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CAS No. : | 51779-32-9 | MDL No. : | MFCD00043309 |
Formula : | C10H19NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XCAQIUOFDMREBA-UHFFFAOYSA-N |
M.W : | 217.26 | Pubchem ID : | 279800 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 56.41 |
TPSA : | 64.63 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.13 cm/s |
Log Po/w (iLOGP) : | 2.6 |
Log Po/w (XLOGP3) : | 2.1 |
Log Po/w (WLOGP) : | 2.45 |
Log Po/w (MLOGP) : | 1.13 |
Log Po/w (SILICOS-IT) : | 0.65 |
Consensus Log Po/w : | 1.78 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.11 |
Solubility : | 1.67 mg/ml ; 0.00769 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.09 |
Solubility : | 0.178 mg/ml ; 0.000817 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.74 |
Solubility : | 3.97 mg/ml ; 0.0183 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.1 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
94% | With sodium hydroxide In tetrahydrofuran; methanol; water | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile. To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60percent dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94percent) of a white solid. |
94% | With sodium hydroxide In tetrahydrofuran; methanol; water | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60percent dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94percent) of a white solid. |
94% | With sodium hydroxide In tetrahydrofuran; methanol; water | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60percent dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94percent) of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.3 g | With triethylamine In dichloromethane at 20℃; for 16 h; | A mixture of 3,3-difluoro-1-(4-methoxy benzyl)piperidin-4-one (10 g, 39.17 mmol) in 1,2-dichloroethane (100 mL) was added to 1-chloroethylchloroformate (16.86 g, 117.52 mmol) in three portion at a period of 30 min and it was reflux for 2 h. After completion of the reaction (TLC), the mixture was cooled to room temperature and then it was concentrated in vacuo to give as a yellow liquid. The yellow liquid was dissolved in methanol (100 mL) and it was reflux for 3 h. The completion of the reaction was monitored by TLC and then the cooled mixture was concentrated in vacuo to give as a brown liquid. A mixture of 3,3-difluoropiperidin-4-one hydrochloride, triethylamine (11.89 g, 117.52 mmol) and Boc anhydride (12.82 g, 58.75 mmol) in dry dichloromethane (100 mL) was stirred at room temperature for 16 h. After completion of the reaction (TLC), the reaction mixture was poured water extracted with dichloromethane (3 x 100 mL) ,dried over Na2SO4 and concentrated in vacuo to obtain the crude product which was purified by column chromatography over silica gel (60-120 mesh) using hexane/ethyl acetate (4:6) as eluent to get pure product. Colorless solid: m.p: 116-118 °C, (8.3 g, 90percent); 1H NMR: 400 MHz, DMSO-d6: δ 6.39 (s, 2H), 3.60 (t, J = 8.68 Hz, 2H), 3.35 (d, J = 7.40 Hz, 2H), 1.67 (s, 2H), 1.39 (s, 9H); MS: m/z 236.2 (M+1). 13C NMR (DMSO-d6, 400 MHz), δ (ppm): 181.6, 154.2, 112.3, 79.6, 50.6, 44.2, 30.8, 25.7, 25.7, 25.7. IR (KBr) 3262, 2983, 2937, 1669, 1430, 1395, 1369, 1342, 1279, 1158, 1211, 1123, 1093, 1058, 999, 975, 908, 879, 858, 834, 767, 704 cm-1. Anal. Calcd for C10H15F2NO3: C, 51.06; H, 6.43; N, 5.95. Found: C, 51.18; H, 6.51; N, 5.99.#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95 - 98% | With sodium hydroxide;tetrabutylammomium bromide; In 2-methyltetrahydrofuran; water; at 20 - 50℃; for 1h; | To an appropriate round bottom flask with 150 mL of 2-METHYLTETRAHYDROFURAN ("2- METHYLTHF") was added di-tert-butylimino-dicarboxylate (25.0 g, 115 MMOL), allyl bromide (16.7 g, 12.0 mL, 138 MMOL), and TERABUTYLAMMONIUM bromide (0.520 g 1.61 MMOL). In a second flask a sodium hydroxide solution is prepared by adding sodium hydroxide pellets (23.0 g, 576 MMOL) to 100.0 mL of process water at 0-5C. At room temperature the solution of sodium hydroxide is added to the reaction. The reaction is heated 40-50C. After 1 hour HPLC (GTP 6354.01 Armor C-18 5 uM 150 x 4.6 cm, 20mM K2HP04-PH 7), showed total consumption of DI-TERT-BUTYLIMINO-DICARBOXYLATE. Separated the layers and the 2-METHYLTHF layer is washed with process water. The organic layer is displaced with isopropanol to a KF of 0.1-0. 2% and used as a solution in isopropanol for the next step. HPLC Method on HP1100 using GTP 6354.01 indicated a main product band at 26.4 minutes with area percent of 96.0%. The yield was 95 to 98%. 'H NMR (400 MHz; CDCI3) : 5 5.78-5. 86 (m, 1H), 5.08-5. 17 (m, 2H), 4.16 (d, J=5.6 Hz, 2H), 1.48 (s, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With caesium carbonate; lithium iodide; In tetrahydrofuran; at 70℃; for 23h; | 4- (Bromomethyl) benzonitrile (5g, 25. 5MMOLES) and di-tert- butyliminodicarboxylate (5.54g, 25. 5mmoles) were dissolved in anhydrous THF (50mL) and cesium carbonate (16.62g, 25. 5MMOLES) and lithium iodide (170. 5mg, 1. 275MMOLES) were added. The mixture was stirred at 70 C for 23h and the reaction was worked up as described in Preparative Example 244, Step B above. The residue was chromatographed on a silica gel column (50x5cm) using 5% ethyl acetate in hexane as the eluant to give 4- (DI-TERT- butoxycarbonylaminomethyl) benzonitrile (7.07g, 83%) : FABMS: m/z 333.2 (MH+) ; HRFABMS: M/Z 333.1816 (MH+). Calcd. for C18H25N204 : m/z 333.1814 ; 8H (CDC13) 1. 45 (18H, S,-COOC (CH3) 3), 4.81 (2H, s, CH2), 7.37 (2H, d, Ar-H) and 7.62 ppm (2H, d, Ar-H); 8C (CDCI3) CH3 : 28.1, 28.1, 28.1, 28.1, 28.1, 28.1 ; CH2 : 49.2 ; CH: 127.8, 127.8, 132.3, 132.3 ; C: 83. 2,83. 2, 111.1, 118.9, 144.1, 152.4, 152.4. |
48% | With caesium carbonate; lithium iodide; In tetrahydrofuran; at 70℃; for 12h; | Step 1: Into a 20-L 4-necked round-bottom flask, was placed a mixture of tert-butylN-[(tert-butoxy)carbonyljcarbamate (1113 g, 5.12 mol, 1.00 equiv), THF (10 L), 4-(bromomethyl)-benzonitrile (1000 g, 5,10 mol, 1.00 equiv), Cs2CO3 (1672 g, 5.13 mol, 1,00equiv) and Lii (34.0 g, 255 mmol, 0.05 equiv). The resulting mixture was stirred for 12 h at70 C, then it was cooled to room temperature and filtered. The filtrate was diluted withEtOAc (10 L), washed with brine, dried over anhydrous Na2504 and concentrated to dryness.The crude product was washed with ethyl acetate/petroleum( 1/2) and the solids werecollected by filtration to afford 820 g (48%) of tert-butyl N-[(tert-butoxy)carbonylj-N-[(4- cyanophenyl)-methyljcarbamate as a white solid. |
With sodium hydride; In tetrahydrofuran; mineral oil; at -10 - 20℃; | To a suspension of NaH (60%, 2.5 g, 61.6 mmol( in THF (100 mL) was added at -5 oC to - 10 oC 4-cyanobenzyl bromide (10 g, 51 mmol), followed by di-tert-butyl iminocarbonate (12.82 g, 59 mmol) in THF (30 mL) dropwise over 15 min. The reaction mixture was stirred at RT overnight, quenched with ice-water, extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4, concentrated in vacuo to afford the crude product, which was washed with hexane, and dried in vacuo, 15.7 g. ESI-MS m/z 333 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In trifluoroacetic acid; for 3h; | To a cold solution of <strong>[134135-41-4]5-(bromomethyl)thiophene-2-carbonitrile</strong> (4.2 g, 20.8 mmol) in THF (500 mL) was added sodium hydride (60% dispersion in oil, 1.0 g, 25 mmol) in portions. To this suspension was added di-t-butyl iminodicarboxylate (4.9 g, 22.9 mmol) in portions. After stirrng for 3 h, the resulting solution was diluted with ethyl acetate (400 mL), washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 1:4) to give 5-(N,N-BOC2-aminomethyl)thiophene-2-carbonitrile as a yellow foam. This solid was dissolved in ethyl acetate (150 mL) and cooled to 0C. HCl gas was bubbled through the solution for 10 min, and the mixture was allowed to warmed to room temperature. The solvent was removed in vacuo to give the title compound as a pale yellow solid (2.4 g, 86%).1H NMR (CD3OD) ? 7.48 (d, 1H), 7.20 (d, 1H), 4.21 (s, 2H)???FAB MS: 175 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With caesium carbonate; In acetonitrile; at 20 - 25℃; for 6h;Inert atmosphere; | Example 4 Preparation of Di(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo ethylimido dicarbonate (VI) Compound V (1.0 eqt), di-t-butyl imidino dicarboxylate (1.0 eqt) and cesium carbonate (1.2 eqt) were mixed together at 20-25 C. in acetonitrile under nitrogen over a period of 6 hr. After completion of reaction, the reaction mass was filtered off and washed with acetonitrile and concentrated under vacuum below 50 C. The residue thus obtained was dissolved in toluene and washed with water followed by brine. The organic fractions were dried over anhydrous sodium sulfate and were concentrated under vacuum below 60 C. to obtain the crude product. The crude compound was slurried with diisopropyl ether, filtered and dried under vacuum at 40-45 C. to obtain the tilted compound. Yield: 64%; purity by HPLC: 99.57% |
With caesium carbonate; In acetonitrile; at 21℃; for 24h; | Cesium carbonate (70.4g) was added to a stirred suspension of 2-bromo-1-(2,2-dimethyl- 4H-1, 3-benzodioxin-6-yl) ethanone, (Glaxo, DE 3513885,1985) (61.8g) and di-t-butyl iminodicarboxylate (47.15g) in acetonitrile (600ml) under nitrogen. After vigorous stirring at [21] for 24 h the mixture was diluted with water [(CA800ML)] and the product was extracted with diethyl ether [(1LITRE,] then [200ML).] The combined organic layers were washed with brine, dried [(MGS04)] and concentrated to [CA400ML.] The white crystals were collected by filtration, washed with diethyl ether and dried to give the title compound (24.4g) [8] [(CDCI3)] 7.78 [(1 H,] dd, J 8,2Hz), 7.65 (1H, brs), 6.87 [(1 H,] d, J 8Hz), 4.97 (2H, s), 4.88 (2H, s), 1.56 (6H, s) and 1.48 (18H, s). Further concentration of the mother liquors gave additional product (13.8g). A third crop (7.1g) was obtained by chromatographing the mother liquors on silica gel, evaporating the appropriate eluate and triturating with diethyl ether. | |
With caesium carbonate; In acetonitrile; at 21℃; for 24h; | Cesium carbonate (70. 4g) was added to a stirred suspension of 2-BROMO-1-(2, 2-DIMETHYL- 4H-1, 3-BENZODIOXIN-6-YL) ETHANONE, (GLAXO, DE 3513885,1985) (61. 8g) and di-t-butyl iminodicarboxylate (47.15g) in acetonitrile (600MI) under nitrogen. After vigorous stirring at 21 for 24 h the mixture was diluted with water (CA800ML) and the product was extracted with diethyl ether (1LITRE, then 200ML). The combined organic layers were washed with brine, dried (MGS04) and concentrated to CA400ML. The white crystals were collected by filtration, washed with diethyl ether and dried to give the title compound (24. 4G) 8 (CDC13) 7.78 (1 H, dd, J 8,2Hz), 7.65 (1H, brs), 6.87 (1 H, d, J 8HZ), 4.97 (2H, s), 4.88 (2H, s), 1.56 (6H, s) and 1.48 (18H, s). Further concentration of the mother liquors gave additional product (13. 8G). A third crop (7. 1G) was obtained by chromatographing the mother liquors on silica gel, evaporating the appropriate eluate and triturating with diethyl ether. |
