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CAS No. : | 39989-43-0 | MDL No. : | MFCD00052681 |
Formula : | C7H7Cl2N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ICIJWOWQUHHETJ-UHFFFAOYSA-N |
M.W : | 176.04 | Pubchem ID : | 457602 |
Synonyms : |
|
Num. heavy atoms : | 10 |
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 : | 44.14 |
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) : | -5.5 cm/s |
Log Po/w (iLOGP) : | 1.99 |
Log Po/w (XLOGP3) : | 2.64 |
Log Po/w (WLOGP) : | 2.3 |
Log Po/w (MLOGP) : | 2.72 |
Log Po/w (SILICOS-IT) : | 2.72 |
Consensus Log Po/w : | 2.47 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.97 |
Solubility : | 0.187 mg/ml ; 0.00106 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.84 |
Solubility : | 0.256 mg/ml ; 0.00145 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.67 |
Solubility : | 0.0375 mg/ml ; 0.000213 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.15 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | 2735 |
Hazard Statements: | H302-H315-H318-H335 | 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 |
---|---|---|
85% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 16h; | EXAMPLE 67 2-Methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid 3,5-dichloro-benzylamide To a solution of 1.2 g (4.6 mmol) 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid in 30 ml CH2Cl2 1.28 ml (9.2 mmol) triethylamine, 0.62 g (4.6 mmol) 1-hydroxy-benzotriazole and 0.88 g (4.6 mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride 1.05 g (6 mmol) <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> were added.. The reaction mixture was stirred for 16 hrs.. The reaction mixture was diluted with 20 ml CH2Cl2, washed with 50 ml 0.5N HCl and 50 ml H2O. The aqueous layers were back extracted with 50 ml CH2Cl2.. The combined organic layers were dried (MgSO4), filtered and evaporated.. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 100:1) to give 1.64 g (85%) 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid 3,5-dichloro-benzylamide as a colorless foam, MS (ISP): 418.1, 420.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Dichlorobenzylamine (117 mg) was added to a solution of intermediate 36 (180 mg) in drydichloroethane (5 mL) under a Nitrogen atmosphere. After stirring for 1 h at r. t. NaBH (OAc) 3 (169 mg) was added and the resulting mixture was stirred at r. t. overnight. Then it was diluted with DCM, washed with an aqueous saturated sodium hydrogen carbonate solution, dried and concentrated in vacuo to give a crude oil, which was purified by flash chromatography (Biotage Flash 25M, CH/AcOEt 4: 1). The two fractions corresponding to products with Rf=0.36 and Rf=0.50 (CH/AcOEt 1: 1, detection with ninhydrine) were collected to give, after evaporation, an oil (40 mg) which was then dissolved, under a Nitrogen atmosphere, in dry MeOH (5 mL) and to which sodium methoxide (4.5 mg) was added. The mixture was refluxed for 5 h, then it was allowed to cool to r. t. and solvent was removed in vacuo. The residue was dissolved in AcOEt, washed with an aqueous saturated sodium hydrogen carbonate solution, dried and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (CH/AcOEt 9: 1) to give the title compound (35 mg) as a colourless oil. T. I. c.: CH/AcOEt 1: 1, Rf=0.5 (detection with ninhydrine). NMR(CDCI3) :6 (ppm) 7.31 (dd, 2H); 7.2 (t,1H) ; 6.98 (t, 2H); 6.83 (d, 2H); 4.25 (d,1H) ; 4.04 (d, 1H) ; 3.76 (b, 2H); 3.01 (td, 1H) ; 2.88 (m, 1H) ; 2.82 (bm, 1H) ; 2.63 (dd, 1H) ; 2.41 (b, 1H) ; 2.18 (bd, 1H) ; 2.05-2. 15 (m, 2H); 1.94 (b, 1H) ; 1.81 (b, 1H) ; 1.69 (m, 1H) ; 1.4 (s, 9H). MS (ES/+): m/z=543 [M+Na] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 0.166667h;Microwave irradiation; | A mixture of [(3,5-dichlorophenyl) methyl]amine (100 mg), 2-bromo- 1,1bis (methyloxy)ethane (123 muL) and K2C03 (95 mg) in anhydrous DMF (2 mL) was processed by microwave irradiation at 150C for 10 min (3 cycles). The mixture was allowed to cool to rt, water was added and mixture extracted three times with AcOEt, the organic phases collected, washed with brine, dried and evaporated under vacuum to give a crude which was purified by flash cromathography eluting with CH: AcOEt= 9: 1 to 85:15 to afford the title compound (120 mg) as a colourless oil. MS (ES/+) : m/z=264 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In ISOPROPYLAMIDE; at 20℃; for 24h; | In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyrindine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (18 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) delta ppm 1.28 (t, 3H) 4.19-4.81 (m, 4H) 6.33-7.81 (m, 4H). MS (ESI) negative ion 363(M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 72h; | t-Butyl 4-(5-(3 ,5-dichlorobenzylamino)-2-nitrophenyl)piperazine-l -carboxylate :; t-Butyl 4-(5-fluoro-2-nitrophenyl)rhoiperazine-l -carboxylate (1.3 mmol), 3-chlorobenzylamine (1.3 mmol), LambdazetaN-diisopropylethylamine (1.3 mmol) were stirred at 80 0C in dry acetonitrile (25 mL) for 72 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25 % ethyl acetate in hexanes to afford the title compound (41 %). 