The residue was purified by flash column chromatographyusing dichloromethane/petroleum ether as eluent to give targetcompounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | General procedure: To a solution of the 3a-d (2 mmol) in dry DMF (10 mL) wasadded sodium hydride (60% dispersion in mineral oil, 96 mg,2.4 mmol) at 0 C. After stirring for 15 min, the alkyl halide(2.4 mmol) was added at 0 C. The resulting mixture was stirredat 75 C for 12 h. Thereafter, the solvent was evaporated off in vacuo. The residue was purified by flash column chromatographyusing dichloromethane/petroleum ether as eluent to give targetcompounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | General procedure: To a solution of the 3a-d (2 mmol) in dry DMF (10 mL) wasadded sodium hydride (60% dispersion in mineral oil, 96 mg,2.4 mmol) at 0 C. After stirring for 15 min, the alkyl halide(2.4 mmol) was added at 0 C. The resulting mixture was stirredat 75 C for 12 h. Thereafter, the solvent was evaporated off in vacuo. The residue was purified by flash column chromatographyusing dichloromethane/petroleum ether as eluent to give targetcompounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydroxide; In water; at 50℃; for 3h;Green chemistry; | General procedure: KOH (2.4mmol), H2O (1.0mL), (pseudo)halides 1 (0.8mmol), and formamides 2 (1.6mmol) were successively added into a reaction tube. Then the reaction mixture was stirred under the conditions shown in Tables 1-5. After the reactions were completed, the mixture was extracted by ethyl acetate, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography to give products 3. |
98% | With NHC-Pd(II)-Im; sodium hydroxide; In water; at 50℃; for 3h;Inert atmosphere; Schlenk technique; | General procedure: Under a N2 atmosphere, NaOH (3.0 equiv), NHC-Pd(II)-Im complex 1 (1.0 mol%), water (1.0 mL), benzyl chloride 2a (0.8 mmol), and N-formylmorpholine 3a (2.0 equiv) were successively added into a Schlenk reaction tube. The mixture was stirred at 50 C for 3 h. After cooling to room temperature, the reaction mixture was extracted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. Then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (eluent: PE/EA = 5:1) to give the pure products 4a. 2-Morpholin-4-ylmethyl-benzonitrile (4i): Colourless liquid; IR (neat): nu 2160, 1454, 1351, 1267, 1115, 1008, 913, 865, 763, 740, 701 cm-1; 1H NMR (300 MHz): delta 7.65 (d, J = 7.5 Hz, 1H), 7.57-7.53 (m, 2H), 7.39-7.28(m, 1H), 3.71 (t, J = 4.5 Hz, 4H), 3.69 (s, 2H), 2.51 (t, J = 4.5 Hz, 4H); 13C NMR (75 MHz): delta 141.9, 132.9, 132.5, 130.0, 127.6, 117.7, 113.0, 66.8, 60.8, 53.3; MS (ESI): 203 [M + H]+; HRMS (ESI): calcd. for C12H15N2O[M + H]+: 203.1179; found: 203.1169. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; sodium chloride; palladium dichloride; cucurbituril; In ethanol; water; at 90℃; for 1h;Inert atmosphere; | General procedure: A round-bottomed flask equipped with a condenser was charged with benzyl chloride (0.5 mmol), arylboronic acid (0.6 mmol), base (0.75 mmol), Pd(II) catalyst (3 mol%) and the mixture was stirred in 5 mL of solvent at 90 C for the required time. After completion, the reaction mixture was diluted with ether (10 mL), water (10 mL) and extracted with ether (3 ×10 mL). The combined extract was dried over MgSO4. After evaporation of the solvent under reduced pressure, the residue was purified by column chromatography to obtain the desired products. |
88% | With potassium carbonate; N,N-dimethyl-formamide; palladium dichloride; In water; at 90℃; for 1h; | General procedure: A round-bottomed flask equipped with a condenser was charged with benzyl chloride (0.5 mmol), aryl boronic acid (0.6 mmol), base (1.0 mmol), PdCl2 (1.0 mol%) and the mixture was stirred in 5 mL of solvent at 90 C for the required time. After completion, the reaction mixture was diluted with ether (10 mL), water (10 mL) and extracted with ether (3 × 10 mL). The combined extract was dried over anhydrous Na2SO4. After evaporation of the solvent under reduced pressure, the residue was purified by column chromatography to obtain the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: A solution of compound 5a (0.2 mmol) was dissolved in DMF (5 ml). Anhydrous K2CO3 (0.2 mmol) and benzyl chloride (0.2 mmol) were added, and the mixture was stirred at room temperature for 4 h. Water (40 ml) was added, and the compound was extracted with dichloromethane, dried with Na2SO4, and the solvent was removed to produce a colorless oily substance, HSP70-(1-20). 