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With hydrogen;5%-palladium/activated carbon; In ethyl acetate;Product distribution / selectivity;
Step 2; (3S, lR)-(-)-3-N-BOC-Aminocyclopentane-l-carboxylic acid; The Step 1 intermediate (8.0 g, 35.2 mmol) in ethyl acetate (100 ml) was reduced with 5 % Pd-C (1.0 g) as described in Intermediate 2, Method A to give 8. 01 g of the product as a white solid, which was identical in all respects with the product obtained from Method A.
With hydrogen;5%-palladium/activated carbon; In methanol; at 20℃; under 2068.65 Torr; for 2h;Product distribution / selectivity;
Step 1 intermediate (8.0 g, 35.2 mmol) in ethyl acetate (100 ml) was reduced with 5 % Pd/C (1.0 g) as described in Intermediate 2, Method A to give 8.01 g of the product as a white solid, which was identical in all respects with the product obtained from Method A.
Example 3 Preparation of (1S-cis)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-2-cyclopentene-1-carboxylic acid (5) To a suspension of (1S-cis)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-2-cyclopentene-1-carboxylic acid (4), compound with (R)-(+)-1-phenylethylamine (34.84 g) in toluene (100 ml) and water (100 ml) was added dropwise, over 5 min, phosphoric acid (11.53 g). Ethyl acetate (200 ml) was added and a clear biphasic mixture obtained. The phases were separated and the organic layer concentrated in vacuo at approximately 50 C. to about one quarter of the original volume. The solution was cooled to ambient temperature and the resulting solid filtered off, washed with toluene (50 ml) followed by 2,2,4-trimethylpentane (50 ml) then dried in vacuo at 35 C. The yield of (1S-cis)-4-[[(1,1-dimethyl ethoxy)carbonyl]amino]-2-cyclopentene-1-carboxylic acid was 21.01 g, 92% of theory, Mp=153-5 C.
9
(1SR,4RS)-4-[(tert-butyloxycarbonyl)amino]cyclopent-2-enecarboxylic acid[ No CAS ]
[ 151907-79-8 ]
Yield
Reaction Conditions
Operation in experiment
With (R)-1-phenyl-ethyl-amine; In ethanol; isopropyl alcohol;Resolution of racemate;
This intermediate was prepared by the optical resolution of Intermediate 1 using (R)-(+)-l- phenylethylamine in a mixture of isopropanol and ethanol; [CI]D - 48.0 (c = 1.0, MeOH).
To a solution of(1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (5.0 g, 46 mmol) in water (30.5 mL) was added aqueous HCl (2 M, 23.0 mL, 46.0 mmol). After heating at about 80 C. for about 2 h, the reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The solid was dried in a vacuum oven at about 70 C. and used without further purification. To a solution of (1S,4R)-4-aminocyclopent-2-enecarboxylic acid hydrochloride (9.20 g, 45.8 mmol) in 1,4-dioxane (15 mL) and water (18.3 mL) at about 0 C. was added DIEA (32.0 mL, 183 mmol). After stirring for about 5 min, a solution of di-tert-butyl dicarbonate (11.7 mL, 50.4 mmol) in 1,4-dioxane (5 mL) was added. The reaction mixture was warmed to ambient temperature and stirred for about 18 h. Solvent was removed under reduced pressure and the crude oil was dried in a vacuum oven at about 65 C. for about 3 h. The crude product was purified by silica gel chromatography eluting with a gradient of 80-100% EtOAc/heptane to afford (1S,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-enecarboxylic acid (5.2 g, 50% over 2 steps): LC/MS (Table 2, Method a) Rt=1.81 min; MS m/z: 226 (M-H)-.
To <strong>[151907-79-8](1S,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-enecarboxylic acid</strong> (2.70 g, 11.8 mmol, Preparation No.17) in DCM (170 mL) was slowly added diethylzinc (1.1 M in toluene, 54.0 mL, 59.4 mmol). The mixture was stirred for about 10 min at ambient temperature, cooled to about 0 C., and treated drop-wise with a solution of chloroiodomethane (4.30 mL, 59.4 mmol) in DCM (24 mL). The reaction mixture was allowed to warm to room temperature and was stirred for about 18 h. Saturated aqueous NH4Cl (10 mL) was added and the mixture was stirred for about 20 min. The layers were separated and the aqueous layer was further extracted with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane to afford (1R,2S,4R,5S)-methyl 4-(ethoxycarbonylamino)bicyclo[3.1.0]hexane-2-carboxylate (0.95 g, 35%): LC/MS (Table 2, Method a) Rt=1.88 min; MS m/z: 228 (M+H)+.
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