(S)-(+)-2-甲基丁酸

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 16.3 g of anhydrous zinc chloride was dissolved in 10.3 g of S-(+)-2-methylbutanoic acid by heating to 110° C. 13.2 g of resorcinol was added to the mixture and then the temperature of the admixture was raised to 150° C. over a period of 30 minutes under stirring. The reaction mixture was then cooled to the room temperature, and a mixture composed of 25 ml of hydrochloric acid and 25 ml of water was added thereto. The reaction mixture was then subjected to extraction for three times, each by using 50 ml of ethyl ether. The extracts were joined together and rinsed with an aquesous solution of NaHCO3 for three times, and then rinsed with water for three times. Anhydrous Na2SO4 was added to the rinsed extract to dry the ethyl ether extract. Ethyl ether was removed to obtain a liquid reaction product which was refined through silica gel column chromatography while using chloroform as the eluent. As a result, 6.2 g of 3-hydroxy-4 -(1-oxo-2-methylbutyl)phenol was obtained. the temperature of the admixture was raised to 150° C. over a period of 30 minutes The reaction mixture was then cooled to the room temperature was added The reaction mixture was then subjected to extraction for three times rinsed with an aquesous solution of NaHCO3 for three times rinsed with water for three times Anhydrous Na2SO4 was added to the rinsed extract to dry the ethyl ether extract Ethyl ether was removed to obtain a liquid reaction product which

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared as described in Example 1E, substituting (tetrahydrofuran-3-yl)methanamine for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and 4-aminobenzoic acid for (S)-2-methylbutanoic acid.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide (1 g, 1.805 mmol), (S)-2-methylbutanoic acid (0.221 g, 2.166 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.519 g, 2.71 mmol) were combined in in dimethylformamide (9.03 mL) at room temperature. 1-Hydroxybenzotriazole hydrate (0.415 g, 2.71 mmol) and diisopropylethylamine (0.946 ml, 5.42 mmol) were added and the reaction mixture was stirred overnight at room temperature. Water and dichloromethane were added and the organics were removed by pipet. Concentration and reverse phase chromatography gave (S)—N-(4-(1-(2-methylbutanoyl)azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=2.4 Hz, 1H), 8.48 (dd, J=4.7, 1.6 Hz, 1H), 8.41 (s, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.46-7.37 (m, 3H), 6.76 (d, J=8.9 Hz, 2H), 4.96 (dd, J=6.3, 3.4 Hz, 1H), 4.62-4.53 (m, 1H), 4.36 (d, J=15.9 Hz, 2H), 4.32-4.22 (m, 1H), 4.11-4.02 (m, 1H), 3.98-3.81 (m, 3H), 3.75 (dd, J=10.6, 3.9 Hz, 1H), 2.36-2.20 (m, 1H), 1.59-1.39 (m, 1H), 1.38-1.20 (m, 1H), 0.96 (dd, J=6.8, 3.9 Hz, 3H), 0.82 (q, J=7.2 Hz, 3H); MS (ESI(+)) m/e 409 (M+H)11. the organics were removed by pipet Concentration

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide (1 g, 1.805 mmol), (S)-2-methylbutanoic acid (0.221 g, 2.166 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.519 g, 2.71 mmol) were combined in in dimethylformamide (9.03 mL) at room temperature. 1-Hydroxybenzotriazole hydrate (0.415 g, 2.71 mmol) and diisopropylethylamine (0.946 ml, 5.42 mmol) were added and the reaction mixture was stirred overnight at room temperature. Water and dichloromethane were added and the organics were removed by pipet. Concentration and reverse phase chromatography gave (S)—N-(4-(1-(2-methylbutanoyl)azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=2.4 Hz, 1H), 8.48 (dd, J=4.7, 1.6 Hz, 1H), 8.41 (s, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.46-7.37 (m, 3H), 6.76 (d, J=8.9 Hz, 2H), 4.96 (dd, J=6.3, 3.4 Hz, 1H), 4.62-4.53 (m, 1H), 4.36 (d, J=15.9 Hz, 2H), 4.32-4.22 (m, 1H), 4.11-4.02 (m, 1H), 3.98-3.81 (m, 3H), 3.75 (dd, J=10.6, 3.9 Hz, 1H), 2.36-2.20 (m, 1H), 1.59-1.39 (m, 1H), 1.38-1.20 (m, 1H), 0.96 (dd, J=6.8, 3.9 Hz, 3H), 0.82 (q, J=7.2 Hz, 3H); MS (ESI(+)) m/e 409 (M+H)11. the organics were removed by pipet Concentration

