* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage 1: Methyl 1-aminocyclobutanecarboxylate Concentrated H2SO4 (10 ml) was added at 0° C. to a solution of 1-(tert-butoxy-carbonylamino)-cyclobutane-1-carboxylic acid (9.29 mmol, 1 equiv.) in MeOH (30 ml), and the reaction was refluxed for 2 hours at 0° C. The solvent was removed under reduced pressure. The residue was taken up in distilled water, adjusted to pH 8-9 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (2*200 ml). The combined organic phases were washed with distilled water (2*150 ml) and saturated NaCl solution (2*50 ml) and dried over sodium sulfate. The solvent was concentrated under reduced pressure to yield the desired product in the form of a white solid. Yield: 75percent
With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃; for 12 h;
To a stirred solution of 1-aminocyclobutane-1-carboxylic acid (2 g, 17 mmol) in 1,4- dioxane: H2O (20: 20 mL), were added NaHCO3 (4.4 g, 57 mmol) and (Boc)2O (4.5 g, 20.4 mmol) at 0°C and stirred the reaction mixture for about 12 hours at room temperature. After complete conversion of starting material, the reaction mixture was washed with EtOAc (30 mL) to remove the impurities, then aqueous layer was acidified with 1N HCl (PH =2-3) and extracted with CH2Cl2 (2x40 mL). The combined organic extracts were washed with water, brine, dried over Na2S04, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography by using 35 percent EtOAc: n-Hexane as an eluent to afford the desired product (2.8 g, yield: 75percent) as an off white solid. 1H MR (300 MHz, CD3OD): δ 2.62-2.53 (m, 2H), 2.25-2.15 (m, 2H), 2.05-1.97 (m, 2H), 1.42 (s, 9H); ES Mass: 238.04 [M+Na]+.
62.41%
With sodium hydroxide In 1,4-dioxane at 0 - 20℃;
To a stirred solution of 1-aminocyclobutane-l-carboxylic acid (30 g, 139.53 mmol, 1.0 eq) in 1,4-dioxane (300 ml) at 0 °C was added 2N NaOH solution (300 ml) followed by (Boc)20 (45.62 g, 209.30 mmol, 1.5 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (50 ml), cooled to 0 °C, pH adjusted to 5 with IN HC1 and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room temperature for about 30 minutes, the obtained solid was filtered and dried under vacuum to give the desired product (35.0 g, yield: 62.41percent) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 12.19 (brs, 1H), 7.70-7.16 (m, 1H), 2.45-2.36 (m, 2H), 2.12-2.03 (m, 2H), 1.86-1.78 (m, 2H), 1.36 (brs, 9H); ESI-MS: m/z 238.13 (M+Na)+.
19%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24 h;
Stage 1. 1 -[(tert-Butoxycarbonyl)am ino]cyclobutanecarboxyl ic acid To a solution of 1-amino-1-cyclobutane carboxylic acid (2.92 g, 25.4 mmol), NaOH (3.04 g, 76.2 mmol), THF (100 mL) and water (100 mL) at RT was added d-tert-buty dcarbonate (8.30 g, 38.1 rnmoD and the reaction was strred for 24 hrs, The reacUon mixture was acdfled to pH5 usng 2M HC and the mixture was extracted w[th EtOAc (2x 200 mL). The cornbned organcs were dried over MgSO4, ifitered and concentrated in vacuo to give the tWe compound as a whfte sod (1.05 g, 19percent). LCMS: m/z 238 [M+Hj.