4.2.1.2 2-(((1-((2-Ethoxythiazol-5-yl)methyl)piperidin-4-yl)(methyl)amino)methyl) benzonitrile (HSP70-2) 1H NMR (300 MHz, CDCl3-d): delta1.45-1.42 (t,3H); delta1.70-1.69 (m,2H); delta1.82 (m,2H); delta2.02 (m,2H); delta2.22 (s,3H); delta2.51 (m,1H); delta3.02-2.99 (m,2H); delta3.56 (s,2H); delta3.78 (s,2H); delta4.46-4.40 (q,2H); delta6.90 (s,1H); delta7.64-7.28 (m,4H). MS(TOF) 370.5 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.29% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | [0140] 0.5 g of the resulting compound was added to a 25 ml single neck round-bottom flask, and dissolved with 10ml of DMF. Thereafter, 0.22 g of anhydrous K2CO3 was added, and finally 0.3 g of <strong>[612-13-5]2-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> was added,followed by stirring at room temperature for 4h, till the reaction was complete as monitored by TLC, and then water wasadded to stop the reaction. The reaction mixture was extracted with DCM, and the DCM phase was separated with thinlayerchromatography. The product band silica gel was scraped off, soaked with anhydrous DCM, and filtered. The filterresidue was washed with a small amount of DCM, and the combined filtrate and washings was subjected to distillationunder reduced pressure in water bath of 30 C to obtain 255 mg of a colorless oily product, yield 48.29%. [0141] 1H-NMR (300 MHz, CDCl3-d): delta 1.66-1.70 (m, 2H); 1.84-1.87 (d, 2H); 2.03-2.09 (t, 2H); 2.22 (s, 3H); 2.52 (m,1H); 2.98-3.01 (d, 2H); 3.65 (s, 2H); 3.79 (s, 2H); 7.34-7.37 (m, 2H); 7.55-7.57 (m, 2H); 7.63-7.65 (d, 2H). MS (TOF)360.9 (M+). |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: Tert-butyl 1-((2-chlorothiazol-5-yl)methyl)piperidin-4-yl(methyl) carbamate (3a, 3.46 g, 10 mmol) was dissolved in dichloromethane (50 ml), and an excess of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 5 h. Solvent was removed under a vacuum to obtain a yellow oily substance consisting of 1-((2-chlorothiazol-5-yl)methyl)-N-methylpiperidin-4-amine. A stirred solution of 5b (0.5 mmol) in DMF (30 ml) at room temperature was treated with substituted benzyl chloride (0.51 mmol) and anhydrous K2CO3 (0.51 mmol) for 4 h. The solution was extracted with dichloromethane, dried with anhydrous MgSO4, filtered, and concentrated to produce a yellow oily residue that was purified by flash chromatographyto yield the desired product as a white powder, HSP70-(21-31). 4.2.2.1 2-(((1-((2-Chlorothiazol-5-yl)methyl)piperidin-4-yl)(methyl)amino)methyl) benzonitrile (HSP70-21) 1H NMR (300 MHz, CDCl3-d): delta1.66-1.70 (m,2H); delta1.84-1.87 (d,2H); delta2.03-2.09 (t,2H); delta2.22 (s,3H); delta2.52 (m,1H); delta2.98-3.01 (d,2H); delta3.65 (s,2H); delta3.79 (s,2H); delta7.34-7.37 (m,2H); delta7.55-7.57 (m,2H); delta7.63-7.65 (d,2H). MS(TOF) 360.9 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: A solution of yellow oily residue 5d (0.3 mmol) was dissolved in DMF (5 ml). Anhydrous K2CO3 (0.31 mmol) and substituted benzyl chloride (0.31 mmol) were added, and the solution was stirred at room temperature for 4 h. A total of 40 ml waterwas added, and the compound was extracted with dichloromethane and dried with Na2SO4, and the solvent was removed to produce a colorless oily substance, HSP70-(35-56). 4.2.4.15 2-(((1-(2-Methoxypyrimidin-4-yl)piperidin-4-yl)(methyl)amino)methyl) benzonitrile (HSP70-49) 1H NMR (300 MHz, CDCl3-d): delta1.60-1.64 (m,2H); delta1.97-2.00 (d,2H); delta2.23 (s,3H); delta2.84-2.94 (m,3H); delta3.82 (s,2H); delta3.95 (s,3H); delta4.49-4.52 (m,2H); delta6.21-6.22 (d,1H); delta7.31-7.39 (m,1H); delta7.57-7.58 (m,2H); delta7.65-7.67 (d,1H); delta8.03-8.04 (d,1H). MS(TOF) 337.4 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: A solution of yellow oily residue 5d (0.3 mmol) was dissolved in DMF (5 ml). Anhydrous K2CO3 (0.31 mmol) and substituted benzyl chloride (0.31 mmol) were added, and the solution was stirred at room temperature for 4 h. A total of 40 ml waterwas added, and the compound was extracted with dichloromethane and dried with Na2SO4, and the solvent was removed to produce a colorless oily substance, HSP70-(35-56). 4.2.4.7 2-((Methyl(1-(2-(methylthio)pyrimidin-4-yl)piperidin-4-yl)amino)methyl) benzonitrile (HSP70-41) 1H NMR (300 MHz, CDCl3-d): delta1.59-1.65 (m,2H); delta1.96-1.99 (d,2H); delta2.21 (s,3H); delta2.51 (s,3H); delta2.82-2.93 (t,3H); delta3.80 (s,2H); delta4.50-4.52 (m,2H); delta6.22-6.23 (d,1H); delta7.35-7.38 (m,1H); delta7.56-7.57 (m,2H); delta7.64-7.66 (d,1H); delta8.01-8.02 (d,1H). MS(TOF) 353.5 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: General procedure 4: 2,4-dichloropyrimidine (40 mmol), tert-butyl methyl(piperidin-4-yl)carbamate (41 mmol), and anhydrous K2CO3 (41 mmol) were added to a 1000 ml three-necked flaskcontaining 300 ml of DMF. The mixture was stirred at room temperaturefor 6 h. A large amount of ice water was added to precipitatea solid. The solid was washed with large amounts of petroleum ether, filtered, and dried in a vacuum. Flash chromatography (ethyl acetate-petroleum ether, 1:2) of the residue was performed to obtain white powder 3b (tert-butyl 1-(2-chloropyrimidin-4-yl) piperidin-4-yl (methyl)carbamate). A solution of yellow oily residue 5d (0.3 mmol) was dissolved in DMF (5 ml). Anhydrous K2CO3 (0.31 mmol) and substituted benzyl chloride (0.31 mmol) were added, and the solution was stirred at room temperature for 4 h. A total of 40 ml waterwas added, and the compound was extracted with dichloromethane and dried with Na2SO4, and the solvent was removed to produce a colorless oily substance, HSP70-(35-56). 4.2.5. General procedure for the synthesis of compounds HSP70-(57-67); General procedure 5: 4, 6-dichloropyrimidine was processed instead of 2, 4-dichloropyrimidine as described in General procedure4 to provide the product HSP70-(57-67). 4.2.5.8 2-(((1-(6-Methoxypyrimidin-4-yl)piperidin-4-yl)(methyl)amino)methyl) benzonitrile (HSP70-64) 1H NMR (300 MHz, CDCl3): delta1.58-1.62 (m,2H); delta1.93-1.96 (m,2H); delta2.20 (s,3H); delta2.72 (m,1H); delta2.83-2.87 (m,2H); delta3.78 (s,2H); delta3.91 (s,3H); delta4.41-4.44 (m,2H); delta5.84 (s,1H); delta7.35 (s,3H); delta7.54 (s,1H); delta7.63-7.65 (d,1H); delta8.32 (s,1H). MS(TOF) 337.4 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.62% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃; for 1h; | A solution of 5.66 g of <strong>[612-13-5]2-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> (R1 is H and R2 is Cl), 6.00 g of 3-methyl-6-chlorouracil and 5.30 g of N, N-diisopropylethylamine in 78 ml of DMSO , The reaction mixture was stirred for 1 h at 60 C. The reaction was cooled to room temperature, 80 ml of ice water was slowly added dropwise, and the mixture was stirred for 1 hour under ice-cooling. The crude compound 9.08 was filtered off with a yield of 88.14%. The crude compound III was beaten with 72.6 ml of ether at 15 C, filtered, washed and dried to give pure 8.82 g of compound III with a purity of 97.14%. The total yield of compound III was 85.62% and the purity was 99.10%. |
With potassium carbonate; potassium iodide; In N,N-dimethyl acetamide; at 50 - 100℃; | Examplel: Protected Alogliptin To the 125cc dimethylacetamide charged 0.28mole potassium carbonate after stirring it for 10-30 min at ambient temperature added 0.18mole of formula-IV with 0.186mole of formula-Ill (Where X= CI), 0.007mole potassium iodide at room temperature and stirred the reaction mass for 45-150 min at elevated temperature of 50-100C. The insitu reaction was carried forwarded by adding 0.17mole of formula- VI and 0.23mole of potassium carbonate at elevated temperature and further stirred for 75-175min. After completion of reaction, 500cc water was slowly