1H NMR (400 MHz, CDCl3): delta 9.38 (br, 1 H), 7.67 (d, 1 H), 7.31 (s, 1 H), 7.21 (s, 2 H), 6.13 (dd, 1 H)5 5.70 (d, 1 H), 4.42 (d, 2 H), 3.54 (m, 4 H), 3.38 (m, 4 H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 481.37; Observed: 482.6 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 18h;Heating / reflux; | l-(2-(3,5-Dichlorobenzylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone; A mixture of 2,2,2,2',4'-pentafluoroacetophenone (1.05 g, 5.0 mmol), 3,5- dichlorobenzylamine (0.88 g, 5.0 mmol), N,iV-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5 % ethyl acetate in hexanes as eluent to yield the title compounds as a yellowish solid (0.78 g, 43%). 1H NMR (400 MHz, CDCl3): delta 9.28 (br s, 1 H), 7.88 (m, 1 H), 7.34 (s, 1 H), 7.22 (s, 2 H), 6.44 (m, 1 H), 6.30 (dd, 1 H), 4.43 (d, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 18h;Heating / reflux; | iV-(3,5-Dichlorobenzyl)-5-fluoro-2-(methylsulfonyl)benzenamine:; A mixture of 2,4-difluoromethylsulfonylbenzene (5.0 mmol), 3,5-dichlorobenzylaniine (5.0 mmol), LambdazetaiV-diisopropylethylamine (10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5 % ethyl acetate in hexanes as eluent to yield the title compounds as a yellowish solid (37 %). 1H NMR (400 MHz, CDCl3): delta 9.28 (br s, 1 H), 7.88 (m, 1 H), 7.34 (s, 1 H), 7.22 (s, 2 H)5 6.44 (m, 1 H)3 6.30 (dd, 1 H), 4.43 (d, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 18h;Heating / reflux; | 1 -(2-(3 ,5-DichloiObenzylamino)-4-fluoro-nitrobenzene:; A mixture of 2,4-difluoronitrobenzene (5.0 mmol), <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (5.0 mmol), N, N- diisopropylethylamine (10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5 % ethyl acetate in hexanes as eluent to yield the title compounds as a yellowish solid (46 %). 1H NMR (400 MHz, CDCl3): delta 9.28 (br s, 1 H)5 7.88 (m, 1 H)5 7.34 (s, 1 H)5 7.22 (s, 2 H), 6.44 (m, 1 H), 6.30 (dd, 1 H), 4.43 (d, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 125 8-hydroxy-6-methyl-[1,6]naphthyridine-7-carboxylic acid 4-fluoro-benzylamide (125) In a manner similar to that for the compound 124H in Example 124, Step 8, substituting <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> with 4-fluorobenzylamine in Step 8, 8-hydroxy-6-methyl-[1,6]naphthyridine-7-carboxylic acid the 4-fluoro-benzylamide (125) was prepared. 1H NMR (400 MHz, CD3OD) delta 9.10 (d, 1H), 8.72 (d, 1H), 7.84 (dd, 1H), 7.43 (dd, 2H), 7.06 (t, 2H), 4.64 (s, 2H), 2.88 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;aluminium trichloride; In toluene; | Step 8 Preparation of 8-hydroxy-6-methyl-[1,6]naphthyridine-7-carboxylic Acid 3,5-dichloro-benzylamide (124H) A mixture of 124G (150 mg, 0.64 mmol), <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (153 mg, 0.87 mmol) and aluminum chloride (27 mg, 0.20 mmol) in toluene (8 mL) was refluxed for 4 h under nitrogen. After cooling to room temperature, the reaction mixture was treated with aqueous saturated NaHCO3 solution and ethylenediaminetetraacetic acid (1 g, 3.4 mmol) to pH 7. The mixture was extracted with chloroform four times. The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by preparative reverse-phase HPLC to give 124H. 1H NMR (400 MHz, DMSO) delta 13.2 (s, 1H), 9.73 (t, 1H), 9.15 (dd, 1H), 8.64 (dd, 1H), 7.83 (dd, 1H), 7.52 (s, 1H), 7.44 (s, 2H), 4.57 (d, 2H), 2.85 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3 Preparation of 8-hydroxy-5-(3-piperidin-1-yl-prop-1-ynyl)-[1,6]naphthyridine-7-carboxylic acid 3,5-dichloro-benzylamide Following the general procedure for addition of <strong>[39989-43-0]3,5-dichloro-benzylamine</strong> to the ester as in Example 1, Step 3 gave the title compound as a brown solid. 1H NMR (CDCl3, 400 MHz) delta 9.26 (1H, d, J=4.21 Hz), 8.66 (1H, d, J=8.61 Hz), 8.44 (1H, s), 7.79 (1H, dd, J=4.21 and 8.61 Hz), 7.32 (1H, s), 7.29 (2H, s), 4.66 (2H, d, J=6.41 Hz), 4.30 (2H, s), 3.70 (4H, m), 2.95 (2H, m), and 2.01 (4H, m) ppm. FAB HRMS exact mass calcd for C24H22Cl2N4O2 469.119258 (MH+), found 469.119314. Anal. Calcd for C24H22Cl2N4O2.1.35 MeOH.0.05 TFA: C, 47.39; H, 3.98; N, 7.51. Found: C, 47.40; H, 3.98; N, 7.