1.09 g
With sodium hydroxide In methanol; water at 0 - 20℃; for 12 h;
Intermediate 68 1-([(1,1-dimethylethyl)oxy]carbonyl}amino)cyclobutanecarboxylic acid [0684] [0685] To a solution of 1-aminocyclobutanecarboxylic acid (626 mg, 5.44 mmol) in 5.6 ml of 1 M aqueous sodium hydroxide and 4 ml of methanol was added Boc-anhydride (1.425 g, 6.53 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 12 hours. After most of the methanol was evaporated, the solution was acidified to pH 2 with 1 M HCl and extracted with ethyl acetate. The organic extracts were combined and washed with brine. Evaporation of the solvent afforded the title compound (1.09 g). [0686] 1H NMR (400 MHz, DMSO-d6): δ ppm 12.21 (1H, s), 7.44 (1H, s), 2.29-2.47 (2H, m), 2.09 (2H, q), 1.74-1.94 (2H, m), 1.36 (9H, s); UPLC: 0.56 min, 216 [M+H]+
Reference：
[1] Patent: WO2017/21922, 2017, A1, . Location in patent: Page/Page column 26
[2] Journal of the American Chemical Society, 1997, vol. 119, # 49, p. 11807 - 11816
[3] Patent: WO2016/178092, 2016, A2, . Location in patent: Page/Page column 51; 52
[4] Patent: WO2014/1802, 2014, A1, . Location in patent: Page/Page column 59; 60
[5] Patent: WO2011/69951, 2011, A1, . Location in patent: Page/Page column 79
[6] Patent: WO2011/154677, 2011, A1, . Location in patent: Page/Page column 72
[7] Patent: WO2012/76877, 2012, A1, . Location in patent: Page/Page column 93
[8] Patent: US2013/267510, 2013, A1, . Location in patent: Paragraph 0684-0686
Reference Example F-2 1-tert-Butoxycarbonylaminocyclobutanecarboxylic acid A 64.28 g (264 mmol) portion of ethyl 1-tert-butoxycarbonylaminocyclobutanecarboxylate was dissolved in 400 ml of methanol, mixed with 400 ml of 1N sodium hydroxide aqueous solution and then stirred overnight at room temperature. After evaporation of the solvent, the resulting residue was mixed with 20percent citric acid aqueous solution-chloroform. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to yield 55.29 g (97percent) of the title compound. 1 H-NMR (CDCl3) δ: 1.45 (9H, s), 2.02-2.08 (2H, m), 2.26 (2H, brs), 2.67 (2H, brs), 5.20 (1H, brs).
Reference：
[1] Patent: US5849757, 1998, A,
6
[ 89691-88-3 ]
[ 120728-10-1 ]
Reference：
[1] Journal of the American Chemical Society, 1997, vol. 119, # 49, p. 11807 - 11816
Step 4:; The diamine 28-4 (1.00 g, 5.0 mmol), N-Boc-1-aminocyclobutanecarboxylic acid (1.07 g, 5.0 mmol), HATU (2.20 g, 5.8 mmol) and Et3N (2.10 mL, 15.0 mmol) were dissolved in DMF (30 mL) and the mixture stirred for 2 days at RT. The reaction mixture was poured onto ice and the precipitated solid collected by filtration. The material was washed with water, dissolved in EtOAc and the extract washed with brine. The solution was then dried (Na2SO4) and concentrated under reduced pressure. The residue was dissolved in AcOH and heated to 80 C for 3 h. HPLC analysis indicated complete conversion to the desired benzimidazole derivative. AcOH was removed under reduced pressure, the residue taken up in EtOAc and the solution washed with aqueous NaHC03 and brine. After drying (MgSO4), removal of solvent gave compound 28-5 as an orange solid (563 mg) that was used directly in the next step.
ethyl 3-[1-(tert-butoxycarbonylamino)cyclobutyl]-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With citric acid; In tetrahydrofuran;
Separately, 55.29 g (0.26 mmol) of 1-tert-butoxycarbonylaminocyclobutanecarboxylic acid was dissolved in 450.0 ml of THF, mixed with 45.81 g (0.28 mmol) of 1,1'-carbonyldiimidazole and then stirred at room temperature for 1.5 hours. To this was added dropwise 450.0 ml of THF solution of the above magnesium salt in 30 minutes, followed by 2 days of stirring at room temperature. After evaporation of the solvent, the resulting residue was distributed between 10% citric acid aqueous solution and ethyl acetate. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent, the title compound was obtained quantitatively. 1 H-NMR (CDCl3) delta: 1.26-1.30 (2H, m), 1.43 (9H, s), 1.87-2.08 (4H, m), 2.66-2.70 (2H, m), 3.54 (2H, s), 4.20 (2H, q), 5.22 (1H, brs).
