CYCLOBUTYL-ACETICACID

Step 2: A solution of 53_2 (15.00 g, 157.66 mmol, 1.00 eq) in HC1 (6 M, 150 mL, 5.71 eq) was stirred at 120°C for 16 hours. The mixture was diluted with water (500 mL) and extracted with EtOAc (200mL*2). The combined organic layers were washed with water (400 mL). The organic layer was dried and concentrated to give 53_3 (16.00 g, 140.18 mmol, 88.9percent yield) as a colorless liquid. NMR (CDC13, 400 MHz) δ 2.69-2.68 (m, 1 H), 2.47-2.45 (m, 2 H), 2.17-2.15 (m, 2H), 1.89-1.87 (m, 2H), 1.75-1.70 (m, 2H).Blank magnesium chips (370 mg, 15.2 mmol) were covered with abs. THF (ca. 0.5 mL). Two drops283 (bromomethyl)cyclobutane (from 2.09 g, 14.0 mmol) were added. As the reaction started, the rest of284 the bromide was solved in abs. THF (4 mL) and the solution was added dropwise with stirring. After285 addition, the mixture was allowed to stand for 18 h at room temperature. The mixture was diluted286 abs. THF (10 mL), warmed near to reflux und slowly poured on crushed dry ice (100 mL). After287 warming up to about 0 °C and addition of EtOAc (10 mL), the mixture was washed with 2 M HCl (10288 mL) and saturated with NaCl. The organic layer was separated and the aqueous layer was extracted289 with EtOAc (10 mL), the combined organic layers were dried over Na2SO4 and concentrated under290 reduced pressure resulting in 1.02 g cyclobutylacetic acid (7a) (64 percent).To a 0 C solution of 2-To a mixture of 2-(4-chloro-3 -fluoro-phenoxy)-N-[ 1 -(hydrazinecarbonyl)-3 - bicyclo[1.1.ljpentanyljacetamide (100 mg, 0.31 mmol) and 2-At room temperature, to the containing N-(3-((3, 8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5-chloro-2-methoxyphenyl)-6-methylnicotinamide (100 mg, 0 . 26 mmol) in dichloromethane solution, adding N, N - diisopropyl ethylamine (100.6 mg, 0 . 78 mmol), added to clarify the solution change At room temperature, to the containing 3-(5-chloro-2-methyl-3-nitrobenzyl)-3, 8-diazabicyclo[3.2.1]octane (synthetic method according to embodiment 1) (1.18 g, 4.0 mmol) in dichloromethane solution, adding N, N - diisopropyl ethylamine (1.55 g, 12.0 mmol), added to clarify the solution after Compound 10 (32 mg, 0.28 mmol, 1.0 eq), Soluble in DMF (2mL), add HATU at room temperature(158 mg, 0.42 mmol, 1.5 eq), Reaction for 10 minutes, Then add compound 9 (100 mg, 0.28 mmol, 1.0 eq)And DIEA (72 mg, 0.55 mmol, 2.0 eq), The reaction was carried out for 16 hours at room temperature.LCMS showed that the starting material was reacted and product was formed.Ethyl acetate (10 mL) and water (10 mL) were added to the mixture.The organic phase was separated and washed three times with saturated brine (30 mL).Dry over anhydrous sodium sulfate, filter, Concentrated to a crude product. Prep-HPLC preparation, The white solid compound EXP 2 (18 mg, yield: 14percent) was obtained.(Preparation of mobile phase conditions: 0.03percent NH3.H2O/H2O).Compound 5 (400 mg, 1.11 mmol, 1 eq), Add to a 100ml single-mouth bottle and add DCM (10ml).Cyclobutyric acid (127 mg, 1.11 mmol, 1 eq), EDC·HCl (255 mg, 1.33 mmol, 1.2 eq)DMAP (13 mg, 0.11 mmol, 0.1 eq), TEA (167 mg, 1.65 mmol, 1 eq), stirred at 17 ° C for 16 h.TLC detects the end of the reaction and spins the reaction. Column chromatography (DCM: MeOH = 70:1) gave pale pink solid(125 mg, 31percent yield in two steps).Blank magnesium chips (370 mg, 15.2 mmol) were covered with abs. THF (ca. 0.5 mL). Two drops283 (bromomethyl)cyclobutane (from 2.09 g, 14.0 mmol) were added. As the reaction started, the rest of284 the bromide was solved in abs. THF (4 mL) and the solution was added dropwise with stirring. After285 addition, the mixture was allowed to stand for 18 h at room temperature. The mixture was diluted286 abs. THF (10 mL), warmed near to reflux und slowly poured on crushed dry ice (100 mL). After287 warming up to about 0 °C and addition of EtOAc (10 mL), the mixture was washed with 2 M HCl (10288 mL) and saturated with NaCl. The organic layer was separated and the aqueous layer was extracted289 with EtOAc (10 mL), the combined organic layers were dried over Na2SO4 and concentrated under290 reduced pressure resulting in 1.02 g General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite® (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Molecular Weight:114.14
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:114.068079557
Monoisotopic Mass:114.068079557
Topological Polar Surface Area:37.3
Heavy Atom Count:8
Complexity:94.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes