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CAS No. : | 389890-43-1 | MDL No. : | MFCD09038208 |
Formula : | C9H17NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WSUMHFNEPOYLJM-UHFFFAOYSA-N |
M.W : | 187.24 | Pubchem ID : | 22594430 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.89 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 48.94 |
TPSA : | 58.56 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.82 cm/s |
Log Po/w (iLOGP) : | 2.19 |
Log Po/w (XLOGP3) : | 0.87 |
Log Po/w (WLOGP) : | 1.03 |
Log Po/w (MLOGP) : | 0.56 |
Log Po/w (SILICOS-IT) : | 0.3 |
Consensus Log Po/w : | 0.99 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.28 |
Solubility : | 9.71 mg/ml ; 0.0519 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.68 |
Solubility : | 3.88 mg/ml ; 0.0207 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.91 |
Solubility : | 23.2 mg/ml ; 0.124 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.88 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride In methanol at 20℃; for 4 h; | The mixture of tert-butyl ((lS,3S)-3-hydroxycyclobutyl)carbamate (seePREPARATION 4A; 187 mg, 1 mmol, 1.0 eqv) in HCl/MeOH 4 N (15 ml) was stirred at room temperature for 4 hours. Reaction mixture was concentrated to give (lS,3S)-3- aminocyclobutanol hydrochloride. (120 mg, 0.98 mmol, 98percentyield) ESI-MS (M+l): 88 calc. for C4H9NO 87 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium tetrahydroborate; water; In tetrahydrofuran; at -70℃; for 4h; | To a solution of tert-butyl N-(3-oxocyclobutyl)carbamate (15.00 g, 80.98 mmol, 1.00 eq) in tetrahydrofuran (150 mL) was added dropwise sodium borohydride (1.53 g, 40.49 mmol, 0.50 eq) in tetrahydrofuran (100 mL) and water (100 mL) at -70 C for 2 h. The mixture was stirred at -70 C for 2 h. Then to the mixture was added water (100 mL) and it was warmed to 20 C. The mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (2 x 400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a white solid. The solid was dissolved with a solution of petroleum ether: ethyl acetate (50 mL, v:v=20:1). The suspension solution was stirred for 0.5 h and then filtered to give tert-butyl N-(3-hydroxycyclobutyl)carbamate (13.80 g, 73.70 mmol, 91% yield).1H-NMR (400MHz, DMSO-d6) d 7.00 (d, J=7.2 Hz, 1H), 4.96 (d, J=5.6 Hz, 1H), 3.62 - 3.82 (m, 1H), 3.33 - 3.47 (m, 1H), 2.35 - 2.47 (m, 2H), 1.63 - 1.76 (m, 2H), 1.36 (s, 9H). |
87.6% | With sodium tetrahydroborate; In tetrahydrofuran; water; at -80 - -50℃; for 5h; | a solution of tert-butyl (3-oxocyclobutyl)carbamate (200 mg, 1.0 eq.) in THF (1 mL) was added dropwise to a cold (below -70 C) solution of NaBH4 (20.4 mg, 0.5 eq.) in THF (1.8 mL) and water (2 mL), maintaining the temperature at -80-70 C (ca. for 2 h for completion of addition). The mixture was stirred at-60- 50 C for 3 h, water (2 mL) was added to the reaction mixture and allowed to warm up to 15 C. The reaction mixture was then extracted with ethyl acetate (2 mL, 2 x 1 mL) and the combined organic layers were washed with brine (1 mL). The organic layer was concentrated under vacuum at 35-40 C, the solid dissolved in toluene (1 mL, 80-90 C) and gradually cooled to 25-30 C for 2.5 h. The mixture was stirred for 2 h at 25-30 C, filtered, and the solid dried in the air to give the product (177 mg with ratio of cis: trans (96.4:3.6), yield: 87.6%) as an off-white solid. |
81% | With lithium tri-sec-butyl(hydrido)borate; In tetrahydrofuran; at -78 - 20℃; | To a solution of tert-butyl (3-oxocyclobutyl)carbamate (1.00 g, 5.40 mmol) in THF (20 mL) at -78 C. was added L-Selectride (1.0M in THF, 6.5 mL) dropwise over 15 min. After stirring for 5 hrs at -78 C. the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was poured over ice water (100 g) and then extracted with EtOAc (4*15 mL). Combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc/Hexane to 2% MeOH/EtOAc) to give I54 A (0.82 g, 81%) as a white solid. LCMS m/z 188.2 (M+H)+. 1H NMR (CD3OD) delta 3.89 (m, 1H), 2.77 (td, J=16.3, 8.0 Hz, 1H), 2.60 (m, 2H), 1.76 (m, 2H), 1.42 (s, 9H). |
74% | Step 1. tert-Butyl ((l S,3S)-3-hydroxycyclobutyl)carbamate (L-Selectride reduction). To a cold ( -78 C) mixture of tert-butyl (3-oxocyclobutyl)carbamate (2g, 10.8 mmol) in THF (20 mL) was added L-selectride (1M in THF, 16.2 mL, 16.2 mmol) dropwise over 30 minutes. The mixture was stirred for 1 hour and then a solution of NaOH (0.66 g) in water (6 mL) was added dropwise over 15 minutes, followed with the addition of ( (30%, 6mL) dropwise over 20 minutes. The mixture was allowed to come to room temperature, diluted with EtOAc (100 mL) and washed with a2S03 (10%) and brine. The organic extracts were dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 1/1 ratio) to afford tert-butyl ((lS,3S)-3-hydroxycyclobutyl)carbamate as white solid (1.49 mg, 74 % yield). NMR (500MHz, CDCk) delta ppm 4.64 (brs, 1H), 4.05-3.99 (m, 1H), 3.67- 3.66 (m, 1H), 2.77-2.74 (m, 2H), 1.94 (m, 1H), 1.82-1.78 (m, 2H), 1.43 (s, 9H). | |
74% | With L-Selectride; In tetrahydrofuran; at -78℃; for 1h; | Step 3: tert-butyl c/s-3-hydroxycyclobutyl)carbamate: a solution of L-Selectride (1M solution in THF) (8.053 mL, 8.05 mmol) was added dropwise over a period of 20 min to a solution of tert-butyl (3-oxocyclobutyl)carbamate (1.0 g, 5.40 mmol) in THF (25 mL) under N2 atmosphere at -78 C and the reaction mixture was stirred for l h at -78 C. To the resulting reaction mixture was added a solution of NaOH (3.25 g) in water (4 mL) over a period of 10 min followed by 30% aqueous H202 (3 mL) over a period of 20 min. The reaction mixture was allowed to warm to room temperature and diluted with ethyl acetate (100 mL). The organic layer was separated off and washed with 10% aq. Na2S03 (40 mL) followed by brine (40 mL). The organic layer dried over Na2S04 and concentrated under reduced pressure to get the crude compound which was further purified by neutral alumina column chromatography using 50 % ethyl acetate in n-hexane as eluent to afford the desired compound. The compound was washed with n-hexane to get the product (0.750 g, 74%) as white solid, m. p. 1 19 C (lit. value 1 17 C). NMR (400 MHz, CDC13) delta 4.63 (br, 1 H), 4.03-3.96 (m, 1 H), 3.66-3.64 (m, 1 H), 2.76-2.72 (m, 2H), 1.91 (br, 1H), 1.79-1.76 (m, 2H), 1.42 (s, 9H). |