Reference Example F-2 1-tert-Butoxycarbonylaminocyclobutanecarboxylic acid A 64.28 g (264 mmol) portion of ethyl 1-tert-butoxycarbonylaminocyclobutanecarboxylate was dissolved in 400 ml of methanol, mixed with 400 ml of 1N sodium hydroxide aqueous solution and then stirred overnight at room temperature. After evaporation of the solvent, the resulting residue was mixed with 20% citric acid aqueous solution-chloroform. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to yield 55.29 g (97%) of the title compound. 1 H-NMR (CDCl3) delta: 1.45 (9H, s), 2.02-2.08 (2H, m), 2.26 (2H, brs), 2.67 (2H, brs), 5.20 (1H, brs).
Step 1; Methyl 4-amino-2,6-dimethoxybenzoate 11-1 (2.00 g, 9.5 mmol), prepared by themethod of Broadhurst et al. (J. Chem. Soc. 1977, 2502), was dissolved in DMSO (20ml_). N-Boc-1-aminocyclobutane-1-carboxylic acid (2.07 g, 9.6 mmol) was addedfollowed by triethylamine (4.18 ml_, 30 mmol, 3.2 equivalents) and TBTU (3.69 g, 11.5mmol, 1.2 equivalent). The mixture was stirred for 24 h at room temperature afterwhich it was added dropwise to a solution of AcOH (15 ml_) in water (150 ml). Thewhite precipitate 11-2 was collected by filtration, washed with water and dried invacuum (3.50 g, 71% yield): MS m/z 409.3 (MH*).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
By allowing 1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid to react with potassium carbonate and iodomethane in DMF at room temperature, methyl 1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylate was obtained.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; for 72h;Heating / reflux;
CDI (0.45 g, 2.8mmol) was added to a solution of l-(tert-butoxycarbonyl)- cyclobutane carboxylic acid (0.3 g, 1.4 mmol) and 2-(thiophene-2-carbonyl)hydrazine carboxylic acid (0.3 g, 2.1 mmol) in THF at room temperature. After the reaction mixture was refluxed for 3 days, it was concentrated under vacuum. The residue thus obtained was purified by silica gel column chromatography to give compound 1-18 (0.3 g, 63%). ESI-MS (M+H+) = 340.
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In tetrahydrofuran; for 16h;
Ammonium carbonate (0.5 g, 1.26 eq.) was added to a stirred solution of 1-(tert-butoxycarbonyl)cyclobutanecarboxylic acid (1.1 g, 1 eq.), pyridine (0.25 mL), and BOC2O (1.5 g, 1.3 eq.) in THF (8 mL). The mixture was stirred for 16 hours. After ethyl acetate was added, the solution was washed with water and 5% H2SO4, dried, and concentrated. The product thus obtained was triturated with ether to give I- 35 (1 g, 92%). ESI-MS (M+Na+) = 237.
-Boc-1-amino-cyclobutane carboxylic acid (6.28 mmol) was submitted to Procedure 12 for reduction to the corresponding N-Boc-1-Amino-cyclobutyl- methanol.; Procedure 12: Synthesis of alcohols via Borane Reduction To a stirring solution of the acid (1.5 mmol) in THF (5 mL) at -100C was slowly added 1.0 M BH3-THF (2.98 mL, 2.98 mmol). The reaction mixture was stirred vigorously for an additional 3 min at -100C, and was then allowed to warm to room temperature overnight. The reaction was quenched by the dropwise addition of a solution of HOAcZH2O (1 :1 v/v, 2.0 mL). The THF was removed by rotary evaporation and sat. aq. NaHCO3 (15 mL) was added. The aqueous layer was extracted with DCM (3 x 5 mL) and the combined organic layers were washed with sat. aq. NaHCO3 (2 x 5 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness.