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A method for making [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate (2), said method comprising (or consisting essentially of or consisting of) reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) or reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl lithium, and then methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3); reacting (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) with phosphorus oxychloride to form (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4); reacting (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4) with p-toluenesulfonic acid to form (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5); reacting (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5) with lithium aluminum hydride to form [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol [(R)-maconelliol] (6), and reacting [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol (6) with oxalyl chloride and (S)-2-methylbutanoic acid to form [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [(R)-maconelliyl (S)-2-methylbutanoate] (2).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A method for making [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate (2), said method comprising (or consisting essentially of or consisting of) reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) or reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl lithium, and then methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3); reacting (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) with phosphorus oxychloride to form (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4); reacting (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4) with p-toluenesulfonic acid to form (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5); reacting (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5) with lithium aluminum hydride to form [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol [(R)-maconelliol] (6), and reacting [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol (6) with oxalyl chloride and (S)-2-methylbutanoic acid to form [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [(R)-maconelliyl (S)-2-methylbutanoate] (2).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Esterification of (R)-(−)-lavandulol {(86% ee, [α]24D−9.6 (c 0.1, MeOH), prepared according to the method described by Cardillo et al. (Cardillo, G., et al., J. Org. Chem., 53: 2354-2356 (1988))} with (S)-(+)-2-methylbutanoic acid using the same procedures as compound 2a gave 75 mg (75% yield) of 1a as clear oil. Optical purity: 99% ee; [α]24D+5.0 (c 0.1, MeOH); 1H NMR (C6D6): δ 0.83 (3H, t, J=7.29 Hz), 1.08 (3H, d, J=7.0 Hz), 1.35 (1H, m), 1.50 (3H, s), 1.59 (3H, t, J=0.80 Hz), 1.61 (3H, d, J=1.13 Hz), 1.68 (1H, m), 2.06 (2H, m), 2.28 (1H, sextet, 6.85 Hz), 2.42 (1H, quintet, 7.00 Hz), 4.12 (2H, m), 4.79 (1H, m), 4.83 (1H, quintet, J=1.51 Hz), 5.11 (1H, t, quintet, J=7.19, 1.52 Hz); 13C NMR (C6D6): δ 175.88, 146.31, 132.70, 122.00, 112.50, 66.68, 45.41, 41.22, 29.13, 26.00, 25.80, 20.00, 17.80, 16.50, 11.52; EI-MS m/z (%): 238 [M]+ (1), 169 (2), 156 (3), 136 (15), 121 (39), 107 (11), 93 (100), 85 (23), 80 (25), 69 (75), 57 (59), 41 (40); HREIMS: obsd. 238.1934, calcd. for C15H16O2 (M+): 238.1933.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2.2 mL (20.1 mmol) of (S)-(+)-2-methylbutanoic acid {Aldrich, 99% ee, [α]24D+24.0 (c 0.1, MeOH)} in 15 mL of benzene was treated with 2.2 mL (25.2 mmol) of oxalyl chloride and 10 μl of DMF. After 1.5 h at room temperature, the benzene and excess oxalyl chloride were removed followed by the addition of another 15 mL portion of benzene. The acid chloride residue was dissolved in 15 mL of benzene, and then a solution of 1.65 g (10.7 mmol) of 6a and 18 ml (22.2 mmol) of pyridine in 15 mL of benzene were added dropwise. After stirring at room temperature for 1 h, the solvent was removed. The residue was treated with 20 mL of water, and extracted with ether. The organic solution was washed with water, 1N hydrochloric acid, 1N aqueous sodium bicarbonate, and brine, dried over sodium sulfate, and concentrated to afford yellow oil. Pure 2a (2.0 g, 79% yield) was obtained by chromatography (silica gel, 2% of ethyl acetate in hexanes). Optical purity: 99% ee; [α]24D−0.79 (c 2.03, MeOH); 1H NMR (C6D6): δ 0.84 (3H, t, J=7.19 Hz), 1.08 (3H, d, J=6.82 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.36 (1H, m), 1.40 (3H, bs), 1.51 (3H, t, J=1.89 Hz), 1.67 (2H, m), 2.05 (1H, m), 2.17 (1H, m), 2.27 (1H, m), 2.48 (1H, ddt, J=14.75, 8.79, 1.52 Hz), 4.15 (2H, d, J=7.57 Hz); 13C NMR (C6D6): δ 175.76, 137.48, 122.55, 65.30, 44.43, 41.39, 39.71, 28.62, 27.79, 27.13, 21.17, 19.60, 18.64, 16.85, 11.80; EI-MS m/z (%): 238 [M]+ (2), 136 (29), 121 (100), 107 (12), 93 (20), 81 (26), 67 (5), 57 (16), 41 (10); HREIMS: obsd. 238.1929, calcd. for C15H26O2 (M+): 238.1933. the benzene and excess oxalyl chloride were removed followed by the addition of another 15 mL portion of benzene The acid chloride residue was dissolved in 15 mL of benzene the solvent was removed The residue was treated with 20 mL of water extracted with ether The organic solution was washed with water, 1N hydrochloric acid, 1N aqueous sodium bicarbonate, and brine dried over sodium sulfate concentrated to afford yellow oil