With caesium carbonate; In acetonitrile; at 21℃; for 24h; | Caesium carbonate (70.4g) was added to a stirred suspension of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone, (Glaxo, DE 3513885,1985) (61.8g) and di- t-butyl iminodicarboxylate (47.15g) in acetonitrile (600ml) under nitrogen. After vigorous stirring at 21 for 24 h the mixture was diluted with water (ca 800ml) and the product was extracted with diethyl ether (1litre, then 200ml). The combined organic layers were washed with brine, dried (MgS04) and concentrated to ca 400ml. The white crystals were collected by filtration, washed with diethyl ether and dried to give the title compound (24.4g) delta (CDCl3) 7.78 (1 H, dd, J 8, 2Hz), 7.65 (1 H, brs), 6.87 (1 H, d, J 8Hz), 4.97 (2H, s), 4.88 (2H, s), 1.56 (6H, s) and 1.48 (18H, s). Further concentration of the mother liquors gave additional product (13.8g). A third crop (7.1g) was obtained by chromatographing the mother liquors on silica gel, evaporating the appropriate eluate and triturating with diethyl ether. | |
With caesium carbonate; at 21℃; for 24h; | Cesium carbonate (70.4g) was added to a stirred suspension of 2-bromo-1-(2, 2-dimethyl- 4H-1, 3-benzodioxin-6-yl) ethanone, (Glaxo, DE 3513885,1985) (61.8g) and di-t-butyl iminodicarboxylate (47.15g) in acetonitrile (600ml) under nitrogen. After vigorous stirring at 21 for 24 h the mixture was diluted with water (ca800mi) and the product was extracted with diethyl ether (litre, then 200ml). The combined organic layers were washed with brine, dried (MgS04) and concentrated to ca400ml. The white crystals were collected by filtration, washed with diethyl ether and dried to give the title compound (24.4g) 8 (CDC13) 7.78 (1 H, dd, J 8,2Hz), 7.65 (1 H, brs), 6.87 (1 H, d, J 8Hz), 4.97 (2H, s), 4.88 (2H, s), 1.56 (6H, s) and 1.48 (18H, s). Further concentration of the mother liquors gave additional product (13.8g). A third crop (7. 1 g) was obtained by chromatographing the mother liquors on silica gel, evaporating the appropriate eluate and triturating with diethyl ether. | |
28 g | With caesium carbonate; In acetonitrile; at 20℃; | 1L single mouth bottle, The compound 1-11 (29g, 0 · 102mo 1), Cesium carbonate (36.25 g, 0 ? 112 mol 1), Di-tert-butoxycarbonylamine (21.75 g, 0.102piomicron1) was dissolved in acetonitrile (300 mL) Stir overnight at room temperature. Add water (300 mL), Ethyl acetate (500 mL) The organic layer was washed with saturated brine (500 mL) Sodium sulfate, filter, concentrate, The concentrated silica gel column (ethyl acetate / petroleum ether = 1/40) was purified to give 28 g of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.1 g | With sodium hydride; In tetrahydrofuran; for 5h; | Step 1: To a cooled solution of <strong>[105942-09-4]4-(bromomethyl)-3-fluorobenzonitrile</strong> (4.00 g;mmol in tetrahydrofuran (400.00 ml) was added sodium hydride (0.90 g; 22.43 mmol).N-[(tert-butoxy)carbonyljcarbamate (4.47 g; 20.56 mmol) was added portion wisethe reaction mixture was stirred for 5h. It was then diluted with EtOAc, washed with water and brine and dried overNa2SO4. The crude was purified by flash chromatography(Heptane/EtOAc 3:1) to give tert-butyl N-[(tert-butoxy)carbonylj-N-[(4-cyano-2- fluorophenyl)methylj carbamate (4.1 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | A suspension of sodium di-tert-butyl-iminodicarboxylate, previously prepared by reaction of di-tert-butyliminodicarboxylate (1.195 g, 5.50 mmol) with NaH (60% suspension in mineral oil)(132 mg, 5.50 mmol) in dryTHF (18 mL), was cannulated to a room temperature solution of (1R,4S)-4-hydroxycyclopent-2-enyl acetate(521 mg, 3.67 mmol), PPh3 (144 mg, 0.55 mmol) and Pd(PPh3)4 (636 mg, 0.55 mmol) in dry THF/DMF(1:1)(16 mL). The reaction mixture was heated at 50 C for 1 day, then diluted with MeOH (10 mL) and dryloaded on to silica. Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/Hex,gradient: 0% 4CV; 0-20% 10CV, 20% 6CV) yielded 17 (463 mg, 42%) as a colourless oil that solidifies upon standing to afford a white solid. | |
tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; | Method L (1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate To a suspension of ether washed sodium hydride (60% dispersion in oil; 0.31 g) in THF (30 ml) was added imidodicarbonic acid bis-(1,1-dimethylethyl)ester (1.84 g). The mixture was stirred at 40 C. for 1 hour. To the mixture, at ambient temperature, was then added (1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) and tetrakis(triphenylphosphine)palladium(0) (0.18 g). The reaction mixture was stirred for 24 hours then purified (SiO2, ethyl acetate: hexane 1:9 as eluant) to give the title compound as a colourless solid (0.90 g). NMR: 1.43 (18H, s), 1.61 (1H, ddd, J=12.3, 7.7, 6.4), 2.54 (1H, dt, J=12.6, 7.4), 4.51-4.57 (1H, m), 4.86 (1H, tq, J=8.0, 1.8), 4.91 (1H, d, J=5.4), 5.71-5.77 (2H, m). | |
tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; | a (1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate To a suspension of ether washed sodium hydride (60% dispersion in oil; 0.31 g) in tetrahydrofuran (30 ml) was added imidodicarbonic acid bis-(1,1-dimethylethyl)ester (1.84 g). The mixture was stirred at 40 C. for 1 hour. To the mixture, at ambient temperature, was then added (1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) and tetrakis(triphenylphosphine)palladium(0) (0.18 g). The reaction mixture was stirred for 24 hours then purified (SiO2, ethyl acetate: hexane 1:9 as eluant) to give the subtitle compound as a colourless solid (0.90 g). NMR deltaH (d6-DMSO) 1.43 (18H, s), 1.61 (1H, ddd, J=12.3, 7.7, 6.4 Hz), 2.54 (1H, dt, J=12.6, 7.4 Hz), 4.51-4.57 (1H, m), 4.86 (1H, tq, J=8.0, 1.8 Hz), 4.91 (1H, d, J=5.4 Hz), 5.71-5.77 (2H, m). |
tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; | a) (1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate To a suspension of ether washed sodium hydride (60% dispersion in oil; 0.31 g) in THF (30 ml) was added imidodicarbonic acid bis-(1,1-dimethylethyl)ester (1.84 g). The mixture was stirred at 40 C. for 1 hour. To the mixture at ambient temperature was then added (1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) and tetrakis(triphenylphosphine)palladium (0) (0.185 g). The reaction mixture was stirred for 24 hours and purified (SiO2, ethyl acetate: hexane 1:9 as eluant) to give the subtitle compound as a colourless solid (0.9 g). NMR deltaH (d6 -DMSO) 1.43 (18H, s), 1.61 (1H, ddd, J=12.3, 7.7, 6.4 Hz), 2.54 (1H, dt, J=12.6, 7.4 Hz), 4.51-4.57 (1H, m), 4.86 (1H, tq, J=8.0, 1.8 Hz), 4.91 (1H, d, J=5.4 Hz), 5.71-5.77 (2H, m). | |
tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; | a) (1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate To a suspension of ether washed sodium hydride (60% dispersion in oil; 0.31 g) in THF (30 ml) was added imidodicarbonic acid bis-(1,1-dimethylethyl)ester (1.84 g). The mixture was stirred at 40 C. for 1 hour. To the mixture, at ambient temperature, was then added (1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) and tetrakis(triphenylphosphine)palladium (0) (0.185 g). The reaction mixture was stirred for 24 hours then purified (SiO2, ethyl acetate:hexane 1:9 as eluant) to give the subtitle compound as a colourless solid (0.9 g). NMR deltaH (d6-DMSO) 1.43 (18H, s), 1.61 (1H, ddd, J=12.3, 7.7, 6.4 Hz), 2.54 (1H, dt, J=12.6, 7.4 Hz), 4.51-4.57 (1H, m), 4.86 (1H, tq, J=8.0, 1.8 Hz), 4.91 (1H, d, J=5.4 Hz), 5.71-5.77 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With caesium carbonate;lithium iodide; In butanone; for 48h;Heating / reflux; | Di-tert-butyl N-3-butenyliminodicarboxyIate (186); To a solution of di-tert-butyliminodicarboxylate (868 mg, 4 mmol), cesium carbonate (2.61 g, 8 mmol), and lithium iodide (28 mg, 0.2 mmol) in 2-butanone (20 mL) was added 4-bromobutene (812 mg, 6mmol) and the mixture was heated at reflux for 48 h. The reaction was allowed to cool and was quenched with brine (40 mL) and extracted with diethyl ether (3 x 20 mL). The combined organic fractions were washed with brine (30 mL), dried, and evaporated to yield the title compound (1.01 g, 3.7 mmol, 93%) as a light brown oil. 1H NMR (CDCl3, 300 MHz): delta 5.77(m, IH, H3); 5.04 (m, 2H, H4); 3.62 (dd, J = 6.0, 8.7 Hz, 2H, Hl); 2.30 (m, 2H, H2); 1.51 (s, 18H, 2 x (CH3)3).Mass Spectrum (ES, +ve) m/z 310 (55%) [MK+], 294 (30%) [MNa+], 272 (40%) [MH+]. HRMS calcd for Ci4H26NO4272.1862, found 272.1848. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With caesium carbonate; lithium iodide; In butanone; at 100℃; for 12h; | Step 2: A stirred mixture of <strong>[61940-21-4]2-bromomethyl-6-nitro-benzoic acid methyl ester</strong> (36.6 g, 134 mmol), di-tert-butyl iminodicarboxylate (29.1 g, 134 mmol), cesium carbonate (89.3 g, 274 mmol), and lithium iodide (0.89 g, 6.7 mmol) in 2-butanone (400 mL) was heated to reflux in a 100 0C oil bath for 12 hours while stirred with a mechanical stirrer. The mixture was allowed to cool to room temperature. To the mixture, was add brine (300 mL), water (300 mL), ethyl acetate (750 mL) and stirred for 10 minutes, then the suspension was filtered through a pad of Celite. The two layers were separated, and the organic layer was evaporated to a less volume and the aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (500 mL), dried over magnesium sulfate while de-colored at the same time with charcoal at room temp for 30 minutes. The black mixture was filtered through a pad of Celite. The filtrate was evaporated to give 2-(di-tert-butoxvcarbonylamino-methyl)-6-nitro-benzoic acid methyl ester as a brown oil (51.53 g, 94% yield). The product was used in the next step without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydride; In tetrahydrofuran; at 20℃; for 28h; | To a suspension of sodium hydride (1.91 g, 47.72 mmol) in anhydrous tetrahydrofuran (30 [ML)] at room temperature under nitrogen, was added a solution [OF 2-] [BROMOMETHYL-5-CHLORO-BENZONITRILE11] (10 g, 43.39 mmol) in anhydrous tetrahydrofuran (35 [ML),] followed by the dropwise addition of [DI-TERT] butyl imino dicarboxylate (10.37 g, 47.72 [MMOL)] in anhydrous tetrahydrofuran (30 [ML).] The reaction mixture was stirred at room temperature for 28 hours under nitrogen. The reaction was quenched with water (50 ml) and the solvent removed under reduced pressure. The aqueous layer was extracted with diethyl ether (3 x 100 ml), the combined organics washed with brine (50 [ML),] dried with magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (4: 1) to give the title compound (13.45 g, 84 [%)] as a pale yellow solid. [1H-NMR] (400 MHz, [CDCI3)] : [9] = 1.46 (s, 18H), 4.98 (s, 2H), 7.28 (d, 1H), 7.53 (d, 1H), 7.61 (d, [1H).] LRMS [(APCI)] : m/z [M + H] [+] [389.] Microanalysis : Found: C, 59.37 ; H, 6.47 ; N, 7.09. [C18H23N204CI] requires C, 58. 93; H, 6.32 ; N, 7.64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | 3-Bromomethyl-benzonitrile (42.9g, 219 mmol, 1 equivalent) is combined with <strong>[51779-32-9]Di-tert-butyl iminodicarboxylate</strong> (50 g, 230.13 mmol, 1.05 equivalents) and cesium carbonate (74.98g, 230.13 mmol, 1.05 equivalents) in Nu,Nu-dimethyl formamide (DMF) (230 mL). The reaction is stirred at room temperature overnight and then partitioned between diethyl ether (500 mL) and water (1L). The aqueous layer is extracted with an additional portion of diethyl ether (250 mL) and the combined ether layers are washed with brine (2x200 mL). The organic layer is then dried (MgSC>4), filtered, and reduced in vacuo to yield oil that slowly crystallized to give 2 (3-cvanophenyl)methyl1-Imidodicarbonic acid 1.3-bis(l.l-dimethylethyl) ester (72 g, 99%). MS: 333 (M+H), 355 (M+Na).1H NMR (300 MHz, CDC13): delta = 1.47 (s, 18H), 4.79 (s, 2H), 7.42 (t, 1H), 7.54-7.60 (m, 3H). |