74% | With L-Selectride; In tetrahydrofuran; at -78℃; for 1.33333h;Inert atmosphere; | : a solution of L-Selectride (1M solution in THF) (8.053 mL, 8.05 mmol) was added dropwise over a period of 20 min to a solution of tert-butyl (3-oxocyclobutyl)carbamate (1.0 g, 5.40 mmol) in THF (25 mL) under N2 atmosphere at -78 C and the reaction mixture was stirred for lh at -78 C. To the resulting reaction mixture was added a solution of NaOH (3.25 g) in water (4 mL) over a period of 10 min followed by 30% aqueous H2O2 (3 mL) over a period of 20 min. The reaction mixture was allowed to warm to room temperature and diluted with ethyl acetate (100 mL). The organic layer was separated off and washed with 10% aq. Na2SC>3 (40 mL) followed by brine (40 mL). The organic layer dried over Na2SC>4 and concentrated under reduced pressure to get the crude compound which was further purified by neutral alumina column chromatography using 50 % ethyl acetate in n-hexane as eluent to afford the desired compound. The compound was washed with n-hexane to get the product (0.750 g, 74%) as white solid, m. p. 119 C (lit. value 117 C). XH NMR (400 MHz, CDC13) delta 4.63 (br, 1H), 4.03-3.96 (m, 1H), 3.66-3.64 (m, 1H), 2.76-2.72 (m, 2H), 1.91 (br, 1H), 1.79-1.76 (m, 2H), 1.42 (s, 9H). |
74% | With L-Selectride; In tetrahydrofuran; at -78℃; for 1h;Inert atmosphere; | a solution of L-Selectride (1M solution in THF) (8.053 mL, 8.05 mmol) was added dropwise over a period of 20 min to a solution of tert-butyl (3-oxocyclobutyl)carbamate (1.0 g, 5.40 mmol) in THF (25 mL) under N2 atmosphere at -78 C and the reaction mixture was stirred for lh at -78 C. To the resulting reaction mixture was added a solution of NaOH (3.25 g) in water (4 mL) over a period of 10 min followed by 30% aqueous H2O2 (3 mL) over a period of 20 min. The reaction mixture was allowed to warm to room temperature and diluted with ethyl acetate (100 mL). The organic layer was separated off and washed with 10% aq. Na2SC>3 (40 mL) followed by brine (40 mL). The organic layer dried over Na2SC>4 and concentrated under reduced pressure to get the crude compound which was further purified by neutral alumina column chromatography using 50 % ethyl acetate in n-hexane as eluent to afford the desired compound. The compound was washed with n-hexane to get the product (0.750 g, 74%) as white solid, m. p. 119 C (lit. value 117 C). XH NMR (400 MHz, CDCI3) delta 4.63 (br, 1H), 4.03-3.96 (m, 1H), 3.66-3.64 (m, 1H), 2.76-2.72 (m, 2H), 1.91 (br, 1H), 1.79-1.76 (m, 2H), 1.42 (s, 9H). |
71% | Tert-butyl (3-oxocyclobutyl)carbamate (280 g, 1.51 mol, 1.0 equiv) was dissolved in anhydrous THF (6.0 L). To this solution under N2 atmosphere at -74 C (acetone/ dry ice bath) was added L-selectride (1 M in THF, 1.82 L, 1.82 mol, 1.2 equiv) drop-wise over 30 min. Upon completion of the addition, the reaction mixture was stirred at -74 C for 2 h and allowed to warm up to RT and stirred overnight. Disappearance of starting material was monitored in LCMS. Upon completion, the reaction mixture was cooled to - 40 C and quenched with ice-cold water (4.0 L). The crude reaction mixture was then extracted with ethyl acetate (2 x 8.0 L) and the combined organic extracts was washed with brine (4.0 L), dried over Na2SC>4, and concentrated under reduced pressure. The crude residue thus obtained was then purified using column chromatography eluting with ethyl acetate/hexanes (20:80) to ethyl acetate/MeOH (98:02) to afford 201g of the tert-butyl ((lS,3S)-3-hydroxycyclobutyl)carbamate (71% yield). LH NMR (300 MHz, CDC13): delta 1.44 (s, 9H), 1.80-1.75 (m, 2H), 2.26 (bs, 1H), 2.80-2.72 (m, 2H), 3.67-3.64 (m, 1H), 4.05-3.98 (m, 1H), 4.69 (bs, 1H). | |
59.0% | With lithium borohydride; In tetrahydrofuran; at -73 - -72℃; for 1.5h; | tert-Butyl (3-oxocyclobutyl)carbamate (43.2 g, 233 mmol) was charged into a 2 L 3-necked flask equipped with a thermometer and an addition funnel. THF (0.7 L) was added and the mixture was cooled to -73 C. internal temperature. Lithium borohydride, 2M in THF (140 mL, 280 mmol) was added over 30 minutes via the addition funnel, during which time the temperature did not exceed -72 C. After stirring for an additional 1 h at that temperature, TLC analysis indicated reaction was complete. Saturated aqueous ammonium chloride (0.3 L) was added and the mixture was warmed to 0 C. After gas evolution ceased, EtOAc (0.3 L) and water (0.3 L) were added and the mixture was stirred vigorously for 1 h. The layers were then separated and the aqueous layer was extracted with EtOAc (1×). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give a yellow solid. This solid was suspended in 3:1 EtOAc/hexane and heated to boiling. The remaining solid was filtered off and additional hexane (100 mL) was added to the filtrate. The filtrate was then cooled in the freezer overnight. The resulting solid was collected by filtration and washed with cold 1:1 EtOAc/hexane solution, then dried to give tert-butyl(cis-3-hydroxycyclobutyl)carbamate (25.8 g, 59.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.36 (s, 9H) 1.68 (qd, J=8.54, 2.93 Hz, 2H) 2.33-2.45 (m, 2H) 3.34-3.44 (m, 1H) 3.65-3.76 (m, 1H) 4.98 (d, J=5.67 Hz, 1H) 7.03 (d, J=7.82 Hz, 1H). |
With L-Selectride; In tetrahydrofuran; at -74 - 20℃; for 12h; | Compound r was obtained through a three-step reaction using SOCl2, NaN 3, and t-BuOH as a starting material, compound q. Then, the compound s was obtained by reduction with alcohol using L-Selectride, subsequently, p-nitrobenzoic acid and triphenylphosphine, compound t was obtained using DEAD. This was reacted again with K2CO3 to give compound u. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at -20 - 20℃; for 0.583333h; | In a round-bottomed flask charged with tert-butyl(cis-3-hydroxycyclobutyl)carbamate (1.11 g, 5.93 mmol) and triethylamine (2.474 ml, 17.79 mmol) was added CH2Cl2 (12 ml). methanesulfonyl chloride (0.505 ml, 6.52 mmol) was added dropwise via syringe at -20 C. over 5 min. The reaction mixture was stirred at room temperature for 30 min, then diluted with water (15 mL) and extracted with CH2Cl2(2*). The organic extract was washed with saturated NH4Cl and dried over MgSO4. It was filtered and concentrated in vacuo to give cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (1.64 g, 6.1 mmol, 100% yield) as a off-white solid. |