added at around 20-60C and further stirred for 10-30 min. The wet solid wasdried at 40-90C to obtain 95% of protected Alogliptin. HPLC Purity: 96-98% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of thiol 1a-c (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, the solvent was evaporated in vacuo, and the reaction product was isolated by columnchromatography (silica gel 60-80 mesh, eluent hexane-CHCl3, 3 : 2). The compounds obtained were recrystallized from the an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of thiol 1a-c (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, the solvent was evaporated in vacuo, and the reaction product was isolated by columnchromatography (silica gel 60-80 mesh, eluent hexane-CHCl3, 3 : 2). The compounds obtained were recrystallized from the an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of thiol 1a-c (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, the solvent was evaporated in vacuo, and the reaction product was isolated by columnchromatography (silica gel 60-80 mesh, eluent hexane-CHCl3, 3 : 2). The compounds obtained were recrystallized from the an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; | General procedure: 6-Chloro-9H-purine (2 g, 12.9 mmol), K2CO3 (2.2 g,14.2 mmol), and the appropriate alkyl bromide or benzyl chloride derivative (14.2 mmol) were combined in DMF (25 mL) in a 100-mL round-bottomed flask, and the resulting mixture was stirred for 24 h at room temperature. After the reaction was completed (TLC), the mixture was poured into water (50 mL), and then extracted with CH2Cl2. The combined organic extracts were washed with water, dried (MgSO4), and concentrated to dryness in vacuo. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to give compounds 1a-1q as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.2% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; | General procedure: Compound 4b (0.2 g, 1.1 mmol) was dissolved in anhydrous DMF (2 mL), alkyl bromide, or benzylchloride derivatives (1.2 mmol) and NaH (0.15 g, 6.4 mmol) were added into this solution and stirredat a room temperature for 0.5-2 h. The mixture was poured into ice water, and then filtered, washedand dried. The compound (4c-t) was isolated and purified by silica gel column chromatography usingCH2Cl2/CH3OH (100:1) as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.5% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20 - 30℃; for 1.5h; | 8-hydroxymethyl-3-methylxanthine (10.Og, 51.0 mmol) was mixed with 70 mL of DMSO,Diisopropylethylamine (6. 6 g, 51.0 mmol) was added,O-<strong>[612-13-5]cyanobenzyl chloride</strong> (6. 8 g, 51.0 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours.TLC showed disappearance of the starting material,To the reaction solution by adding water lOOmL, precipitation of solid, filtration, the product 9. lg, yield 53. 5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.8% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 3h; | 7- (2-cyanobenzyl) -8-hydroxymethyl-3-methylxanthine(5.00 g, 16.1 mmol) was mixed with 50 mL of DMF, the reaction was carried out at 50 C for 3 hours. TLC showed the disappearance of the starting material, 500 mL of water was added thereto, and the mixture was suction-filtered, washed with water and dried over anhydrous magnesium sulfate (20 mL, The filter cake was dissolved in ethyl acetate and washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give 5.2 g of a 75.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With tetrakis(triphenylphosphine) palladium(0); In toluene; at 75℃; for 7.5h;Inert atmosphere; | General procedure: A Schlenk tube fitted with a Teflon vacuum stopcock and micro stirbar was flame-heated under vacuum and refilled with Ar. Benzylic chlorides 1 (0.50 mmol) and carbamoylsilane 2 (0.60 mmol) were charged to the cooled Schlenk tube under argon, followed by addition of 23 mg (0.02 mmol) of [(Ph)3P]4Pd(0) and 1.5 mL of dry toluene. The sealed reaction mixture was stirred at 75 C until no carbamoylsilane could be detected by TLC (using pre-coated silica gel plates (Merck 60 pF254)). Volatiles were removed under vacuum to afford the crude product which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate combination) to give aryl acetamides 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboline 1 (3.72 g, 20 mmol) was added to NaH (0.80 g, 20 mmol; 60% suspension in oil) in anhydrous DMF (30 mL) at cooling with ice. After hydrogen stopped to evolve, chloromethylbenzonitrile 2a-c (3.03 g, 20 mmol) in anhydrous DMF (20 mL) was added, purged with argon and stirred for 16 h at 25 C. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (3x40 mL). The combined organic extract was washed with water and saturated aqueous solution of NaCl, and dried with anhydrous Na2SO4. The drying agent was filtered off, the filtrate was concentrated in vacuo. The residue was purified by column chromatography, using ethyl acetate-triethylamine (9 : 1) as an eluent. The fractions containing product were combined, the solvent was evaporated in vacuo. The target benzonitriles 3a-c were dissolved in ethanol (50 mL), followed by the addition of 40% aqueous solution of NaOH (10 mL) and reflux for 6-10 h. The reaction mixture was concentrated, the residue was dissolved in water with heating and acidified with concentrated hydrochloric acid to pH ~1. A precipitate of acid hydrochloride 4a-c was filtered off, dried, and recrystallized from methanol or ethanol. Compounds 3a-c and 4a-c were used without additional characterization. Acid hydrochloride 4a-c (0.36 g, 1 mmol) was dissolved in anhydrous DMF (3 mL), followed by the addition of carbonyldiimidazole (0.36 g, 2.2 mmol). The reaction mixture was stirred for 2 h at 25 C, followed by the addition of a solution of 2-nitrooxyethylamine in anhydrous DMF (3 mL) (obtained from 2-nitrooxyethylamine hydronitrate (0.38 g, 2.2 mmol) and N-ethylpiperidine (0.25 g, 2.2 mmol)). The reaction mixture was stirred for 16 h at 25 C, diluted with dichloromethane, washed with 5% aqueous solution of NaHCO3 (10 mL), and water, and dried with anhydrous Na2SO4. The drying agent was filtered off, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluent: ethyl acetate- triethylamine, 9 : 1) to obtain carboline N-(2-nitrooxyethyl) carboxamides 5a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.3% | In a 100 ml round bottom flask,Weigh 1.44g (2mmol) of erythromycin A-6,9-9,12-spiroketal,Add 10ml of dichloromethane,Dissolved to clarify,Further, 0.06 g (1 mmol) of potassium hydroxide,0.11 g (1 mmol) of sodium carbonate,TBAB (tetrabutylammonium bromide) 0.32 g (1 mmol),Stir at room temperature for 15-20 minutes,To the reaction flask, 0.38 g (2.5 mmol) of <strong>[612-13-5]o-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> was added,The reaction was stirred at 45-50 C,TCL detection Erythromycin A-6,9-9,12-spiroketal points disappear after the reaction was stopped,Filtration, the filtrate was washed with saturated sodium bicarbonate solution, washed with water, the solution was evaporated to dryness, medium pressure preparative column was separated, the mobile phase was methanol and water,Get the target 1.3g, the yield of 78.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 5-Amino-1,3,4-thiadiazole-2-thiol 1 was dissolved in a mixture of NaOH in absolute EtOH. After 10 min, the corresponding benzyl chlorides (R-PhCH2-Cl) or bromine halogenated hydrocarbon (R-Br) was added dropwise with vigorous stirring at room temperature. The reaction was monitored by TLC and completed within 10 h. The mixture was poured into water, and the precipitate was washed with water to yield 2a-2s. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | 4-Isopropyl-N',N'-dimethyl-1,2,3-thiadiazole-5-carbohydrazide (130 mg, 0.61 mmol) was dissolved in abs. tetrahydrofuran (5 ml) under argon, and sodium hydride (29 mg, 0.73 mmol, 60% purity) was added at room temperature. Stirring at room temperature for 30 minutes was followed by the addition of <strong>[612-13-5]2-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> (92 mg, 0.61 mmol), and the resulting reaction mixture was stirred under reflux conditions for approx. two-and-a-half hours. After cooling to room temperature, sat. sodium hydrogencarbonate solution, water and dichloromethane were added. The aqueous phase was repeatedly extracted vigorously with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification of the resulting crude product by column chromatography gave 4-isopropyl-N',N'-dimethyl-N-(2-cyanobenzyl)-1,2,3-thiadiazole-5-carbohydrazide in the form of a viscous oil (30 mg, 15% of theory). 