To a stirring solution of the acid (1.5 mmol) in THF (5 mL) at -10C was slowly added 1.0 M BH3-THF (2.98 mL, 2.98 mmol). The reaction mixture was stirred vigorously for an additional 3 min at -10C, and was then allowed to warm to room temperature overnight. The reaction was quenched by the dropwise addition of a solution of HOAc/H20 (1 :1 v/v, 2.0 mL). The THF was removed by rotary evaporation and sat. aq. NaHC03 (15 mL) was added. The aqueous layer was extracted with DCM (3 x 5 mL) and the combined organic layers were washed with sat. aq. NaHC03 (2 x 5 mL), brine (10 mL), dried over Na2S04, filtered and concentrated to dryness.; N-Boc-l-amino-cyclobutyl-methanolN-Boc-l-amino-cyclobutane carboxylic acid (6.28 mmol) was submitted to Procedure 12 for reduction to the corresponding N-Boc-l-Amino-cyclobutyl- methanol.
Synthesis of alcohols via Borane Reduction: To a stirring solution of the acid (1.5 mmol) in THF (5 mL) at -10C was slowly added 1.0 M BH3-THF (2.98 mL, 2.98 mmol). The reaction mixture was stirred vigorously for an additional 3 min at -10C, and was then allowed to warm to room temperature overnight. The reaction was quenched by the dropwise addition of a solution of HOAc/H20 (1 :1 v/v, 2.0 mL). The THF was removed by rotary evaporation and sat. aq. NaHC03 (15 mL) was added. The aqueous layer was extracted with DCM (3 x 5 mL) and the combined organic layers were washed with sat. aq. NaHC03 (2 x 5 mL), brine (10 mL), dried over Na2S04, filtered and concentrated to dryness.
With borane-THF; In tetrahydrofuran; at -10 - 20℃;
N-Boc-l-amino-cyclobutane carboxylic acid (6.28 mmol) was submitted to Procedure 12 for reduction to the corresponding N-Boc-l-Amino-cyclobutyl- methanol.
Procedure 19: Synthesis of alcohols via Borane ReductionTo a stirring solution of the acid (1.5 mmol) in THF (5 mL) at -100C was slowly added 1.0 M BH3-THF (2.98 mL, 2.98 mmol). The reaction mixture was stirred vigorously for an additional 3 min at -10C, and was then allowed to warm to room temperature overnight. The reaction was quenched by the dropwise addition of a solution of HOAc/H2O (1 :1 v/v, 2.0 mL). The THF was removed by rotary evaporation and sat. aq. NaHCO3 (15 mL) was added. The aqueous layer was extracted with DCM (3 x 5 mL) and the combined organic layers were washed with sat. aq. NaHCO3 (2 x 5 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness. N-Boc-1-amino-cyclobutyl-methanolN-Boc-1 -amino-cyclobutane carboxylic acid (6.28 mmol) was submitted to Procedure 19 for reduction to the corresponding N-Boc-1 -Amino-cycl obutyl- methanol.
-Boc-1-amino-cyclobutane carboxylic acid (6.28 mmol) was submitted to Procedure 12 for reduction to the corresponding N-Boc-1-Amino-cyclobutyl- methanol.; Procedure 12: Synthesis of alcohols via Borane Reduction To a stirring solution of the acid (1.5 mmol) in THF (5 mL) at -100C was slowly added 1.0 M BH3-THF (2.98 mL, 2.98 mmol). The reaction mixture was stirred vigorously for an additional 3 min at -100C, and was then allowed to warm to room temperature overnight. The reaction was quenched by the dropwise addition of a solution of HOAcZH2O (1 :1 v/v, 2.0 mL). The THF was removed by rotary evaporation and sat. aq. NaHCO3 (15 mL) was added. The aqueous layer was extracted with DCM (3 x 5 mL) and the combined organic layers were washed with sat. aq. NaHCO3 (2 x 5 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness.