87% | With caesium carbonate; lithium iodide; In tetrahydrofuran; at 70℃; for 22h; | 3-(Bromomethyl) benzonitrile (5g, 25. 5mmoles) and di-tert- BUTYLIMINODICARBOXYLATE (5.54g, 25. 5MMOLES) were dissolved in anhydrous THF (50mL) and cesium carbonate (16.62g, 25. 5mmoles) and lithium iodide (170. 5mg, 1. 275mmoles) were added. The mixture was stirred at 70 C FOR 22H and the reaction was worked up as described in Preparative Example 89, Step B above. The residue was chromatographed on a silica gel column (60x5cm) using 5% ethyl acetate in hexane as the eluant to give 3- (DI-TERT- BUTOXYCARBONYLAMINO) BENZONITRILE (7.39g, 87%): FABMS: m/z 333.2 (MH+) ; HRFABMS: m/z 333.1815 (MH+) ; Calcd. for C18H25N204 : m/z 333.1814 ; 8H (CDCI3) 1.52 (18H, S,-COOC (CH3) 3), 4. 84 (2H, s, CH2), 7.48 (1H, m, Ar-H), 7.60 (2H, m, Ar-H) and 7.65 ppm (1H, m, Ar-H); 8c (CDCI3) CH3 : 28.1, 28.1, 28.1, 28.1, 28.1, 28.1 ; CH2 : 48.4 ; CH: 129.2, 131.0, 131.0, 131.9 ; C: 83.2, 83.2, 112.5, 118.8, 140. 1, 152.5, 152.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution OF TRIPHENYLPHOSPHINE (5.61 g, 21.4 mmol) in anhydrous THF (40 ml) was added DIAD (4.21 ml, 21.4 mmol). The solution was stirred until a white precipitate was formed (2 to 10 min). After additional 60 min, a solution of di-tert-butyliminodicarboxylate (3.10 g, 14.3 mmol) and (R)-3-butyn-2-ol (1.0 g, 14.3 mmol) in THF (25 ml) was added and stirring was continued for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography over silica gel with ethyl acetate/hexane (1/20-1/1) to give N, N BIS- Boc-1 (S)-METHYL-PROP-2-YNYLAMINE (0.643 g) as colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | (2 3-Dioxo-2, 3-DIHYDRO- ? H-INDOL-5-YL1-CARBAMIC ACID TERT-BUTYL ESTER [0360] 5-NITRO-1 H-INDOLE-2, 3-dione (500 mg, 2.60 mmol) was dissolved in methanol (8 ML). Pd/C (5%) (333 mg, 0.16 mmol) was added under nitrogen. The round bottom flask was charged with hydrogen (BALLOON). DI-T-BUTYLDICARBAMATE (840 mg, 3.90 mmol) was added. It was stirred for 6 h at room temperature. 4- (DIMETHYLAMINO) pyridine (16 mg, 0.13 mmol) was added and it was stirred for another 5h. The reaction mixture was filtered through a pad of cellite, the solvent was removed and the residue was purified by silica gel chromatography ethyl acetate/hexane = 3/2). The title compound was obtained as a yellow solid (191 mg, 28%). [0361J H-NMR (400 MHz, D6-DMSO) o 1. 47 (s, 9H), 6. 83 (D, J = 8. 6 Hz, 1H), 7.58 (DD, J = 2.0, 8.2 Hz, 1 H), 7.61 (s, 1 H), 9.42 (S, 1 H), 10.89 (s, 1 H) ; MS m/z (relative intensity, %) 263.3 ([M+1]+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; N-methyl-acetamide; mineral oil; | Step 1: 3-Guanidinomethylbenzoic Acid Trifluoroacetate: 4.34 g (20.0 mmol) of di(t-butyl) iminodicarboxylate was added to a mixture of 800 mg (20.0 mmol) of sodium hydride (60% dispersion in mineral oil) and 50 ml of dimethylformamide. 1.71 g (10.0 mmol) of 3-chloromethylbenzoic acid was added to the obtained mixture, and they were stirred at 80 C. for 2 hours. After the concentration under reduced pressure, 40 ml of dioxane containing 4 M of hydrogen chloride was added to the residue, and they were stirred at room temperature overnight. A white precipitate thus formed was taken by the filtration and washed with ethyl acetate to obtain 3-aminomethylbenzoic acid hydrochloride as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In N-methyl-acetamide; water; | Example 127 Synthesis of N-(2-methyl-3-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester A solution of <strong>[60468-54-4]2-methyl-3-nitrobenzyl chloride</strong> (1.07 g) in dimethylformamide (30 ml) was added dropwise to a solution of di-t-butyl iminodicarboxylate (1.38 g) and sodium hydride (content, 60%; 0.30 g) in dimethylformamide (30 ml) at 0 C. Following 1-h stirring at room temperature, the temperature of the mixture was raised to 80 C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to give 1.49 g of the titled compound (yield, 96%). 1H-NMR(CDCl3) delta: 1.46(9H,s), 1.48(9H,s), 2.43(3H,s), 4.37-4.41(2H,m), 7.30(1H, dd, J=8.1, 8.0 Hz), 7.51(1H, d, J=8.0 Hz), 7.69(1H, d, J=8.1 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.2 g (100%) | With hydrogenchloride; NaH; In tetrahydrofuran; diethyl ether; ethyl acetate; | D) Preparation of 2-cyano-5-(aminomethyl)thiophene-HCl To a cold (0 C.) solution of <strong>[134135-41-4]2-cyano-5-(bromomethyl)thiophene</strong> (6.0 g, 30 mmol) in THF (50 mL) under nitrogen was added NaH (60% dispersion in oil, 1.3 g, 33 mmol) in portions. To this stirring suspension was added a solution of di-t-butyl iminodicarboxylate (7.1 g, 33 mmol) in THF (50 mL) over 30 min. After stirring for 3 h, saturated aqueous ammonium chloride (100 mL) was added. Volatile solvents were then removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo to give 10.5 g (100%) of 2-cyano-5-Boc2 NCH2 thiophene which crystallized upon standing. This solid was dissolved in EtOAc (200 mL) and cooled to 0 C. using an ice/water bath. Anhydrous HCl gas was bubbled through the solution for 10 min and the mixture was stirred for 2 h while warming to room temperature. Solvents were removed in vacuo and the resulting solid was suspended in diethyl ether and isolated by filtration. The white solid was dried overnight under vacuum to give 5.2 g (100%) of 2-cyano-5-(aminomethyl)thiophene.HCl. 1 H NMR FD-MS, m/e 139 (M+) Analysis for C6 H7 N2 SCl: Calc: C, 41.26; H, 4.04; N, 16.04; Found: C, 41.19; H, 4.12; N, 15.82. |
5.2 g (100%) | With hydrogenchloride; NaH; In tetrahydrofuran; diethyl ether; ethyl acetate; | D) Preparation of 2-cyano-5-(aminomethyl)thiophene.HCl To a cold (0 C.) solution of <strong>[134135-41-4]2-cyano-5-(bromomethyl)thiophene</strong> (6.0 g, 30 mmol) in THF (50 mL) under nitrogen was added NaH (60% dispersion in oil, 1.3 g, 33 mmol) in portions. To this stirring suspension was added a solution of di-t-butyl iminodicarboxylate (7.1 g, 33 mmol) in THF (50 mL) over 30 min. After stirring for 3 h, saturated aqueous ammonium chloride (100 mL) was added. Volatile solvents were then removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo to give 10.5 g (100%) of 2-cyano-5-Boc2 NCH2 -thiophene which crystallized upon standing. This solid was dissolved in EtOAc (200 mL) and cooled to 0 C. using an ice/water bath. Anhydrous HCl gas was bubbled through the solution for 10 min and the mixture was stirred for 2 h while warming to room temperature. Solvents were removed in vacuo and the resulting solid was suspended in diethyl ether and isolated by filtration. The white solid was dried overnight under vacuum to give 5.2 g (100%) of 2-cyano-5-(aminomethyl)thiophene.HCl. 1 H NMR FD-MS, m/e 139 (M+) Analysis for C6 H7 N2 SCl: Calc: C, 41.26; H, 4.04; N, 16.04; Found: C, 41.19; H, 4.12; N, 15.82. |
5.2 g (100%) | With hydrogenchloride; NaH; In tetrahydrofuran; diethyl ether; ethyl acetate; | D) Preparation of 2-cyano-5-(aminomethyl)thiophene.HCl To a cold (0 C) solution of <strong>[134135-41-4]2-cyano-5-(bromomethyl)thiophene</strong> (6.0 g, 30 mmol) in THF (50 mL) under nitrogen was added NaH (60% dispersion in oil, 1.3 g, 33 mmol) in portions. To this stirring suspension was added a solution of di-t-butyl iminodicarboxylate (7.1 g, 33 mmol) in THF (50 mL) over 30 min. After stirring for 3 h, saturated aqueous ammonium chloride (100 mL) was added. Volatile solvents were then removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo to give 10.5 g (100%) of 2-cyano-5-Boc2NCH2 -thiophene which crystallized upon standing. This solid was dissolved in EtOAc (200 mL) and cooled to 0 C. using an ice/water bath. Anhydrous HCl gas was bubbled through the solution for 10 min and the mixture was stirred for 2 h while warming to room temperature. Solvents were removed in vacuo and the resulting solid was suspended in diethyl ether and isolated by filtration. The white solid was dried overnight under vacuum to give 5.2 g (100%) of 2-cyano-5-(aminomethyl)thiophene.HCl. 1 H NMR FD-MS, m/e 139 (M+) Analysis for C6 H7 N2 SCl: Calc: C, 41.26; H, 4.04; N, 16.04; Found C, 41.19; H, 4.12; N, 15.82. |
5.2 g (100%) | With hydrogenchloride; NaH; In tetrahydrofuran; diethyl ether; ethyl acetate; | D) Preparation of 2-cyano-5-(aminomethyl)thiophene.HCl To a cold (0 C.) solution of <strong>[134135-41-4]2-cyano-5-(bromomethyl)thiophene</strong> (6.0 g, 30 mmol) in THF 50 mL) under nitrogen was added NaH (60% dispersion in oil, 1.3 g, 33 mmol) in portions. To this stirring suspension was added a solution of di-t-butyl iminodicarboxylate (7.1 g, 33 mmol) in THF (50 mL) over 30 min. After stirring for 3 h, saturated aqueous ammonium chloride (100 mL) was added. Volatile solvents were then removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo to give 10.5 g (100%) of 2-cyano-5-Boc2 NCH2 -thiophene which crystallized upon standing. This solid was dissolved in EtOAc (200 mL) and cooled to 0 C. using an ice/water bath. Anhydrous HCl gas was bubbled through the solution for 10 min and the mixture was stirred for 2 h while warming to room temperature. Solvents were removed in vacuo and the resulting solid was suspended in diethyl ether and isolated by filtration. The white solid was dried overnight under vacuum to give 5.2 g (100%) of 2-cyano-5-(aminomethyl)thiophene.HCl. 1 H NMR FD-MS, m/e 139 (M+) Analysis for C6 H7 N2 SCl: Calc: C, 41.26; H, 4.04; N, 16.04; Found: C, 41.19; H, 4.12; N, 15.82. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.5 g (94%) | With sodium hydroxide; In tetrahydrofuran; methanol; water; | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile. To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60% dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94%) of a white solid. |
18.5 g (94%) | With sodium hydroxide; In tetrahydrofuran; methanol; water; | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60% dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94%) of a white solid. |
