ethyl 3-chloropropanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reaction mixture of 1.54 g (10 mmol) of 2-amino-4-nitrophenol, 1.36 g (10 mmol) of ethyl 3-chloropropionate and 20 g polyphosphoric acid is stirred for 2 hours at 170° C. Then the mixture is neutralized by the addition of saturated sodium hydrogen carbonate solution at ambient temperature. The aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (20:1)). Yield: 0.3 g (15.8% of theory); C9H6N2O3 (M=190.16); calc.: molecular ion peak (M+H)+: 191; found: molecular ion peak (M+H)+: 191; Rf value: 0.8 (silica gel, dichloromethane/ethanol (20:1)). The aqueous phase is extracted with dichloromethane The organic phase is dried over sodium sulfate The purification

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 60% sodium hydride (15 g) in dimethylformamide (30 ml) was added a N,N-dimethylformamide solution of 5-benzyloxyindole (5.0 g) at 0° C. After 15 minutes a solution of ethyl-3-chloropropionate (3.1 ml) in N,N-dimethylformamide was added dropwise and the reaction mixture stirred for a further 5 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 15%-ethyl acetate in n-hexanes to yield the title product (6.81 g). extracted with ethyl acetate The organic layer was washed with water dried over magnesium sulfate concentrated in vacuo The residue was chromatographed on silica gel eluting with 15%-ethyl acetate in n-hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 60% sodium hydride (15 g) in dimethylformamide (30 ml) was added a N,N-dimethylformamide solution of 5-benzyloxyindole (5.0 g) at 0° C. After 15 minutes a solution of ethyl-3-chloropropionate (3.1 ml) in N,N-dimethylformamide was added dropwise and the reaction mixture stirred for a further 5 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 15%-ethyl acetate in n-hexanes to yield the title product (6.81 g). extracted with ethyl acetate The organic layer was washed with water dried over magnesium sulfate concentrated in vacuo The residue was chromatographed on silica gel eluting with 15%-ethyl acetate in n-hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This material is prepared according to the procedure for Preparation 6 wherein Hagemann's ester (ethyl 2-methyl-4-oxocyclohex-2-enyl-1-carboxylate) is substituted for carvone and ethyl 3-chloropropionate is substituted for ethyl vinyl ketone. This material is prepared

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This material is prepared according to the procedure for Preparation 6 wherein Hagemann's ester (ethyl 2-methyl-4-oxocyclohex-2-enyl-1-carboxylate) is substituted for carvone and ethyl 3-chloropropionate is substituted for ethyl vinyl ketone. This material is prepared

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 33b was prepared by the same procedure as described for the preparation of 6a and 33a using 4b (260 mg, 0.84 mm), ethyl 3-chloropropionate (138 mg, 1.0 mm), DIEA (53 mg, 0.07 ml, 0.41 mm), and DMF (4 ml). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH), a glassy sticky solid was obtained: yield 153 mg (44%), MS: m/z 409 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.10 (bs, 2H, 6-NH2), 5.71 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.32 (bd, 1H, OH-2′, J2′-2′OH=5.0 Hz), 5.16 (bd, 1H, OH-3′, J3′-3′OH=5.1 Hz), 5.12 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=5.7 Hz, J2′-2′OH=5.0 Hz), 4.14 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.1 Hz, J3′-3′OH=5.1 Hz), 4.01 (q, 2H, CH3—CH2), 3.91-3.98 (m, 1H, H-4′), 2.87 (q, 2H, CH2 of 8-Et), 2.71-2.79 (m, 1H, 5′-CH2), 2.51-2.65 (m, 3H, 5′-CH2, CO—CH2), 2.38 (t, 2H, NCH3—CH2), 2.16 (bs, 3H, N—CH3), 1.30 (t, 31-1, CH3 of 8-Et), 1.15 (t, 3H, OCH2—CH3). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH) a glassy sticky solid was obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 33b was prepared by the same procedure as described for the preparation of 6a and 33a using 4b (260 mg, 0.84 mm), ethyl 3-chloropropionate (138 mg, 1.0 mm), DIEA (53 mg, 0.07 ml, 0.41 mm), and DMF (4 ml). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH), a glassy sticky solid was obtained: yield 153 mg (44%), MS: m/z 409 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.10 (bs, 2H, 6-NH2), 5.71 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.32 (bd, 1H, OH-2′, J2′-2′OH=5.0 Hz), 5.16 (bd, 1H, OH-3′, J3′-3′OH=5.1 Hz), 5.12 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=5.7 Hz, J2′-2′OH=5.0 Hz), 4.14 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.1 Hz, J3′-3′OH=5.1 Hz), 4.01 (q, 2H, CH3—CH2), 3.91-3.98 (m, 1H, H-4′), 2.87 (q, 2H, CH2 of 8-Et), 2.71-2.79 (m, 1H, 5′-CH2), 2.51-2.65 (m, 3H, 5′-CH2, CO—CH2), 2.38 (t, 2H, NCH3—CH2), 2.16 (bs, 3H, N—CH3), 1.30 (t, 31-1, CH3 of 8-Et), 1.15 (t, 3H, OCH2—CH3). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH) a glassy sticky solid was obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 13b was prepared by the same procedure as described for the preparation of 13a using 4b (260 mg, 0.84 mmol), ethyl 3-chloropropionate (138 mg, 1.0 mmol), DIEA (53 mg, 0.07 mL, 0.41 mmol), and DMF (4 mL). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH), a glassy sticky solid was obtained: yield 153 mg (44%), MS: m/z 409 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.10 (bs, 2H, 6-NH2), 5.71 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.32 (bd, 1H, OH-2′, J2′-2′OH=5.0 Hz), 5.16 (bd, 1H, OH-3′, J3′-3′OH=5.1 Hz), 5.12 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=5.7 Hz, J2′-2′OH=5.0 Hz), 4.14 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.1 Hz, J3′-3′OH=5.1 Hz), 4.01 (q, 2H, OCH2CH3), 3.91-3.98 (m, 1H, H-4′), 2.87 (q, 2H, CH2 of 8-Et), 2.71-2.79 (m, 1H, 5′-CH2), 2.51-2.65 (m, 3H, 5′-CH2, CO—CH2), 2.38 (t, 2H, N(CH3)—CH2), 2.16 (bs, 3H, N—CH3), 1.30 (t, 3H, CH3 of 8-Et), 1.15 (t, 3H, OCH2CH3). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH) a glassy sticky solid was obtained