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In (R)-N-[3,5-(bistrifluoromethyl)benzyl]-7,8-dihydro-7-([1,1,2,2-2H4]-4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-1,7-naphthylidine-6-carboxamide; N-[3,5-bis(trifluoromethyl)benzyl]-5-(3,4-dichlorophenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamide; | (Step 1) The compound obtained in Step 2 in Reference Example 2 and <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> were reacted and treated in the same manner as in Step 4 in Reference Example 2 whereby N-(3,5-dichlorobenzyl)-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamide was obtained as colorless crystal. Melting point: 232-233 C. (recrystallized from THF-isopropyl ether). NMR (200 MHz, CDCl3) ppm: 2.45 (3H, s), 4.44 (2H, d, J=6.4 Hz), 7.1-7.3 (5H, m), 7.34 (2H, d, J=7.6 Hz), 7.43 (1H, bt), 7.59 (2H, m), 8.95 (1H, dd, J=4.0, 2.2 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 30 2-[3,5-Dichlorobenzylamino]-4-[benzimidazol-1-yl]pyrimidine 2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (EI): m/e 370.3 (M+1). 1H NMR (500 MHz, CDCl3): delta 8.58 (s, 1H); 8.45 (d, J=5.5 Hz, 1H); 7.98 (br s, 1H); 7.86 (m, 1H); 7.38 (m, 2H); 7.31 (s, 2H); 6.89 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.72 (d, J=6.4 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B: 3,5-Dichlorobenzylamine Borane-tetrahydrofuran complex, 1 molar in tetrahydrofuran (0.054 mol) was added to a cooled (0, ice/water) solution of O-methyl-3,5-dichlorobenzyaldoxime (0.0493 mol) in dry tetrahydrofuran (50 ml). The reaction was refluxed 2 hours, then was cooled, water (20 ml) followed by 10% aqueous sodium hydroxide (20 ml) were carefully added, and the reaction was refluxed an additional 2 hours. After cooling, the phases were separated. The aqueous phase was extracted with ether, then the combined organic phases were extracted into 3N hydrogen chloride. The acidic solution was cooled and basified with 50% aqueous sodium hydroxide and extracted into ether. After drying over sodium sulfate and concentrating, 5.34 g (62%) of yellow oil was obtained. | ||
B: 3,5-Dichlorobenzylamine The reaction of 3,5-dichlorobenzaldehyde methoxime, (17.4 g, 85.7 mmole) and 0.98M borane in tetrahydrofuran (86 ml) substantially as described in 1B above produced 10.5 g (70%) of the title compound as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.5 g (100%) | With ammonium acetate; | C: N-(3,5-Dichlorobenzyl)-2-nitroaniline A mixture of 2-fluoronitrobenzene (1.2 g, 8.5 mmole) <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (4.47 g, 25.4 mmole), and ammonium acetate (0.5 g) was reacted substantially as described in 1C above to give 2.5 g (100%) of the title compound as orange crystals: mp 138-140. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 264 N-(3,5-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B using <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI-) m/z 357 (M-H)-; 1H NMR (DMSO, 300 MHz) delta 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.13 (s, 2H), 7.42 (s, 1H), 7.78 (t, J 7.8, 11H), 7.89 (d, J 6.5, 11H), 8.17 (d, J 8.1, 1H), 8.23 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J 5.8, 1H), 9.51 (s, 1H). | ||
EXAMPLE 264 N-(3,5-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B using <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI-) m/z 357 (M-H)-; 1H NMR (DMSO, 300 MHz) delta 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.13 (s, 2H), 7.42 (s, 1H), 7.78 (t, J 7.8, 11H), 7.89 (d, J 6.5, 11H), 8.17 (d, J 8.1, 1H), 8.23 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J 5.8, 1H), 9.51 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 80℃; for 1.5h; | Example 124: Synthesis of 4-Chloro-6-(3,5-dichloro-benzylamino)-2H-phthalazin-l- one; <n="103"/>A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (97mg, 0.374 mmol), 3,5- dichlorobenzylamine (0.057mL, 0.424 mmol), Pd2(dba)3 (29mg, 0.032 mmol), rac- BINAP (70mg, 0.112 mmol) and NaO'Bu (104mg, 1.08 mmol) in DMA (5mL) was heated at 8O0C for 1.5h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,5-dichloro -benzylamino)-2H-phthalazin-l-one (3 mg) as a white solid, 1H (400 MHz, CDCl3) delta: 4.40 (s, 2H), 6.84 (m, IH), 6.99 (m, IH), 7.22 (m, 3H), 8.14 (m, IH), 10.80 (s, IH) ppm; m/z (M+l) 353.83. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Compound Ij (+/-)-/V-r(3,5-dichlorophenyl)methyll-2-(4-methyl-1-piperazinyl)-2-(1- naphthalenvDethanamide; To a suspension of 1.1 1 g of (4-methyl-1-piperazinyl)(1-naphthalenyl)acetic acid (intermediate 1 , 3.9 mmole) in DMF (10 ml), were added 1.36 ml of DIPEA (7.82 mmole, Aldrich) and 1.5 g of TBTU (4.69 mmole, Fluka). After 10 minutes were added 0.625 ml of <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (4.69 mmole, Maybridge). The solution became clear and dark and it was stirred at room temperature for two days. Then it was diluted with AcOEt and washed with a saturated solution of NaHCO3 (20 ml). The phases were separated and the organic layer was extracted with AcOEt (3x30 ml). The combined organic layers were washed again with water and ice (2x50 ml), dried over Na2SO4 and concentrated to dryness to give the crude compound that was purified by flash chromatography on 25 g silica gel cartridge, using a gradient of DCM/MeOH 10/0 to 8/2 as an eluent. Solvents were removed under reduced pressure to give the title compound as a beige foam (782 mg, 46%). 