With borane-THF; In tetrahydrofuran; at -10 - 20℃;
N-Boc-l-amino-cyclobutyl-methanol N-Boc-l-amino-cyclobutane carboxylic acid (6.28 mmol) was submitted to Procedure 19 for reduction to the corresponding N-Boc-1-Amino-cyclobutyl- methanol. Procedure 19: Synthesis of alcohols via Borane Reduction To a stirring solution of the acid (1.5 mmol) in THF (5 mL) at -1O0C was slowly added 1.0 M BH3-THF (2.98 mL, 2.98 mmol). The reaction mixture was stirred vigorously for an additional 3 min at -10C, and was then allowed to warm to room temperature overnight. The reaction was quenched by the dropwise addition of a solution of HOAc/H2O (1 :1 v/v, 2.0 mL). The THF was removed by rotary evaporation and sat. aq. NaHCO3 (15 mL) was added. The aqueous layer was extracted with DCM (3 x 5 mL) and the combined organic layers were washed with sat. aq. NaHCO3 (2 x 5 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 16h;
Example 165: 4-[(S)-4-Carboxy-2-({5-[(1 -cyclopropylcarbamoyl-cyclobutylcarbamoyl)- methoxy]-1 -phenyl-1 H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1 -carboxylic acid ethyl ester; i) 1-tert-Butoxycarbonylamino-cyclobutanecarboxyIic acid benzyl ester; To a solution of 2.0 g N-Boc-1-aminocyclobutane carboxylic acid in 100 ml dichloromethane were added 2.1 g EDC, 1.4 g DMAP, 2.2 ml pyridine and 4.8 ml benzyl alcohol. After stirring for 16 h the mixture was diluted with dichloromethane and washed with 0.1 M HCI and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by chromatography on silica using heptane/ethyl acetate 2/1 as eluent.Yield: 2.2 g
N-Boc-l-amino-cyclobutane carboxylic acid1 -Amino-cyclobutane carboxylic acid ethyl ester (1.0 g, 6.28 mmol) was dissolved in IN HCl (10 mL) and the reaction was heated to a reflux for 2 hours. The reaction mixture was then concentrated to dryness to yield a crude which was submitted to Procedure 7 for Boc protection to yield the desired N-Boc-1 -Amino-cyclobutane carboxylic acid.; Procedure 7: N-Boc ProtectionTo a stirring solution of the amine (4.64 mmol) in THF (10 mL) was added IN NaOH (10 mL), followed by Boc-anhydride (5.57 mmol) and the reaction progress was checked by MS. Once complete, the THF was removed by rotary evaporation and water (40 mL) was added. The aqueous phase was separated and extracted with Et2O (2 x 30 ml). The aqueous phase was acidified to pH 3 by the addition of dilute H3PO4 and was then extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H2O (2 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness.
1-Amino-cyclobutane carboxylic acid ethyl ester (1.0 g, 6.28 mmol) was dissolved in IN HC1 (10 mL) and the reaction was heated to a reflux for 2 hours. The reaction mixture was then concentrated to dryness to yield a crude which was submitted to Procedure 7 for Boc protection to yield the desired N-Boc- 1-Amino-cyclobutane carboxylic acid.
N-Boc-l-amino-cyclobutane carboxylic acid1 -Amino-cyclobutane carboxylic acid ethyl ester (1.0 g, 6.28 mmol) was dissolved in IN HCl (10 mL) and the reaction was heated to a reflux for 2 hours. The reaction mixture was then concentrated to dryness to yield a crude which was submitted to Procedure 7 for Boc protection to yield the desired N-Boc-1 -Amino-cyclobutane carboxylic acid.; Procedure 7: N-Boc ProtectionTo a stirring solution of the amine (4.64 mmol) in THF (10 mL) was added IN NaOH (10 mL), followed by Boc-anhydride (5.57 mmol) and the reaction progress was checked by MS. Once complete, the THF was removed by rotary evaporation and water (40 mL) was added. The aqueous phase was separated and extracted with Et2O (2 x 30 ml). The aqueous phase was acidified to pH 3 by the addition of dilute H3PO4 and was then extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H2O (2 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness.