18.5 g (94%) | With sodium hydroxide; In tetrahydrofuran; methanol; water; | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60% dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94%) of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | N-[[3-Cyanopyridin-2-yl]methyl]iminodicarboxylic acid bis(1,1-dimethylethyl)ester A solution of 3.8 g (17.5.10-3 mol) of di-t-butyl iminodicarboxylate in 25 ml of THF is prepared and 0.525 g (17.5.10-3 mol) of sodium hydride (as an 80% dispersion in oil) is added. After stirring for 15 min at room temperature, a solution of 3.45 g (17.5.10-3 mol) of <strong>[158626-15-4]6-bromomethyl-3-cyanopyridine</strong> in 50 ml of THF is added dropwise. After stirring for 30 minutes at room temperature, the mixture is concentrated under reduced pressure and the residue is purified by chromatography on silica gel using dichloromethane as the eluent to give 4 g of the expected product in the form of white crystals (yield=68.5%). M.p.=65-70 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.2 g (100%) | With hydrogenchloride; NaH; In tetrahydrofuran; ethyl acetate; | D) Preparation of 2-cyano-5-(aminomethyl)thiophene.HCl To a cold (0 C.) solution of <strong>[134135-41-4]2-cyano-5-(bromomethyl)thiophene</strong> (6.0 g, 30 mmol) in THF (50 mL) under nitrogen was added NaH (60% dispersion in oil, 1.3 g, 33 mmol) in portions. To this stirring suspension was added a solution of di-t-butyl iminodicarboxylate (7.1 g, 33 mmol) in THF (50 mL) over 30 min. After stirring for 3 h, saturated aqueous ammonium chloride (100 mL) was added. Volatile solvents were then removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo to give 10.5 g (100%) of 2-cyano-5-Boc2 NCH2 -thiophene which crystallized upon standing. This solid was dissolved in EtOAc (200 mL) and cooled to 0 C. using an ice/water bath. Anhydrous HCl gas was bubbled through the solution for 10 min and the mixture was stirred for 2 h while warming to room temperature. Solvents were removed in vacuo and the resulting solid was suspended in diethyl ether and isolated by filtration. The white solid was dried overnight under vacuum to give 5.2 g (100%) of 2-cyano-5-(aminomethyl)thiophene.HCl. 1 H NMR FD-MS, m/e 139 (M+) Analysis for C6 H7 N2 SCl: Calc: C, 41.26; H, 4.04; N, 16.04; Found: C, 41.19; H, 4.12; N, 15.82. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran; water; ethyl acetate; mineral oil; | Part 1 Preparation of tert-butyl ((tert-butoxycarbonyl)(3-cyanobenzyl)amino) methanoate: To a stirred suspension of sodium hydride (2.2 g, 56 mmol; 60% dispension in mineral oil) in THF (100 mL) was added <strong>[263159-64-4]2-bromo-m-tolunitrile</strong> (10 g, 51 mmol). To this mixture was slowly added a solution of di-t-butyl iminodicarboxylate (12.2 g, 56 mmol). After stirring for 20 hrs, the reaction mixture was diluted with a mixture of EtOAc (300 mL) and water (150 mL). The organic phase was dried over Na2SO4, and solvent evaporated to give the title compound as a solid (100% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran; water; ethyl acetate; mineral oil; | Part 1 Preparation of tert-butyl ((tert-butoxycarbonyl)(4-cyanobenzyl)amino) methanoate: To a stirred suspension of sodium hydride (2.2 g, 56 mmol; 60% dispension in mineral oil) in THF (100 mL) was added <strong>[42872-73-1]2-bromo-p-tolunitrile</strong> (10 g, 51 mmol). To this mixture was slowly added a solution of di-t-butyl iminodicarboxylate (12.2 g, 56 mmol). After stirring for 20 hrs, the reaction mixture was diluted with a mixture of EtOAc (300 mL) and water (150 mL). The organic phase was dried over Na2SO4, and solvent evaporated to give the title compound as a solid (100% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 50℃; for 15h; | Reference example 24 Di-tert-butyl N-(5-fluoro-2-nitrobenzyl)imidodicarbonate A mixture of 2-bromoethyl-4-fluoro-1-nitrobenzene (0.427 g), sodium hydride (0.117 g, purity 60%) and di-tert-butyl iminodicarboxylate (0.635 g) in N,N-dimethylformamide was stirred at an external temperature of 50 C for 15 hours. After standing to cool, to the mixture were added water and dichloromethane. The organic layer was separated and concentrated under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (eluent:hexane-ethyl acetate) to give di-tert-butyl (5-fluoro-2-nitrobenzyl)carbamate (0.538 g). 1H-NMR (CDCl3) delta ppm: 1.46 (18H, s), 5.18 (2H, s), 7'.00-7.15 (2H, m), 8.15 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With caesium carbonate; lithium iodide; In butanone; at 100℃; for 12h; | Step 2: A stirred mixture of 5-bromomethyl-2-nitro-benzoic acid methyl ester (50.5 g, 184 mmol), <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (40.15 g, 185 mmol), cesium carbonate (123.1 g, 377.7 mmol), and lithium iodide (1.23 g, 9.21 mmol) in 2-butanone (556 mL) was heated to reflux in a 100 C. oil bath for 12 hours while stirred with a mechanical stirrer. The mixture was allowed to cool to room temperature. To the mixture, was added brine (300 mL), water (300 mL), and ethyl acetate (750 mL), and the mixture was stirred for 10 minutes. The suspension was filtered through a pad of Celite. The two layers were separated, and the organic layer was evaporated to a less volume. The aqueous layer was extracted with ethyl acetate (2*150 mL). The combined organic layers were washed with brine (500 mL), dried over magnesium sulfate while de-colored at the same time by charcoal at room temp with stirring for 30 minutes. The black mixture was filtered through a pad of Celite. The filtrate was evaporated to give 5-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil (74.18 g, 98% yield). The product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | With caesium carbonate; lithium iodide; In butanone; at 100℃; for 12h; | Step 2: A stirred mixture of 4-bromomethyl-2-nitro-benzoic acid methyl ester (66.3 g, 241.9 mmol), <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (52.72 g, 242.6 mmol), cesium carbonate (161.58 g, 495.9 mmol), and lithium iodide (1.62 g, 12 mmol) in 2-butanone (700 mL) was heated to reflux in a 100 C. oil bath for 12 hours while stirred with a mechanical stirrer. The mixture was allowed to cool to room temperature. To the mixture, was added brine (300 mL), water (300 mL), and ethyl acetate (600 mL), and the mixture was stirred for 10 minutes. The suspension was filtered through a pad of Celite. The two layers were separated, and the organic layer was evaporated to a less volume. The aqueous layer was extracted with ethyl acetate (2*150 mL). The combined organic layers were washed with brine (1*500 mL), dried over magnesium sulfate while de-colored at the same time by charcoal at room temperature with stirring for 30 minutes. The black mixture was filtered through a pad of Celite, and the filtrate was evaporated to give 4-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil (96.0 g, 96.7% yield). The product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 25℃; for 12h; | To a solution of t-butyloxycarbonyl (tBOC)-glycine (0.25 g, 1.4 mmol) and compound IV (0.57 g, 1.4 mmol) in 10 mL of tetrahydrofuran was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.41 g, 2.1 mmol), stirred at 25 C. for 12 hours, and concentrated to dryness under vacuum in a rotary evaporator. The residue was suspended in water, and the product was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and concentrated to dryness under vacuum to give compound V (0.67 g, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | NaH (18.0mg, 0.430mmol) was suspended in THF (1mL) under an argon atmosphere. Di-tBu-imino-dicarboxylate (100mg, 0.460mmol) was dissolved in THF (1mL) and added to the suspension at 0oC. The resulting mixture was stirred for 15 min and 3-bromoprop-1-yne (0.077mL, 0.69mmol) was added. The reaction was allowed to reach rt and stirred for 16h. Brine (5mL) and water (15mL) were added and the mixture was extracted using Et2O (3 x 10mL). The organic phases were combined, dried (MgSO4) and concentrated under vacuum. The crude mixture was purified by flash chromatography on silica gel using Et2O and hexanes (1:9). The title compound was obtained as colorless oil (97.6 mg, 83%).1H NMR (300 MHz, CDCl3) (ppm) 4.35 (d, 2H, J = 7.4 Hz), 2.18 (t, 1H, J = 2.5 Hz), 1.52 (s, 18H). 13C NMR(75 MHz, CDCl3) (ppm) 151.6, 83.1, 79.6, 70.5, 35.8, 28.0. IR (NaCl) (cm-1) 3276, 2980, 1727, 1368. LRMS (m/z, relative intensity) 256 (M+, 33), 200 (78), 161 (100). HRMS calculated for C13H22N1O4: 256.1549, found: 256.1550. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | N-Di-(fert-butoxycarbonyl)-4-(3-methyl-butyryl)-benzylamine; Add di-tert-butyl- iminodicarboxylate (5.2 g, 24 mmol) to a slurry of sodium hydride (60% dispersion in mineral oil, 0.7 g, 17.6 mmol) in anhydrous DMF (75 mL) and stir at room temperature under nitrogen for 5 min. Add a solution of l-(4-bromomethyl-phenyl)-3-methyl-butan-l- one in DMF (20 mL) and stir under nitrogen for 2 h. Quench with slow addition of water (50 mL) and partition between EtO Ac/water (1:1, 500 mL). Separate and dry the organic phase over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (5.4 g, 85%) as a brown oily solid suitable for use without additional purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 2h; | To a solution of 3-bromomethyl-6-phenylpyridazine (120 mg, 0.482 mmol) obtained in Reference Example 2-(a) in N,N-dimethylformamide (1.57 ml) were added <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (127 mg, 0.585 mmol) and potassium carbonate (134 mg, 0.970 mmol), followed by stirring at 50C for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 1:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (180 mg) as a slightly yellow solid. (Yield: 97%) Mass spectrum (FAB, m/z): 386 (M++1). 1H-NMR spectrum (CDCl3, ppm): 8.10-8.07 (m, 2H), 7.83 (d, J=8.8Hz, 1H), 7.56-7.49 (m, 3H), 7.44 (d, J=8.8Hz, 1H), 5.19 (s, 2H), 1.47 (s, 9H), 1.47 (s, 9H). |
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 2h; | 2-(b) 3-[Bis(tert-butoxycarbonyl)aminomethyl]-6-phenylpyridazine To a solution of 3-bromomethyl-6-phenylpyridazine (120 mg, 0.482 mmol) obtained in Reference Example 2-(a) in N,N-dimethylformamide (1.57 ml) were added <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (127 mg, 0.585 mmol) and potassium carbonate (134 mg, 0.970 mmol), followed by stirring at 50C for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1? 1:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (180 mg) as a slightly yellow solid. (Yield: 97%) Mass spectrum (FAB, m/z): 386 (M++1). 1H-NMR spectrum (CDCl3, deltappm): 8.10-8.07 (m, 2H), 7.83 (d, J=8.8Hz, 1H), 7.56-7.49 (m, 3H), 7.44 (d, J=8,8Hz, 1H), 5.19 (s, 2H), 1.47 (s, 9H), 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | To a solution of 4-(thiazol-2-yl)benzyl bromide (1.25 g, 4.92 mmol) obtained in Reference Example 4-(b) in N,N-dimethylformamide (16 ml) were added <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (1.28 g, 5.89 mmol) and potassium carbonate (1.35 g, 9.76 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (2.05 g) substantially quantitatively as a colorless oil. 1H-NMR spectrum (CDCl3, ppm): 7.95-7.89 (m, 2H), 7.85 (d, J=3.4Hz, 1H), 7.39-7.34 (m, 2H), 7.32 (d, J=3.4Hz, 1H), 4.81 (s, 2H), 1.46 (s, 9H), 1.46 (s, 9H). |
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | 4-(c) 2- {4-[Bis(tert-butoxycarbonyl)aminomethyl]phenyl}thiazole To a solution of 4-(thiazol-2-yl)benzyl bromide (1.25 g, 4.92 mmol) obtained in Reference Example 4-(b) in N,N-dimethylformamide (16 ml) were added <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (1.28 g, 5.89 mol) and potassium carbonate (1.35 g, 9.76 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (2.05 g) substantially quantitatively as a colorless oil. 1H-NMR spectrum (CDCl3, deltappm): 7.95-7.89 (m, 2H), 7.85 (d, J=3.4Hz, 1H), 7.39-7.34 (m, 2H), 7.32 (d, J=3.4Hz, 1H), 4.81 (s, 2H), 1.46 (s, 9H), 1.46 (s, 9H). |
