* 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.
To a solution of compound 1 H-imidazole-2-carbaldehyde (5g, 52.08 mmol) in MeOH (50 mL) was added sodium borohydride (3.93g, 104.16 mmol) portion-wise, at 5 00, and the reaction mixture was allowed to stir at RT for 3h. The reaction mixture was quenched with brine (25 mL) and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with 10percent MeOH/CHCI3) to obtain (1H-imidazol-2-yl)-methanol as a pale yellow solid (4g, 78percent).R:0.1 (10percent MeOH/CHCI3).1H NMR (400MHz, CD3OD): O 6.97 (5, 2H), 4.61 (5, 2H).
51%
With sodium tetrahydroborate In methanol at 20℃; for 1 h; Inert atmosphere
To a solution of 2-imidazolecarboxyaldehyde (18-1) (1.92 g, 20 mmol, 1.0 eq.) was suspended in methanol (30 ml), NaBH4 (1.52g, 40 mmol, 2.0 eq.) was added portion-wise. The reaction mixture was stirred at room temperature for 1 h under N2. It was quenched with 5 ml of brine. The solvent was removed and the solid was purified with silica gel column chromatography (DCM : MeOH = 20: 1) to afford 18-2 as a white solid. (1.0g, Yield: 51percent).
51%
at 20℃; for 1 h; Inert atmosphere
Compound 26-2 (0449) To a solution of 2-imidazolecarboxyaldehyde (26-1) (1.92 g, 20 mmol, 1.0 eq) was suspended in methanol (30 mL), NaBH4 (1.52 g, 40 mmol, 2.0 eq) was added portion-wise. The reaction mixture was stirred at room temperature for 1 h under N2. It was quenched with 5 mL of brine. The solvent was removed and the solid was purified with silica gel column chromatography (DCM:MeOH=20:1) to afford a white solid. (1.0 g, Yield: 51percent).
45.2%
With sodium tetrahydroborate In methanol; dichloromethane
Part A Preparation 2-hydroxymethyl-1H-imidazole 2-Imidazolecarboxyaldehyde (5.0 g, 52.0 mmol) was suspended in 200 mL of methanol. NaBH4 (3.95 g, 0.10 mol) was added portion-wise. The reaction mixture was stirred at room temperature for 1 h under N2. It was quenched with 10 mL of brine. The solvent was removed. The solid was washed with 5percent MeOH in CH2Cl2. The inorganic solid was filtered off. The filtrate was concentrated and chromatographed with 5percent MeOH in CH2Cl2 to give 2.32 g off-white solid (45.2percent yield). 1H NMR (DMSO-d6): δ 6.86 (s, 2H), 4.40 (s, 2H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 827 - 833
[2] Patent: WO2015/36759, 2015, A1, . Location in patent: Page/Page column 200
[3] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3208 - 3213
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5849 - 5853
[5] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 302
[6] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1729 - 1744
[7] Patent: US2003/144287, 2003, A1,
[8] Biological and Pharmaceutical Bulletin, 1998, vol. 21, # 9, p. 958 - 963
[9] Journal of Medicinal Chemistry, 2004, vol. 47, # 15, p. 3707 - 3709
2
[ 10111-08-7 ]
[ 16042-25-4 ]
Yield
Reaction Conditions
Operation in experiment
97.5%
With dihydrogen peroxide In water at 20℃; for 72 h;
An aqueous 30percent H2O2 solution (10g) was added dropwise to a stirred solution of imidazole-2-carboxaldehyde (2.88g 0.030mol) in water (10ml). The reaction was allowed to proceed at room temperature for 72h, following which the water was removed in vacuo at room temperature to afford a white crystalline solid. This solid was washed with a stirred mixture of diethylether/water (4:1) to remove the excess peroxide. Note: heating causes decarboxylation. Yield: 97.5percent. Mp=156–158°C. δH (400MHz, D2O): 7.56 (2H, s, Im-H); δC (400MHz, D2O): 158.86, 141.02, 120.49ppm. IR ν (KBr): 3392(m), 3124(m), 2861(m), 1618(s), 1502(m), 1462(m), 1421(s), 1388(s), 1322(m), 1108(s), 925(s), 910(s), 819(m), 797(s), 774(m) cm−1. Anal. Calc. for C4H6N2O3 (130.11); C, 36.92; H, 4.65; N, 21.53percent. Found: C, 37.18; H, 4.94; N, 21.47percent.
Reference：
[1] Journal of Inorganic Biochemistry, 2015, vol. 145, p. 11 - 18
3
[ 16681-56-4 ]
[ 68-12-2 ]
[ 10111-08-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 0.166667 h; Stage #2: With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 0.5 h; Stage #3: at -20℃; for 0.5 h;
To a solution of 2-bromo-1H-imidazole (0.65 g, 4.4 mmol, 1.0 equiv.)in dry THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol,1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was addeddropwise during 5 min, while maintaining the temperature below 20 C. The resulting mixturewas stirred at that temperature for 0.5 h, dry DMF (0.32 g, 4.4 mmol, 1.0 equiv.) was added to20 C. The resulting mixture was warmed to 20 C in 0.5 h and quenched with water (6 mL).After stirring the mixture below 20 C for 10 min, the phases were separated and the water phasewas extracted one additional time with ethyl acetate. The resulting suspension was allowed to reachroom temperature and fitered through a 0.5 1cm pad of silica gel eluted with 10 mL of ethyl acetate.The filtrate was concentrated and the residue was purified by flash chromatography on silica gel(eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3k as pale yellow solid, 0.38 g (yield:91percent), m.p.: 205–206 C. 1H-NMR (600 MHz, DMSO) 13.60 (s, 1H), 9.64 (s, 1H), 7.42 (s, 2H). 13C-NMR(151 MHz, DMSO) 181.66, 146.09.1H-Imidazole-4-carbaldehyde (3l): To a
Reference：
[1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 2, p. 611 - 620
9
[ 10111-08-7 ]
[ 31722-49-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With bismuth(lll) trifluoromethanesulfonate; acetylhydroxamic acid In acetonitrile for 14 h; Reflux
General procedure: 4-Isopropylbenzaldehyde 1a (0.50 g, 3.37 mmol), acetohydroxamic acid (0.30 g, 4.05 mmol), acetonitrile (5 ml), and Bi(OTf)3 (0.11 g, 0.17 mmol) were taken into a 25 ml round-bottomed flask fitted with a condenser and calcium chloride guard tube. The mixture was refluxed for 14 h and after completion of the reaction (GC, 10percent SE-30 on Chromosorb, 10' .x. 1/8 column), the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product obtained was purified by normal column chromatography(silica gel 100-200 mesh, ethyl acetate/hexane = 1:20) to obtain 4-isopropylbenzonitrile 3a (0.47 g, 97percent).
41%
With hydroxylamine hydrochloride; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In N,N-dimethyl-formamide at 100℃; for 4 h;
Compound 234.1. lH-Imidazole-2-carbonitrile. Into a 1-L round-bottom flask, was placed a solution of lH-imidazole-2-carbaldehyde (5 g, 52.04 mmol) in NN- dimethylformamide (200 mL). Triethylamine (10.8 mL, 77.97 mmol), hydroxylamine hydrochloride (3.95 g, 56.84 mmol, 1.10 equiv), 1-propanephosphonic anhydride solution and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution (T3P) (36.4 g, 114.40 mmol) were added to the reaction. The reaction mixture was stirred for 4h at 100 °C, cooled and then quenched with 500 mL of water/ice. The aqueous phase was extracted with 3 x 1L of ethyl acetate, then the combined organic layers was washed with 2 x 1L of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/2) as eluent to furnish 2 g (41percent) of the title compound as an off-white solid.
With potassium carbonate In ethanol; N,N-dimethyl-formamide at 50℃; for 5 h;
Stir at room temperature To a solution of 1H-imidazole-2-carbaldehyde (250 mg, 2.6 mmol) and K2CO3 (431 mg, 3.12 mmol) in DMF (2.5 mL) was added methyl iodide (442 mg, 3.12 mmol). The mixture was stirred at 50° C. for 5 h and allowed to cool to remove solids. Water was added to the filtrate and extracted three times with ethyl acetate. The combined extracts were washed with saturated saline and dried over anhydrous sodium sulfate. The mixture was concentrated by suction and filtered to give 1-methyl-1H-imidazole-2-carboxaldehyde as a pale yellow oil (168 mg, yield 59percent).