Stage 1: Methyl 1-aminocyclobutanecarboxylate Concentrated H2SO4 (10 ml) was added at 0 C. to a solution of 1-(tert-butoxy-carbonylamino)-cyclobutane-1-carboxylic acid (9.29 mmol, 1 equiv.) in MeOH (30 ml), and the reaction was refluxed for 2 hours at 0 C. The solvent was removed under reduced pressure. The residue was taken up in distilled water, adjusted to pH 8-9 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (2*200 ml). The combined organic phases were washed with distilled water (2*150 ml) and saturated NaCl solution (2*50 ml) and dried over sodium sulfate. The solvent was concentrated under reduced pressure to yield the desired product in the form of a white solid. Yield: 75%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h;
l-(6-Iodo-[l,8]naphthyridin-2-yl)-cyclobutyl]-carbamic acid tert-butyl esterHN(CH3)OCH3 rH MnRr ff H , Boc-1-aminocyclobutane-l-carboxylic acid (10.0 g, 45.1 mmol), HATU (20.5 g, 54.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.93 g, 49.6 mmol) were combined in DMF (100 mL). To this solution was added diisopropylethylamine (31.4 mL, 180.3 mmol). The reaction was stirred for 2 h, diluted with EtOAc and poured into H2O. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined and washed with brine, dried (Nua2SO/t), decanted and concentrated in vacuo. The resultant solid was purified via normal phase flash chromatography on silica gel (10-50% EtO Ac-heptane) to afford [ 1 -(methoxy-methyl- carbamoyl)-cyclobutyl]-carbamic acid tert-butyl ester as a white solid (11.5 g, 99%).
87%
To a solution of 1-fert-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added N,O-dimethylhydroxylaminexHCl (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0 0C and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in 100 mL EtOAc and washed twice with 10 % citric acid (aq) and saturated NaHCOs(aq) solution. The organic phase was dried with Na2SO4, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1 : 1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87 % yield.
87%
Step a) [l-(Methoxy-methyl-carbamoyn-cyclobutyll-carbamic acid tert-butyl ester (BBl-a) To a solution of 1-teri-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added Nu,Omicron-dimethylhydroxylamine x HCl (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0 C and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with 10 % citric acid (aq) and saturated NaHC03(aq) solution. The organic phase was dried with Na2S04, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1 : 1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87 % yield.
87%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0℃; for 2h;
To a solution of 1 -teri-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added Nu,Omicron-dimethylhydroxylamine x HC1 (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0 C and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with 10 % citric acid (aq) and saturatedNaHCC>3(aq) solution. The organic phase was dried with Na2SC>4, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1 : 1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87 % yield.
87%
Preparation of Building Block 1 (BB1 . a PI building block BB1-c BB1 Step a) 2-(l-((tert-butoxycarbonyl)amino)cyclobutyl)-2-hydroxyacetic acid (BBl-a)To a solution of 1-teri-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added Nu,Omicron-dimethylhydroxylamine x HC1 (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0 C and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with 10 % citric acid (aq) and saturatedNaHC03(aq) solution. The organic phase was dried with Na2S04, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1 : 1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87 % yield.
83%
To a stirred solution of 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid from Sigma-Aldrich cat.no.630802 1 (30 g, 0.14 mol) in dry DMF (500 mL) was added N,O-dimethylhydroxylamine.HCl (13.6 g, 0.14 mol) and DIEA (95.4 mL, 0.56 mol). The reaction was cooled to 0 oC and after 10 minutes HATU (52.9 g, 0.139 mol) was added to the stirred solution which turned yellow on addition. Once the reaction was deemed to havereached completion after about 2 h, DMF was removed by concentration in vacuo. The residue was dissolved in300 mL EtOAc and washed twice with 10 % citric acid (aq) and then sat. aq. NaHCO3. The organic layer wasdried with Na2SO4, filtered and concentration in vacuo onto silica. The product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate (1:1) to give 2 as a colorless oil that solidified onstanding (30 g) in 83 % yield.