100% | With potassium carbonate; In dichloromethane; at 20℃; for 3h; | 2-(c) 2-{4-[Bis(tert-butoxycarbonyl)aminomethyl]phenyl}thiazole To 16 ml of an N,N-dimethylformamide solution containing 1.25 g (4.92 mmol) of 4-(thiazol-2-yl)benzyl bromide obtained in Reference example 2-(b) were added 1.28 g (5.89 mmol) of <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> and 1.35 g (9.76 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separating the liquids was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1 (V/V)), and the fractions containing the objective material were concentrated under reduced pressure to obtain 2.05 g of the title compound as colorless oil substantially quantitatively. 1H-NMR spectrum (CDCl3, delta ppm): 7.95-7.89 (m, 2H), 7.85 (d, J=3.4 Hz, 1H), 7.39-7.34 (m, 2H), 7.32 (d, J=3.4 Hz, 1H), 4.81 (s, 2H), 1.46 (s, 9H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | di-tert-butyl 2-(2,5-dimethylphenyl)-2-oxoethyliminodicarbonateIn an oven-dried flask, <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (2.566 g, 11.81 mmol, 1.10 eq) was combined with sodium hydride (60% on mineral oil, 0.586 g, 14.6 mmol, 1.37 eq) and 30 mL N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1.5 hours, and then 2-bromo-l-(2,5-dimethylphenyl)ethanone (2.432 g, 10.71 mmol, 1 eq) was added. The reaction was stirred at room temperature for an additional 1.5 hours, and then partitioned between ethyl acetate and water. The organic portion was washed with water and brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 40% ethyl acetate in heptanes) to obtain 3.008 g (77%) of di-tert-butyl 2-(2,5- dimethylphenyl)-2-oxoethyl-iminodicarbonate. LCMS (ESI) m+Na = 386.2. | |
77% | To an oven-dried flask charged with <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (2.566 g, 11.81 mmol, 1.10 equiv) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.586 g, 14.6 mmol, 1.37 equiv, 60% in mineral oil) at room temperature. After 1.5 hours, 2-bromo-1-(2,5-dimethylphenyl)ethanone (2.432 g, 10.71 mmol, 1.00 equiv) was added to the reaction mixture at room temperature. After an additional 1.5 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic portion was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (0 to 40% ethyl acetate in heptanes) to obtain 3.01 g (77%) of di-tert-butyl 2-(2,5-dimethylphenyl)-2-oxoethyliminodicarbonate. LCMS (ESI) m+Na=386.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In acetonitrile; at 20℃; for 2h;Reflux; | HN(Boc)2 (8.84 g, 40.7 mmol) and K2CO3 (8.45 g, 61.1 mmol) were added to a solution of 2-(bromomethyl)quinoline 9 (9 g, 40.7 mmol) in acetonitrile (54 mL) at 20 C. The mixture was then heated at reflux for 2 h. After cooling, water (54 mL) and ethyl acetate (30 mL) were added successively. The organic layer was washed with water (54 mL) and concentrated under reduced pressure. The orange oily residue was purified through a silica gel column chromatography (AcOEt/MCH: 97/3). White solid; 80% yield; mp 96 C; 1H NMR (300 MHz, CDCl3) 1.44 (18H, s, CH3), 5.11 (2H, s, CH2), 7.32 (1H, m, CHar), 7.52 (1H, m, CHar), 7.70 (1H, m, CHar), 7.80 (1H, m, CHar), 8.04 (1H, m, CHar), 8.14 (1H, m, CHar); 13C NMR (75 MHz, CDCl3) 28.04, 51.89, 81.98, 117.99, 126.05, 127.13, 127.54, 129.08, 129.52, 136.65, 147.65, 152.48, 158.40; HRMS (ESI) m/z calculated for C20H27O4N2 [M+H]+: 359.19653, found: 359.19614. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; | Preparation 111 : di-tert-Butyl 3-methoxy-4-nitrobenzylbiscarbamate; [00281 ] 4-(Bromomethyl)-2-methoxy-1 -nitrobenzene (Preparation 104, 246mg, 1 mmol), di-tert-butyl iminodicarbonate (217mg, 1 mmol) and potassium carbonate (280mg, 2mmol) were added to dry DMF (5ml). The reaction was stirred at room temperature for 24 hours. The solid was filtered and the organic solution was diluted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude was purified by silica gel column chromatography eluting with 50% hexane in dichloromethane to afford the title compound as a white powder (320mg, 84%). 1 H-NMR (500 MHz, CDCI3): delta 1 .47 (s, 6H), 3.93 (s, 3H), 4.8 (s, 2H), 6.95 (d, J = 8.1 Hz, 1 H), 7.05 (s, 1 H), 7.82(d, J = 8.1 Hz, 1 H) |
84% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; | Preparation 111 di-tert-Butyl 3-methoxy-4-nitrobenzylbiscarbamate 4-(Bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 104, 246 mg, 1 mmol), di-tert-butyl iminodicarbonate (217 mg, 1 mmol) and potassium carbonate (280 mg, 2 mmol) were added to dry DMF (5 ml). The reaction was stirred at room temperature for 24 hours. The solid was filtered and the organic solution was diluted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude was purified by silica gel column chromatography eluting with 50% hexane in dichloromethane to afford the title compound as a white powder (320 mg, 84%). 1H-NMR (500 MHz, CDCl3): delta 1.47 (s, 6H), 3.93 (s, 3H), 4.8 (s, 2H), 6.95 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), 7.82 (d, J=8.1 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Example 3 Preparation of N-(12-(bis-tert-butoxycarbonyl)amino)dodecyl-N-vinylformamide (N-bis Boc aminododecyl N-VFA) amine monomer A dry 250 ml Schlenk flask was equipped with a magnetic stir bar, dropping funnel, and sealed with a rubber septum. The flask was purged with nitrogen and charged with di-tert-butyl-iminodicarboxylate (45.6 mmol) and anhydrous THF (100 ml). The flask was cooled to 10C in an ice bath, potassium tert-butoxide totaling 5.57 g (45.6 mmol) were added in three separate portions over 45 minutes through the top of the flask under nitrogen flow. 1,12-dibromododecane (100 mmol) was added in three separate portions to the reaction mixture over 30 minutes. After addition, the reaction was allowed to warm up to room temperature and stir overnight. The solvent was removed in vacuo, and diluted with 150 ml of water. The water layer was extracted with diethyl ether (3 x 100 ml), dried over magnesium sulfate, and concentrated in vacuo. The material was further purified by column chromatography over silica (hexanes/ethyl acetate, 4:1 v/v). Yields were in the range of 60-80% and purity and structure were validated by 1H NMR. | |
In tetrahydrofuran; water; | Example 3 Preparation of N-(12-(bis-tert-butoxycarbonyl)amino)dodecyl-N-vinylformamide (N-bis Boc aminododecyl N-VFA) amine monomer A dry 250 ml Schlenk flask was equipped with a magnetic stir bar, dropping funnel, and sealed with a rubber septum. The flask was purged with nitrogen and charged with di-tert-butyl-iminodicarboxylate (45.6 mmol) and anhydrous THF (100 ml). The flask was cooled to 10 C. in an ice bath, potassium tert-butoxide totaling 5.57 g (45.6 mmol) were added in three separate portions over 45 minutes through the top of the flask under nitrogen flow. 1,12-dibromododecane (100 mmol) was added in three separate portions to the reaction mixture over 30 minutes. After addition, the reaction was allowed to warm up to room temperature and stir overnight. The solvent was removed in vacuo, and diluted with 150 ml of water. The water layer was extracted with diethyl ether (3*100 ml), dried over magnesium sulfate, and concentrated in vacuo. The material was further purified by column chromatography over silica (hexanes/ethyl acetate, 4:1 v/v). Yields were in the range of 60-80% and purity and structure were validated by 1H NMR. N-(3-tert-butoxycarbonylamino)propyl-N-vinylformamide (N-Boc aminopropyl N-VFA) was made by the same process using 1,12-dibromopropane rather than 1,12-dibromododecane. These amine monomers have the following structures: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Step 7: Preparation of 3-aminomethyl-7-chloro-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one bis(tert-butyl carbamate) In a 10 mL round bottom flask, di-tert butyl iminodicarboxylate (52.3 mg, 0.24 mmol) and 60% sodium hydride (20 mg, 0.5 mmol) were added sequentially to anhydrous DMF (3 mL). The reaction was stirred at room temperature for 30 min. to give a light yellow solution. Then 3-bromomethyl-7-chloro-2-oxazol-2-yl-l -phenyl- lH-quinolin-4-one (0.10 g, 0.24 mmol) was added and the mixture was stirred at room temperature for 5 hr. The reaction was quenched with a few drops of water and concentrated to dryness. The crude material was purified by HPLC using 25% ethyl acetate-hexane to obtain 3-aminomethyl- 7-chloro-2-oxazol-2-yl- l-phenyl-lH-quinolin-4-one bis(ieri-butyl-carbamate) (50 mg, 38% yield). MS calcd. for C29H30CIN3O6 [(M+H)+] 553, obsd. 553. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.8% | With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 45℃; under 760.051 Torr;Inert atmosphere; | Step 4: Preparation of 3-aminomethyl-2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one bis(tert-butyl carbamate) To a mixture of 3-bromomethyl-2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one (320 mg, 0.837 mmol), THF (2.79 mL) and DMF (2.79 mL) was added <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (182 mg, 0.837 mmol) and sodium hydride (60% in mineral oil, 33.5 mg, 0.837 mmol). The reaction mixture was heated at 45 C overnight which turned into a clear yellow solution. The reaction was diluted with a saturated aqueous ammonium chloride solution (30 mL) and was extracted into methylene chloride (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (30%-50% ethyl acetate-hexanes) afforded 3-aminomethyl- 2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one bis(tert-butyl carbamate) (298.7 mg, 68.8%) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | CS2CO3 (7.70 g, 23.7 mmol) was added to a solution of di-t-butyl iminodicarboxylate (5.14 g, 23.7 mmol) in DMSO (100 ml) at rt and the mixture was stirred for 30 min before intermediate J (4.50 g, 15.8 mmol) in DMSO (5 ml) was added. The mixture was stirred at rt overnight. Et2O and water was added. Organic phase was washed with water and then evaporated. The residue was purified by flash chromatography using 5-10% EtOAc in iso-hexane, Yield: 4.44 g (69%); colourless oil. HPLC: RT = 2.08 min, 100% (60-90% MeCN in 10 mM buffer, 3 min, XBridge). 1H NMR (400 MHz, CDCl3): delta 1.51 (s, 18H), 2.88-2.92 (m, 2H), 3.78-3.81 (m, 2H), 6.83 (d, J 5.6 Hz, 1H), 7.21 (d, J 5.6 Hz, 1H). | |