1H NMR (400 MHz, CDCI3) delta 2.25 - 2.37 (3H, m), 2.38 - 2.78 (8H, m), 4.36 (1 H, dd), 4.49 (1 H, dd), 4.76 - 4.82 (1 H, m), 6.96 - 7.01 (2H, m), 7.20 - 7.25 (1 H, m), 7.29 - 7.39 (1 H, m), 7.43 - 7.63 (4H, m), 7.86 (2H, dd), 8.37 (1 H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (2'-ethylaminomethyl-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.170 g, 0.43 mmol) in CH2Cl2 (2 mL) at 0 C. was added diisopropylethylamine (0.19 mL, 1.08 mmol), followed by phosgene (20% in toluene; 0.34 mL, 0.64 mmol), and the mixture was stirred for 1.5 hours. 3,5-Dichlorobenzylamine (0.091 g, 0.52 mmol) was added, followed by triethylamine (0.12 mL, 0.86 mmol), and the reaction was warmed to room temperature and stirred for 45 minutes. Additional triethylamine (0.12 mL, 0.86 mmol) was added, and the reaction was stirred for 1.5 hours. Another portion of triethylamine (0.25 mL, 17.9 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was worked up with CH2Cl2 and H2O, and the aqueous layer was extracted twice with CH2Cl2The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 0.25h; | Example 45 Synthesis of Compound 46 (S)-9-fluorenylmethyl 10-(3,5-dichlorobenzyl)-2,2-dimethyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaiscos-19-en-8-ylcarbamate To <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (0.49 g, 2.8 mmol) in DCM (5 mL) was added the alpha,beta-unsaturated ketone 45 (2.12 mmol) in DCM (10 mL). After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (1.35 g, 3.1 mmol) and DIC (0.5 mL, 3.2 mmol) was added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum ether:EtOAc (1:1 to 0:1), providing compound 46 (0.48 g, 22%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; | Example 10 Synthesis of Compound 10 N-(4-(3,5-dichlorobenzylamino)-2-oxobutyl)-2-naphthamide To a solution of <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (12 mg, 0.068 mmol) in DCM (0.2 mL) was added a solution of 9 (13 mg, 0.054 mmol) in DCM (0.5 mL) at room temperature. The resulting mixture was stirred until all of the 9 had been consumed (within one hr) and then was used straight in the next reaction.MS (ESI) 415 (M+1); HPLC tR 6.00 min. | |
In dichloromethane; at 20℃; for 1h; | Example 10 - Synthesis of Compound 10 N-(4-(3,5-dichlorobenzylamino)-2-oxobutyl)-2- naphthamideN-(4-(3,5-dichlorobenzylamino)- 2- oxobutyl) -2-naphthamideTo a solution of <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (12 mg, 0.068 mmol) in DCM (0.2 mL) was added a solution of 9 (13 mg, 0.054 mmol) in DCM (0.5 mL) at room temperature. The resulting mixture was stirred until all of the 9 had been consumed (within one hr) and then was used straight in the next reaction. MS (ESI) 415 (M+1 ); HPLC fe 6.00 min. | |
In dichloromethane; at 20℃; for 1h; | To a solution of <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (12 mg, 0.068 mmol) in DCM (0.2 ml.) was added a solution of 9 (13 mg, 0.054 mmol) in DCM (0.5 ml_) at room temperature. The resulting mixture was stirred until all of the 9 had been consumed (within one hr) and then was used straight in the next reaction. MS (ESI) 415 (M+1 ); HPLC fe 6.00 min. |
In dichloromethane; at 20℃; for 1h; | To a solution of <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (12 mg, 0.068 mmol) in DCM (0.2 mL) was added a solution of 9 (13 mg, 0.054 mmol) in DCM (0.5 mL) at room temperature. The resulting mixture was stirred until all of the 9 had been consumed (within one hr) and then was used straight in the next reaction. MS (ESI) 415 (M+1); HPLC tR 6.00 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of intermediate 28 (29 g) in dry DMF (280 mL), DIPEA (33 mL) and TBTU (27.1 g) were added, the solution became dark and after 45 minutes of stirring at r. t. , 3,5- dichlorobenzylamine (14.2 g) was added; the reaction mixture turned to orange; it was stirred for 1 h at r. t. under a Nitrogen atmosphere then it was diluted with AcOEt (800 mL) and washed withice/water 1/1 (4 x 400 mL). The organic phase was dried and concentrated in vacuo to give the crude title compound (38.8 g) as a pale orange foam. This material was purified by flash chromatography (Biotage Flash 75L, CH/AcOEt 85: 15) to obtain the title compound (38.6 g) as a white foam. T.I. c.: CH/AcOEt 7: 3, Rf=0.45 (detection with ninhydrine). MS (ES/+):m/z=557 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