99.5% | With triethylamine; In dichloromethane; at 0℃; | At 0 C, a solution of tert-butyl ((1s,3s)-3 -hydroxycyclobutyl)carbamate (936.2 mg, 5 mmol) and triethylamine (approximately 1.012 g, 1.394 mL, 10.00 mmol) in dichloromethane (10 mL) was treated with methanesulfonyl chloride (approximately 687.3 mg, 464.4 muL, 6.000 mmol) in dichloromethane (5 mL) dropwise over 10 minutes. After stirring overnight while warming up, ethyl acetate and aqueous ammonium chloride were added. The organic layer was collected and concentrated to yield (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (1.32 g, 4.975 mmol, 99.5%). 1H MR (300 MHz, CDCh) delta 4.73 (tt, J = 7.6, 6.9 Hz, 1H), 3.85 (s, 1H), 3.01 (s, 3H), 2.93 (dtt, J = 9.9, 7.1, 3.3 Hz, 1H), 2.28 - 2.08 (m, 2H), 1.45 (s, 9H) ppm. |
89% | With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; | MsCl (5.386 g, 46.83 mmol, 2.00 eq.) was added dropwise to a cold solution of tert-butyl N-[trans-3- hydroxycyclobutyl] carbamate (4.379 g, 23.39 mmol, 1.00 eq.) and TEA (7.095 g, 70.12 mmol, 3.00 eq.) in dichloromethane (25 mL at 0C. The resulting solution was stirred for 3 hours at room temperature and it was then diluted with 200 mL of dichloromethane. The resulting mixture was washed with water (2x100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was recrystallized from dichloromethane/hexane in the ratio of 1 : 1 to give 5.548 g (89%) of tert-butyl N-[cis-3- (methanesulfonyloxy)cyclobutyl] carbamate as an off-white solid. |
With triethylamine; In dichloromethane; at -10℃; for 2h; | Step 4: c/s-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate: triethylamine (1.0 g, 9.93 mmol) was added to a cold (- 10 C ) solution of tert-butyl (cis-3- hydroxycyclobutyl)carbamate (0.62 g, 3.31 mmol) in DCM (30 mL) followed by dropwise addition of methanesulfonyl chloride (0.45 g, 3.97 mmol) and the reaction mixture was stirred at -10 C for 2h. The reaction mixture was diluted with DCM ( 100 mL) and washed with water (5 mL) followed by dilute citric acid (30 mL) and brine (30 mL). The organic layer was dried over Na2S04, concentrated under reduced pressure to get the product (0.800 g, crude) as white solid which was used as such in next step without further purification. NMR (400 MHz, CDC13) delta 4.73-4.66 (m, 2H), 3.85-3.80 (m, 1H), 2.98 (s, 3H), 2.93-2.86 (m, 2H), 2.20-2.13 (m, 2H), 1 .42 (s, 9H). | |
With triethylamine; In dichloromethane; at -10℃; for 2h; | triethylamine (1.0 g, 9.93 mmol) was added to a cold (-10 C ) solution of tert-butyl (cis-3- hydroxycyclobutyl)carbamate (0.62 g, 3.31 mmol) in DCM (30 mL) followed by dropwise addition of methanesulfonyl chloride (0.45 g, 3.97 mmol) and the reaction mixture was stirred at -10 C for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with water (5 mL) followed by dilute citric acid (30 mL) and brine (30 mL). The organic layer was dried over Na2S04, concentrated under reduced pressure to afford the product (0.800 g, crude) as white solid which was used as such in next step without further purification. NMR (400 MHz, CDC13) delta 4.73-4.66 (m, 2H), 3.85-3.80 (m, 1H), 2.98 (s, 3H), 2.93-2.86 (m, 2H), 2.20- 2.13 (m, 2H), 1.42 (s, 9H). | |
With triethylamine; In dichloromethane; at -10℃; for 2h; | triethylamine (1.0 g, 9.93 mmol) was added to a cold (-10 C ) solution of tert-butyl (cis-3- hydroxycyclobutyl)carbamate (0.62 g, 3.31 mmol) in DCM (30 mL) followed by dropwise addition of methanesulfonyl chloride (0.45 g, 3.97 mmol) and the reaction mixture was stirred at -10 C for 2h. The reaction mixture was diluted with DCM (100 mL) and washed with water (5 mL) followed by dilute citric acid (30 mL) and brine (30 mL). The organic layer was dried over Na2SC>4, concentrated under reduced pressure to get the product (0.800 g, crude) as white solid which was used as such in next step without further purification. XH NMR (400 MHz, CDCI3) delta 4.73-4.66 (m, 2H), 3.85-3.80 (m, 1H), 2.98 (s, 3H), 2.93-2.86 (m, 2H), 2.20-2.13 (m, 2H), 1.42 (s, 9H). | |
5.48 g | With triethylamine; In tetrahydrofuran; at 0 - 0.35℃; for 3h; | Methanesulfonyl chloride (2.84 g) was added to a solution of <strong>[389890-43-1]tert-butyl N-[cis-3-hydroxycyclobutyl]carbamate</strong> (3.89 g) and triethylamine (3.13 g) in THF (80 mL) at 0 C. The mixture was stirred at room temperature for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (5.48 g). This product was subjected to the next reaction without further purification. 1H NMR (300 MHz, CDCl3) delta1.44 (9H, s), 2.13-2.25 (2H, m), 2.85-2.96 (2H, m), 2.99 (3H, s), 3.69-3.94 (1H, m), 4.45-4.81 (2H, m); MS m/z 210.1 [M+1-(tBu)]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 48h;Cooling with ice; | Step 1: /rans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate: To an ice-cooled solution of tert-butyl (c/s-3-hydroxycyclobutyl)carbarnate (1.5 g, 80.1 1 mmol) and 4-nitrobenzoic acid (1.47 g, 88.12 mmol) in dry THF (60 mL) was added triphenyl phosphine (3.15 g, 12.01 mmol) followed by dropwise addition of DIAD (8.09 g, 40.05 mmol) and the reaction mixture was stirred at room temperature for 2 days. Solvent was removed under reduced pressure to get the crude compound which was purified by silica gel (100-200 mesh) column chromatography. Elution with 50 % ethyl acetate in n-hexane followed by washing with diethyl ether (4 mL x 2) gave the product (2.3 g, 85%) as a white solid. -NMR (400 MHz, CDC13) delta 8.29-8.27 (q, 2H, J = 8.92 Hz), 8.21 -8.19 (q, 2H, J= 8.92 Hz), 5.37-5.32 (m, I H), 4.77 (br, I H), 4.41 -4.38 (m, I H), 2.64-2.58 (m, 2H), 2.47-2.40 (m, 2H), 1.44 (s, 9H); LC- MS: (M+H)+ = 336.8 |
85% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 48h; | To an ice-cooled solution of tert-butyl (c 5-3-hydroxycyclobutyl)carbamate ( 1.5 g, 80.1 1 mmol) and 4-nitrobenzoic acid (1.47 g, 88.12 mmol) in dry THF (60 mL) was added triphenylphosphine (3.15 g, 12.01 mmol) followed by dropwise addition of DIAD (8.09 g, 40.05 mmol) and the reaction mixture was stirred at room temperature for 2 days. The solvent was removed under reduced pressure to afford the crude compound which was purified by silica gel (100-200 mesh) column chromatography. Elution with 50 % ethyl acetate in n-hexane followed by washing with diethyl ether (4 mL x 2) gave the product (2.3 g, 85%) as a white solid. -NMR (400 MHz, CDC ) delta 8.29-8.27 (q, 2H, J= 8.92 Hz), 8.21 -8.19 (q, 2H, J= 8.92 Hz), 5.37-5.32 (m, I H), 4.77 (br, IH), 4.41 -4.38 (m, IH), 2.64-2.58 (m, 2H), 2.47-2.40 (m, 2H), 1.44 (s, 9H); LC-MS (ES, M/Z): [M+H]+ = 336.8. |
85% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 48h; | To an ice-cooled solution of tert-butyl (cw-S-hydroxycyclobuty carbamate (1.5 g, 80.11 mmol) and 4-nitrobenzoic acid (1.47 g, 88.12 mmol) in dry THF (60 mL) was added triphenyl phosphine (3.15 g, 12.01 mmol) followed by dropwise addition of DIAD (8.09 g, 40.05 mmol) and the reaction mixture was stirred at room temperature for 2 days. Solvent was removed under reduced pressure to get the crude compound which was purified by silica gel (100-200 mesh) column chromatography. Elution with 50 % ethyl acetate in n-hexane followed by washing with diethyl ether (4 mL x 2) gave the product (2.3 g, 85%) as a white solid. ^-NMR (400 MHz, CDC13) delta 8.29-8.27 (q, 2H, J = 8.92 Hz), 8.21-8.19 (q, 2H, J= 8.92 Hz), 5.37-5.32 (m, 1H), 4.77 (br, 1H), 4.41-4.38 (m, 1H), 2.64-2.58 (m, 2H), 2.47-2.40 (m, 2H), 1.44 (s, 9H); LC- MS: (M+H)+ = 336.8. |
85% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 48h; | To an ice-cooled solution of tert-butyl (czs-3-hydroxycyclobutyl)carbamate (1.5 g, 80.11 mmol) and 4-nitrobenzoic acid (1.47 g, 88.12 mmol) in dry THF (60 mL) was added triphenyl phosphine (3.15 g, 12.01 mmol) followed by dropwise addition of DIAD (8.09 g, 40.05 mmol) and the reaction mixture was stirred at room temperature for 2 days. Solvent was removed under reduced pressure to get the crude compound which was purified by silica gel (100-200 mesh) column chromatography. Elution with 50 % ethyl acetate in n-hexane followed by washing with diethyl ether (4 mL x 2) gave the product (2.3 g, 85%) as a white solid. ^-NMR (400 MHz, CDC13) delta 8.29-8.27 (q, 2H, J = 8.92 Hz), 8.21-8.19 (q, 2H, J= 8.92 Hz), 5.37-5.32 (m, 1H), 4.77 (br, 1H), 4.41-4.38 (m, 1H), 2.64-2.58 (m, 2H), 2.47-2.40 (m, 2H), 1.44 (s, 9H); LC- MS: (M+H)+ = 336.8 . |
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 12h; | Compound r was obtained through a three-step reaction using SOCl2, NaN 3, and t-BuOH as a starting material, compound q. Then, the compound s was obtained by reduction with alcohol using L-Selectride, subsequently, p-nitrobenzoic acid and triphenylphosphine, compound t was obtained using DEAD. This was reacted again with K2CO3 to give compound u. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a solution of tert-butyl ((lS,3S)-3-hydroxycyclobutyl)carbamate (seePREPARATION 4A; 187 mg, 1 mmol) in DMF (20 mL) at RT was added sodium hydride (60% wt in mineral oil) (48 mg, 2 mmol). The mixture was stirred at RT for 10 mins and then bromomethyl-benzene (171 mg, 1 mmol) was added. The reaction mixture was stirred at RT for lh and then diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2S04, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give tert-butyl ((lS,3S)-3- (benzyloxy)cyclobutyl)carbamate (146 mg, 0.5 mmol, 50% yield). ESI-MS (M+l): 278 calc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.6% | With caesium carbonate; In dimethyl sulfoxide; at 80℃; | To a mixture of <strong>[4858-85-9]2,3-dichloro-pyrazine</strong> ( 3.0 g, 20 mmol ) and tert-butyl ((1S,3S)- 3-hydroxycyclobutyl)carbamate (see PREPARATION 4A; 3.65 g, 20 mmol) in DMSO (50 mL) was added CS2CO3 ( 13.2 g, 40 mmol), and then the mixture was stirred at 80C overnight. The reaction mixture was diluted with water and filtered. The filter cake was washed with water, and dried to give tert-butyl ((lS,3S)-3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (5.7 g, 19.0 mmol, 96.6%). ESI-MS (M+l): 300 calc. for Ci3Hi8ClN303 299. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | To a solution of tert-butyl ((lS,3S)-3-((3-bromopyridin-2- yl)oxy)cyclobutyl)carbamate (see PREPARATION 4A; 1.08 g, 3.8 mmol) in DMF (20 mL) at RT was added sodium hydride (60percent wt in mineral oil) (0.18 g, 7.6 mmol). The mixture was stirred at RT for 10 min and then <strong>[36178-05-9]3-bromo-2-fluoro-pyridine</strong> (665 mg, 3.8 mmol) was added. The reaction mixture was stirred at RT for lh and then diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2S04, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (5percent to 30percent EtOAc in hexanes) to give tert-butyl ((l S,3S)-3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (391 mg, 1.14 mmol, 30percent) as white solid. ESI-MS (M+l): 343 calc. for Ci4Hi9BrN203 342. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With caesium carbonate; In dimethyl sulfoxide; at 80℃; | To a mixture of 3-bromo-2,5-difluoro-pyridine (500 mg, 2.58 mmol ) and tert- butyl ((l S,3S)-3-hydroxycyclobutyl)carbamate (see PREPARATION 4A; 485 mg, 2.58 mmol) in DMSO (20 mL) was added CS2CO3 (1.68 g, 5.16 mmol), and then the mixture was stirred at 80C overnight. The reaction mixture was diluted with water and extracted with EtOAc (3 x 50 mL), washed with brine and dried over Na2S04. The dried organic layers were concentrated to tert-butyl ((l S,3S)-3-((3-bromo-5-fluoropyridin-2-yl)oxy)cyclobutyl)carbamate (380 mg, 1.06 mmol, 41%). ESI-MS (M+l): 361 calc. for Ci4H18BrFN203 360. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With caesium carbonate; In acetonitrile; at 20.0℃; | To a mixture of <strong>[866755-20-6]3-bromo-2,6-dichloropyridine</strong> (4.5 g, 20 mmol ) and tert-butyl ((l S,3S)-3-hydroxycyclobutyl)carbamate (see PREPARATION 4A; 3.65 g, 20 mmol) in acetonitrile (50 mL) was added CS2CO (13.2 g, 40 mmol), and then the mixture was stirred at RT overnight. The reaction mixture was filtered and concentrated under vacuum to give tert- butyl ((l S,3S)-3-((3-bromo-6-chloropyridin-2-yl)oxy)cyclobutyl)carbamate (4.2 g, 11.2 mmol, 56%). ESI-MS (M+1): 377 calc. for Ci4Hi8BrClN203 376. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride; In methanol; at 20℃; for 4h; | The mixture of tert-butyl ((lS,3S)-3-hydroxycyclobutyl)carbamate (seePREPARATION 4A; 187 mg, 1 mmol, 1.0 eqv) in HCl/MeOH 4 N (15 ml) was stirred at room temperature for 4 hours. Reaction mixture was concentrated to give (lS,3S)-3- aminocyclobutanol hydrochloride. (120 mg, 0.98 mmol, 98%yield) ESI-MS (M+l): 88 calc. for C4H9NO 87 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 4h; | 6-Fluoro-1-methyl-H-imidazo[4,5-b]pyridin-2(3H)-one (0.377 g, 2.256 mmol), tert-butyl(cis-3-hydroxycyclobutyl)carbamate (0.422 g, 2.256 mmol), and triphenylphosphine (0.887 g, 3.38 mmol) were mixed in THF (8 mL) under an argon atmosphere. The mixture was cooled to 0 C. before diisopropyl azodicarboxylate (0.665 mL, 3.38 mmol) was added dropwise via syringe. The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with acetone in hexanes to yield crude tert-butyl(trans-3-(6-fluoro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)cyclobutyl)carbamate (1.136 g) as a white solid. The material was used without further purification. Hydrogen chloride (4.0 M in 1,4-dioxane, 8.44 mL, 33.8 mmol) was added to a stirred mixture of crude tert-butyl(trans-3-(6-fluoro-1-methyl-2-oxo-H-imidazo[4,5-b]pyridin-3(2H)-yl)cyclobutyl)carbamate (1.136 g, 3.38 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was partially concentrated in vacuo. The resulting precipitate was filtered to yield 3-(trans-3-aminocyclobutyl)-6-fluoro-1-methyl-1H-imidazo[4,5-b]pyridin-2(3h)-one hydrochloride (0.469 g, 1.720 mmol, 76.2% yield) as an off-white solid. M+1: 237.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.9% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 19h; | 5-Bromo-3,3-difluoro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (1.19 g, 4.78 mmol), tert-butyl(cis-3-hydroxycyclobutyl)carbamate (0.895 g, 4.78 mmol), and triphenylphosphine (1.88 g, 7.17 mmol) were mixed in THF (18 mL) under an argon atmosphere. The mixture was cooled to 0 C. before diisopropyl azodicarboxylate (1.409 mL, 7.17 mmol) was added dropwise via syringe. The reaction mixture was warmed to room temperature and stirred for 19 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified via silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.477 g, 1.141 mmol, 23.9% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | To a cooled (0 C.) solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (0.250 g, 1.335 mmol), 6-bromo-1-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.334 g, 1.309 mmol) and triphenylphosphine (0.520 g, 1.983 mmol) in THF (10 ml) was added DIAD (0.400 ml, 2.032 mmol) dropwise via syringe. After 10 min the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH/EtOAc, evaporated onto silica gel and purified by flash chromatography (Isco (25 gram)) eluting with EtOAc:hexanes (0:1-1:1) to give a light-yellow solid. ESI MS 445.9, 447.8 [M+Na] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.240 g | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; | To a cooled solution (0 C.) of tert-butyl(cis-3-hydroxycyclobutyl)carbamate (Intermediate 71) (1.032 g, 5.51 mmol), 1-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.9715 g, 5.51 mmol), and triphenylphosphine (1.917 ml, 8.27 mmol, Sigma Aldrich) in THF (30.5 ml) was added diethyl azodicarboxylate, 40 wt. % solution in toluene (3.26 ml, 8.27 mmol, Chem Impex International) dropwise. After 10 mins, the round bottomed flask was removed from the ice bath and allowed to warm to room temperature to stir. Solvent was evaporated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (2.240 g, 6.49 mmol, 118% yield). LCMS showed product peak at 2.007 min (m+1=346.0). NMR showed biproduct from DEAD reagent. The product was carried on assuming 100% yield without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.2% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 22h;Inert atmosphere; | 3,3,5-Trifluoro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.248 g, 1.318 mmol), tert-butyl(cis-3-hydroxycyclobutyl)carbamate (0.247 g, 1.318 mmol), and triphenylphosphine (0.519 g, 1.978 mmol) were mixed in THF (5 mL) under an argon atmosphere. The mixture was cooled to 0 C. before diisopropyl azodicarboxylate (0.389 mL, 1.978 mmol) was added dropwise via syringe. The reaction mixture was warmed to room temperature and stirred for 22 h. The reaction mixture was diluted with sat. NaHCO3 and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.241 g, 0.674 mmol, 51.2% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3 g | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 50℃; | At 0 C, to a solution of 4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidine (607.0 mg, 2.00 mmol, 1.00 equiv) in THF (20 mL) were added tert-butyl N-[(lS,3S)-3- hydroxycyclobutyl] carbamate (374.70 mg, 2.00 mmol, 1.00 equiv) and PPh3 (524.89 mg, 2.00 mmol, 1.00 equiv). This was followed by the slow addition of DIAD (404.66 mg, 2.00 mmol, 1.00 equiv) at 0 C. The resulting solution was stirred overnight at 50 C in an oil bath. The reaction mixture was concentrated under reduced pressure. The residue was purified in a silica gel column eluting with a gradient of 10-40% EtOAC in hexane to yield tert-butyl N-[(lR,3R)-3- [4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]cyclobutyl]carbamate as a colorless syrup (1.3g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Step 4. tert-Butyl ((lS,3S)-3-((2-bromo-4- phenoxybenzyl)oxy)cyclobutyl)carbamate. Sodium hydride (60% dispersion in mineral oil; 235 mg, 5.88 mmol) was added into a cold (0 C) mixture of tert-butyl ((lS,3S)-3- hydroxycyclobutyl)carbamate (1.1 mg, 5.86 mmol) and anhydrous THF (10 mL). After stirring for 1 hour, 2-bromo-l-(bromomethyl)-4-phenoxybenzene (2.01 g, 5.88 mmol) was added and the mixture was allowed to come to room temperature and stirred for 8 hours. Then, the mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (2x). The organic extracts were dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 6/1 ratio) to afford tert-butyl ((lS,3S)-3-((2-bromo-4- phenoxybenzyl)oxy)cyclobutyl)carbamate as oil (2.16g, 82% yield). 