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4a (500 mg, 1.69 mmol), ethyl 3-chloropropionate (270 mg, 1.97 mmol), DIEA (109 mg, 0.14 mL, 0.84 mmol), and DMF (5 mL) was heated at 60° C. for 2 days. Starting material remained but since the solution was getting darker, heating was stopped. The reaction mixture was concentrated to dryness. The product was purified by column chromatography (7:1:0.1 chloroform:methanol:NH4OH) to give a sticky solid: yield 210 mg (31%); MS m/z 395 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.74 (d, 1H, H-1′, J1′,2′=5.6 Hz), 5.33 (bd, 1H, OH-2′), 5.16 (bd, 111, OH-3′), 5.12 (bdd, 1H, H-2′, J1′,2′=5.6 Hz, J2′,3′=5.5 Hz), 4.21 (bdd, 1H, H-3′, J2′,3′=5.5 Hz, J3′,4′=4.3 Hz), 4.01 (q, 2H, OCH2CH3), 3.91-4.00 (m, 1H, H-4′), 2.70-2.77 (m, 1H, 5′-CH2), 2.54-2.66 (m, 3H, 5′-CH2, CO—CH2), 2.53 (s, 3H, 8-CH3), 2.38 (t, 2H, N(CH3)—CH2), 2.16 (bs, 3H, N—CH3), 1.15 (t, 3H, OCH2CH3). heating The reaction mixture was concentrated to dryness The product was purified by column chromatography (7:1:0.1 chloroform:methanol:NH4OH) to give a sticky solid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[3-(1H-indol-5-yl)-propyl]-[1,8]naphthyridine (0.180 g, 0.627 mmol) in DMF (2 mL) was added sodium hydride (24.0 mg. 1.00 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. After cooling to 0° C., 3-chloro-propionic acid ethyl ester (85.0 mg, 0.63 mmol) was added and stirred overnight at room temperature. Ice water was added and the resulting mixture was extracted with methylene chloride. The combined organic layers were washed with water and brine, and dried over Na2SO4. Chromatography of the crude product on silica gel (methylene chloride/methanol, 95:5) gave the title product (0.11 g, 45% yield). 1H NMR (CDCl3) δ 9.08 (d, 1H), 8.13 (d, 1H), 8.08 (d, 1H), 7.30-7.50 (m, 4H), 7.10 (m, 2M), 6.40 (dd, 1H), 4.40 (t, 2H), 4.10 (m, 2H), 3.10 (t, 2H), 2.80 (m, 4H), 2.25 (m, 2H), 1.20 (q, 3H). After cooling to 0° C. stirred overnight at room temperature the resulting mixture was extracted with methylene chloride The combined organic layers were washed with water and brine dried over Na2SO4

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclohexylamine (0.86 g, 8.7 mmol) and 3-chloro-propionic acid ethyl ester (1.18 g, 8.67 mmol) were combined neat and K2CO3 (1.2 g, 8.7 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 5 mg) was added. The mixture was heated at 80° C. overnight. The resulting mixture was then partitioned between water and dichloromethane. The organic layer was dried (MgSO4) and concentrated to afford 1.25 g (72%) of the title compound. The resulting mixture was then partitioned between water and dichloromethane The organic layer was dried (MgSO4) concentrated