1H-NMR (400 MHz, CDCl3 delta, ppm) 7.81-7.77 (m, 2H), 7.65 (m, 1H), 7.59 (m, 1H), 5.12 (s, 2H), 4.08-4.02 (sept, 1H), 3.50 (s, 6H), 1.48 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | 3,6-Dichloropyridazine-4-carboxylic acid (700 mg, 3.63 mmol) was dissolved in abs. dichloromethane (10 ml), and triethylamine (0.33 ml, 1.52 mmol) was added. After stirring at room temperature for 5 minutes, N,N-dimethylhydrazine (0.33 ml, 4.35 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (3.24 ml, 5.44 mmol, 50% solution in tetrahydrofuran) were added. The resulting reaction mixture was stirred at room temperature for a further 30 minutes, and then water, sat. sodium hydrogencarbonate solution and dichloromethane were added. The aqueous phase was repeatedly extracted vigorously with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification of the resulting crude product by column chromatography gave 3,6-dichloro-N?,N?-dimethylpyridazin-2-ylcarbohydrazide in the form of a colorless solid (270 mg, 32% of theory). 1H-NMR (400 MHz, CDCl3 delta, ppm) 10.01 (br. S, 1H, NH), 8.29 (s, 1H), 2.71 (s, 6H). 3,6-Dichloro-N?,N?-dimethylpyridazin-2-ylcarbohydrazide (135 mg, 0.57 mmol) was then dissolved in abs. tetrahydrofuran (4 ml) under argon, and sodium hydride (28 mg, 0.69 mmol, 60% purity) was added at room temperature. Stirring at room temperature for 15 minutes was followed by the addition of <strong>[612-13-5]2-chloromethylbenzonitrile</strong> (87 mg, 0.57 mmol), and the resulting reaction mixture was stirred at 60 C. for two-and-a-half hours. After cooling to room temperature, sat. sodium hydrogencarbonate solution, water and dichloromethane were added. The aqueous phase was repeatedly extracted vigorously with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification of the resulting crude product by column chromatography gave 3,6-dichloro-N-(2-cyanobenzyl)-N?,N?-dimethylpyridazin-4-ylcarbohydrazide in the form of a colorless viscous oil (10 mg, 5% of theory). 1H-NMR (400 MHz, CDCl3 delta, ppm) 8.29 (s, 1H), 7.68 (m, 1H), 7.64-7.57 (m, 2H), 7.47-7.43 (m, 1H), 4.77 (s, 2H), 3.51 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | 2-(Difluoromethyl)thiophene-3-carboxylic acid (600 mg, 3.37 mmol) was dissolved in abs. dichloromethane (20 ml), and triethylamine (1.41 ml, 10.10 mmol) was added. After stirring at room temperature for 5 minutes, N,N-dimethylhydrazine (0.31 ml, 4.04 mmol) and 2,4,6- tripropyl- 1 ,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (3.01 ml, 5.05 mmol, 50% solution in tetrahydrofuran) were added. The resulting reaction mixture was stirred at room temperature for a further 30 minutes, and then water, sat. sodium hydrogencarbonate solution and dichioromethane were added. The aqueous phase was repeatedly extracted vigorously with dichioromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification of the resulting crude product by column chromatography gave 2-(difluoromethyl)-N?, N?-dimethylthiophene-3-carbohydrazide in the form of a colorless solid (760 mg, 97% of theory). ?H-NMR (400 MHz, CDC13 oe, ppm) 7.99 (m, 1H), 7.27 (m, 1H), 6.98-6.70 (br. t, 1H, CHF2) 6.56 (bt s, 1H, NH), 2.66 (s, 6H). 2-(Difluoromethyl)-N?,N?-dimethylthiophene-3-carbohy- drazide (130 mg, 0.59 mmol) was dissolved in abs. tetrahydrofuran (5 ml) under argon, and sodium hydride (28 mg, 0.71 mmol, 60% purity) was added at room temperature. Stirring at room temperature for 30 minutes was followed by the addition of <strong>[612-13-5]2-chloromethylbenzonitrile</strong> (89 mg, 0.59 mmol), and the resulting reaction mixture was stirred under reflux conditions for approx. 