'H NMR (500MHZ, CDCh) 5 ppm 7.38-7.34 (m, 3H), 7.18 (d, J = 2.5 Hz, 1H), 7.15 (dt, J= 7.5 Hz, 1.5 Hz, 1H), 7.09-7.0 (m, 2H), 6.96 (dd, J= 9.0, 2.5 Hz 1H, ), 4.63 (brs, 1H), 4.43 (s, 2H), 3.83-3.77 (m, 2H), 2.76-2.74 (m, 2H), 1.87-1.81 (m, 2H), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Step 2. tert-Butyl ((lS,3S)-3-((4-bromo-2- fluorobenzyl)oxy)cyclobutyl)carbamate. Sodium hydride (60% dispersion in mineral oil; 51.2 mg, 1.28 mmol) was added into a cold (0 C) mixture of tert-butyl ((lS,3S)-3- hydroxycyclobutyl)carbamate (200 mg, 1.07 mmol) and anhydrous THF (3 mL). After stirring for 1 hour, 4-bromo-l-(bromomethyl)-2-fluorobenzene (294.6 mg, 1.1 mmol) was added and the mixture was allowed to come to room temperature and stirred for 8 hours. Then, the mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (2x). The organic extracts were dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 4/1 ratio) to afford tert-butyl ((l S,3S)-3-((4-bromo-2- fluorobenzyl)oxy)cyclobutyl)carbamate as oil (386.2 mg, 91%> yield). lR NMR (500MHz, CDCk) delta ppm 7.27-7.21 (m, 3H), 4.61 (brs, 1H), 4.41 (s, 2H), 3.78-3.72 (m, 2H), 2.71 (m, 2H), 1.82-1.76 (m, 2H), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With di-isopropyl azodicarboxylate; diphenyl phosphoryl azide; triphenylphosphine; In tetrahydrofuran; at 0 - 30℃; for 2h; | a solution of PPh3 (315 mg) and DIAD (243 mg) in THF (3 mL) was stirred for 20 min at 0- 10 C. A solution of tert- butyl (cis-3-hydroxycyclobutyl)carbamate (150 mg, 1.0 eq.) and DPPA (265 mg, 1 .2 eq.) in THF (1 ml) was added dropwise and mixture was then warmed to 25-30 C and stirred for 2 h. Brine (3 mL) was added to the reaction mixture, extracted with ethyl acetate (3 mL) and then concentrated under vacuum to give the crude oil. The mixture was purified by Si02 column chromatography and eluted with ethyl acetate/petroleum ether (0%~10%) gradually. The product was suspended in n-heptane (0.3 mL) and stirred for 0.5 h at 20-25 C. The mixture was filtered and the solid dried in air to give the product in 85% yield and ratio of cis/trans = 4:96 checked by 'H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 96.17h; | Intermediate 3 (500 mg, 2.00 mmo[), cis-tert-butyl. 3-hydroxycyclobutylcarbamate (488.2 mg, 2.6 mmo[) and triphenylphosphine (2104 mg, 8.0 mmo[) were combined in THF (10 mL) and cooled to 0 C. DIAD (0.79 mL, 4.0 mmol) was added dropwiseand the reaction mixture stirred for 10 mm then allowed to warm to RT and stirred for a further 96 h. The reaction mixture was concentrated under reduced pressure, and purified by Biotage lsolera chromatography (silica gel, eluting with heptaneEtOAc, 9:1 to 3:7) to afford 1.6 mg (74% yield) of the title compound as a colourless oil.1H NMR (500 MHz, Chloroform-d): 6 [ppm] 8.09 (t, J = 1.4 Hz, 1H), 7.54 (dd, J =2.4, 1.6 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.44 (dd, J = 2.5, 1.4 Hz, 1H), 4.94-4.87(m, 1H), 4.31 (5, 1H), 3.93 (5, 3H), 2.63 - 2.53 (m, 2H), 2.52 (d, J = 1.2 Hz, 3H),2.48- 2.39 (m, 2H), 1.45 (5, 9H).LCMS (Analytical Method A) Rt = 1.53 mm, MS (ESIpos): m/z = 419.05 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 2h; | triphenylphosphine (15.97 g, 60.89mmol, 1.50 eq.), 2,3-dihydro- lH-isoindole-l,3-dione (7.17 g, 48.73mmol, 1.20 eq.) and DIAD (12.31 g, 60.94mmol, 1.50 eq.) were added to a solution of tert-butyl N-[cw-3-hydroxycyclobutyl]carbamate (7.6 g, 40.59mmol, 1.00 eq.) in THF (100 mL). The solution was stirred for 2 hours at room temperature and it was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 15). This resulted in 3.5 g (27%) of tert-butyl N-ffrara-S^l^-dioxo^^-dihydro-lH-isoindol^- yl)cyclobutyl] carbamate as a white solid. LC-MS (ES, m/z): [M+H]+ = 317.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 168h; | Triphenylphosphine (1 .04 g, 3.96 mmol) was added to a solution of 5-fluoro-2- methoxyphenol (1 .85 g, 10.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to 0 C, and terf-butyl ((c/s)-3-hydroxycyclobutyl)carbamate (494 mg, 2.64 mmol) was added, followed by DIAD (0.77 mL, 4.0 mmol). The reaction mixture was then warmed to room temperature, stirred for 1 week, and partially concentrated. The remaining material was diluted with water and EtOAc, partitioned, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water, dried over MgSC>4 , filtered and concentrated. The residue was purified on silica gel eluting with a 30%-80% EtOAc-hexanes gradient to give the title compound (601 mg, 73%) as a white solid. 1H NMR (400 MHz, CDCI3) delta 1 .46 (s, 9 H), 2.34-2.46 (m, 2 H), 2.63-2.70 (s, 2 H), 3.85 (s, 3 H), 4.25-4.34 (m, 1 H), 4.70-4.87 (m, 2 H), 6.41 (dd, J = 10, 3 Hz, 1 H), 6.60 (d, J = 3 Hz, 1 H), 6.80 (dd, J = 9, 5 Hz, 1 H); LC-MS (LC-ES) M+H- Boc = 212. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | General procedure: To a solution of (S)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-1-yl)-6-chloro-3- methyl-1H-pyrazolo[3,4-d]pyrimidine (435b) (150 mg, 0.39 mmol), triphenylphosphine (206 mg, 0.79 mmol), tert-butyl cis-4-hydroxycyclohexylcarbamate (127 mg, 0.59 mmol) in THF (3 mL) at 0 C was added dropwise DIAD (0.12 mL, 0.59 mmol). The reaction mixture was stirred at RT overnight, concentrated in vacuum and the residue obtained was purified by flash column chromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%] to furnish tert-butyl ((tra5)-4-(4-((S)-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-l-yl)- 6-chloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclohexyl)carbamate (435c) (150 mg, 66 % yield) as a white solid;1H MR (300 MHz, DMSO-d) delta 6.83 (d, J = 7.9 Hz, 1H), 4.54 - 4.38 (m, 2H), 3.90 - 3.63 (m, 4H), 3.32 - 3.22 (m, 1H), 2.55 (s, 3H), 2.13 - 1.75 (m, 10H), 1.39 (s, 1 1H), 0.82 (s, 9H), -0.05 (s, 6H); MS (ES+): 579.3 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | [00551] To a slurry of Example 108b (1.87 g, 10.0 mmol) in THF (150 mL) at 0C was added NaH (480 mg, 12 mmol, 60% in mineral oil), which was stirred for 30 min. Then Example 108a (2.75 g, 10.0 mmol) was added at 0C and the mixture was warmed to r.t. for overnight. Water (1 mL) was added to the mixture, which was then concentrated under reduced pressure. The residue was directly purified by silica gel chromatography (Petroleum Ether/EtOAc = 2/1-0/1) to give the desired product Example 108c (2.80 g, yield 73%) as a white solid. LCMS [M+l]+ = 380.9/382.