Reference：
[1] Patent: CN103570683, 2018, B, . Location in patent: Paragraph 0711; 0715-0717
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 363 - 386
[3] Chemico-Biological Interactions, 2016, vol. 259, p. 85 - 92
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 5 h;
To a suspension of 1H-imidazole-2-carbaldehyde (480 mg, 5 mmol) and potassium carbonate (936 mg, 6 mmol) in N,N-dimethylformamide (7 mL) was added iodoethane (829 mg, 6 mmol) and the mixture was heated at 50° C. for 5 hrs. Solvent was removed under reduced pressure. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL.x.3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 1-ethyl-1H-imidazole-2-carbaldehyde as light yellow oil (520 mg, yield 84percent). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.42-1.46 (t, J=7.2 Hz, 3H), 4.42-4.47 (q, 2H), 7.19 (s, 1H), 7.29 (s, 1H), 9.82 (s, 1H). LC-MS (ESI) m/z: 125 (M+1)+.
[2-{5-[3-(1<i>H</i>-imidazol-2-ylmethylene)-2-oxo-2,3-dihydro-1<i>H</i>-indol-5-yl]-pyridin-3-yloxy}-1-(1<i>H</i>-indol-3-ylmethyl)-ethyl]-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
An oily suspension of 20.8 g sodium hydride in mineral oil (50%, 0.52 mol) was washed mineral oil free by stirring with hexane 3-times and suspended in 400 ml DMF. Under stirring at ambient temperature 50.0 g (0.520 mol) imidazole-2-carbaldehyde was added to the suspension. After 1.5 h, 101.0 ml (0.572 mol) 2-(trimethylsilanyl)ethoxymethyl chloride was added and the reaction was stirred a further hour. Then excess water was added to the suspension and the reaction mixture was extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The raw material was then purified by column chromatography (DCM) to yield 85.0 g (0.376 mol) of the SEM-protected imidazole-2-carbaldehyde. Yield = 72%. MH+ = 227.1 (C10H18N2O2Si, Mr=226.35). 1H NMR (DMSO-d6, 500MHz): delta 9.83 (s, 1H); 7.86 (s, 1H); 7.39 (s, 1H); 5.75 (s, 2H); 3.58 (t, 2H); 0.95 (t, 2H); 0.02 (s, 9H).
72%
1.3: l-(2-Trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carbaldehydeAn oily suspension of 20.8 g sodium hydride in mineral oil (50%>, 0.52 mol) was washed mineral oil free by stirring with hexane 3 -times and suspended in 400 ml DMF. Under stirring at ambient temperature 50.0 g (0.520 mol) imidazole-2- carbaldehyde was added to the suspension. After 1.5 h, 101.0 ml (0.572 mol) 2- (trimethylsilanyl)ethoxymethyl chloride was added and the reaction was stirred a further hour. Then excess water was added to the suspension and the reaction mixture was extracted three times with ethyl acetate. The organic phase was dried over Na2S04 and the solvent was evaporated off under reduced pressure. The raw material was then purified by column chromatography (DCM) to yield 85.0 g (0.376 mol) of the SEM- protected imidazole-2-carbaldehyde.Yield = 72%.MH+ = 227.1 (CioHi8N202Si, Mr=226.35).1H NMR (DMSO-d6, 500MHz): delta 9.83 (s, 1H); 7.86 (s, 1H); 7.39 (s, 1H); 5.75 (s, 2H); 3.58 (t, 2H); 0.95 (t, 2H); 0.02 (s, 9H)..
58%
With potassium carbonate; In acetone; at 60℃; for 8h;
Example 61;3H-Imidazole-2,4-dicarboxylic acid 2-amide 4-{ [2-(4,4-dimethyl-cyclohex-l-enyl)- phenyl] -amide}; a) 1 -(2-Trimethylsilanyl-ethoxymethyl)- lH-imidazole-2-carbaldehyde; A mixture of lH-imidazole-2-carbaldehyde (1.1 g, 11 mmol), potassium carbonate (3.0 g, 23 mmol), and SEM-Cl (2.4 mL, 14 mmol) in 10 mL of acetone was heated to 60 0C for 8 h. The mixture was diluted with EtOAc (100 mL) and washed with NaHCO3 (2 x 100 mL) and brine (100 mL) and the organic layer dried (Na2SO4) and concentrated. The title compound was purified by elution from a 20-g SPE column with 50 % EtOAc to give 1.5 g (58 %) of a colorless oil. 1H-NMR (CDCl3, 400 MHz): delta 9.82 (s, IH), 7.38 (d, J = 1.0 Hz, IH), 7.34 (d, J = 1.0 Hz, IH), 5.78 (s, 2H), 3.55 (m, 2H), 0.94 (m, 2H), -0.02 (s, 9H).
32%
To a suspension of NaH (60% in mineral oil, 1.45 g, 36.2 mmol) in DMF (30 mL) was added 2-imidazolecarboxaldehyde (3.00 g, 30.3 mmol) portionwise, and the mixture was stirred at RT for 1 h, then treated with 2-(trimethylsilyl)ethoxymethyl chloride (5.91 mL, 33.3 mmol). The mixture was stirred at RT overnight, then treated with sat. aq. NH4C1 and extracted with EtOAc (3 X 45 mL). The combined organic layers were washed with sat. aq. NaC1 (6 X 30 mL), dried over Na2 SO4, and concentrated under reduced pressure. The residue was purified by Si02 gel chromatography (0/o to 25% EtOAc in CH2C12) to give the title compound as a colorless oil (2.18 g, 32%). ?HNMR (400 MHz. CDC13) oe 9.86 (s, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 5.80 (s, 2H), 3.66-3.47 (m, 2H), 0.98-0.90 (m, 2H), 0.01 (s, 9H).
With sodium chloride; In N-methyl-acetamide; ethyl acetate;
Reference Example 8 1-(2-trimethylsilyl)ethoxymethyl-2-formylimidazole STR1362 To a suspension of 2-formylimidazole (7.2 g) in dimethylformamide (150 ml) was added sodium hydride (3 g, 60% content) at 0 C. The reaction mixture was stirred at 0 C. for 30 min and at room temperature for 1 h. To the reaction mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (13.3 ml) at 0 C. The reaction mixture was stirred at 0 C. for 30 min and at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate =2:1) to give the title compound (14.96 g) having the following physical data. TLC: Rf 0.50 (hexane:ethyl acetate=1:1); NMR (CDCl3): delta9.86 (1H, s), 7.39 (1H, s), 7.36 (1H, s), 5.80 (2H, s), 3.59 (2H, t, J=8.0 Hz), 0.94 (2H, t, J=8.0 Hz), 0.00 (9H, s).
85 g
Step 3: 1 -(2-Trimethylsilanyl-ethoxymethyl)-1 H-imidazole-2-carbaldehyde An oily suspension of 20.8 g sodium hydride in mineral oil (50%, 0.52 mol) was washed mineral oil free by stirring with hexane 3-times and suspended in 400 ml DMF. Under stirring at ambient temperature 50.0 g (0.520 mol) imidazole-2- carbaldehyde was added to the suspension. After 1.5 h, 101 ml (0.572 mol) 2- (trimethylsilanyl)ethoxymethyl chloride was added and the reaction was stirred a further hour. Then excess water was added to the suspension and the reaction mixture was extracted three times with ethyl acetate. The organic phase was dried over Na2S04 and the solvent was evaporated off under reduced pressure. The raw material was then purified by column chromatography (DCM) to yield 85.0 g (0.376 mol) of the SEM-protected imidazole-2-carbaldehyde. Yield = 72% MH+ = 227.1 (CioH18N202Si, Mr=226.35) 1 H NMR (DMSO-d6, 500MHz): delta 9.83 (s, 1 H); 7.86 (s, 1 H); 7.39 (s, 1 H); 5.75 (s, 2H); 3.58 (t, 2H); 0.95 (t, 2H); 0.02 (s, 9H)
To a mixture of sodium hydride (500 mg, 12.5 mmol) in N,N-dimethylformamide (10 mL) was added lH-imidazole-2-carbaldehyde (1.00 g, 10.4 mmol). The reaction mixture was stirred at rt for 1.5 hrs. Then 2-(chloromethoxy)ethyl-trimethyl-silane (2.08 g, 12.5 mmol) was added at 0 C. The reaction mixture was stirred at rt for 16 hrs. On completion, the mixture was quenched by water (50 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (petroleum ether: ethyl acetate = 5: 1) to give the title compound. LH MR (400 MHz, CDC13) delta = 9.85 (s, 1H), 7.39 (s, 1H), 7.35 (s, 1H), 5.80 (s, 2H), 3.59 (t, J = 8.4 Hz, 2H), 0.92 - 1.00 (m, 2H), 0.003 (s, 9H).