3 hours. After cooling to room temperature, sat. sodium hydrogencarbonate solution, water and dichloromethane were added. The aqueous phase was repeatedly extracted vigorously with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification of the resulting crude product by column chromatography gave N-(2-cyanobenzyl)-2-(difluoromethyl)-N?,N?-dimethylthio- phene-3-carbohydrazide in the form of a viscous oil (113 mg, 57% of theory). ?H-NMR (400 MHz, CDC13, ppm) 7.89 (m, 1H), 7.76 (m, 1H), 7.67 (m, 1H), 7.58 (m, 1H), 7.49 (m, 1H), 7.18 (m, 1H), 6.92-6.64 (bt t, 1H, CHF2), 5.16 (s, 2H), 2.50 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 90℃; for 1h;Inert atmosphere; | Step 1. To a stirred solution of tert-butyl 4-(4-(5-hydroxypyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (8) (60.00 mg,1.74 mmol) in ACN (10.00 mL) under N2 atmosphere containingCs2CO3 (62.23 mg, 0.19 mmol) was added benzylchloride (9b)(24.18 mg, 0.19 mmol). The reaction mixture stirred at 90 C for 1 h.The solvent was removed in rotary evaporator. The residue waspurified by column chromatography (EA:Hex 3:1) to give theintermediate product tert-butyl 4-(4-(5-(benzyloxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a white solid(41.02 mg, 54%); 1H NMR (400 MHz, CDCl3): delta 8.38 (s, 1H, PyH), 8.24(d, 1H, J 2.4 Hz, PyH), 7.78 (s, 1H, Pyrazole), 7.70 (s, 1H, Pyrazole),7.46-7.32 (m, 6H, PyH, ArH), 5.15 (s, 2H, CH2), 4.34-4.27 (m, 3H,Piperidine-CH2, CH), 2.91 (br s, 2H, Piperidine-CH2), 2.17 (d, 2H,J 10.8 Hz, Piperidine, CH2), 1.96 (qd, 2H, J 12.4 Hz, 4.4 Hz,Piperidine-CH2), 1.48 (s, 9H, Piperidine-N(Boc)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of 3-cyanopyridine-2(1H)-thione 1a-f (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, then the solvent was evaporated in vacuo, and the product was isolated by column chromatography (silica gel 60-80 mesh, the eluent was hexane-CHCl3 = 3 : 2) and crystallized from an appropriate solvent. 3-Cyano-2-(2-cyanobenzylthio)-4,6-dimethylpyridine (3a). The yield was 1.04 g (93%), m.p. 131-132 C (CHCl3-MeOH). Found (%): C, 69.02; H, 4.53; N, 15.14; S, 11.70. C16H13N3S. Calculated (%): C, 68.79; H, 4.69; N, 15.04; S, 11.48. IR, nu/cm-1: 2236 (CN), 2220 (CN), 1584, 1376, 1272, 876, 772. 1H NMR (DMSO-d6), delta: 2.36 (s, 3 H, 4-Me); 2.51 (s, 3 H, 6-Me); 4.66 (s, 2 H, CH2S); 7.09 (s, 1 H, C(5)HPy); 7.44 (t, 1 H, C(5)HBzn, J = 7.3 Hz); 7.64 (t, 1 H, C(4)HBzn, J = 7.3 Hz); 7.72 (d, 1 H,C(3)HBzn, J = 7.3 Hz); 7.81 (d, 1 H, C(6)HBzn, J = 7.3 Hz). 13C NMR (DMSO-d6), delta: 19.67 (4-Me), 24.15 (6-Me), 31.90 (CH2S), 103.94 (CPy(3)), 112.18 (CBzn(1)), 114.90 (CNPy), 117.62(CNBzn), 120.92 (CPy(5)), 128.20 (CBzn(5)), 130.52 (CBzn(3)), 132.89 (CBzn(6)), 133.26 (CBzn(4)), 141.54 (CBzn(2)), 152.75 (CPy(4)), 159.37 (C(Py2)), 161.70 (CPy(6)).* |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of 3-cyanopyridine-2(1H)-thione 1a-f (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, then the solvent was evaporated in vacuo, and the product was isolated by column chromatography (silica gel 60-80 mesh, the eluent was hexane-CHCl3 = 3 : 2) and crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of 3-cyanopyridine-2(1H)-thione 1a-f (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, then the solvent was evaporated in vacuo, and the product was isolated by column chromatography (silica gel 60-80 mesh, the eluent was hexane-CHCl3 = 3 : 2) and crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of 3-cyanopyridine-2(1H)-thione 1a-f (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, then the solvent was evaporated in vacuo, and the product was isolated by column chromatography (silica gel 60-80 mesh, the eluent was hexane-CHCl3 = 3 : 2) and crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of 3-cyanopyridine-2(1H)-thione 1a-f (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, then the solvent was evaporated in vacuo, and the product was isolated by column chromatography (silica gel 60-80 mesh, the eluent was hexane-CHCl3 = 3 : 2) and crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In chloroform; for 0.666667h;Reflux; | General procedure: Triethylamine (0.84 mL, 6 mmol) was added to a solution of 3-cyanopyridine-2(1H)-thione 1a-f (4 mmol) and <strong>[612-13-5]2-(chloromethyl)benzonitrile</strong> 2 (0.65 g, 4 mmol) in CHCl3 (5 mL). The reaction mixture was refluxed for 40 min, then the solvent was evaporated in vacuo, and the product was isolated by column chromatography (silica gel 60-80 mesh, the eluent was hexane-CHCl3 = 3 : 2) and crystallized from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium methylate; In methanol; at 25℃; for 4h; | The 2 - (chloromethyl) benzonitrile (500 mg, 3 . 30 mmol) is dissolved in the sodium methoxide methanol solution (33%, 5 ml) in, 25 C reaction 4 hours, saturated ammonium chloride aqueous solution quenching, ethyl acetate extraction, anhydrous sodium sulfate drying, filtering steaming did the oil of bombycinous 450 mg, crude yield 93% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iron(III) chloride; at 80℃; for 12h; | (1) Add 151.5g of <strong>[612-13-5]o-<strong>[612-13-5]cyanobenzyl chloride</strong></strong>, 500g of benzene, 12g of ferrous chloride to a 1000mL four-necked bottle with exhaust gas absorption, and heat up to 80 C for 12 hours, until the tail gas rises to normal temperature. Pour into a four-necked flask containing 800 mL of water, stir and wash, separate the organic layer, and distill off the benzene sleeve at normal pressure for the next batch. The substrate is o-cyanodiphenylmethane and proceed to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.9% | In acetonitrile; at -0.16 - 79.84℃; for 24.1667h; | A mixture of 4,40-bipyridine (3.101 g,20 mmol), <strong>[612-13-5]2-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> (3.129 g, 20 mmol) andacetonitrile (30 ml) was added to a 100 ml distillation flask,stirred at room temperature for 10 min, and then heated andrefluxed at 353 K for 24 h. Filtration after cooling to roomtemperature gave colourless block-shaped crystals of salt 1 in61.9% yield based on 4,40-bipyridine. Analysis calculated (%) for C18H14ClN3: C 70.24, H 4.58, N 13.65; found: C 70.30, H4.64, N 13.82. IR (KBr, cm-1): 3439 (m), 3040 (m), 2352 (m),2224 (m), 1637 (s), 1531 (w), 1481 (w), 1403 (s), 1215 (m), 1159(s), 1065 (w), 971 (m), 805 (s), 772 (s), 688 (m), 616 (w), 564(w), 493 (w), 446 (w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 12.1667h; | Preparation of the final product IV,Take 10mL of methylene chloride in a 25mL round bottom flask,At 0 , add DIEA (2mmol),Triethylamine (2mmol) was stirred for 10 minutes,Add intermediate III (1.2mmol),Add <strong>[612-13-5]o-<strong>[612-13-5]cyanobenzyl chloride</strong></strong> (1mmol) and stir for 10 minutes,Move to room temperature and react for 12 hours. Using TCL, the reaction materials in the reaction solution no longer decrease.After removing most of the solvent under reduced pressure, use a silica gel column,Column chromatography was carried out with petroleum ether: ethyl acetate = 3: 1, the solution was collected, and vacuum dried.To obtain a white solid,As shown in III, the yield is 67%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With palladium diacetate; cesium fluoride; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; at 80℃; for 12h;Inert atmosphere; | In a 25 mL reactor, add 2-cyanobenzyl chloride (0.031 g, 0.2 mmol), pinacol ester of allyl borate (0.067 g, 0.4 mmol), palladium acetate (2.2 mg, 0.01 mmol), cesium fluoride (0.091g, 0.6 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (8.7mg, 0.015mmol), stirred at 80C under nitrogen for 12h. Column chromatography separation (silica gel, 200-300 mesh; developing agent, petroleum ether: ethyl acetate = 10:1) gave o-cyano-3-butenylbenzene 0.023 g, yield 72%. |
Tags: 612-13-5 synthesis path| 612-13-5 SDS| 612-13-5 COA| 612-13-5 purity| 612-13-5 application| 612-13-5 NMR| 612-13-5 COA| 612-13-5 structure
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Sorry,this product has been discontinued.
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