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2.2 mL (20.1 mmol) of (S)-(+)-2-methylbutanoic acid {Aldrich, 99% ee, [α]24D+24.0 (c 0.1, MeOH)} in 15 mL of benzene was treated with 2.2 mL (25.2 mmol) of oxalyl chloride and 10 μl of DMF. After 1.5 h at room temperature, the benzene and excess oxalyl chloride were removed followed by the addition of another 15 mL portion of benzene. The acid chloride residue was dissolved in 15 mL of benzene, and then a solution of 1.65 g (10.7 mmol) of 6a and 18 ml (22.2 mmol) of pyridine in 15 mL of benzene were added dropwise. After stirring at room temperature for 1 h, the solvent was removed. The residue was treated with 20 mL of water, and extracted with ether. The organic solution was washed with water, 1N hydrochloric acid, 1N aqueous sodium bicarbonate, and brine, dried over sodium sulfate, and concentrated to afford yellow oil. Pure 2a (2.0 g, 79% yield) was obtained by chromatography (silica gel, 2% of ethyl acetate in hexanes). Optical purity: 99% ee; [α]24D−0.79 (c 2.03, MeOH); 1H NMR (C6D6): δ 0.84 (3H, t, J=7.19 Hz), 1.08 (3H, d, J=6.82 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.36 (1H, m), 1.40 (3H, bs), 1.51 (3H, t, J=1.89 Hz), 1.67 (2H, m), 2.05 (1H, m), 2.17 (1H, m), 2.27 (1H, m), 2.48 (1H, ddt, J=14.75, 8.79, 1.52 Hz), 4.15 (2H, d, J=7.57 Hz); 13C NMR (C6D6): δ 175.76, 137.48, 122.55, 65.30, 44.43, 41.39, 39.71, 28.62, 27.79, 27.13, 21.17, 19.60, 18.64, 16.85, 11.80; EI-MS m/z (%): 238 [M]+ (2), 136 (29), 121 (100), 107 (12), 93 (20), 81 (26), 67 (5), 57 (16), 41 (10); HREIMS: obsd. 238.1929, calcd. for C15H26O2 (M+): 238.1933. the benzene and excess oxalyl chloride were removed followed by the addition of another 15 mL portion of benzene The acid chloride residue was dissolved in 15 mL of benzene the solvent was removed The residue was treated with 20 mL of water extracted with ether The organic solution was washed with water, 1N hydrochloric acid, 1N aqueous sodium bicarbonate, and brine dried over sodium sulfate concentrated to afford yellow oil

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 16.3 g of anhydrous zinc chloride was dissolved in 10.3 g of S-(+)-2-methylbutanoic acid by heating to 110° C. 13.2 g of resorcinol was added to the mixture and then the temperature of the admixture was raised to 150° C. over a period of 30 minutes under stirring. The reaction mixture was then cooled to the room temperature, and a mixture composed of 25 ml of hydrochloric acid and 25 ml of water was added thereto. The reaction mixture was then subjected to extraction for three times, each by using 50 ml of ethyl ether. The extracts were joined together and rinsed with an aquesous solution of NaHCO3 for three times, and then rinsed with water for three times. Anhydrous Na2SO4 was added to the rinsed extract to dry the ethyl ether extract. Ethyl ether was removed to obtain a liquid reaction product which was refined through silica gel column chromatography while using chloroform as the eluent. As a result, 6.2 g of 3-hydroxy-4 -(1-oxo-2-methylbutyl)phenol was obtained. the temperature of the admixture was raised to 150° C. over a period of 30 minutes The reaction mixture was then cooled to the room temperature was added The reaction mixture was then subjected to extraction for three times rinsed with an aquesous solution of NaHCO3 for three times rinsed with water for three times Anhydrous Na2SO4 was added to the rinsed extract to dry the ethyl ether extract Ethyl ether was removed to obtain a liquid reaction product which

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 9 g (88 mmol) of the (S)-(+)-2-methylbutyric acid obtained by the method of the above Referential Example 1 was mixed with 20.24 g of 99.5% by vol. ethanol containing 0.4 g of conc. sulfuric acid and heated under reflux for 4 hours. After the completion of the reaction, the mixture was cooled to room temperature and poured into 150 ml of a saturated aqueous solution of sodium chloride. The oily layer was extracted with n-hexane and thus separated from the aqueous layer. Then it was further washed with a saturated aqueous solution of sodium chloride twice and dehydrated over calcium chloride. After distilling off the n-hexane under atmospheric pressure, the temperature was further elevated. Thus 9.3 g of (S)-(+)-ethyl 2-methylbutyrate (boiling point: 135° C./760 mmHg) was obtained (yield: 81.3%). heated under reflux for 4 hours After the completion of the reaction The oily layer was extracted with n-hexane thus separated from the aqueous layer Then it was further washed with a saturated aqueous solution of sodium chloride twice After distilling off the n-hexane under atmospheric pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared as described in Example 1E, substituting (tetrahydrofuran-3-yl)methanamine for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and 4-aminobenzoic acid for (S)-2-methylbutanoic acid.