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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; for 18h; | Example 42 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3,5-dichloro-benzyl)-3-methoxy-benzamide (I-42) A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.059 g (0.33 mmole) of <strong>[39989-43-0]3,5-dichloro-benzylamine</strong>, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluding with hexanes-ethyl acetate (gradient, 80:20-0:100) to give 0.078 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3,5-dichloro-benzyl)-3-methoxy-benzamide (I-42) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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22% | Example 28 - Synthesis of Compound 24 (S)-9-fluorenylmethyl 10-(3,5-dichlorobenzyl)- 2,2-dimethyl-4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaiscos-19-en-8-ylcarbamate24(lSr)-9-fluorenylmethyl 10-(3,5-dichlorobenzyl)-2,2-dimethyl- 4,9,13,16-tetraoxo-3,17-dioxa-5,10,15-triazaiscos-19-en-8- ylcarbamateTo <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (0.49 g, 2.8 mmol) in DCM (5 ml_) was added the alpha,beta- unsaturated ketone 23 (2.12 mmol) in DCM (10 ml_). After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (1.35 g, 3.1 mmol) and DIC (0.5 ml_, 3.2 mmol) was added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1 :1 to 0:1 ), providing compound 24 (0.48 g, 22percent). | |
22% | To <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (0.49 g, 2.8 mmol) in DCM (5 mL) was added the alpha,beta-unsaturated ketone 23 (2.12 mmol) in DCM (10 mL).After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (1.35 g, 3.1 mmol) and DIC (0.5 mL, 3.2 mmol) was added.The reaction was stirred at room temperature overnight.The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1:1 to 0:1), providing compound 24 (0.48 g, 22percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | To <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (0.49 g, 2.8 mmol) in DCM (5 ml.) was added the alpha,beta- unsaturated ketone 24 (2.12 mmol) in DCM (10 ml_). After stirring at room temperature for 15 mins, Fmoc-diaminobutyric acid(Boc)-OH (1.35 g, 3.1 mmol) and DIC (0.5 ml_, 3.2 mmol) was added. The reaction was stirred at room temperature overnight. The DCM was removed by rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum spirit:EtOAc (1 :1 to 0:1 ), providing compound 25 (0.48 g, 22percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.8% | l-(3,5-dichlorophenyl)methylamine (90 mg, .513 mmol) was added to a solution of methyl l-[(2-chlorophenyl)methyl]-5-([2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-2,4-dihydroxy-6-oxo- l,6-dihydro-3-pyridinecarboxylate (Id, 150 mg, .342 mmol) in chloroform (3 ml). The solution solidified upon standing. The mixture was heated in a microwave (1500C, 30 min). The solution was washed with IN HCl (2ml). The organic layer was concentrated in-vacuo and the residue dissolved in ethanol (6 ml) and treated with 6N NaOH. The mixture was stirred at rt over night. Upon completion of the saponification the solution was diluted with ethyl acetate (20 ml) and washed with IN HCl (7 ml). The organic layer was concentrated in-vacuo and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and purified by HPLC (acetonitrile, 0.1% NH4OH water) to yield the title compound as a white solid. Yield: 66 mg, 30.8%, MS (ES+): [M+H]+ = 554.0, 1H NMR (400 MHz, OMSO-d6) delta ppm 3.81 (d, J=4.80 Hz, 2 H), 4.36 (br. s., 2 H), 5.11 (s, 2 H), 6.65 - 6.82 (m, 1 H), 7.22 (dd, J=5.81, 3.54 Hz, 2 H), 7.33 (s, 2 H), 7.42 (dd, J=5.68, 3.66 Hz, 2 H), 8.08 (br. s., 4 H), 9.69 (br. s., 1 H), 10.26 (br. s., 1 H), 16.15 (br. s., 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PyBOP; N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; N,N-dimethyl-formamide; | Example 1 Deoxyactagardine B (<strong>[39989-43-0]3,5-dichlorobenzylamine</strong>)monocarboxamide Deoxyactagardine B [DAB] (200 mg), <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (38 mg) and diisopropylethylamine (35 muL) were dissolved in dry dimethylformamide (1 mL). A solution of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (84 mg) in dry DMF (2 mL) was added portionwise. The reaction was followed by analytical hplc (See Table 1) and PyBOP was added until the starting material had been consumed (). The crude reaction mixture was poured into 30% aqueous methanol and the resulting solution was loaded on to a Varian Bond Elut C18 column (30 g). The column was then washed sequentially with 50%, 60%, 70%, 80%, 90% aqueous methanol, with most of the desired material eluting in the 70% fraction () Column chromatography on silica gel (eluent dichloromethane:ethanol:ammonia 10:8:1) gave material of >90% purity by U.V. at 210 nm. Yield 107 mg (50%). Mass calculated for (M+F2H)+2 1015.5, found 1015.57. Calculated for [M+H+Na]+2 1026, found 1025.32 Samples were analysed by LC-MS using the conditions described in Table 2. | |