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In ethanol; at 0 - 20℃; for 3h; | To a solution of <strong>[1219019-22-3]cis-3-aminocyclobutanol hydrochloride</strong> (900 mg, 7.3 mmol, 1.0 eq) in ethanol (5 mL) and Et3N (5 mL) at 0 C. was added Boc2O (800 mg, 3.7 mmol, 0.5 eq) and the mixture was allowed to warm to RT and stirred for 3 h. The mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (40 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (1.2 g, 88%) as a yellow solid, which was used for the next step without further purification. LCMS: [M+H]+ 188.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step b): tert-Butyl ((1s,3s)-3-(1-(5-bromopyridin-2-yl)ethoxy)cyclobutyl)carbamate. tert-Butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (318.9 mg, 1.703 mmol) was dissolved in toluene (15 mL) and the solution was evaporated in vacuum and was dissolved in 15 ml of anhydrous THF and cooled to 5 C. To this was added 60% sodium hydride in mineral oil (103 mg, 2.555 mmol). The suspension was stirred for 15 minutes and 5-bromo-2-(1-bromoethyl) pyridine (475.0 mg, 1.793 mmol) was added. The reaction mixture was stirred at room temperature for 68 hours, and then overnight at 50 C. After removing of THF in vacuum, water was added and products were extracted twice with EtOAc, washed with water and brine and dried with MgSO4. Purified by chromatography. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 1.55 (d, J=1.95 Hz, 3H) 1.66-1.77 (m, 1H) 1.77-1.88 (m, 1H) 2.49 (br. s., 1H) 2.72 (br. s., 1H) 3.58-3.72 (m, 2H) 4.45 (q, J=6.34 Hz, 1H) 4.58 (br. s., 1H) 7.30 (d, J=8.30 Hz, 1H) 7.79 (d, J=8.30 Hz, 1H) 8.57 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 50℃; for 24h;Inert atmosphere; | Step a: (1s, 3s)-3-((tert-Butoxycarbonyl)amino)cyclobutyl 4-bromobenzenesulfonate. tert-Butyl (cis-3-hydroxycyclobutyl)carbamate (210 mg, 0.82 mmol), and diisopropylethylamine (1 mL, 5.75 mmol) were added into a stirring solution of 4-bromobenzene-sulfonyl chloride (308 mg, 1.64 mmol) in dichloromethane (5 mL) at 0 C. and under argon. The resulting reaction mixture was refluxed at 50 C. for 24 hours. The reaction mixture was diluted with Et2O and washed with water and brine. The organic layer was left to crystallize overnight at -20 C. and then filtered and washed with hexanes to afford (1s, 3s)-3-((tert-butoxycarbonyl)amino) cyclobutyl 4-bromobenzenesulfonate (186 mg, 56% yield) as white solid. 1H NMR (500 MHz, d6-DMSO) delta 7.91 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.147 (d, J=8.5 Hz, 1H), 4.59-4.53 (m, 1H), 3.59-3.3.51 (m, 1H), 2.48-2.43 (m, 2H), 2.02-1.96 (m, 2H), 1.34 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24%; 64% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 50℃; for 12h; | Diethyl azodicarboxylate (27 mL of 40% w/w, 59.29 mmol) was added to a cooled (0C.) mixture of tert-butyl (cis-3-hydroxycyclobutyl)carbamate (10.09 g, 53.89 mmol) and triphenylphosphine (15.78 g, 60.16 mmol) in THF (150 mL) followed by the addition of 3-(trifluoromethyl)-4H-pyrazole (8.18 g, 60.11 mmol). The reaction was heated at 50C. for 12 hours. The solvent was removed and the residue was purified by column chromatography (SiO2) eluting with a gradient of heptanes to ethyl acetate isolating two regioisomers.Peak 1 (minor product) as tert-butyl (trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate (4.09 g, 24% yield) 1H NMR (400 MHz, CDCl3)delta7.57 (d, J=1.9 Hz, 1H), 6.62 (d, J=1.9 Hz, 1H), 5.06 (t, J=7.2 Hz, 1H), 4.81 (s, 1H), 4.39 (s, 1H), 3.02 (ddd, J=13.7, 8.2, 5.7 Hz, 1H), 2.56 (d, J=21.7 Hz,2H), 1.49 (d, J=2.1 Hz, 9H). ESI-MS m/z 319.4.Peak 2 (major product) as tert-butyl (trans-3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate. (10.82 g, 64%) 1H NMR (400 MHz, CDCl3)delta7.54-7.42 (m, 1H), 6.54 (d, J=2.4 Hz, 1H), 5.00-4.87 (m, 1H), 4.81 (s, 1H), 4.37 (s, 1H), 3.00-2.84 (m, 2H), 2.59 (s, 2H), 1.48 (s, 9H). ESI-MS m/z 319.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 50℃; for 2h; | General procedure: Step 1: tert-Butyl trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)carbamate cis-tert-Butyl N-(3-hydroxycyclobutyl)carbamate (8.06 g, 43 mmol) and triphenylphosphine (12.42 g, 11 mL, 47.4 mmol) were taken into THF (120 mL) and cooled to 0 C. Diethylazodicarboxylate (DEAD) (20.62 g, 21.6 mL of 40% w/w, 47.4 mmol) was added to the solution followed by the addition of 3,4,5-trifluorophenol (7.01 g, 47.4 mmol). The reaction was stirred at room temperature for 1 hour then heated at 50 C. for 1 h. The solvent was removed and the reaction was dissolved in 100 ml of dichloromethane and washed twice with 2N sodium hydroxide. The organic layer was evaporated and the crude product purified by column chromatography (SiO2) eluting with a gradient of 10-50% ethyl acetate in hexanes to provide 12.1 g (89% yield) of the desired product. 1H NMR (300 MHz, CDCl3) delta 6.46-6.31 (m, 2H), 4.74 (d, J=10.4 Hz, 1H), 4.68 (td, J=6.9, 3.5 Hz, 1H), 4.30 (s, 1H), 2.55 (ddd, J=11.9, 8.2, 3.6 Hz, 2H), 2.41 (dd, J=12.7, 6.3 Hz, 2H), 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.79 g | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 50℃; for 1h; | Step 1: tert-butyl (trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)-carbamate Diethyl azodicarboxylate (3.375 g, 3.530 mL of 40% w/w, 7.752 mmol) was added to a solution of tert-butyl (cis-3-hydroxycyclobutyl)carbamatecarbamate (1.33 g, 7.11 mmol), 2-(trifluoromethyl)pyrimidin-5-ol (1.06 g, 6.46 mmol) and triphenylphosphine (2.033 g, 1.796 mL, 7.752 mmol) in THF (20 mL) was added a dropwise at room temperature. The reaction was heated to 50 C. for 1 hour. The reaction was evaporated in vacuo and the residue purified by column chromatography (SiO2) eluting with a gradient of heptane to 100% ethyl acetate. The desired fractions were combined and evaporated in vacuo to afford 1.79 g of the title product. 