1'(1H-imidazol-2-ylmethyl)-3,3"-dimethyl-1',2'3',4',5',6'-hexahydro-[2,2';6',2"]terpyridine[ No CAS ]
[ 155742-57-7 ]
Yield
Reaction Conditions
Operation in experiment
58%
With triethylamine; In methanol; dichloromethane;
EXAMPLE 69 COMPOUND 69: 1'(1H-imidazol-2-ylmethyl)-3,3"-dimethyl-1',2'3',4',5',6'-hexahydro-[2,2';6',2"]terpyridine To a suspension of 2-imidazolecarboxaldehyde (1.01 g, 10.51 mmol) in CH2Cl2 (25 mL) was added Et3N (2.9 mL, 21.02 mmol) and tosyl chloride (3.01 g, 15.77 mmol) and the reaction mixture was heated to reflux overnight. Then the mixture was cooled and washed with saturated NH4Cl (4*30 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a dark brown oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded 1-(toluene-4-sulfonyl)-1H-imidazole-2-carbaldehyde as a yellow oil (1.53 g, 58%). 1H NMR (CDCl3) delta 2.45 (s, 3H), 7.31 (s, 1H), 7.49 (d, 2H, J=6.0 Hz), 7.83 (s, 1H), 8.00 (d, 2H, J=7.5 hz), 9.78 (s, 1H).
Example 6 N-(1-(Imidazol-2-ylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N'-phenylmethylcarbamide (26HCH66-06) The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). <strong>[10111-08-7]Imidazole-2-carboxaldehyde</strong> (58 mg, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3*6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1620, 1190, 1100, 805, 700, 620 cm-1; LC-MS: (M+H)+ 418.2, tr 2.05 min.
The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). <strong>[10111-08-7]Imidazole-2-carboxaldehyde</strong> (58 mg, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3 X 6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1620, 1190, 1100, 805, 700, 620 cm"1; LC- MS: (M+H)+ 418.2, tr 2.05 min.
With sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; In methanol; dichloromethane; acetic acid;
c) 1-[1-(1H-2-Imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 3-(4-Phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 5.81 mmol), 1H-<strong>[10111-08-7]2-imidazolecarbaldehyde</strong> (77 mg, 0.806 mmol), sodium triacetoxyborohydride (113 mg, 0.537 mmol) and glacial acetic acid (48 mg, 0.806 mmol) were mixed with 1,2-dichloroethane (4 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (90:10) as mobile phase to give 1-[1-(1H-2-imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 83%). 1H NMR (DMSO-d6) delta 2.33 (m, 2H), 2.81 (m, 4H), 3.15 (m, 1H), 3.69 (s, 2H), 5.38 (m, 1H), 6.90 (s, 2H), 7.15 (m, 5H), 7.44 (m, 2H), 7.66 (m, 2H), 8.24 (s, 1H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33*4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+ 453.4, Rt=2.17 min.
Example 11 (1H-Imidazol-2-ylmethyl)-(2-isopropyl-6-methyl-phenyl)-amine To a solution of 2-isopropyl-6-methyl-aniline (1.49 g, 10 mmol) in methanol (10 ml) was added imidazole-2-carboxyaldehyde (0.96 g, 10 mmol). After stirring the mixture overnight at 60 C., sodium borohydride (0.567 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute Flash-NH2 (Separtis); eluent: heptane/ethyl acetate=1:1) to yield a white solid (1.29 g, 56%); MS (ISP): 230.1 ((M+H)+.).
a) (1H-Imidazol-2-ylmethyl)-(3-fluoro-phenyl)-amine To a solution of 3-fluoroaniline (0.33 g, 3.0 mmol) in methanol (7 ml) was added imidazole-2-carboxyaldehyde (0.29 g, 3.0 mmol) and the mixture was stirred overnight at 60 C. After cooling, sodium borohydride (0.17 g, 4.5 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate) to yield a light yellow solid (0.315 g, 55%); MS (ISP): 192.1 ((M+H)+.).
With sodium cyanoborohydride; zinc(II) chloride; In methanol; at 60℃;
b) (3,4-Dichloro-phenyl)-(1H-imidazol-2-ylmethyl)-isopropyl-amine (3,4-Dichloro-phenyl)-isopropyl-amine (0.30 g, 1.47 mmol) was dissolved in methanol (10 ml). Then imidazole-2-carboxaldehyde (0.22 g, 2.20 mmol), zinc chloride (0.60 g, 4.4 mmol) and sodium cyanoborohydride (0.19 g, 2.9 mmol) were added and the reaction mixture was allowed to stir at 60 C. overnight. After cooling, the reaction mixture was concentrated in vacuo and the residue was purified using flash chromatography (SiO2; eluent: dichloromethane/methanol gradient) to yield a white solid (0.007 g, 2%); MS (ISP): 286.0 ([37Cl M+H]+.), 284.0 ([35Cl M+H]+).
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 1.5h;Inert atmosphere;
Example 60c. l-(4-Nitrophenyl)-lH-imidazole-2-carbaldehydeK2CO3 (14.35 g, 104.0 mmol) was added to a mixture of l-fluoro-4-nitrobenzene 1 (8.48 mL, 80.0 mmol) and lH-imidazole-2-carbaldehyde (8.45 g, 88.0 mmol) in dry DMF (75 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 80 0C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and H2O (400 mL) was added with vigorous stirring. The resultant precipitate was filtered, washed with H2O (5 x 100 mL) and dried in vacuo to afford the tile compound 3 (12.81 g, 74% yield) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): delta ppm 7.32 (s, 1 H) 7.49 (s, 1 H) 7.58 - 7.53 (m, 2H) 8.40 - 8.36 (m, 2 H) 9.86 (s, 1 H)
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
To a solution of 4-fluoronitrobenzene (7.87 g) and 2-imidazole-carboxaldehyde (5.90 g) in DMF (60 mL) was added K2CO3 (9.26 g). The mixture was heated at 80 C. under N2 for 16 h. The mixture was poured into water, and the precipitate was filtered to give 6.70 g of yellow solid. The filtrate was then extracted with EtOAc, and the organic layer was washed brine, dried over MgSO4, and concentrated to a yellow solid (5.40 g). Both batch were identified as the 4-[(2'-carboxaldehyde)imidazol-1'-yl]nitrobenzene. ESI mass spectrum z (rel. intensity) 218 (M+H, 100).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
Preparation of 4-[(2'-dimethylaminomethyl)imidazol-1'-yl]aniline. To a solution of 4-fluoronitrobenzene (7.87 g) and 2-imidazole-carboxaldehyde (5.90 g) in DMF (60 mL) was added K2CO3 (9.26 g). The mixture was heated at 80C under N2 for 16 h. The mixture was poured into water, and the precipitate was filtered to give 6.70 g of yellow solid. The filtrate was then extracted with EtOAc, and the organic layer was washed brine, dried over MgSO4, and concentrated to a yellow solid (5.40 g). Both batch were identified as the 4-[(2'-carboxaldehyde)imidazol-1'-yl]nitrobenzene. ESI mass spectrum z (rel. intensity) 218 (M+H, 100).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃; for 6h;
To a suspension of imidazole-2-carboxyaldehyde (2.50 g) and potassium carbonate (4.31 g) in DMF (25 ml) was added bromomethylcyclopropane (4.21 g) and the mixture was heated for 6 hours under nitrogen atmosphere at 50C. The mixture was allowed to be at room temperature, ethyl acetate was added to the mixture, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to give 1-cyclopropylmethylimidazole-2-carboxyaldehyde (3.90 g) as brown oil. 1H-NMR (200 MHz, CDCl3) delta 0.38 to 0.43 (2H, m), 0.60 to 0.69 (2H, m), 1.20 to 1.34 (1H, m), 3.28 (2H, d, J = 7.2 Hz), 7.26 to 7.31 (2H, m), 9.82 (1H, s)
With potassium carbonate; In acetonitrile; at 0 - 40℃;
To a solution of 1H-imidazole-2-carbaldehyde (240 mg, 2.4 mmol) and potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (5 mL) at 0 C. was added dropwise (bromomethyl)benzene (493 mg, 2.88 mmol). The mixture was stirred at 40 C. for 4 hr. Then the mixture was filtrated, evaporated to remove the acetonitrile from the filtrate, added EtOAc to extract the residues, and washed the extract with brine and water. The organic layer was dried with anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column (EtOAc:hexane=1:9) to obtain the title compound (430 mg, yield 95%). LC-MS (ESI) m/z: 187 (M+1)+
95%
With potassium carbonate; In acetonitrile; at 0 - 40℃; for 4h;
Example 1489-(4-Fluorophenyl)-8-(lH-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-oneExample 148A1 -Benzyl- lH-imidazole-2-carbaldehyde[00828] To a solution of lH-imidazole-2-carbaldehyde (240 mg, 2.4 mmol) and potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (5 mL) at 0 C was added dropwise (bromomethyl)benzene (493 mg, 2.88 mmol). The mixture was stirred at 40 C for 4 hr. Then the mixture was filtrated, evaporated to remove the acetonitrile from the filtrate, added EtOAc to extract the residues, and washed the extract with brine and water. The organic layer was dried with anhydrous Na2S04; concentrated, and chromatographed on a silica gel column (EtOAc: hexane = 1 : 9) to obtain the title compound ( 430 mg, yield 95%). LC-MS (ESI) m/z: 187 (M+1)
With potassium carbonate; In acetonitrile; at 40℃; for 3h;
1-Benzyl-1-H-imidazole-2-carbaldehyde. A suspension of 1-H-imidazole-2-carbaldehyde (2.35 g, 0.025 mole) in, 120 mL of CH3CN was treated with K2CO3 (4.0 g, 0.029 mole) followed by benzyl bromide (3.7 g, 0.022 mole) and stirred for three hr at 40 C. The solvent was removed in vacuo and the residue dissolved in EtOAc/CH2Cl2. The solution was washed with NaHCO3, pH 7 buffer,and brine, filtered and evaporated to give solids that were triturated with CH2Cl2/petroleum ether to give 1-Benzyl-1-H-imidazole-2-carboxaldehyde as a light yellow solid. 1H NMR (300 MHz, CDCl3) delta 9.8 (s, 1H), 7.4-7.3 (m, 4H), 7.2 (m, 2H), 7.15 (s, 1H), 5.5 (s, 2H).