69% | With caesium carbonate; In dimethyl sulfoxide; at 20℃; | Cs2C03 (7.70 g, 23.7 mmol) was added to a solution of di-t-butyl iminodicarboxylate (5.14 g, 23.7 mmol) in DMSO (100 ml) at rt and the mixture was stirred for 30 min beforeintermediate J (4.50 g, 15.8 mmol) in DMSO (5 ml) was added. The mixture was stirred at rt overnight. Et20 and water was added. Organic phase was washed with water and then evaporated. The residue was purified by flash chromatography using 5-10% EtOAc in iso- hexane, Yield: 4.44 g (69%); colourless oil. HPLC: RT = 2.08 min, 100% (60-90% MeCN in 10 mM buffer, 3 min, XBridge). 1H NMR (400 MHz, CDC13): 6 1.51 (s, 18H), 2.88-2.92 (m, 2H), 3.78-3.81 (m, 2H), 6.83 (d, J 5.6 Hz, 1H), 7.21 (d, J 5.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.3 g | With triethylamine; In dichloromethane; at 20℃; for 16h; | A mixture of 3,3-difluoro-1-(4-methoxy benzyl)piperidin-4-one (10 g, 39.17 mmol) in 1,2-dichloroethane (100 mL) was added to 1-chloroethylchloroformate (16.86 g, 117.52 mmol) in three portion at a period of 30 min and it was reflux for 2 h. After completion of the reaction (TLC), the mixture was cooled to room temperature and then it was concentrated in vacuo to give as a yellow liquid. The yellow liquid was dissolved in methanol (100 mL) and it was reflux for 3 h. The completion of the reaction was monitored by TLC and then the cooled mixture was concentrated in vacuo to give as a brown liquid. A mixture of 3,3-difluoropiperidin-4-one hydrochloride, triethylamine (11.89 g, 117.52 mmol) and Boc anhydride (12.82 g, 58.75 mmol) in dry dichloromethane (100 mL) was stirred at room temperature for 16 h. After completion of the reaction (TLC), the reaction mixture was poured water extracted with dichloromethane (3 x 100 mL) ,dried over Na2SO4 and concentrated in vacuo to obtain the crude product which was purified by column chromatography over silica gel (60-120 mesh) using hexane/ethyl acetate (4:6) as eluent to get pure product. Colorless solid: m.p: 116-118 C, (8.3 g, 90%); 1H NMR: 400 MHz, DMSO-d6: delta 6.39 (s, 2H), 3.60 (t, J = 8.68 Hz, 2H), 3.35 (d, J = 7.40 Hz, 2H), 1.67 (s, 2H), 1.39 (s, 9H); MS: m/z 236.2 (M+1). 13C NMR (DMSO-d6, 400 MHz), delta (ppm): 181.6, 154.2, 112.3, 79.6, 50.6, 44.2, 30.8, 25.7, 25.7, 25.7. IR (KBr) 3262, 2983, 2937, 1669, 1430, 1395, 1369, 1342, 1279, 1158, 1211, 1123, 1093, 1058, 999, 975, 908, 879, 858, 834, 767, 704 cm-1. Anal. Calcd for C10H15F2NO3: C, 51.06; H, 6.43; N, 5.95. Found: C, 51.18; H, 6.51; N, 5.99. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Sealed tube; | General procedure: The alkyl bromide 2a-i (1 equiv), Cs2CO3 (2 equiv; for 2a 3 equiv) and HNBoc2 (1.1 equiv; for2a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 C overnight.For workup H2O was added and the reaction mixture was extracted with EtOAc (3x). Thecombined organic layers were dried over MgSO4, concentrated in vacuo and purified bycolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; potassium iodide; In acetonitrile; at 60℃; for 30h;Inert atmosphere; | into a 100 mL round bottom under nitrogen and using a reflux condenser was added 1- tosyl- 11 -(3,4,7-triaza-4,6, 10-triphenyl-adamantan- 1-yl methoxy)-3,6,9-trioxaundecane (prepared as described in PCT/US2012/060301 for Product 2.2) (4.0 g, 5.5 mmol, 1.0 equiv), di(tert-butyl) imidodicarbonate (1.43 g, 6.6 mmol, 1.2 equiv), potassium carbonate (1.9 g, 13.7 mmol, 2.5 equiv), potassium iodide (0.137 g, 0.82 mmol, 0.15 equiv) followed by acetonitrile (25 mL). The reaction was stirred at room temperature for 5 minutes followed by stirring at 60C for 30 hours. The reaction was quenched by adding water (25 mL) and ieri-butyl methyl ether (125 mL). The organic layer was separated and the aqueous layer extracted with ieri-butyl methyl ether (75 mL). The combined organic layers were washed with saturated aqueous sodium chloride (20 mL), then dried (sodium sulfate), filtered and concentrated under vacuum. The residue was applied onto a silica gel column (195 g, 6.5 cm X 12 cm) and eluted with 20% ieri-butyl methyl ether in 80% hexanes up to 100% ieri-butyl methyl ether. The tubes containing product were pooled and concentrated under vacuum, which resulted in 3.7 g (4.79 mmol, 87%) of Compound C. [000160] 1H NMR (400 MHz DMSO-d6): delta = 1.42 (s, 18H, C[C£CH3J3]2), 2.72 (s, 2H, CCH2N, isomer), 2.88 (s, 2H, CCH2N, isomer), 3.2-3.6 (m, 20H), 5.25 (s, 2H, NCHPh, isomer), 5.70 (s, 1H, NCHPh, isomer), 7.3-7.8 (m, 15H, phenyl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a solution of Cs2CO3 (3.62g, 11.1mmol, 1.10equiv) in DMF (11.1mL) were added Boc2NH (2.41g, 11.1mmol, 1.10equiv) and 2-iodobenzylbromide (3.00g, 10.1mmol, 1.00equiv) at room temperature. After being stirred at the same temperature for 16h, the reaction mixture was poured into water and the aqueous layer was extracted with two portions of diethyl ether. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (12% ethyl acetate in hexane) to give N-(bis-tert-butoxycarbonyl)-2-iodobenzylamine (1a) (4.81g, 11.1mmol, quant.) as a colorless oil. 1H NMR (400MHz, CDCl3) delta 7.81 (d, J=7.7Hz, 1H), 7.31 (dd, J=7.7, 7.7Hz, 1H), 7.08 (d, J=7.7Hz, 1H), 6.94 (dd, J=7.7, 7.7Hz, 1H), 4.77 (s, 2H), 1.43 (s, 18H). 13C NMR (100MHz, CDCl3) delta 152.2, 140.2, 139.2, 128.4, 128.3, 125.7, 96.9, 82.8, 54.9, 27.9. IR (chloroform solution): 2934, 1790, 1715, 1586, 1566, 1417, 1368, 1228, 1146, 1047, 1013, 961, 933, 894, 855, 747cm-1. HRMS (ESI-TOF) calcd for C17H25NO4I [M+H]+ 434.0828, found 434.0807 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In acetonitrile; at 50℃; for 12h; | Step 2 To a solution of <strong>[156001-53-5]5-bromo-2-(bromomethyl)benzonitrile</strong> (4.4 g, 16.00 mmol, 1 eq) and tert-butyl N-tert-butoxycarbonylcarbamate (4.17 g, 19.20 mmol, 1.2 eq) in acetonitrile (50 mL) was added potassium carbonate (4.42 g, 32.01 mmol, 2 eq). The reaction mixture was stirred at 50 C. for 12 hours. LCMS showed most of <strong>[156001-53-5]5-bromo-2-(bromomethyl)benzonitrile</strong> was consumed. Water (100 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1 to 5:1). tert-Butyl N-[(4-bromo-2-cyano-phenyl)methyl]-N-tert-butoxycarbonyl-carbamate (6.4 g, 15.56 mmol, 97% yield) was obtained as a colorless oil. |
37% | To a solution of Boc2NH (13 g, 58 mmol, 1.2 eq) in THF (150 mL) was added NaH (2.9 g, 73 mmol, 1.5 eq) at 0 C and the mixture was stirred at rt for 2 h. To the mixture was added 5-bromo-2- (bromomethyl)benzonitrile and the reaction was stirred at rt for 16 h, quenched upon the addition of water (250 mL), and extracted with EtOAc (250 mL * 3). The combined organics were washed with brine, dried, concentrated in vacuo to afford a solid which was purified by chromatography (petroleum ether EtOAc 10:1) to give the title compound (6.2 g, yield 37%) as a colorless oil. ESI-MS (M+H)+: 411.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrabutylammomium bromide; sodium hydroxide; In tetrahydrofuran; at 20 - 40℃; for 8h; | (Step 1)5 A solution of 21 (0.20 g, 2.0 mmol) and triethylamine (0.33 mL, 2.4 mmol) in dichloromethane (10 mL)was treated with methanesulfonyl chloride (0.16 mL, 2.1 mmol) at 0 C. After stirring for 2 h at the sametemperature, the resulting mixture was diluted with water and extracted with dichloromethane. The combinedextracts were washed with a 1 M hydrochloric acid and saturated aqueous sodium hydrogen carbonate. Theorganic layer was dried over sodium sulfate and concentrated to obtain (E)-4-methoxybut-2-en-1-ylmethanesulfonate (23) (0.42 g) as a pale yellow oil. The crude product was used without purification. (Step 2)A mixture of 23 (0.23 g, 1.3 mmol), <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong>6 (0.22 g, 1.0 mmol), tetrabutylammoniumbromide (5 mg, 0.02 mmol) was dissoleved in THF (2.0 mL) and the solution was treated with a 50 wt.% sodiumhydroxide aqueous solution (0.5 mL) at room temperature. The mixture was stirred for 8 h at 40 C and quenchedwith saturated aqueous ammonium chloride. Extractive workup and purification of the residue bychromatography on silica gel (n-hexane/ethyl acetate = 5/1 as the eluent) gave (E)-N,N-di(tert-butoxycarbonyl)-N-(4-methoxy-2-buten-1-yl)amine (24) (0.25 g, 83% yield) as a colorless oil. (Step 3) A solution of 24 (0.60 g,2.0 mmol) in THF (4 mL) was treated with a 0.7 M LDA THF/n-hexane solution (6.3 mL, 4.4 mmol) at -78 Cunder an argon atmosphere and stirred for 3 h at the same temperature. The resulting mixture was poured intosaturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extractes were washedwith brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silicagel (n-hexane/ethyl acetate = 30/1 as the eluent) to afford Z-1g (0.18 g, 53% yield) as a white solid. |
With tetrabutylammomium bromide; sodium hydroxide; In tetrahydrofuran; water; at 40℃; for 8h; | General procedure: (Step 1) Sodium hydride (60 wt.% in oil, 0.26 g, 6.5 mmol) was added to a solution of (Z)-2-buten-1,4-diol(1.7 mL, 21 mmol) in THF (20 mL) at 0 C under an argon atmosphere and the mixture was stirred for 30 min at room temperature. The resulting mixture was cooled to 0 C and treated with iodomethane (0.31 mL, 5.0mmol). After stirring for 17 h at room temperature, the resulting mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (n-hexane/ethyl acetate= 1/2 as the eluent) to give (Z)-4-methoxybut-2-en-1-ol (7) (378 mg, 74% yield) as a pale yellow oil. (Step2) A solution of 7 (0.20 g, 2.0 mmol) and triethylamine (0.33 mL, 2.4 mmol) in dichloromethane (10 mL) wastreated with methanesulfonyl chloride (0.16 mL, 2.1 mmol) at 0 C. After stirring for 2 h at the same temperature, the resulting mixture was diluted with water and extracted with dichloromethane. The combined extracts were washed with a 1 M hydrochloric acid followed by saturated aqueous sodium hydrogen carbonate.The organic layer was dried over sodium sulfate and concentrated to obtain (Z)-4-methoxybut-2-en-1-ylmethanesulfonate (8) (0.42 g) as a pale yellow oil. The crude product was used without purification. (Step3) A mixture of 8 (0.23 g, 1.3 mmol), <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> 1 (0.22 g, 1.0 mmol),tetrabutylammonium bromide (6 mg, 0.02 mmol) was dissolved in THF (2.0 mL) and the solution was treated with a 50 wt.% sodium hydroxide aqueous solution (0.5 mL) at room temperature. The mixture was stirred for 8 h at 40 C and quenched with saturated aqueous ammonium chloride. Extractive workup and purification of the residue by chromatography on silica gel (n-hexane/ethyl acetate = 5/1 as the eluent) gaveZ-1a (0.25 g, 83% yield) as a colorless oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Under an argon atmosphere, to a solution of (4-chloro-3-20 {4-[4-(2,2-dimethylpropoxy)phenyl]-6-methoxy-1,3,5-triazin-2-yl}phenyl)methanol (1.3 g, 3.2 mmol) obtained in the above-mentioned (2) and triethylamine (0.58 ml, 4.2 mmol) in tetrahydrofuran (13 ml) was added methanesulfonyl chloride (0.29 ml, 3.8 mmol) under ice-cooling, and the mixture was warmed to room temperature. After stirring for 0.5 hr, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (13 ml) were added cesium carbonate (3.1 g, 9.5 mmol) and <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (0.83 g, 3.8 mmol), and the mixture was stirred for 3 hr. To the reaction mixture were added water and ethyl acetate and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1-7/3) to give the title compound (1.6 g, yield 82%). (0593) 1H-NMR (400 MHz, CDCl3) delta: 1.06 (9H, s), 1.48 (18H, s), 3.69 (2H, s), 4.18 (3H, s), 4.83 (2H, s), 6.96-7.01 (2H, m), 7.39 (1H, dd, J=8.2, 2.2 Hz), 7.48 (1H, d, J=8.2 Hz), 7.98 (1H, d, J=2.2 Hz), 8.51-8.57 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Under an argon atmosphere, to a solution of {4-chloro-3-[4-(3-fluoro-4-methylphenyl)-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol (0.44 g, 1.2 mmol) obtained in the above-mentioned (2) in tetrahydrofuran (13 ml) were added triethylamine (0.22 ml, 1.6 mmol) and methanesulfonyl chloride (0.10 ml, 1.3 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was added to a solution of <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (0.32 g, 1.5 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in N,N-dimethylformamide (3.0 ml) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to give the title compound (0.64 g, yield 94%). (0726) 1H-NMR (CDCl3) delta: 1.48 (18H, s), 2.37 (3H, d, J=1.6 Hz), 4.19 (3H, s), 4.83 (2H, s), 7.31 (1H, t, J=7.9 Hz), 7.40 (1H, dd, J=8.4, 2.3 Hz), 7.49 (1H, d, J=8.4 Hz), 8.00 (1H, d, J=2.3 Hz), 8.22 (1H, dd, J=10.7, 1.6 Hz), 8.28 (1H, dd, J=7.9, 1.