With PyBOP; N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; N,N-dimethyl-formamide; | Deoxyactagardine B (<strong>[39989-43-0]3,5-dichlorobenzylamine</strong>) monocarboxamide Deoxyactagardine B [DAB] (200 mg), <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (38 mg) and diisopropylethylamine (35 muL) were dissolved in dry dimethylformamide (1 mL). A solution of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (84 mg) in dry DMF (2 mL) was added portionwise. The reaction was followed by analytical hplc (See Table 1) and PyBOP was added until the starting material had been consumed. The crude reaction mixture was poured into 30% aqueous methanol and the resulting solution was loaded on to a Varian Bond Elut C18 column (30 g). The column was then washed sequentially with 50%, 60%, 70%, 80%, 90% aqueous methanol, with most of the desired material eluting in the 70% fraction () Column chromatography on silica gel (eluent dichloromethane:ethanol:ammonia 10:8:1) gave material of >90% purity by U.V. at 210 nm. Yield 107 mg (50%). Mass calculated for (M+2H)+2 1015.5. found 1015.57. Calculated for [M+H+Na]2 1026, found 1025.32 Samples were analysed by LC-MS using the conditions described in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Compound 1: Deoxyactagardine B (<strong>[39989-43-0]3,5-dichlorobenzylamine</strong>)monocarboxamide [0393] <strong>[39989-43-0]3,5-dichlorobenzylamine</strong> (38 mg) and diisopropylethylamine (35 muL) were dissolved in dry dimethylformamide (1 mL). A solution of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (84 mg) in dry DMF (2 mL) was added portionwise. The reaction was followed by analytical HPLC (See Table 1) and PyBOP was added until the starting material had been consumed. [TABLE-US-00001] TABLE 1 Analytical HPLC conditions for the separation of lantibiotic (e.g. actagardine, actagardine B, or deoxy-actagardine B) and diaminoalkane derivatised products. Column: Zorbax 5mu C18(2) 150 × 4.6 mm Mobile Phase A: 30% Acetonitrile in 20 mM potassium phosphate buffer pH 7.0 Mobile Phase B: 65% Acetonitrile in 20 mM potassium phosphate buffer pH 7.0 Flow rate: 1 mL/min Gradient: Time 0 min 100% A 0% B Time 10 min 0% A 100% B Time 11 min 0% A 100% B Time 11.2 min 100% A 0% B Cycle time 15 min Injection volume: 10 muL Detection: 210 nm [0395] The crude reaction mixture was poured into 30% aqueous methanol and the resulting solution was loaded on to a Varian Bond Elut C18 column (30 g). The column was then washed sequentially with 50%, 60%, 70%, 80%, 90% aqueous methanol, with most of the desired material eluting in the 70% fraction. Column chromatography on silica gel (eluent dichloromethane:ethanol:ammonia 10:8:1) gave material of >90% purity by U.V. at 210 nm. Yield 107 mg (50%). Mass calculated for (M+2H)+2 1015.5, found 1015.57. Calculated for [M+H+Na]+2 1026, found 1025.32. [0396] Samples were analysed by LC-MS using the conditions described in Table 2. [TABLE-US-00002] TABLE 2 LC/MS conditions for the analysis of lantibiotic (e.g. deoxy-actagardine B) and derivatised products. Column: Zorbax 5mu C18(2) 150 × 4.6 mm Mobile Phase A: 10% acetonitrile, 0.1% formic acid Mobile Phase B: 90% acetonitrile, 0.1% formic acid Flow rate: 1 mL/min Gradient: Time 0 min 100% A 0% B Time 10 min 0% A 100% B Time 11 min 0% A 100% B Time 11.1 min 100% A 0% B Cycle time 15 min Injection volume: 20 muL Mass Spectrometer parameters Ionisation Electrospray +ve Mass range 250-1500 mu Capillary voltage 3.10 KV Cone voltage 40 V Skimmer lens offset 5 V Ion energy 1.4 V |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In 1,2-dimethoxyethane; at 90℃; under 7500.75 Torr; for 1h;Microwave irradiation; | General procedure: Compound 12a, 12b or 12c (0.55 mmol), the appropriate amine(1.1 mmol) and 1,2-dimethoxyethane (1 mL) were heated in amicrowave reactor (150 Watt, Power Max On, 90 C, 10 bar) for1 h. The solvent was removed under reduced pressure and the residuewas purified by column chromatography (silica gel, ethylacetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | To a solution of <strong>[39989-43-0](3,5-dichlorophenyl)methanamine</strong> (27.1 mg, 146 muiotaetaomicron) in acetonitrile (2 ml) was added N,N'-carbonyldiimidazole (24.9 mg, 154 muiotaetaomicron) at room temperature, then after 2 h triethylamine (59.2 mg, 585 muiotaetaomicron) and (lH-benzo[d][l,2,3]triazol-5-yl)(2,7- diazaspiro[3.5]nonan-2-yl)methanone hydrochloride (intermediate 1.2; 45 mg, 146 muiotaetaomicron) were added. The light yellow suspension was heated at reflux for 30 min and was then partitioned between ethyl acetate and sat. aq. sodium hydro gencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25 to 90: 10:0.25) afforded the title compound (37 mg, 53%). White foam, MS: 473.