Step a: 1-Benzyl-1H-imidazole-2-carbaldehydeTo a solution of the compound 1H-imidazole-2-carboxaldehyde (5 g, 52.0 mmol) in methanol (20 mL) was added acetone (40 mL), potassium carbonate (21.56 g, 156.2 mmol) and tetrabutyl ammonium bromide (catalytic amount). The reaction mixture was stirred at room temperature for 1 hour followed by the addition of benzyl bromide (8.9 g, 52.0 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was filtered through sintered funnel and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 0.5% methanol in dichloromethane to furnish the title compound.
With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃;
1-Trityl-1-H-imidazole-2-carboxaldehyde (4A). A suspension of 2-imidazole carboxaldehyde (7.3 g, 0.076 mole, Aldrich) in 76 mL of degassed DMF was treated with triethylamine (9.2 g, 12.7 mL, 0.091 mole) followed by trityl bromide (27 g, 0.084 mole) and stirred overnight at room temperature. The light purple suspension was poured into 800 mL H2O and extracted with CH2Cl2 three times the combined organic layers were washed with NaHCO3 and dried over Na2SO4, filtered and evaporated to give solids that were triturated with CH2Cl2/petroleum ether to give 1-Trityl-1-H-imidazole-2-carboxaldehyde (4A) as a light yellow solid. 1H NMR (300 MHz, CDCl3) delta 9.2 (s, 1H), 7.3 (m, 9H overlaps CHCl3), 7.22 (s, 1H), 7.1 (m, 6H), 7.0 (s, 1H).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 40h;
A mixture of 2-formylimidazole (5.17 g), ethyl 4-bromobutyrate (9.2 ml) and potassium carbonate (11.1 g) in DMF (50 ml) was stirred for 40 hours at 80C. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1), to give ethyl 4-(2-formyl-1H-imidazol-1-yl) butyrate (8.36 g) as pale yellow oil. 1H-NMR (200 MHz, CDCl3) delta 1.26 (3H, t, J = 7.2 Hz), 2.08 to 2.19 (2H, m), 2.29 to 2.36 (2H, m), 4.14 (2H, q, J = 7.2 Hz), 4.47 (2H, t, J = 7.1 Hz), 7.18 (1H, d, J = 1.1 Hz), 2.30 (1H, d, J = 1.1 Hz), 9.81 (1H, s). IR (neat) 1732, 1682, 1476, 1412, 1337, 1188, 1159, 772 cm-1
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃; for 6h;
To a suspension of imidazole-2-carboxyaldehyde (2.50 g) and potassium carbonate (4.31 g) in DMF (25 ml) was added 1-bromopentane (4.71 g) and the mixture was heated for 6 hours under nitrogen atmosphere at 50C. The mixture was allowed to be at room temperature, ethyl acetate was added to the mixture, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to give 1-pentylimidazole-2-carboxyaldehyde (4.32 g) as brown oil. 1H-NMR (200 MHz, CDCl3) delta 0.90 (3H, t, J = 6.8 Hz), 1.20 to 1.45 (4H, m), 1.71 to 1.85 (2H, m), 4.39 (2H, t, J = 7.2 Hz), 7.15 (1H, s), 7.28 (1H, s), 9.81 (1H, s)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,4-dioxane; at 20℃; for 120h;
[1220] To a suspension of imidazole-2-carboxaldehyde (2.3 g, 23.4 mmol) in 50 mL dioxane is added to ethyl isocyanoacetate (2.9 g, 25.8 mmol) and DBU (3.9 g, 25.8 mmol). After stirring at RT for 5 days, the reaction is neutralized with 10% AcOH. The solvent is removed in vacuo. The residue is taken up in EtOAc/H2O, the aqueous layer is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40M, eluting with 5% MeOH/EtOAc). Ethyl imidazo[1,2-c]pyrimidine-7-carboxylate is obtained (1.4 g, 32%) as an off-white solid. 1H NMR (400 MHz, CDCl3) delta9.14, 8.43, 7.88, 7.81, 4.54-4.48, 1.49-1.44.
1-Amino-1,2,3,4-tetrahydronapthalene (0.154 g, 1.05 mmol) was condensed with imidazole-2-carboxaldehyde (0.103 g, 1.07 mmol) in methanol (10 mL) overnight. The resulting imine was then hydrogenated (30 psi, room temperature) over Pd/C (10%, 34 mg) overnight. The mixture was filtered through celite and the cake was washed with methanol. The combined filtrates were evaporated under reduced pressure and the residue was purified by radial chromatography on silica gel (2 mm plate, 20:1 CH2Cl2-CH3OH containing 1% NH4OH) to give a colorless oil (0.202 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 6h;
General procedure: To a solution of 1H-imidazole-2-carbldehyde (13 mmol) and potassium carbonate (16 mmol) in DMF (13 mL) was added alkyl bromide (16 mmol), and the reaction mixture was stirred at 50 C for 6 h. The inorganic solids were removed by filtration, and the filtrate was diluted with water and extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, and the volatile components were evaporated under vacuum to give the respective product.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃; for 6h;
To a suspension of imidazole-2-carboxyaldehyde (2.50 g) and potassium carbonate (4.31 g) in DMF (25 ml) was added 2-bromobutane (4.27 g), and the mixture was heated for 6 hours under nitrogen atmosphere at 50C. The mixture was allowed to be at room temperature, ethyl acetate was added to the mixture, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to give 1-(2-butyl)imidazole-2-carboxyaldehyde (3.45 g) as brown oil. 1H-NMR (200 MHz, CDCl3) delta 0.84 (3H, t, J = 7.2 Hz), 1.45 (3H, d, J = 7.0 Hz), 1.71 to 1.86 (2H, m), 5.30 to 5.40 (1H, m), 7.29 (1H, s), 7.32 (1H, s), 9.83 (1H, s)
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 20h;
A mixture of 2-formylimidazole (5.16 g), bromoethyl acetate (7.1 ml) and potassium carbonate (11.1 g) in DMF (50 ml) was stirred for 20 hours at 60C. The insolubles were removed by filtration, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1), to give ethyl (2-formyl-1H-imidazol-1-yl)acetate (1.10 g) as pale yellow oil. 1H-NMR (200 MHz, CDCl3) delta 1.29 (3H, t, J = 7.1 Hz), 4.25 (2H, q, J = 7.1 Hz), 5.13 (2H, s), 7.15 (1H, s), 7.33 (1H, d, J = 0.6 Hz), 9.79 (1H, d, J = 0.6 Hz). IR (neat) 1752, 1684, 1478, 1416, 1375, 1339, 1302, 1215, 1024, 775 cm-1
Commercially available methyl bromomethylbenzoate (10.01 g) was dissolved in DMF (100 ml), and the solution was added with potassium phthalimide (9.70 g) and stirred at room temperature for 1.5 hours. After completion of reaction, the solution was concentrated, and water was added to the concentrate. Then, extraction was performed with chloroform. The resultant solution was washed with brine and dried with anhydrous sodium sulfate, and the solvent was distilled of f , to thereby obtain a white solid (12.91 g). Subsequently, a portion (7.56 g) of the obtained solid was dissolved in methanol (100 ml), and the solution was added with hydrazine monohydrate (6.25 ml) and stirred at 60C for 1.5 hours. After completion of reaction, the precipitated solid was separated by filtration, and the solvent was distilled off. Water was added to the residue, and extraction was performed with chloroform. The resultant solution was washed with 0.3 mol/l of a sodium hydroxide aqueous solution and brine and dried with anhydrous sodium sulfate, and the solvent was distilled off. Methanol (120 ml) and 2-imidazolecarboaldehyde (2.35 g) were added to the residue, followed by stirring at roomtemperature for 2 days. After completion of reaction, the precipitated solid was separated by filtration. The liquid layer was exsiccated by concentration, and washing was performed by adding anhydrous methanol (30 ml). Then, the solid was separated by filtration. The resultant solid and the solid that had been previously separated by filtration were suspended in methanol (86 ml) , and sodium borohydride (1.42 g) was added under ice-cooling. The solution was stirred at room temperature for 1 hour, and the solvent was distilled off. After addition of water, extraction was performed with chloroform, and the organic layer was washed with brine and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure and drying, to thereby obtain colorless viscous liquid (4.32 g). A portion (4.28 g) of the liquid was dissolved in DMF (65 ml), and the solution was added with di-t-butyldicarbonate (8.9 ml) and stirred at room temperature for 1 hour. After completion of reaction, the solvent was distilled off, and the residue was dissolved in chloroform, followed by washing with brine. After drying with anhydrous sodium sulfate, the solvent was distilled off, and THF (43 ml), methanol (43 ml), and 1 mol/l of a sodium hydroxide aqueous solution (43 ml) were added to the residue, followedby stirring at room temperature for 14 hours. After completion of reaction, the solvent was distilled off, and water (5 ml) was added to the residue. Further, 1 mol/l of a hydrochloric acid aqueous solution was carefully added to the solution, and the acid-precipitate was separated by filtration and dried, to thereby obtain the subject compound (4.87 g) as a white solid. MS(FAB,Pos.):m/z=332[M+1]+
With sodium cyanoborohydride; In methanol; for 40h;
To a stirred solution of N-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N'-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (174 mg, 0.38 mmol) in dry MeOH (5 mL) was added 2-imidazolecarboxaldehyde (75 mg, 0.78 mmol) and sodium cyanoborohydride (55 mg, 0.88 mmol) and the mixture was stirred for 40 h. The reaction mixture was concentrated in vacuo and partitioned between CH2C2 (30 mL) and aqueous 1 N sodium hydroxide (30 mL). The aqueous layer was washed with CH2Cl2 (2×20 mL) and the combined organic extracts washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) afforded the imidazole derivative (48 mg, 24%) as a clear oil.
