* 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.
With ammonium chloride; zinc In methanol at 20℃; for 18 h; Inert atmosphere
Butyl-5,5-dichloro-6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.65 g, 5.89 mmol, 1.0 eq)Zinc powder (0.85 g, 15.0 mmol, 2.6 eq)Ammonium chloride (1.2 g, 22.0 mmol, 3.8 eq) was added to methanol (30 mL) and reacted at room temperature for 18 h under nitrogen. After completion of the reaction, water (40 mL) was added, EA (30 mL x 2) was extracted, dried, , PE: EA (v / v) = 5: 1 column chromatography to give 0.8 g of product as a white solid in 66.0percent yield.
0.42 g
With acetic acid; zinc In 1,4-dioxane at 0 - 20℃; for 15 h;
Step 3: Preparation tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate [0219] A solution of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2- carboxylate (1 g, 3.5 mmol) in dioxane (20 mL) was added drop wise to a suspension of zinc powder (0.7 g, 10.71 mmol) in acetic acid (20 mL) at 0 °C and the reaction mixture was stirred at room temperature for 15 h. Then the reaction mixture was filtered through celite, filtrate was basified with 33percent sodium hydroxide solution and extracted with ethyl acetate (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The crude material was purified by combiflash purifier using 30percent ethyl acetate in hexane to afford the title compound tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (0.42 g, 58 percent yield) as a pale yellow solid. 1H NMR (400 MHz, CDC13) δ 4.12 (s, 4H), 3.28 (s, 4H), 1.45 (s, 9H).
With sodium tetrahydroborate In methanol at 0℃; for 0.5 h; Inert atmosphere
Step 8 terf-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate [00179] To a solution of ferf-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (507 mg, 2.4 mmol) in MeOH (5.0 mL) was added NaBH4 (182 mg, 4.8 mmol) at 0 °C under N2. It was stirred at 0 °C for 30 min. The solution was concentrated by evaporator in vacuo to give crude solid. A saturated solution of NaHCO3 (30 mL) was added. The aqueous mixture was extracted with DCM (4x30 mL). The combined organic solution was dried over anhydrous Na2SO4 and then concentrated by evaporation in vacuo to afford terf-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (5 mg, 100percent) as a white solid. [00180] 1HNMR (300 MHz, CDCI3): δ 4.18 (m, 1 H), 3.88 (d, 4 H), 2.53 (m, 2 H), 2.08 (m, 2 H), 1.42 (s, 9 H).
95%
With sodium tetrahydroborate In methanol at 20℃; for 1 h;
Tert-Butyl tert-butyl tert-butyl tert-butyl tert-butyl t-butyl-6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (0.23 g, 1.1 mmol, 1 eq)To the methanol (8 mL), sodium borohydride (0.12 g, 3.2 mmol, 2.9 eq) was added in portions and reacted at room temperature for 1 h. After the reaction, water (20 mL) was added and extracted with EA (20 mL x 2) The residue was dried over sodium sulf
93.7%
at 0 - 25℃; for 1 h; Inert atmosphere
Tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (4.22 g, 20 mmol) was added in methanol (30 mL), cooled under nitrogen gas protection to 0°C, and sodium borohydride (1.52 g, 40 mmol) was added. After addition, the reaction solution was heated to 25°C and stirred for 1 h, after completing reaction as measured by LC-MS, water (1 mL) was added to quench reaction, solvent was removed by vacuum distillation, water (100 mL) and ethyl acetate (100 mL) were added, the phases were separated, the organic phase was washed with hydrochloric acid (1 mol/L, 50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain the title compound in white color (4.0 g, yield 93.7 percent).