65%
General procedure: To a solution of 2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (CAS 102185-35-3, 500 mg, 2.16 mmol) in DCM (5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (497 mg, 2.59 mmol) and stirred for 10 minutes at rt. A solution of N,O-dimethylhydroxylamine hydrochloride (253 mg, 2.59 mmol) and DIPEA (0.429 mL, 2.59 mmol) in DCM (5 mL) was added and the reaction mixture was left to stir at rt over weekend. The mixture was diluted with DCM (30 mL) and extracted with saturated aqueous NaHCO3 (50 mL). The organic phase was washed with water before being dried over MgSO4 and evaporated to give the title compound (466 mg, 79%).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 23℃; for 18h;Inert atmosphere;
Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added the commercially available l-((tertbutoxycarbonyl)amino)cyclobutanecarboxylic acid (2.0 g, 9.3 mmol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride (996 mg, 10.2 mmol, 1.1 equiv), HATU (4.2 g, 11.2and dichloromethane (15 mL). EtN(iPr)2 (3.3 mL, 18.6 mmol, 2.0 equiv) was then added to the reaction mixture. The yellow suspension was stirred at room temperature for 18 h. LCMS analysis revealed conversion to product. The reaction mixture was quenched with sat. aqueous ammonia chloride (50 mL) and extracted with CH2C12 (3 50 ml) using a 250 mL separatory funnel. The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting yellow oil was dried under vacuum and used directly without further purification.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 18h;
2-Amino-1-(4-bromo-phenyl)-ethanone HCl (5.8 g, 23 mmol) in DMF (75 mL) was treated with l-tert-butoxycarbonylamino-cyclobutanecarboxylic acid (5.0 g, 23 mmol), HATU (9.7 g, 25 mmol), and DIPEA (12.9 mL, 34 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (25 mL), and washed with saturated NaHCO3 (3 10 mL), H 2O (10 mL), and brine (10 mL). The solution was dried over MgSO4 to afford crude { l-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclobutyl}-carbamic acid tert- butyl ester, which was used without further purification. This material (6.54 g, 16 mmol) in xylenes (40 mL) was treated with ammonium acetate (6.1 g, 80 mmol). The reaction was stirred at 130C in a sealed tube for 18 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO3 (50 mL). The solution was dried over MgSO4 to afford crude {l-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-cyclobutyl}- carbamic acid t°rf-butyl ester, which was used without further purification: MS (ESI) mlz 393 [M + H]+.
2,2'-(biphenyl-4,4'-diyl)bis(2-oxoethane-2,1-diyl)bis(1-(tert-butoxycarbonylamino)cyclobutanecarboxylate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.25 g
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;
EXAMPLE N-10 Step a [0416] [0417] To a solution of 1,1?-(biphenyl-4,4?-diyl)bis(2-bromoethanone) (0.25 g, 0.631 mmol) and Boc-1-amino-1-cyclobutanecarboxylic acid (0.285 g, 1.326 mmol) in DCM was added DIEA (0.243 mL, 1.389 mmol). The reaction mixture was stirred at rt for 3 hrs. The reaction mixture was charged to a 40 g silica gel cartridge which was eluted with a 15 min gradient of 0-100% EtOAc in hexane. The product 2,2?-(biphenyl-4,4?-diyl)bis(2-oxoethane-2,1-diyl)bis(1-(tert-butoxycarbonylamino)cyclobutanecarboxylate) (0.25 g) was collected as a white solid. LC/MS (Cond. N-1): [M+Na]+ 687.47, Rt=4.37 min.
0.25 g
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;
To a solution of l,l'-(biphenyl-4,4'-diyl)bis(2-bromoethanone) (0.25 g, 0.631 mmol) and Boc-1 -amino- 1 -eye lobutanecarboxylic acid (0.285 g, 1.326 mmol) in DCM was added DIEA (0.243 mL, 1.389 mmol). The reaction mixture was stirred at rt for 3 hrs. The reaction mixture was charged to a 40 g silica gel cartridge which was eluted with a 15 min gradient of 0-100% EtOAc in hexane. The product 2,2'- (biphenyl-4,4'-diyl)bis(2-oxoethane-2, 1 -diyl) bis( 1 -(tert- butoxycarbonylamino)cyclobutanecarboxylate) (0.25 g) was collected as a white solid. LC/MS (Cond. N-l): [M+Na 687.47, Rt= 4.37 min.
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