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N'-(2-aminoethyl)-N'-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (333 mg, 0.57 mmol) in dry MeOH (5 mL) was added 2-imidazolecarboxaldehyde (110 mg, 1.14 mmol) and the mixture was stirred for 17 hours. To this solution was added sodium borohydride (110 mg, 2.91 mmol) in one portion and the mixture was stirred for 40 min. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 (25 mL) and saturated aqueous sodium bicarbonate (25 mL). The aqueous layer was washed with CH2Cl2 (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude amine was dissolved in THF (10 mL) and protected with di-t-butyldicarbonate (1.0 g, 4.59 mmol). Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 96:4 followed by 9:1) gave the desired product (110 mg, 22%) as a yellow oil.
2,2,2-trifluoroethyl p-toluene sulfinate[ No CAS ]
[ 10111-08-7 ]
[ 497855-74-0 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 110℃; for 6h;
To a suspension of imidazole-2-carboxyaldehyde (2.50 g) and potassium carbonate (4.31 g) in DMF (25 ml) was added 2,2,2-trifluoroethyl p-toluene sulfinate (7.93 g), and the mixture was heated for 6 hours under nitrogen atmosphere at 110C. The mixture was allowed to be at room temperature, ethyl acetate was added to the mixture, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate = 1:1), to give 1-(2,2,2-trifluoroethyl)imidazole-2-carboxyaldehyde (2.56 g) as brown oil. 1H-NMR (200 MHz, CDCl3) delta 5.17 (2H, q, J = 8.4 Hz), 7.26 (1H, s), 7.38 (1H, s), 9.85 (1H, s)
With potassium carbonate; sodium iodide; In DMF (N,N-dimethyl-formamide); at 80℃; for 48h;
A mixture of 2-formylimidazole (2.50 g), 3-chloropropyl acetate (3.8 ml), sodium iodide (4.7 g) and potassium carbonate (5.4 g) in DMF (25 ml) was stirred for 2 days at 80C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1), to give propyl 3-(2-formyl-1H-imidazol-1-yl) acetate (4.37 g) as pale yellow oil. 1H-NMR (200 MHz, CDCl3) delta 2.07 to 2.20 (5H, m), 4.08 (2H, t, J = 6.1 Hz), 4.50 (2H, t, J = 7.0 Hz), 7.17 (1H, s), 7.30 (1H, s), 9.81 (1H, s)
ethyl 2-(2-formyl-1H-imidazol-1-yl) benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 20h;
A mixture of 2-formylimidazole (2.50 g), 2-iodo-ethyl benzoate (8.61 g) and potassium carbonate (5.4 g) in DMF (25 ml) was stirred for 20 hours at 80C. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1), to give ethyl 2-(2-formyl-1H-imidazol-1-yl) benzoate (4.69 g) as pale yellow oil. 1H-NMR (200 MHz, CDCl3) delta 4.62 to 4.67 (2H, m), 4.77 to 4.84 (2H, m), 7.21 to 7.22 (1H, m), 7.31 (1H, d, J = 0.8 Hz), 7.40 to 7.48 (2H, m), 7.54 to 7.63 (1H, m), 7.93 to 7.98 (2H, m), 9.85 (1H, d, J = 0.8 Hz). IR (neat) 1721, 1682, 1476, 1453, 1412, 1273, 1117, 772, 712 cm-1
With piperidine; 1-methyl-pyrrolidin-2-one; dmap; 4-phenoxy benzaldehyde; sodium cyanoborohydride; acetic acid; N-ethyl-N,N-diisopropylamine; methylamine; trifluoroacetic acid; diisopropyl-carbodiimide; In tetrahydrofuran; methanol; DMF (N,N-dimethyl-formamide); 1,2-Dichloropropane; dichloromethane; for 48h;
Step A: The product resin from general procedure C, step A, is used. To 0.18 g of this resin are added sequentially a solution of 0.468 mmol Boc-Lys(Fmoc)-OH in 1.6 ml of 1,2-dichloropropane/tetrahydrofuran (1:1), 0.045 ml (0.288 mmol) of diisopropylcarbodiimide, and a solution of 0.036 mmol of 4-dimethylamino pyridine in 0.2 ml of 1,2-dichloropropane. The mixture is shaken for 15 hours. The liquids are filtered off and the resin is washed with dimethylformamide (2 x 2 ml), tetrahydrofuran (2 x 2 ml), and dichloromethane (2 x 2 ml). Step B: The resin obtained by step A is shaken with a mixture of 2.5 ml trifluoroacetic acid/dichloromethane 1:1 for one hour. The liquids are filtered off and the resin is washed with tetrahydrofuran (2 x 2 ml), tetrahydrofuran/ethyidiisopropylamine 3:1 (3 x 2 ml), methanol (2 ml) and tetrahydrofuran (2 ml). Step C: To the resin obtained by step B, a solution of 0.36 mmol of 4-phenoxybenzaldehyde in 1.7 ml of 1-methyl-2-pyrrolidone and 0.1 ml of acetic acid are added. The mixture is shaken for three hours. The liquids are filtered off. The resin is shaken with a solution of 0.9 mmol of sodium cyanoborohydride in 1.7 ml of dichloromethane/methanol 1:1 for one hour. The liquids are filtered off. The resin is washed with methanol (2 x 2 ml), dichloromethane/ methanol 1:1 (2 ml), dichloromethane/ethyidiisopropylamine 19:1 (2 x 2 ml), and tetrahydrofuran (2 x 2.5 ml). Step D: To the resin obtained by step C, a solution of 0.468 mmol of Boc-Tyr (Me)-OH in 1.6 mi of 1,2-dichloropropane/tetrahydrofuran 1:1 is added, followed by a solution of 0.288 mmol of diisopropylcarbodiimide in 0.2 mi of 1,2-dichloropropane. The mixture is shaken for 30 minutes. 0.043 mi (0.252 mmol) of ethyldiisopropylamine is added, and shaking is continued for 14 hours. The liquids are filtered off and the resin is washed with tetrahydrofuran (2x2.5 ml). The same amounts of Boc-Tyr (Me) -OH and diisopropylcarbodiimide as described above are added and the mixture is shaken for 45 minutes. 0.043 mi (0.252 mmol) of ethyidiisopropylamine is added, and shaking is continued for 7 hours. The liquids are filtered off and the resin is washed with dimethylformamide (2 x 2 ml) and tetrahydrofuran (2 x 3 ml). Step E: The resin obtained by step D is shaken with a mixture of 1.5 ML of dimethylformamide and 0.5 ml of piperidine for 30 min. The liquids are filtered off and the resin is washed with dimethylformamide (2x2 mi) and tetrahydrofuran (2 x 3 ml). Step F: To the resin obtained by step E, a suspension of 0.36 mmol of imidazole-2-carbaldehyde in 1.8 ml of 1-methyl-2-pyrrolidone / tetrahydrofuran 17:1 is added, followed by 0.1 ml of acetic acid. The mixture is shaken for 2.5 hours. The liquids are filtered off and the resin is washed with dichloromethane (4x2 ml). A solution of 0.90 mmol of sodium cyanoborohydride in 1.7 ml of dichloromethane/methanol 1:1 and 0.05 ml of acetic acid are added and the mixture is shaken for one hour. The liquids are filtered off and the resin is washed with methanol (2 x 2 ml), dichloromethane/methanol 1:1 (2 ml), tetrahydrofuran (2x3 ml), dichloromethane/ethyldiisopropyiamine 8: 1 (2 x 1.8 ml), and dichloromethane (5x2 ml). Step G: The resin obtained by step F is shaken with 2.5 ml of dichloromethane/ trifluoroacetic acid 1:1 for 30 minutes. The liquids are filtered off and the resin is washed with dichloromethane (2x2 ml), tetrahydrofuran (2x2.5 ml), and methanol (2x2.5 ml). Step H: To the resin obtained by step G, 2.0 ML of dichloromethane and 1.0 ml of 40 % methylamine in methanol are added. The mixture is shaken for 3.5 hours. The mixture is filtered and the filtrate is collected. The resin is washed with 3.5 ml of dichloromethane/ methanol 6:1 and the washing filtrate is collected. Both filtrates are mixed and evaporated to give a residue. Step I: The residue obtained by step H is dissolved in a mixture of 4.8 ml of water, 3.2 ml of acetonitrile and 0.8 ml of 1 M aqueous hydrochloric acid and purified by HPLC. Addition of dilute aqueous hydrochloric acid and freeze-drying afforded 12.2 mg of the product. HPLC-MS (Method B): m/z = 568 (M+1); Rt = 4.67 min
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 70℃; for 17h;
Reference Example 7Production of 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol [66.1] (i) Production of [1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazol-2-yl]methanol A suspension of 1-tert-butoxy-4-(4-iodobutyl)benzene (10.0 g), 2-formyl-1H-imidazole (3.47 g) and potassium carbonate (4.16 g) in DMF (100 ml) was stirred at 70C for 17 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water (3 times) and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazole-2-carbaldehyde as a pale brown oil. Sodium borohydride (1.25 g) was added to a solution of the compound in methanol (200 ml) at 0 C, and the mixture was stirred at 0C for 1 hr. The reaction mixture was combined with water, concentrated and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex, 100-200 mesh, Fuji silicia chemical) (eluent; hexane:ethyl acetate = 1:3 to ethyl acetate) to give the titled compound (8.29 g) as a colorless amorphous form.1H-NMR (CDCl3) delta: 1.32 (9H, s), 1.58-1.86 (4H, m), 2.60 (2H, t, J = 7.2 Hz), 3.99 (2H, t, J = 7.4 Hz), 4.62 (2H, s), 6.80-6.93 (4H, m), 7.03 (2H, d, J = 8.4 Hz). IR (KBr): 1505, 1366, 1235, 1163, 897 cm-1.
4-benzothiazol-2-yl-N5-(1H-imidazol-2-ylmethylene)-1H-pyrazole-3,5-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
In methanol;Heating / reflux;
A mixture [OF 4-BENZOTHIAZOL-2-YL-1H-PYRAZOLE-3,] 5-diamine (50 mg, 0.22 mmol) and 2-imidazolecarbonylaldehyde (22 mg, 0.22 mmol) in methanol (10 mL) were [REFLUXED] overnight. The solvent was evaporated and the resulting crude material was purified by flash column chromatography eluting with [CH2CI2] : MeOH = 20: 1 to yield 21 mg [(31%)] of the title compound. MS (m/z, ES+): 310.1 [(M+1,] 15%), 232.1 (M-77, 60%), 142.0 [(M-167,] 68%), 101.1 (100%).
With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 20℃; for 22h;
To a mixture of 2-imidazoIecarboxaldehyde (3.0g) and azetidine hydrochloride (3.21g) inanhydrous tetrahydrofuran (180ml) was added sodium triacetoxyborohydride (9.99g)followed by glacial acetic acid (1.72ml). The resultant mixture was stirred at roomtemperature for 22h, after which the insoluble material was filtered and washed with ethylacetate. The filtrate was concentrated under reduced pressure and the residue purifiedusing silica SPE (eluting with DCM, methanol, methanol:20% aqueous ammonia) to givethe title compound (2.63g) as a beige solid.Gas Chromatograph Mass spectrum: Found: MH+ 138
Synthesis Example 1-5: Synthesis of (S)-2-(4-(N-Boc-N-2-picolyl aminomethyl) benzoyl)-5-((imidazol-2-ylmethyl)amino) valerate 1-naphthalenemethylamide (Compound XIII-1) 60.0 mg of the compound obtained in Synthesis Example 1-4 was dissolved in 2.2 ml of anhydrous methanol, and then 10.2 mg of 2-imidazole carboxyaldehyde was added to the solution and the resultant mixture was stirred for 1 hour at room temperature. After the solvent was distilled off, 1.2 ml of anhydrous methanol was added to the solution and the resultant solution was cooled down to 0C. Subsequently, 7.6 mg of sodium borohydride was added to the solution and the resultant mixture was stirred for 1.5 hours at room temperature. The residue obtained by concentrating the reaction solution was purified by means of silica gel column chromatography (6 g, chloroform/methanol = 20/1 to 9/1), and 46.7 mg of the above-mentioned compound was obtained as a white crystal. MS(FAB,Pos.):m/z= 676[M+1]+ 1H-NMR(500MHz,CDCl3):delta=1.45 and 1.47(9H,2s),1.92-2.22(4H,m), 2.66-2.74(2H,m),3.71-3.81(2H,m),4.46-4.55(2H,m),4.57(2H,brs), 4.68(1H,d,J=4.5Hz),4.72-4.75(1H,m),4.82-4.86(1H,m),4.99-5.03 (1H,m),6.88(2H,s),6.99(2H,s),7.18-7.26(3H,m),7.29-7.31(1H,m),7.40-7.53(4H,m),7.63-7.69(3H,m),7.80-7.81(1H,m),7.85-7.86(1H,m),7.86-7.88(1H,m),8.00-8.02(1H,m),8.12(1H,brs),8.52(1H,brs).
(S)-2-(4-((imidazole-2-yl methyl) aminomethyl) benzoylamino)-5-((imidazol-2-ylmethyl) amino) valerate 1-naphthalenemethylamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Synthesis Example 20: Production of (S)-2-(4-((imidazole-2-yl methyl) aminomethyl) benzoylamino)-5-((imidazol-2-ylmethyl) amino) valerate 1-naphthalenemethylamide [Compound No. 21] 16.8 mg of the compound obtained in Synthesis Example 19-3 was dissolved in 0.6 ml of methanol, and then 7.1mg of triethylamine and 7.1 mg of 2-imidazole carboxyaldehyde were added to the solution and the whole was stirred for 2 hours at room temperature. After the solvent was distilled off, 0.6 ml of anhydrous methanol was added to the resultant and the whole was cooled to 0ºC. Then, 8.0 mg of sodium borohydride was added thereto and the whole was stirred for 30 minutes while being gradually returned to room temperature. On completion of the reaction, the solvent was distilled off. The residue was purified by means of silica gel column chromatography (0.8 g, chloroform/methanol/water = 7/3/0.5). The resultant compound was dissolved in a 1 mol/l hydrochloric acid and then water was distilled off, and 15.9 mg of hydrochloride of the above-mentioned compound was obtained as a white solid product. MS(FAB,Pos.):m/z=595[M+1]+ 1H-NMR(500Mz,DMSO-d6):delta=1.71-1.90(4H,m),3.05-3.17(2H,m),4.34(2H,m),4.43(2H,m),4.55(1H,m),4.77(2H,d,J=2.2Hz),7.47(2H,m),7.56(2H,m),7.64(6H,m),7.86(1H,m),7.96(1H,m),7.98(1H,m),8.06(1H,m),8.70(2H,m),9.94(1H,brs).
Synthesis Example 38-2: Synthesis of Nalpha-(4-(N-(imidazol-2-yl methyl) aminomethyl) benzoyl)-Ndelta-Cbz-L-ornithine 1-naphthalene methylamide (Compound XXIV-2) 107.2 mg of the compound obtained in Synthesis Example 38-1 was dissolved in 5 ml of methanol, and then 28 mul of triethylamine and 19 mg of 2-imidazole carboxyaldehyde were added to the solution. After the mixture was stirred for 2 days, 23 mg of sodium borohydride was added thereto. After 20 minutes, a small amount of silica gel was added to the reaction solution and the whole was concentrated. The residue thus obtained was purified by means of silica gel column chromatography (5 g, chloroform/methanol = 5/1), and 72.2 mg of the above-mentioned compound was obtained as a light-yellow solid product. MS(FAB,Pos.):m/z=619 [M+1]+ 1H-NMR(500MHz,DMSO-d6): delta=1.41-1.58 (2H,m), 1.70-1.84 (2H,m), 2.97-3.05 (2H,m), 4.48-4.53 (1H,m), 4.75 (2H,d,J=5.6Hz), 4.98 (2H,s), 6.79 (1H,s), 7.02 (1H,s), 7.26-7.38 (6H,m), 7.42-7.48 (4H,m), 7.51-7.57 (2 H,m), 7.82-7.90 (3H,m), 7.93-7.96 (1H,m), 8.04-8.08 (1H,m), 8.44 (1H, d,J=8.1Hz),8.51(1H,t, J=5.7Hz).