89.2%
With sodium tetrahydroborate In ethyl acetate at 0 - 20℃; for 0.666667 h;
t-Butyl 2-oxo-6-azaspiro[3.3]heptane-6-carboxylate (2.00 g, 9.47 mmol) was dissolvedin EtOAc (40 mL). The mixture was cooled to 0 °C, and sodium borohydride (548 mg, 14.19 mmol) was added in portions, the mixture was stirred for 10 min at 0 °C, and then further stirredat rt for 30 min. The mixture was cooled to 0 °C, and quenched with saturated aqueousammonium chloride (2.0 mL). The mixture was stirred for 30 min, water (20 mL) and ethylacetate (50 mL) were added, and the mixture was stirred for 10 min. After the mixture waspartitioned, the water phase was extracted with ethyl acetate (100 mL x 2). The combined organicphases were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated in vacuo to get the title compound as an off-white solid(1.80 g, 89.2percent).MS (ESI, pos. ion) m/z:236.1 [M+Ht
Reference：
[1] Patent: WO2013/13308, 2013, A1, . Location in patent: Paragraph 00178-00180
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5663 - 5672
[3] Patent: CN106565706, 2017, A, . Location in patent: Paragraph 0179; 0180; 0181
[4] Patent: EP3281942, 2018, A1, . Location in patent: Paragraph 0105; 0106
[5] Patent: WO2018/133858, 2018, A1, . Location in patent: Paragraph 00221
[6] Patent: US2012/129830, 2012, A1, . Location in patent: Page/Page column 13
[7] Tetrahedron, 2016, vol. 72, # 46, p. 7268 - 7275
With ammonium chloride; zinc; In methanol; at 20℃; for 18h;Inert atmosphere;
Butyl-5,5-dichloro-6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.65 g, 5.89 mmol, 1.0 eq)Zinc powder (0.85 g, 15.0 mmol, 2.6 eq)Ammonium chloride (1.2 g, 22.0 mmol, 3.8 eq) was added to methanol (30 mL) and reacted at room temperature for 18 h under nitrogen. After completion of the reaction, water (40 mL) was added, EA (30 mL x 2) was extracted, dried, , PE: EA (v / v) = 5: 1 column chromatography to give 0.8 g of product as a white solid in 66.0percent yield.
With ammonium chloride; zinc; In methanol; at 20℃; for 12h;Cooling with ice;
11.2.tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate15.13 g (0.283 mmol) of ammonium chloride are added to a solution containing 13.21 g (47.15 mmol) of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, obtained in the preceding step, in 250 mL of methanol.The reaction medium is cooled with the aid of an ice/water bath, and 30.83 g (0.471 mmol) of zinc are added.After stirring at room temperature for 12 hours, the Celite is filtered off and rinsed with methanol.The filtrate is evaporated to dryness.The residue obtained is taken up in water and extracted several times with ethyl acetate.The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure.After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 90/10 mixture of cyclohexane and ethyl acetate.1.78 g of pure product are thus obtained in the form of a white powder.m.p. (° C.): 117-119° C.LC-MS: M+H=2121H NMR (DMSO) delta (ppm): 4.05 (s, 4H); 3.30 (s, 4H); 1.40 (s, 9H).
With acetic acid; zinc; In 1,4-dioxane; at 0 - 20℃; for 16h;
9.66 g (147.73 mmoles) of Zn powder are suspended in 150 ml of glacial acetic acid. The medium is cooled to 0° C. and the crude solution of tert-butyl 5,5-dichloro-6-oxo-2-aza-spiro[3.3]-heptane-2-carboxylate, obtained in stage 10.1, in 30 ml of dioxan is added drop by drop. After stirring for 16 hrs at ambient temperature, the medium is slowly poured in portions into a saturated aqueous solution of sodium carbonate. After rebasification with sodium carbonate, the medium is stirred for one hour, then filtered on a fritted filter and the filtrate is extracted three times with ethyl acetate. The combined organic phases are washed once with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography eluting with a 90/10 then 80/20 and 60/40 mixture of cyclohexane and ethyl acetate. 2.4 g of the expected product are obtained in the form of a brown gum.1H NMR (DMSO) delta (ppm): 4.05 (s, 4H); 3.30 (s, 4H); 1.40 (s, 9H).
