6-methoxy-6-oxohexanoic acid

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

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

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

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

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of adipic acid monomethyl ester (4.8 g, 30 mmol) in DMF (30 mL), was added CDI (4.9 g, 30 mmol), and the resulting mixture was stirred under N2 at 40° C. for 1 hour. t-Butanol (4.4 g, 60 mmol) and DBU (4.6 g, 30 mmol) were added, and stirring proceeded at 40° C. for 70 hours. The mixture was poured into ether (100 mL), and this mixture was washed with 10% aq. HOAc (100 mL), 10% aq. K2CO3 (100 mL), and water (3×100 mL), dried (MgSO4), and evaporated, providing 5.1 g of hexanedioic acid tert-butyl ester methyl ester, in 78% yield; 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.59-1.67 (m, 4H), 2.21-2.26 (m, 2H), 3.67 (s, 3H). stirring proceeded at 40° C. for 70 hours this mixture was washed with 10% aq. HOAc (100 mL), 10% aq. K2CO3 (100 mL), and water (3×100 mL) dried (MgSO4) evaporated

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

Procedure: Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.0362 g, 41.92 mmol), 4-(dimethylamino)pryidine (1.0525 g, 8.62 mmol) and adipic acid monomethyl ester (6.71 g, 41.90 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(5-chloro-2-methoxy-phenyl)-ethanone hydrochloride (10.99 g, 46.55 mmol) and triethylamine (9.42 g, 93.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 21 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter off the drying agent and concentrate in vacuo to afford 9.39 g of the crude titled product: mass spectrum: m/z=342.1 (M+H). to stir at ambient temperature for 21 hours Dilute wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×) Dry the organic layer with MgSO4 Filter off the drying agent concentrate in vacuo

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

Procedure: Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.57 g, 18.62 mmol), 4-(dimethylamino)pryidine (463.8 mg, 3.79 mmol) and adipic acid monomethyl ester (2.97 g, 18.55 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(2-methoxy-phenyl)-ethanone hydrochloride (3.74 g, 18.55 mmol) and triethylamine (3.75 g, 37.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 22 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter the drying agent and concentrate in vacuo to afford 4.57 g of the titled product (80%): mass spectrum: m/z=308.1 (M+H). to stir at ambient temperature for 22 hours Dilute wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×) Dry the organic layer with MgSO4 Filter the drying agent concentrate in vacuo

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

Procedure: Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.57 g, 18.62 mmol), 4-(dimethylamino)pryidine (463.8 mg, 3.79 mmol) and adipic acid monomethyl ester (2.97 g, 18.55 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(2-methoxy-phenyl)-ethanone hydrochloride (3.74 g, 18.55 mmol) and triethylamine (3.75 g, 37.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 22 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter the drying agent and concentrate in vacuo to afford 4.57 g of the titled product (80%): mass spectrum: m/z=308.1 (M+H). to stir at ambient temperature for 22 hours Dilute wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×) Dry the organic layer with MgSO4 Filter the drying agent concentrate in vacuo

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

Procedure: To a stirred mixture of adipic acid monomethyl ester (9.27 g, 57.9 mmol, 1.50 equiv.) in THF (50 mL) was added N,N′-carbonyldiimidazole (9.39 g, 57.9 mmol, 1.50 equiv.) and the mixture was stirred at room temperature. After stirring for 30 min, the reaction mixture was cooled to 0° C. followed by dropwise addition of 4-bromo-2-(carboxymethyl)benzoic acid (10.0 g, 38.6 mmol) in THF (25 mL). The reaction was stirred gradually from 0° C. to room temperature for 48 h. Upon completion of the reaction, 0.5 N HCl (25 mL) solution was added and extracted with EtOAc (2×25 mL). The organic layer was washed with aqueous sat. NaHCO3, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-15% EtOAc/hexanes to give 1.5 g of methyl 5-(6-bromo-1-oxo-1H-isochromen-3-yl)pentanoate as a white solid. After stirring for 30 min the reaction mixture was cooled to 0° C. The reaction was stirred gradually from 0° C. to room temperature for 48 h was added extracted with EtOAc (2×25 mL) The organic layer was washed with aqueous sat. NaHCO3 dried over Na2SO4 filtered evaporated to dryness The residue was purified by column chromatography on silica gel eluting with 0-15% EtOAc/hexanes

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

Procedure: Step 1, Compound 4: Adipic acid monomethyl ester is treated with one molar equivalent of DCC, DMAP and N-hydroxysuccinimide in DMF for 30 min. To this a molar equivalent of the compound obtained from Step 3a (Example 1) is added and stirred at ambient temperature for 8 h. Dicylcohexylurea formed during the course of the reaction is filtered off and the product is extracted into ethyl acetate, washed with sodium bicarbonate solution followed by standard workup. The methyl ester thus obtained is treated with LiOH in THF/water to obtain compound 4.

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

Procedure: Step 1, Compound 4: Adipic acid monomethyl ester is treated with one molar equivalent of DCC, DMAP and N-hydroxysuccinimide in DMF for 30 min. To this a molar equivalent of the compound obtained from Step 3a (Example 1) is added and stirred at ambient temperature for 8 h. Dicylcohexylurea formed during the course of the reaction is filtered off and the product is extracted into ethyl acetate, washed with sodium bicarbonate solution followed by standard workup. The methyl ester thus obtained is treated with LiOH in THF/water to obtain compound 4.

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

Procedure: 5-Carbomethoxypentanoic acid (12), wherein alk is methyl, was reacted with thionyl chloride and then N-bromosuccinimide (NBS) followed by base hydrolysis to give 2-bromo-5-carbomethoxypentanoic acid (13). Compound (13) was reacted with methyl-3-mercaptopropionate (m=1, R1 '=H and R2 '=OCH3) to yield 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanoic acid (14). Compound (14) reacted first with diborane and then with dimethylsulfoxide and trifluoroacetic anhydride to afford 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanal (15). Compound (15) was reacted under Wittig conditions with tridecyltriphenylphosphonium ylid to yield methyl-5-[(2-carbomethoxyethyl)thio]-6(Z)-nonadecenoate (16) which was saponified to afford a compound of the formula (IV) wherein m is 1, R1 is hydrogen, and R2 is hydroxyl.