Synthesis Example 39-2: Synthesis of Nalpha-4-(imidazol-2-ylmethyl aminomethyl) naphthoylamino-Ndelta- Cbz-L-ornithine 1-naphthalene methylamide (Compound XXIV-3) 304.0 mg of the compound obtained in Synthesis Example 39-1 was dissolved in 9 ml of methanol, and then 55 mg of 2-imidazolecarboxyaldehyde was added to the solution. After the solution was stirred for 3 days, 59 mg of sodium borohydride was added thereto. After 1 hour, a small amount of silica gel was added to the reaction solution to concentrate. The residue thus obtained was roughly purified by means of silica gel column chromatography (10 g, chloroform/methanol = 10/1), and 204.4 mg of the above-mentioned compound was obtained as a light-yellow solid product.
Synthesis Example 52-1: Synthesis of Nalpha-(4-((imidazol-2-ylmethyl) aminomethyl) benzoyl)-NG-Pmc-L-arginine 1-naphthalenemethyl amide (Compound XXXII-2) 85.5 mg of the compound obtained in Synthesis Example 51-2 was dissolved in 1.7 ml of methanol and then 12.2 mg of 2-imidazolylcarboaldehyde was added to the solution and the whole was stirred for 2 days and 15.5 hours at room temperature. On completion of the reaction, the solvent was distilled off and then vacuum drying was performed, followed by the addition of 1.7 ml of anhydrous methanol. It was cooled to 0C and then 10.7 mg of sodium borohydride was added thereto, followed by stirring for 3 hours at room temperature. On completion of the reaction, the solvent was distilled off and then the residue was purified by means of silica gel column chromatography (5 g, chloroform/methanol = 5/1), and 75.6 mg of a white frothy product was obtained. MS(FAB,Pos.):m/z=793[M+1]+ 1H-NMR(500MHz,DMSO-d6): delta=1.23(6H,s), 1.38-1.58(2H,m),1.65-1.82 (2H,m),1.73(2H,t,J=6.8Hz),2.00(3H,s),2.45(3H,s),2.46(3H,s),2.5 0-2.58(2H,t,J=6.8Hz),3.00-3.08(2H,m),3.66(2H,s),3.73(2H,s),4. 46-4.55(1H,m),4.75(2H,d,J=5.1Hz),6.37(1H,brs),6.70(1H,brs),6. 79 (1H,s), 7.02 (1H,s), 7.41-7.50 (4H,m), 7.52-7.58 (2H,m), 7.84 (1H,t,J=4.6Hz), 7.86 (2H,d,J=8.5Hz), 7.93-7.96 (1H,m), 8.02-8.06 (1H,m), 8.44 (1H,d,J=7.8Hz), 8.53 (1H,t,J=5.6Hz).
8-chloro-5-{3-[(1H-imidazol-2-ylmethyl)-amino]-propyl}-3-methyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium cyanoborohydride; In methanol; at 70℃; for 18h;
Example 244 Preparation of 8-Chloro-5-{3-[(1H-imidazol-2-ylmethyl)-amino]- PROPYL}-3-METHYL-2, 5-dihydro-pyrazolo [4, 3-c] quinolin-4-one :; The title compound was prepared from Example 32. 1H-Imidazole-2-carbaldehyde (0. 063 g, 0. 66 mmol) and NaBH3CN (0. 040 mg, 1. 1 mmol) were added to a solution of5- (3-amino-propyl)-8-chloro-3-methyl-2, 5- dihydro-pyrazolo [4, 3-c] quinolin-4-one (0. 20 g, 0. 69 mmol) in CH30H (5 mL), and the mixture was heated at 70C for 18 h. After the reaction was cooled to 25C, it was partitioned between CH2C12 and saturated aqueous NAHC03. The aqueous layer was extracted with CH2C12 and the combined organic layers were dried over MGS04, filtered, and concentrated in vacuo. Purification by C-18 RP LC-MS chromatography afforded the title compound. LCMS : Method FA, Rt = 0. 80 min, [MH+= 370. 9]. 1H NMR 300 MHz (CD30D) 8 8. 34 (bs, 1H), 8. 13 (d, 1H), 7. 57 (M, 2H), 7. 14 (s, 2H), 4. 43 (t, 2H), 4. 18 (s, 2H), 2. 98 (t, 2H), 2. 67 (s, 3H), 2. 03-2. 15 (m, 2H).
Commercially available methyl bromomethylbenzoate (manufactured by Aldrich Corporation) (10.0 g) was dissolved in DMF (100 ml), and the solution was added with potassium phthalimide potassium salt (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (9.70 g) and stirred at room temperature for 1.5 hours. After completion of the reaction, the solution was concentrated, and water was added to the concentrate. Then, extraction was performed with chloroform. The resultant solution was washed with saturated saline solution and dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining a white solid (12.9 g). Subsequently, 7.56 g of the solid was dissolved in methanol (100 ml), and the solution was added with hydrazine monohydrate (manufactured by Nacalai Tesque, Inc.) (6.25 ml) and stirred at 60(C for 1.5 hours. After completion of the reaction, the precipitated solid was separated by filtration, and the solvent was distilled off. Water was added to the residue, and extraction was performed with chloroform. The resultant solution was washed with a 0.3 mol/l sodium hydroxide aqueous solution and saturated saline solution and dried with anhydrous sodium sulfate, and the solvent was distilled off. Methanol (120 ml) and 2-imidazole carboxaldehyde (manufactured by Aldrich Corporation) (2.35 g) were added to the residue, followed by stirring at room temperature for 2 days. After completion of the reaction, the precipitated solid was separated by filtration. The liquid layer was evaporated to dryness, and washing was performed by adding anhydrous methanol (30 ml). Then, the solid was separated by filtration. The resultant solid and the solid that had been previously separated by filtration were suspended in methanol (86 ml), and sodium borohydride (1.42 g) was added under ice-cooling. The solution was stirred at room temperature for 1 hour, and the solvent was distilled off. After addition of water, extraction was performed with chloroform, and the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure and drying, thereby obtaining a colorless viscous liquid (4.32 g). 4.28 g of the liquid was dissolved in DMF (65 ml), and the solution was added with di-t-butyl dicarbonate (8.90 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform, followed by washing with saturated saline solution. After drying with anhydrous sodium sulfate, the solvent was distilled off, and THF (43 ml), methanol (43 ml), and a 1 mol/l sodium hydroxide aqueous solution (43 ml) were added to the residue, followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off, and water (5 ml) was added to the residue. Further, a 1 mol/l hydrochloric acid aqueous solution was carefully added to the solution, and the acid-precipitate was separated by filtration and dried, thereby obtaining the subject compound (4.87 g) as a white solid. MS(FAB,Pos.):m/z=332[M+H]+
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 120h;
In DMF (15 ml), 2-imidazole carboxaldehyde (300 mg) was dissolved. Then, the compound (1.01 g) obtained in Example 92-1 and sodium hydride (137 mg) were added to the solution, and the whole was stirred at room temperature for 5 days. After completion of the reaction, the solvent was distilled off and the residue was then added with chloroform, followed by washing with water and saturated saline solution. The resultant was dried with anhydrous sodium sulfate, and the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (457 mg) as a yellow viscous liquid. 1H-NMR(500MHz,DMSO-d6):delta=3.21(3H,s),3.82 (2H,t,J=5.1Hz),4.55(2H,s),4.62(2H,t,J=5. 1Hz),7.28(1H,d,J=0.9Hz),7.28(1H,s),9.82(1H,d,J=0.9Hz).
With sodium cyanoborohydride; acetic acid; In methanol; for 18h;pH 5;
The compound (390 mg) obtained in Example 36-2 was dissolved by the addition of anhydrous methanol (20 ml), and the solution was added with imidazole-2-carboxaldehyde (453 mg) and sodium cyanoborohydride (341 mg), and adjusted to pH 5 by the addition of acetic acid (0.5 ml), followed by stirring for 18 hours. After completion of the reaction, the methanol was distilled off and the residue was then added with 1 mol/l sodium hydroxide (20 ml), followed by extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous magnesium sulfate. After that, the solvent was distilled off and the residue was then dried, thereby obtaining the subject compound (680 mg) as a white solid. MS(FAB,Pos.):m/z=376[M+H]+ 1H-NMR(500MHz,CDCl3):delta=3.49(4H,s),4.00(3H,s),4.14(2H,s),7.06(4H, s),7.51-7.64(3H,m),8.06(1H,d,J=7.6Hz),8.30(1H,d,J=7.8Hz), 8.90(1H,d,J=7.8Hz).