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Under an argon atmosphere, to a solution of {4-chloro-3-[4-(4-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol (0.15 g, 0.41 mmol) obtained in the above-mentioned (2) and triphenylphosphine (0.16 g, 0.62 mmol) in chloroform (1.5 ml) was added carbon tetrabromide (0.20 g, 0.62 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. The reaction mixture was applied to silica gel column chromatography (eluent: n-hexane/ethyl acetate=30/1-10/1) and concentrated under reduced pressure. (0744) A solution of the residue in N,N-dimethylformamide (1.5 ml) was added to a solution of <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (0.089 g, 0.41 mmol) and sodium hydride (0.016 g, 60 wt % oil dispersion) in N,N-dimethylformamide (0.70 ml) under ice-cooling, and the mixture was stirred at room temperature for 15 min. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (0.20 g, yield 85%). (0745) 1H-NMR (CDCl3) delta: 1.30 (6H, d, J=7.0 Hz), 1.47 (18H, s), 2.94-3.05 (1H, m), 4.19 (3H, s), 4.83 (2H, s), 7.34-7.41 (3H, m), 7.48 (1H, d, J=8.4 Hz), 8.00 (1H, d, J=2.3 Hz), 8.49-8.53 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Under an argon atmosphere, to a solution of {4-chloro-3-[4-(4-isobutoxyphenyl)-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol (0.24 g, 0.61 mmol) obtained in the above-mentioned (2) in tetrahydrofuran (2.0 ml) were added triethylamine (0.11 ml, 0.79 mmol) and methanesulfonyl chloride (0.052 ml, 0.67 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (1.5 ml) were added cesium carbonate (0.59 g, 1.8 mmol) and <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (0.16 g, 0.73 mmol) at room temperature, and the mixture was stirred for 1.5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to give the title compound (0.34 g, yield 92%). (0762) 1H-NMR (CDCl3) delta: 1.05 (6H, d, J=6.7 Hz), 1.47 (18H, s), 2.08-2.18 (1H, m), 3.82 (2H, d, J=6.5 Hz), 4.18 (3H, s), 4.82 (2H, s), 6.96-7.00 (2H, m), 7.39 (1H, dd, J=8.3, 2.3 Hz), 7.48 (1H, d, J=8.3 Hz), 7.99 (1H, d, J=2.3 Hz), 8.52-8.56 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Under an argon atmosphere, to a solution of {4-chloro-3-[4-methoxy-6-(4-propoxyphenyl)-1,3,5-triazin-2-yl]phenyl}methanol (0.95 g, 2.5 mmol) obtained in the above-mentioned (2) in tetrahydrofuran (13 ml) were added triethylamine (0.45 ml, 3.2 mmol) and methanesulfonyl chloride (0.23 ml, 3.0 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (13 ml) were added cesium carbonate (2.4 g, 7.4 mmol) and <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (0.64 g, 3.0 mmol) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give the title compound (1.3 g, yield 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Under an argon atmosphere, to a solution of {4-chloro-3-[4-(3-cyclopropyl-4-fluorophenyl)-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol (0.32 g, 0.82 mmol) obtained in the above-mentioned (2) in tetrahydrofuran (3.3 ml) were added triethylamine (0.15 ml, 1.1 mmol) and methanesulfonyl chloride (0.076 ml, 0.98 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (3.3 ml) were added cesium carbonate (0.80 g, 2.5 mmol) and <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (0.21 g, 0.98 mmol) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/1) to give the title compound (0.40 g, yield 83%). (0866) 1H-NMR (CDCl3) delta: 0.84-0.88 (2H, m), 1.01-1.07 (2H, m), 1.47 (18H, s), 2.09-2.18 (1H, m), 4.18 (3H, s), 4.83 (2H, s), 7.11 (1H, dd, J=9.7, 8.6 Hz), 7.40 (1H, dd, J=8.3, 2.2 Hz), 7.49 (1H, d, J=8.3 Hz), 8.00 (1H, d, J=2.2 Hz), 8.19 (1H, dd, J=7.5, 2.2 Hz), 8.36-8.41 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 60℃; for 5h; | To a stirred solution of di-terf-butyl iminodicarboxylate (640 mg, 2.95 mmol), K2CO3 (900 mg, 6.5 mmol) and Kl(34 mg, 0.2 mmol ) in DMF (30 mL) was added 2-(chloromethyl)-6- (6-fluoro-1 -(phenylsulfonyl)-1 -/-indol-3-yl)benzo[d]oxazole (Intermediate 79, 1 g, 2.27 mmol) at 60 C. The mixture was stirred at 60 C for 5 hours. The reaction was neutralized with HCI (12 M) and filtered. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 1 .4 g (100%) of the title compound as a black oil. LC-MS for C32H32FN3O7S2+H+ [M-Boc+H]+ : calcd. 522.2 ; found: 522.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 3h; | To a solution of ethyl 5- [3 -(hydroxymethyl)cyclobutyl]- 1,3,4-thiadiazole-2-carboxylate (1.8 g, 7.43 mmol, 1.00 eq.) in tetrahydrofuran (100 mL) was added triphenyl phosphine (3.9 g, 14.87 mmol, 2.00 eq.) in portions at 0 C in 10 mm. This was followed by the addition of DIAD (3 g, 14.78 mmol, 2.00 eq.) and <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (2.4 g, 11.05 mmol, 1.50 eq.). The resulting solution was stirred for 3hours at 2 5C and then diluted with water (200 mL). The resulting solution was extracted with ethyl acetate (3x200 mL) and the organic layers combined. The mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column using ethyl acetate/petroleum ether (1:5) to give the product (1.1 g, 33%) as a yellow solid. LC-MS: [M+H] 442.3 |
33% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 3h; | Step 2d: ethyl 5-(3-((bis((tert-butoxy)carbonyl)amino)methyl)cyclobutyl)-l,3,4- thiadiazole-2-carboxylate: To a solution of ethyl 5-[3-(hydroxymethyl)cyclobutyl]- 1 ,3,4- thiadiazole-2-carboxylate (1.8 g, 7.43 mmol, 1.00 eq.) in tetrahydrofuran (100 mL) was added triphenyl phosphine (3.9 g, 14.87 mmol, 2.00 eq.) in portions at 0 C in 10 min. This was followed by the addition of DIAD (3 g, 14.78 mmol, 2.00 eq.) and <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (2.4 g, 1 1.05 mmol, 1.50 eq.). The resulting solution was stirred for 3 hours at 2 5C and then diluted with water (200 mL). The resulting solution was extracted with ethyl acetate (3x200 mL) and the organic layers combined. The mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column using ethyl acetate/petroleum ether (1 :5) to give the product (1.1 g, 33%) as a yellow solid. LC-MS: [M+H]+ 442.3 |
33% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 25℃; for 3h; | To a solution of ethyl 5-[3-(hydroxymethyl)cyclobutyl]-l,3,4- thiadiazole-2-carboxylate (1.8 g, 7.43 mmol, 1.00 eq.) in tetrahydrofuran (100 mL) was added triphenyl phosphine (3.9 g, 14.87 mmol, 2.00 eq.) in portions at 0 C in 10 min. This was followed by the addition of DIAD (3 g, 14.78 mmol, 2.00 eq.) and <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (2.4 g, 11.05 mmol, 1.50 eq.). The resulting solution was stirred for 3 hours at 2 5C and then diluted with water (200 mL). The resulting solution was extracted with ethyl acetate (3x200 mL) and the organic layers combined. The mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column using ethyl acetate/petroleum ether (1 :5) to give the product (1.1 g, 33%) as a yellow solid. LC-MS: [M+H]+ 442.3 |
33% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 3h; | To a solution of ethyl 5-[3-(hydroxymethyl)cyclobutyl]-l,3,4- thiadiazole-2-carboxylate (1.8 g, 7.43 mmol, 1.00 eq.) in tetrahydrofuran (100 mL) was added triphenyl phosphine (3.9 g, 14.87 mmol, 2.00 eq.) in portions at 0 C in 10 min. This was followed by the addition of DIAD (3 g, 14.78 mmol, 2.00 eq.) and <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong> (2.4 g, 11.05 mmol, 1.50 eq.). The resulting solution was stirred for 3 hours at 2 5C and then diluted with water (200 mL). The resulting solution was extracted with ethyl acetate (3x200 mL) and the organic layers combined. The mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column using ethyl acetate/petroleum ether (1 :5) to give the product (1.1 g, 33%) as a yellow solid. LC-MS: [M+H]+ 442.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | With potassium carbonate; In acetonitrile; at 60℃; for 0.666667h; | To a solution of <strong>[208465-72-9]methyl 2-(chloromethyl)oxazole-4-carboxylate</strong> (300 mg, 1.7 mmol, 1.00 eq) in CH3CN (5 mL) were added K2C03 (708.5 mg, 5.1 mmol, 3.00 eq) and tert- butyl N-tert-butoxycarbonylcarbamate (1.11 g, 5.13 mmol, 3.00 eq). The mixture was stirred at 60 C for 40 min. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Si02, PE:EtOAc = 3: 1) to afford methyl 2-[[bis(tert-butoxycarbonyl)amino]methyl]oxazole-4-carboxylate (200 mg, 561.2 umol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.7% | With sodium hydride; In tetrahydrofuran; at 0 - 25℃; for 16h; | A solution of N,N-(bis-tert-butoxycarbonyl)amine (582 mg, 2.68 mmol) in THF (8 mL) was added to NaH (125 mg, 3.13 mmol) at 0C. Next <strong>[158626-15-4]6-(bromomethyl)nicotinonitrile</strong> (440 mg, 2.233 mmol) in THF (8 mL) at 0C was added, and the solution was allowed to warm to 25C. The reaction mixture was stirred at this temperature for 16 hours and then concentrated in vacuo. The residue was taken up in EtOAc (100 mL), washed with saturated (aq) ammonium chloride (100 mL) and brine, dried over MgSO2, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (40 g Si02) eluting with a gradient of 0-40% EtOAc in hexanes to give the title compound as a light yellow solid (415 mg, 55.7%). ?H NMR (400 MHz, CDC13) oe ppm 1.47 (s, 18 H), 4.99 (s, 2 H), 7.32 (dd, J=8.2, 0.6 Hz, 1 H), 7.93 (dd, J=8.2, 2.1 Hz, 1 H), 8.82 (dd, J=2.0, 0.8 Hz, 1 H); ESI-MS m/z [M+Hj 334. |
1.2 g | With sodium hydride; In tetrahydrofuran; mineral oil; at 25℃; for 5h;Cooling with ice; | Step 1: 6-(Bromomethyl)pyridine-3-carbonitrile (680 mg, 3.45 mmol) was dissolved in THF (70 ml). The solution was stirred in an ice bath and sodium hydride (60%, 0.17 g, 4.14 mmol) was added. Di(tert-butyl) imidodicarbonate (0.82 g, 3.8 mmol) was then addedin portions and the reaction was stirred to 25 C. After 5 h, the reaction was taken up in ethyl acetate and aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted once with ethyl acetate. The combined organics were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to givetert-butyl N- [(tert-butoxy)carbonyl] -N-[(5 -cyanopyridin-2-yl)methylj carbamate (1.2 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 0.5h; | [4-(3-bromopropoxy)-2,6-difluoro-phenyl]methanol (320 mg, 1.14 mmol) was dissolved in 11 mL of dry dimethylformamide (QS 0.1 M). Tert-butyl N-tertbutoxycarbonylcarbamate (247.33 mg, 1.14 mmol) and cesium carbonate (370.91 mg, 1.14 mmol) were added and the reaction mixture was stuffed at 70C for 30 mm. The solvent was removed. The crude was dissolved in ethyl acetate, washed with water, dried over Na2SO4. The solvent was removed. The crude was purified by flash chromatography using as eluent a mixture of Cy/EA (90/10) to give 500mg of tert-butyl N-tert-butoxycarbonyl-N- [3- [3 ,5-difluoro-4-(hydroxymethyl)phenoxy]propyl]carbamate as a colorless oil, leading to a 95 %yield.MS: [M+H] mlz = 344.?H NMR (DMSO-d6): oe (ppm) 1.41 (s, 18H) ; 1.87-1.96 (q, J= 12.6, 6.1 Hz, 2H); 3.64 (t, J = 6.9 Hz, 2H) ; 3.99 (t, J = 5.7 Hz, 2H) ; 4.39 (d, J = 5.7 Hz, 2H) ; 5.08(t, J= 5.4 Hz, 2H) ; 6.59-6.68 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Di-tert-butoxycarbonylamine (2.49 g, 12 mmol) was dissolved in N, N-dimethylformamide (20 ml)Under nitrogen, sodium hydride (0.58 g, 14.4 mmol) was added and stirred at room temperature for 1 h,Then ethyl bromoacetate (2.0 g, 12 mmol) was