0.42 g
With acetic acid; zinc; In 1,4-dioxane; at 0 - 20℃; for 15h;
Step 3: Preparation tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate [0219] A solution of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2- carboxylate (1 g, 3.5 mmol) in dioxane (20 mL) was added drop wise to a suspension of zinc powder (0.7 g, 10.71 mmol) in acetic acid (20 mL) at 0 °C and the reaction mixture was stirred at room temperature for 15 h. Then the reaction mixture was filtered through celite, filtrate was basified with 33percent sodium hydroxide solution and extracted with ethyl acetate (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The crude material was purified by combiflash purifier using 30percent ethyl acetate in hexane to afford the title compound tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (0.42 g, 58 percent yield) as a pale yellow solid. 1H NMR (400 MHz, CDC13) delta 4.12 (s, 4H), 3.28 (s, 4H), 1.45 (s, 9H).
With sodium tetrahydroborate; In methanol; at 0℃; for 0.5h;Inert atmosphere;
Step 8 terf-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate [00179] To a solution of ferf-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (507 mg, 2.4 mmol) in MeOH (5.0 mL) was added NaBH4 (182 mg, 4.8 mmol) at 0 C under N2. It was stirred at 0 C for 30 min. The solution was concentrated by evaporator in vacuo to give crude solid. A saturated solution of NaHCO3 (30 mL) was added. The aqueous mixture was extracted with DCM (4x30 mL). The combined organic solution was dried over anhydrous Na2SO4 and then concentrated by evaporation in vacuo to afford terf-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (5 mg, 100%) as a white solid. [00180] 1HNMR (300 MHz, CDCI3): delta 4.18 (m, 1 H), 3.88 (d, 4 H), 2.53 (m, 2 H), 2.08 (m, 2 H), 1.42 (s, 9 H).
100%
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 6h;
To a solution of <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (845 mg) in MeOH (20 mL) was added NaBH4(152 mg) at 0 C. The mixture was stirred at r.t. for 6 hrs. TLC showed the reaction was complete. The mixture was concentrated and the residue was purified by column chromatography (silica gel, 1 % ~ 10 % MeOH in DCM) to give tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (853 mg, quantitive) as white solid. 1H NMR (400 MHz, DMSO-d6 ) d 5.00 (d, J = 6.2 Hz, 1H), 3.92 (q, J = 7.0 Hz, 1H), 3.75 (d, J = 21.0 Hz, 4H), 2.37 (ddd, J = 11.8, 6.1, 2.6 Hz, 2H), 1.95 - 1.86 (m, 2H), 1.35 (s, 9H). LC MS: m/z (M+l)+ 214.
95%
With sodium tetrahydroborate; In methanol; at 20℃; for 1h;
Tert-Butyl tert-butyl tert-butyl tert-butyl tert-butyl t-butyl-6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (0.23 g, 1.1 mmol, 1 eq)To the methanol (8 mL), sodium borohydride (0.12 g, 3.2 mmol, 2.9 eq) was added in portions and reacted at room temperature for 1 h. After the reaction, water (20 mL) was added and extracted with EA (20 mL x 2) The residue was dried over sodium sulf
93.7%
With methanol; sodium tetrahydroborate; at 0 - 25℃; for 1h;Inert atmosphere;
Tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (4.22 g, 20 mmol) was added in methanol (30 mL), cooled under nitrogen gas protection to 0C, and sodium borohydride (1.52 g, 40 mmol) was added. After addition, the reaction solution was heated to 25C and stirred for 1 h, after completing reaction as measured by LC-MS, water (1 mL) was added to quench reaction, solvent was removed by vacuum distillation, water (100 mL) and ethyl acetate (100 mL) were added, the phases were separated, the organic phase was washed with hydrochloric acid (1 mol/L, 50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain the title compound in white color (4.0 g, yield 93.7 %).