[4-(4-[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-butyl]-dipropylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (81.2 mg) obtained in Example 60-4 was dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (27.4 mg), acetic acid (3.00 ml), and 2-imidazole carboxaldehyde (31.4 mg), followed by stirring under a nitrogen atmosphere at 60C for 4 days. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The aqueous layer was washed with chloroform and then evaporated to dryness. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining the subject compound (63.0 mg) as a white solid. MS(FAB,Pos.):m/z=453[M+H]+ 1H-NMR(500MHz,DMSO-d6+D2O):delta=0.88(6H,t,J=7.2Hz),1.42(2H,t,J=6.9Hz),1.69-1.79(6H,m),2.89-2.91(4H,m),2.92-3.00(2H,m),3.44(2H,t,J=6.1Hz),4.16(4H,s),4.39(2H,s),4.72(2H, s),7.27(2H,d,J=8.2Hz),7.43(2H,d,J=8.2Hz),7.50(2H,s),7.52(2H, s).
N,N-bis(1H-imidazol-2-ylmethyl)-N',N'-dipropylnonane-1,9-diamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1h;
The compound (6.0 mg) obtained in Example 69-3 was dissolved in anhydrous methanol (2.0 ml) and added with 2-imidazole carboxaldehyde (6.00 mg), followed by gradual addition of sodium borohydride (3.00 mg) under ice-cooling. The solution was heated back to room temperature and then stirred for 1 hour. After completion of the reaction, methanol was distilled off and the organic layer was extracted with the addition of water and chloroform. The extract was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), followed by washing with ethyl acetate. Consequently, hydrochloride (5.80 mg) of the subject compound was obtained as a pale-yellow viscous liquid. MS(FAB,Pos.):m/z=403[M+H]+ 1H-NMR(500MHz,DMSO-d6):delta=0.90(6H,t,J=7.3Hz),1.12-1.37(12H,m),1.60-1.68(6H,m),2.36-2.40(2H,m),2.94-3.02(6H,m),4.12(4H,s),7.67(4H,s).
{2-[4-(4-[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxy)-phenyl]-ethyl}-dipropylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (67.0 mg) obtained in Example 79-3 was dissolved in anhydrous methanol (1.5 ml) and then added with sodium cyanoborohydride (20.0 mg), acetic acid (1.50 ml), and 2-imidazole carboxaldehyde (23.0 mg), followed by stirring under a nitrogen atmosphere at 60C for 2 days. After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=501[M+H]+
[4-(4-[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyloxymethyl)-benzyl]-dipropylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (136 mg) obtained in Example 80-4 was dissolved in anhydrous methanol (3.0 ml) and then added with sodium cyanoborohydride (40.6 mg), acetic acid (1.00 ml), and 2-imidazole carboxaldehyde (46.6 mg), followed by stirring under a nitrogen atmosphere at 60C overnight. After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (109 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=501[M+H]+1H-NMR(500MHz,DMSO-d6+D2O):delta=0.87(6H,t,J=7.2Hz),1.78-1.90(4H,m),2.89-3.08(4H,m),4.11(2H,s),4.15(2H,s),4.58(4H,s),4.76(4H,s),7.41-7.53(8H,m),7.55(4H,s).
With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 48h;pH 5;
The compound (242 mg) obtained in Example 87-4 and 2-imidazole carboxaldehyde (63.4 mg) were dissolved in anhydrous methanol (7.2 ml). Then, the solution was added with sodium cyanoborohydride (96.9 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 2 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. Subsequently, the extract was washed with saturated saline solution and the residue was then dried with anhydrous magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (282 mg) as a white solid. MS(FAB,Pos.):m/z=632[M+H]+
[4-(6-[(1H-imidazol-2-ylmethyl)-amino]-methyl)-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropyl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (130 mg) obtained in Example 125-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg), followed by stirring for 1 hour. Then, the solution was cooled to 0C. The solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (64.0 mg) as a pale-yellow viscous substance.
The compound (130 mg) obtained in Example 3-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg) and the whole was stirred for 1 hour. After having been cooled to 0C, the solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (64.0 mg) as a pale-yellow oily substance.
[4-(6-[bis-(1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropyl-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (130 mg) obtained in Example 125-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg), followed by stirring for 1 hour. Then, the solution was cooled to 0C. The solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (16.4 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=505[M+H]+1H-NMR(500MHz,DMSO-d6):delta=0.91(6H,t,J=7.3Hz),0.99(3H,t,J=7.3Hz),1.66-1.71(4H,m),1.78-1.82(4H,m),1.83-1.96(2H,m),2.97-3.00(4H,m),3.08-3.16(2H,m),3.25(2H,t,J=7.2Hz),3.87(2H,s),4.16(4H,s),4.54(2H, t,J=7.7Hz),7.52-7.7.55(1H,m),7.61(3H,s),7.64-7.70(1H,m),8.43(1H,s),10.31(1H,br).
The compound (130 mg) obtained in Example 3-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0. 130 ml) and 2-imidazole carboxaldehyde (37.3 mg) and the whole was stirred for 1 hour. After having been cooled to 0C, the solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (16.4 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=505[M+H]+ 1H-NMR(500MHz,DMSO-d6):delta=0.91(6H,t,J=7.3Hz),0.99(3H,t,J=7.3Hz),1.66-1.71(4H,m),1.78-1.82(4H,m),1.83-1.96(2H,m),2.97-3.00(4H,m),3.08-3.16(2H,m),3.25(2H,t,J=7.2Hz),3.87(2H,s),4.16(4H,s),4.54(2H,t,J=7.7Hz),7.52-7.55(1H,m),7.61(3H,s),7.64-7.70(1H,m),8.43(1H,s),10.31(1H,br).
The compound (45.0 mg) obtained in Example 127-13 was dissolved in methanol (2.25 ml) and added with 2-imidazole carboxaldehyde (19.5 mg) and trimethyl orthoformate (43.1 mg), followed by stirring at room temperature for 1 hour. Under ice-cooling, sodium borohydride (15.4 mg) was added to the solution, and the whole was stirred at room temperature for 30 minutes. The reaction solution was added with water and then subjected to separation/extraction with chloroform. The extract was washed with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (54.8 mg) as a yellow oily substance. MS(FAB,Pos.):m/z=412[M+H]+
With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 16h;pH ~ 5;
The compound (800 mg) synthesized in Example 2-1 was dissolved in methanol (32 ml) and then the solution was added with 2-imidazole carboxaldehyde (345 mg) and sodium cyanoborohydride (307 mg). Then, the solution was adjusted to approximately pH 5 with acetic acid and stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off and the residue was then suspended in chloroform, followed by washing with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. Subsequently, the resultant was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was dissolved in methanol (10 ml) and a 1 mol/l sodium hydroxide aqueous solution (10 ml), followed by stirring at room temperature for 2.5 hours. After completion of the reaction, the organic solvent portion was distilled off. Then, the residue was adjusted to pH 6 by the addition of 1 mol/l hydrochloric acid. The aqueous layer was washed with chloroform. The solution was concentrated to remove water and the residue was then added with methanol. After the insoluble matter had been removed through filtration, the methanol was distilled off and the residue was then concentrated under reduced pressure, thereby obtaining the subject compound (1.05 g). MS(FAB,Pos.):m/z=312[M+H]+1H-NMR(500MHz,DMSO-d6):delta=3.70(2H,s),3.90(4H,s),7.32 (4H,s), 7.52(2H,d,J=8.2Hz),7.86(2H,d,J=8.2Hz).
4-[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminobutyl)-benzenesulfonamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (114 mg) obtained in Example 24-4 was dissolved in anhydrous methanol (7.0 ml), and then the solution was added with 2-imidazole carboxaldehyde (73.0 mg), sodium cyanoborohydride (42.0 mg), and acetic acid (0.1 ml) in that order, followed by stirring at room temperature for 2 days. The methanol was distilled off and a 1 mol/l sodium hydroxide aqueous solution (1.8 ml) was then added to the residue. The solution was extracted with chloroform and the extract was then dried with anhydrous sodium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and then treated with hydrochloric acid, thereby obtaining hydrochloride (160 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=502[M+H]+1H-NMR(500MHz,DMSO-d6):delta=0.89(6H,t,J=7.4Hz),1.40-1.44(2H,m),1.60-1.70(6H,m),2.67-2.72(2H,m),2.93-3.01(6H,m),3.76-3.80(2H,m),4.14-4.16(4H,m),7.48-7.84(8H,m),9.94(1H,brs).
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