1H NMR (400 MHz, CDCl3) delta 8.40 (s, 2H), 5.02-4.86 (m, 1H), 4.80 (s, 1H), 4.35 (s, 1H), 2.63 (ddd, J=11.7, 8.2, 3.4 Hz, 2H), 2.55 (d, J=5.7 Hz, 2H), 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 15℃; for 15h; | To a solution of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (17.04 g, 81.07 mmol, 1.10 eq), tert-butyl N-(3-hydroxycyclobutyl)carbamate (13.80 g, 73.70 mmol, 1.00 eq) and triphenylphosphine (25.13 g, 95.82 mmol, 1.30 eq) in tetrahydrofuran (150 mL) was added dropwise diisopropyl azodicarboxylate (19.37 g, 95.82 mmol, 1.30 eq) at 0 C. The mixture was warmed to 15 C. The mixture was stirred at 15 C for 15 h. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to give dimethyl 4-[3-(tert- butoxycarbonylamino)cyclobutoxy]benzene-1,2-dicarboxylate (25.50 g, 67.21 mmol, 91% yield) as a red oil. LC/MS (ESI) m/z: 402.1 [M+23] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75%Spectr.; 81% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 4h; | To a solution of I54 A (0.82 g, 4.38 mmol) in DMF (15 mL) at RT was added imidazole (0.74 g, 10.9 mmol) followed by a solution of TBDPSCl (1.70 mL, 6.44 mmol) dropwise. The reaction mixture was stirred at RT for 4 hrs, whereupon it was diluted with ethyl acetate (150 mL), washed with sat. aq. NH4Cl (3*15 mL), and brine (5*25 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-2% MeOH/DCM) to give a mixture of I54B (75% by weight, determined by 1HNMR) and tert-butyldiphenylsilanol (2.02 g, 81%) as a clear, colorless oil; used without further purification in the next step. LCMS m/z 448.3 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium tert-butylate; In tetrahydrofuran; at 90℃; for 1h; | To a stirred solution of Intermediate 5 (2.47 g, 8.38 mmol) and tert-butyl (cis-3 hydroxycyclobutyl)carbamate (1.88 g, 10.1 mmol) in tetrahydrofuran (60 mL) was added potassium tert-butoxide (1.03 g, 9.22 mmol). The reaction was heated at 90 C. for one hour, cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and aqueous ammonium chloride solution. The organic layer was dried (MgSO4) and concentrated to afford crude product which was purified by automated flash chromatography (Combiflash instrument; 0 to 100% ethyl acetate in dichloromethane; 120 g silica column). The title compound was obtained as a white solid (2.50 g, 67%). MS: 446 m/z (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 60℃; for 3h; | 1.2 Step 2: Preparation of tert-butyl ((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)carbamate To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (5.7 g, 20.8 mmol), tert-butyl (1,3-cis)-N-(3-hydroxycyclobutyl)carbamate (3.9 g, 20.8 mmol) and PPh3 (6.5 g, 24.9 mmol) in THF (50 mL) stirred under hydrogen at 60° C. was added DEAD (4.3 g, 24.9 mmol). The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the crude product (11 g, 17.4 mmol, 70% purity, 83% yield) as a yellow solid. |
|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 60℃; | 1 Step 1 Into a 100-mL round-bottom flask, was placed PPI13 1.5 equiv), THF (30 mL), DIAD 1.2 equiv), tert-butyl N-[(ls,3s)-3-hydroxycyclobutyl]carbamate (500 mg, 1 equiv), and 2-(2,6- dioxopiperidin-3-yl)-5-hydroxy-2,3-dihydro-lH-isoindole-l,3-dione 1 equiv). The resulting solution was stirred for overnight at 60 °C in an oil bath. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (40 mL). The resulting mixture was washed with brine (40 mL). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1/1). The collected fractions were combined and concentrated. This resulted in 1.5 g (crude) of tert-butyl N-[(lr,3r)-3-[[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5- yl]oxy]cyclobutyl]carbamate as a yellow solid. | |
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51 % | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 50 - 60℃; Inert atmosphere; | 93.1 Step 93.1: Synthesis of tert-butyl ((1r,3r)-3-(3-fluoro-4-(trifluoromethoxy)phenoxy)cyclobutyl)carbamate To the solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (100 mg, 0.53 mmol) in THF (0.5 M), 3-fluoro-4-(trifluoromethoxy)phenol [CAS No.177596-38-2] (100 mg, 0.53 mmol), PPh3(1.5 eq) and diisopropyl azodicarboxylate (1.5 eq) were added at rt. The reaction mixture was stirred at 50 - 60 °C for 16 h under N2atmosphere. Reaction mixture was diluted with water and extracted with EtOAc (3x’s). The combined organic portion was washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g SiliCycle column, 0 - 20% EtOAc in Hexane elution) to provide tert- butyl ((1r,3r)-3-(3-fluoro-4-(trifluoromethoxy)phenoxy)cyclobutyl)carbamate (100 mg, 51%).1H NMR (300 MHz, CDCl3) δ 7.15 (t, J = 8.7 Hz, 1H), 7.69 (dd, J = 11.1, 3.0 Hz, 1H), 6.62 - 6.58 (m, 1H), 4.77 - 4.69 (m, 1H), 4.33 - 4.27 (m, 1H), 2.60 - 2.51 (m, 2H), 2.43 - 2.35 (m, 2H), 1.45 (s, 9H). |
51 % | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 50 - 60℃; Inert atmosphere; | 93.1 Step 93.1: Synthesis of tert-butyl ((1r,3r)-3-(3-fluoro-4-(trifluoromethoxy)phenoxy)cyclobutyl)carbamate To the solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (100 mg, 0.53 mmol) in THF (0.5 M), 3-fluoro-4-(trifluoromethoxy)phenol [CAS No.177596-38-2] (100 mg, 0.53 mmol), PPh3(1.5 eq) and diisopropyl azodicarboxylate (1.5 eq) were added at rt. The reaction mixture was stirred at 50 - 60 °C for 16 h under N2atmosphere. Reaction mixture was diluted with water and extracted with EtOAc (3x’s). The combined organic portion was washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g SiliCycle column, 0 - 20% EtOAc in Hexane elution) to provide tert- butyl ((1r,3r)-3-(3-fluoro-4-(trifluoromethoxy)phenoxy)cyclobutyl)carbamate (100 mg, 51%).1H NMR (300 MHz, CDCl3) δ 7.15 (t, J = 8.7 Hz, 1H), 7.69 (dd, J = 11.1, 3.0 Hz, 1H), 6.62 - 6.58 (m, 1H), 4.77 - 4.69 (m, 1H), 4.33 - 4.27 (m, 1H), 2.60 - 2.51 (m, 2H), 2.43 - 2.35 (m, 2H), 1.45 (s, 9H). |
Tags: 389890-43-1 synthesis path| 389890-43-1 SDS| 389890-43-1 COA| 389890-43-1 purity| 389890-43-1 application| 389890-43-1 NMR| 389890-43-1 COA| 389890-43-1 structure
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H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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