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | To a solution of triphosgene (35 mg, 0.12 mmol) in dichloromethane (3 mL) was added a solution of ethyl 9-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9- azabicyclo[3.3.1]nonane-3-carboxylate (100 mg, 0.29 mmol) in dichloromethane (3 mL) and Et3N (58 mg, 0.58 mmol). The mixture was stirred at rt for 2.5 h, followed by (3,5- dichlorophenyl)methanamine (56 mg, 0.32 mmol) and Et3N (58 mg, 0.58 mmol). The mixture was stirred at rt for 16 h. To the reaction mixture was added methanol (10 mL) and the solvent was evaporated. The residue was purified with prep-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish ethyl 9-(5-((3,5- dichlorobenzyl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carbonyl)-9- azabicyclo[3.3.1]nonane-3-carboxylate as a yellow oil (89 mg, yield 56%). LCMS m/z 548.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of ethyl 9-(5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepine- 2-carbonyl) -9-azabicyclo[3.3.1]nonane-3-carboxylate (138 mg, 0.38 mmol) in dichlormethane (3 mL) was added triphosgene (45 mg, 0.15 mmol) and Et3N (46 mg, 0.46 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 30 min. Then <strong>[39989-43-0](3,5-dichlorophenyl)methanamine</strong> (80 mg, 0.46 mmol) and Et N (76 mg, 0.76 mmol) were added, and the mixture was stirred at room temperature for 12 h. The reaction mixture was purified by prep-TLC (DCM / MeOH = 10 / 1) to give ethyl 9-(5-((3,5- dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carbonyl)- 9-azabicyclo[3.3.1]nonane-3-carboxylate. To a mixture of above ester (100 mg, 0.18 mmol, 1.0 eq) in MeOH (5 mL) and H20 (5 mL) was added NaOH (29 mg, 0.72 mmol). The mixture was stirred at 60 C for 2 h. The organic solvent was removed under reduced pressure. The resulting mixture was acidified to pH = 5 with HC1 (1 N). The precipitate was filtered, washed with water (5 mL) and dried to give the target compound 9-(5-((3,5- dichlorobenzyl)carbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[ 1 ,5-a] [ 1 ,4]diazepine-2-carbonyl)- 9-azabicyclo[3.3.1]nonane-3-carboxylic acid as a white solid (62 mg, yield 30%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | General procedure: A mixture of carboxylic acid 12 or 14 (0.5 mmol), anh. DMF (5 mL), and Et3N (70 muL, 0.5 mmol) was stirred at room temperature for 5 min. Then, BPC (197 mg, 0.5 mmol) was added and the mixture was stirred at rt for 1 h (activation of carboxylic acid). Next, amine (0.5 mmol) and Et3N (70 muL, 0.5 mmol) were added and stirring at rt was continued for 24 h. Volatile components were evaporated in vacuo (2 mbar, 50 C), dichloromethane (5 mL) was added, and the mixture was evaporated in vacuo (first at 2 mbar/50 C, then at 0.01 mbar/80 C) to give 15 or 16. The crude product was purified by FC (silica gel, first EtOAc/hexanes to elute the non-polar impurities, then EtOAc/MeOH, CHCl3/MeOH, or CHCl3/MeOH/Et3N to elute the product). Fractions containing the product were combined, and evaporated in vacuo to give the purified carboxamide 15 or 16. The following compounds were prepared in this manner. |
Yield | Reaction Conditions | Operation in experiment |
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53% | Example 9 2-(1H-Benzo[d][1,2,3]triazole-5-carbonyl)-N-(3,5-dichlorobenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide To a solution of <strong>[39989-43-0](3,5-dichlorophenyl)methanamine</strong> (27.1 mg, 146 mmol) in acetonitrile (2 ml) was added N,N'-carbonyldiimidazole (24.9 mg, 154 mmol) at room temperature, then after 2 h triethylamine (59.2 mg, 585 mmol) and (1H-benzo[d][1,2,3]triazol-5-yl)(2,7-diazaspiro[3.5]nonan-2-yl)methanone hydrochloride (intermediate 1.2; 45 mg, 146 mmol) were added. The light yellow suspension was heated at reflux for 30 min and was then partitioned between ethyl acetate and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25 to 90:10:0.25) afforded the title compound (37 mg, 53%). White foam, MS: 473.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With zinc(II) chloride; at 120℃; for 3h; | 2-(4-((1H-pyrazol-1-yl)methyl)benzyl)-N-(3,5-dichlorobenzyl)-2H-pyrazolo[3,4-d]pyrimidin-4-amineInto a 8-mL vial, was placed a solution of 2-(4-((1H-pyrazol-1-yl)methyl)benzyl)-4-chloro-2H-pyrazolo[3,4-d]pyrimidine (400 mg, 1.00 equiv)(Example 23) in 1-ethoxy-2-(2-ethoxyethoxyl)ethane (5 mL), <strong>[39989-43-0](3,5-dichlorophenyl)methanamine</strong> (422 mg, 2.40 mmol, 2.00 equiv) and zinc dichloride (1.68 g, 12.32 mmol, 10.00 equiv). The resulted solution was stirred for 3 h at 120 C. The reaction mixture was cooled to room temperature and diluted with 5 mL of DMSO. The residue was purified by silica gel column chromatography eluted with EA:PE:MeOH (1:5:0 to 0:0:1). The crude product was purified by Prep-HPLC with the following conditions. Column: Waters X-bridge RP18, 19×150 mm, 5 um; mobile phase: water (it contains 0.05% ammonia) and acetonitrile with a gradient 56% to 61% acetonitrile in 5 min; flow rate: 20 mL/min; detector UV wavelength: 254 nm and 220 nm. This resulted in 108.2 mg (19%) of 2-(4-((1H-pyrazol-1-yl)methyl)benzyl)-N-(3,5-dichlorobenzyl)-2H-pyrazolo[3,4-d]pyrimidin-4-amine as white solid. 