added,Add and stir at room temperature.TLC monitoring reaction is completed,Water (120 ml) and ethyl acetate (30 ml) were slowly added,Separate the organic layer,The aqueous layer was extracted with ethyl acetate (30 ml * 2)The combined organic layers were washed with saturated sodium chloride solution (100 ml)The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude solid,Recrystallization from petroleum ether / ethyl acetate (100: 1) gave 3.31 g of product,Yield was 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 100℃;Inert atmosphere; | 3-Bromo-4-(bromomethyl)benzonitrile (1) (8 g, 29.1 mmol), was dissolved in THF (80 mL) and DMF (80 mL) and the solution was stirred at room temperature under a nitrogen atmosphere. Di-tert- butylimino carboxylate (9.48 g, 43.6 mmol) and potassium carbonate (6.0 g, 43.6 mmol) were added and the reaction was heated at 100 °C overnight. The mixture was diluted with EtOAc (250 mL) and water (250 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (250 mL). The combined organic extracts were washed with brine (120 mL), dried (MgS04), filtered, and evaporated to dryness. The crude product was purified by trituration with the minimal amount of methanol (~20 mL) and the solid was collected via filtration to give the desired product (10.3 g, 86percent) as a white solid. NMR (400 MHz, CDCI3): 7.84 (1 H, d), 7.59 (1 H, dd), 7.23 (1 H, d), 4.88 (2H, s), 1 .46 (18H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | To a 3-L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[(tert-butoxy)carbonyl] carbamate (59.7 g, 274.78 mmol, 1.20 equiv) and N,N-dimethylformamide (350 mL), followed by the addition of NaH (60%) (11 g, 1.20 equiv), in portions at 0 C. The resulting solution was stirred at 0 C for 2 h. To this was added a solution of (4- bromo-5-fluoropyridin-2-yl)methyl methanesulfonate (65 g, 228.79 mmol, 1.00 equiv) in N,N- dimethylformamide (300 mL) dropwise with stirring at 0 C. The resulting solution was stirred at 60 C for an additional 2 h, cooled to room temperature, quenched by the addition of 1.2 L of water/ice, and extracted with 3x500 mL of ethyl acetate. The combined organic layers were washed with 2x400 mL of water, 1x400 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/19) to afford 60 g (65%) of tert-butyl N-[(4-bromo-5-fluoropyridin-2-yl)methyl]-N-[(tert- butoxy)carbonyl]carbamate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Caesium carbonate (60 g, 184 mmol, 2 eq) is addedin portions to a solution of <strong>[51779-32-9]di-tert-butyl iminodicarboxylate</strong>(20 g, 92 mmol) in 1 L of DMF under an argon atmosphereand at ambient temperature. Vigorous stirring is maintained for 1 hour, before 1,4-dibromobutane (99.2 g, 459 mmol, 5 eq) is added. Afier 24 hours at ambient temperature, the reaction mixture is filtered over Celite and concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel using as eluant a heptane/ AcOEt gradient (100% to 90:10). Intermediate 204 (26.1 g, 74.1 mmol) is obtained in the form of an colourless oil with a yield of 81%. | |
41.6 g | Di-tert-butyl 2-imidodicarbonate (CAS 51779-32-9, 27.0 g, 124 mmol) was solved in 510 ml_ DMF and 500 ml_ THF and sodium hydride (4.97 g, 60 % purity, 124 mmol) was added portionswise to the reaction mixture. After complete addition it was stirred at 65 for 2 hours. Then it was cooled to room temperature and 1 ,4-dibromobutane (CAS 110-52-1 , 65 ml_, 550 mmol) was added dropwise into the reaction mixture. It was stirred at 65 for 3 hours. Under cooling the mixture was diluted with methyl tert. butyl ether and water. The layers were seperated and the aqueous layer was extracted with ether twice. The organic layers were dried using a waterresistant filter. The clear filtrate was concentrated under reduced pressure. The crude product was purified using a 340 g silica column (Gradient: hexane/ethyl acetate 0-60) to provide the target compound in 95% purity: 41.6 g. 1 H-NMR (400MHz, DMSO-d6): d [ppm]= 1.45 (s, 18H), 1.56 - 1.66 (m, 2H), 1.71 - 1.82 (m, 2H), 3.46 - 3.52 (m, 2H), 3.52 - 3.56 (m, 2H). | |
41.6 g | Di-tert-butyl 2-imidodicarbonate (CAS 51779-32-9, 27.0 g, 124 mmol) was solved in 510 ml_ DMF and 500 ml_ THF and sodium hydride (4.97 g, 60 % purity, 124 mmol) was added portionswise to the reaction mixture. After complete addition it was stirred at 65 for 2 hours. Then it was cooled to rt and 1,4-dibromobutane (CAS 1 10-52-1, 65 ml_, 550 mmol) was added dropwise into the reaction mixture. It was stirred at 65 for 3 hours. Under cooling the mixture was diluted with methyl tert. butyl ether and water. The layers were seperated and the aqueous layer was extracted with ether twice. The organic layers were dried using a waterresistant filter. The clear filtrate was concentrated under reduced pressure. The crude product was purified using a 340 g silica column (Gradient: hexane/ethyl acetate 0-60) to provide the target compound in 95% purity: 41.6 g. 1H-NMR (400MHz, DMSO-d6): d [ppm]= 1.45 (s, 18H), 1.56 - 1.66 (m, 2H), 1.71 - 1.82 (m, 2H), 3.46 - 3.52 (m, 2H), 3.52 - 3.56 (m, 2H). |
41.6 g | Di-tert-butyl 2-imidodicarbonate (CAS 51779-32-9, 27.0 g, 124 mmol) was solved in 510 mL DMF and 500 mL THF and sodium hydride (4.97 g, 60 % purity, 124 mmol) was added portionswise to the reaction mixture. After complete addition it was stirred at 65 for 2 hours. Then it was cooled to rt and 1,4-dibromobutane (CAS 110-52-1, 65 ml, 550 mmol) was added dropwise into the reaction mixture. It was stirred at 65 for 3 hours. Under cooling the mixture was diluted with methyl tert. butyl ether and water. The layers were seperated and the aqueous layer was extracted with ether twice. The organic layers were dried using a waterresistant filter. The clear filtrate was concentrated under reduced pressure. The crude product was purified using a 340g silica column (Gradient: hexane/ethyl acetate 0-60) to provide the target compound in 95% purity: 41.6 g. 1H-NMR (400MHz, DMSO-d6): d [ppm]= 1.45 (s, 18H), 1.56 - 1.66 (m, 2H), 1.71 - 1.82 (m, 2H), 3.46 - 3.52 (m, 2H), 3.52 - 3.56 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | To a soln of di-fe f- butyl-iminodicarboxylate (153 mg, 0.704 mmol) in DMF (3.2 ml_) was added potassium tert- butoxide (1 M in THF, 700 muIota_, 0.700 mmol). After 30 min at rt, a solution of 2-((4f?,5aS,8aS)- 3-(benzyloxy)-2,8-dioxooctahydro-7H-1 ,4-methanopyrrolo[3,4-d][1 ,3]diazepin-7-yl)ethyl methanesulfonate (262 mg, 0.640 mmol) in DMF (2 ml_, 2x500 muIota_ washes) was added. It was stirred at rt for 10 min, heated to 50 C for 100 min then stirred at rt for 12 h, whereupon it was diluted with EtOAc and washed with brine ( saturated). The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were dried over Na2S04/MgS04, filtered and concentrated in vacuo. The crude residue was purified via silica get chromatography (EtOAc-heptane, 0-90%), affording the title compound (293 mg, 86%) as a white solid. LCMS: Rt = 0.87 min; m/z = 431 .4 (M - Boc +1) Method 2m_acidic. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.3% | [00349] To a solution of tert-butyl N-fert-butoxycarbonylcarbamate (7.33 g, 33.74 mmol, 1.0 equiv) in DMF (80 mL) was added NaH (1.62 g, 40.49 mmol, 60% purity, 1.2 equiv) at 0 C. The mixture was stirred at 0 C for 30 min and then 5-(bromomethyl)-2-chloro- pyrimidine (7 g, 33.74 mmol, 1 equiv) was added. The reaction mixture was stirred at room temperature for 1.5 h and then the mixture was poured into sat. H4CI (300 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 x 80 mL) and the combined organic phases were washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20: 1 to 1 : 1 petroleum ether/EtOAc) to afford tert-butyl N-tert-butoxycarbonyl-N-[(2-chloro pyrimidin-5-yl)methyl]carbamate (7.0 g, 60.3% yield) as a white solid. LCMS (ESI) m/z: [M + H] calcd for 344.14; found 344.2. | |
60.3% | To a solution of tert-butyl N-tert-butoxycarbonylcarbamate (7.33 g, 33.74 mmol, 1.0 equiv) in DMF (80 mL) was added NaH (1.62 g, 40.49 mmol, 60 wt.%, 1.2 equiv) at 0 C. The mixture was stirred at 0 C for 30 min and then 5-(bromomethyl)-2-chloro- pyrimidine (7 g, 33.74 mmol, 1 equiv) was added. The reaction mixture was stirred at room temperature for 1.5 h and then the mixture was poured into sat. NH4Cl (300 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 x 80 mL) and the combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20:1 to 1:1 petroleum ether/EtOAc) to afford tert-butyl N-tert-butoxycarbonyl-N-[(2-chloro pyrimidin-5-yl)methyl]carbamate (7.0 g, 60.3% yield) as a white solid. LCMS (ESI) m/z: [M + H] calcd for C15H22ClN3O4: 344.14; found 344.2. | |
60.3% | To a solution of tert-butyl N-tert-butoxycarbonylcarbamate (7.33 g, 33.74 mmol, 1.0 equiv) in DMF (80 mL) was added NaH (1.62 g, 40.49 mmol, 60 wt.%, 1.2 equiv) at 0 C. The mixture was stirred at 0 C for 30 min and then 5-(bromomethyl)-2-chloro- pyrimidine (7 g, 33.74 mmol, 1 equiv) was added. The reaction mixture was stirred at room temperature for 1.5 h and then the mixture was poured into sat. NH4Cl (300 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 x 80 mL) and the combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20:1 to 1:1 petroleum ether/EtOAc) to afford tert-butyl N-tert-butoxycarbonyl-N-[(2-chloro pyrimidin-5-yl)methyl]carbamate (7.0 g, 60.3% yield) as a white solid. LCMS (ESI) m/z: [M + H] calcd for C15H22ClN3O4: 344.14; found 344.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.1% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; | A mixture of 2-(2-((5-(benzyloxy)pentyl)oxy)ethoxy)ethyl methanesulfonate (1.8 g, 5.00 mmol), HNBoc2 (1.2 g, 5.5 mmol) and K2CO3 (1.4 g, 10.00 mmol) in DMF (30 mL) was heated to 100 C under N2 and the mixture was stirred for 3 h. It was then cooled to room temperature. The reaction mixture was quenched with water (100 mL), and extracted with EA (40mL x 3). The organic phase was washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated. The residue was purified by column chromatography (PE/EA=10/1 to 3/1) to giveN,N-diBoc-2-(2-((5- (benzyloxy)pentyl)oxy)ethoxy)ethan- 1 - amine (2. Og, 83.1%); 1HNMR(400MHz, CDCL): d 7.26-7.34 (m, 5H), 4.50 (s, 2H), 3.74-3.80 (m, 2H), 3.53-3.63(m, 6H), 3.42-3.48 (m, 4H), 1.58-1.65 (m, 4H), 1.49 (s, 18H), 1.39-1.45 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium hydride; In tetrahydrofuran; hexane; mineral oil; at 0 - 20℃; for 16h;Inert atmosphere; | In a dry round bottom flask under Ar, NaH (60% in mineral oil; 508 mg, 12.7 mmol) was washed 3x with hexanes. Anhyd THF was added and the suspension cooled to 0 C. A solution of <strong>[104436-60-4]4-(bromomethyl)-3-methoxybenzonitrile</strong> (1.1 g, 4.88 mmol) was added followed by dropwise addition of di-tert-butyl-iminodicarboxylate (1.38 g, 6.36 mmol) in THF. Reaction mixture was stirred for 16 h at ambient temperature then quenched with H2O. THF was removed in vacuo and the aqueous layer filtered through a fritted funnel. The crude product was recrystallized with hot EtOAc to furnish tert-butyl (tert-butoxycarbonyl)(4-cyano-2-methoxybenzyl)carbamate as a white crystalline solid (1.11 g, 63% yield). |
[ 274693-55-9 ]
2-(((3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol
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