1H NMR (300 MHz, DMSO-d6): delta 8.70 (br, 1H), 8.36 (s, 1H), 8.21 (s, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.49 (s, 1H), 7.44 (s, 1H), 7.39 (d, J=1.8 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 6.25 (t, J=2.1 Hz, 1H), 5.55 (s, 2H), 5.32 (s, 2H), 4.71 (d, J=6.0 Hz, 2H). MS (ESI) m/z found for C23H19Cl2N7: 464 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With triethylamine; In tetrahydrofuran; at 20℃; for 1h;Reflux; Cooling with ice; | General procedure: General procedure for the preparation of amides from Gil: In an oven-dried round bottom flask with stir bar, Gil (1 equiv.) was dissolved in tetrahydrofuran (0.05 M).Thionyl chloride (1.2 equiv.) was added, and the reaction was 10573] General procedure for the preparation of amides from Gil: In an oven-dried round bottom flask with stir bar, Gil (1 equiv.) was dissolved in tetrahydrofuran (0.05 M).Thionyl chloride (1.2 equiv.) was added, and the reaction was 10574] Gi 9a: Prepared from <strong>[39989-43-0]3,5-dichlorobenzylamine</strong>.10575] Yield: 26.6 mg, 35%.10576] 1H NMR (CDC13, 500 MHz): oe 7.27 (t, J=l.9 Hz,1H), 7.22 (t, J=7.6 Hz, 1H), 7.20 (s, 1H), 7.19 (s, 1H), 7.07 (d,J=7.5 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 5.90 (br s, 1H), 4.49(dd, 0.1=14.9, 6.4 Hz, 1H), 4.36 (dd, J=14.9, 6.0 Hz, 1H),4.07 (s, 1H), 2.95 (t, J=8.5 Hz, 1H), 2.70 (d, J=15.l Hz, 1H),2.44 (dd, J=17.6, 3.7 Hz, 1H), 2.17 (s, 3H), 2.10 (U, J=7.3, 3.5Hz, 1H), 1.89 (dd, J=ll.9, 3.5 Hz, 1H), 1.83-1.72 (m, 2H),1.63 (dt, J=6.4, 3.3 Hz, 1H), 1.38 (d, J=ll.5 Hz, 1H), 1.04 (s,3H).10577] HRMS(ESI): mlzcalc. for C25H26N02C12 [M+H]:442.1341. found: 442.1342. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; at 80℃; for 0.5h; | (a) Succinic anhydride (1 eq) and (3,5-dieh1oropheny{)memanamine (I eq) in dioxane was heaied to 80 C for 30 min. The solvent was evaporated off and residue was purified via flash column chromatography directly eluting with 20% MeOH in DCM to yield 4-((3,5-dichlorobenzyl)amino)-4-oxobutanoic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h; | To a solution of 3,5-diehlorobenzylamine (133 mg, 0.756 mmol) and DIPEA (0.756 mmol) in 10 ml of DCM was added ethyl malonyi chloride (0.756 mmol) in 3 ml of DCM at 0 C with stirring. The reation was performed at 0 C for 2h. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash column chromatography to give ethyl 2~(3,5~ dichlorobenzylcarbamoyi)acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | 3-(5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)-3-propionamidopropanoic acid (1 eq), DIPEA (3 eq), (3,5-dichlorophenyi)methanainine (2 eq) were dissolved in DMF, then EDC (1 ,5 eq ) and HOBt (1.5 eq) were added, the resulting mixture was stirred at r.t. for 3h. The solvent was removed under vacuum and the residue was dissolved in DCM and washed with sat. sodium bicarbonate and brine. The organic layer was dried over Na2S04 and concentrated under vacuum. The residue was purified by flash coiumn chromatography (DCM/MeOH), yielding compound 1968. LC/ += 455.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | A solution of 2-((5-ch3oro-3H- m dazo[4,5-b]pyridin-2-yI)amino)acetic acid (leq), <strong>[39989-43-0](3,5-dichlorophenyl)methanamine</strong> ( ieq), EDC ( 1.5 eq), HOBt (1.5 eq) and DIPEA (2eq) in DMF was stirred at room temperature overnight. The soivent was then removed under vacuum. The residue was dissolved in DCM. The organic layer was washed with brine, dried and concentrated under vacuum. Purification by chromatography afforded 1 70: 2-((5- chloro-3H-imidazo[4,5-bjpyrid -2-yty^ LC/MS: (ESI) (M +H)+= 385.5. |
Tags: 39989-43-0 synthesis path| 39989-43-0 SDS| 39989-43-0 COA| 39989-43-0 purity| 39989-43-0 application| 39989-43-0 NMR| 39989-43-0 COA| 39989-43-0 structure
[ 90389-22-3 ]
3,5-Dichloro-N-methylbenzylamine hydrochloride
Similarity: 0.92
[ 10541-69-2 ]
(2,5-Dichlorophenyl)methanamine
Similarity: 0.92
[ 90389-22-3 ]
3,5-Dichloro-N-methylbenzylamine hydrochloride
Similarity: 0.92
[ 10541-69-2 ]
(2,5-Dichlorophenyl)methanamine
Similarity: 0.92
[ 90389-22-3 ]
3,5-Dichloro-N-methylbenzylamine hydrochloride
Similarity: 0.92
[ 10541-69-2 ]
(2,5-Dichlorophenyl)methanamine
Similarity: 0.92
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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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