89.2%
With sodium tetrahydroborate; In ethyl acetate; at 0 - 20℃; for 0.666667h;
t-Butyl 2-oxo-6-azaspiro[3.3]heptane-6-carboxylate (2.00 g, 9.47 mmol) was dissolvedin EtOAc (40 mL). The mixture was cooled to 0 C, and sodium borohydride (548 mg, 14.19 mmol) was added in portions, the mixture was stirred for 10 min at 0 C, and then further stirredat rt for 30 min. The mixture was cooled to 0 C, and quenched with saturated aqueousammonium chloride (2.0 mL). The mixture was stirred for 30 min, water (20 mL) and ethylacetate (50 mL) were added, and the mixture was stirred for 10 min. After the mixture waspartitioned, the water phase was extracted with ethyl acetate (100 mL x 2). The combined organicphases were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated in vacuo to get the title compound as an off-white solid(1.80 g, 89.2%).MS (ESI, pos. ion) m/z:236.1 [M+Ht
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
0.494 g (13.06 mmoles) of sodium borohydride is added in portions at 0 C. to a solution of 2.30 g (10.89 mmoles) of tert-butyl 6-oxo-2-aza-spiro[3.3]-heptane-2-carboxylate, obtained in stage 10.2, in 55 ml of methanol. The reaction mixture is stirred for 1 hr at ambient temperature. After evaporation of the solvent, water is added to the reaction mixture, the aqueous phase is separated, it is extracted several times with dichloromethane, and the combined organic phases are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and the filtrate is concentrated under reduced pressure. After crystallisation of the residue in diisopropyl ether, filtration of the solid obtained and drying under vacuum at 60 C., 2.24 g of product are obtained in the form of a beige powder.1H NMR (DMSO) delta (ppm): 5.00 (d, 1H); 3.95 (hex, 1H); 3.75 (d, 4H); 2.40 (m, 2H); 1.95 (m, 2H); 1.40 (s, 9H).
tert-butyl 6-(4-(5-fluoro-2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-(2,2,2-trifluoroacetoxy)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
tert-butyl 6-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 4-chloro-2-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (83 mg, 0.191 mmol) in tetrahydrofuran (500 mL), at -78°C under nitrogen was added 1.6 M n-butyl lithium in hexane (251 0.401 mmol). The mixture was stirred for 2 minutes and a solution of tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (81 mg, 0.382 mmol) in tetrahydrofuran (250 vL) was added by syringe. The mixture was stirred at -78°C for 1 hour and was slowly warmed to ambient temperature overnight. The mixture was poured into 15 mL saturated aqueous ammonium chloride and ethyl acetate was added (10 mL). The organic layer was washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column, 0-70percent ethyl acetate/hexane, linear gradient) afforded the title compound. lH NMR (500 MHz, dimethylsulfoxide-d6) delta 8.29 (d, J= 5.3 Hz, 1H), 8.20 - 8.13 (m, 2H), 7.44 - 7.35 (m, 3H), 6.88 (s, 1H), 5.83 (s, 1H), 3.96 (s, 2H), 3.80 (s, 2H), 3.05 (d, J= 12.9 Hz, 2H), 2.65 (d, J= 12.5 Hz, 2H), 2.34 (s, 3H), 1.37 (s, 9H). MS (ESI+) m/z 518.3 (M+H)+.
(E)-10-amino-1-methoxy-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4,3-j][1]azacyclododecin-14(9H)-one[ No CAS ]
[ 75-07-0 ]
(E)-tert-butyl 6-(ethyl(1-methoxy-3-methyl-14-oxo-5,6,9,14,15,16-hexahydrobenzo[c]pyrido[4,3-j][1]azacyclododecin-10-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.2%
(a) (E)-tert-butyl 6-(ethyl(l-methoxy-3-methyl-14-oxo-5,6,9,14,15,16- hexahydrobenzo [c] pyrido [4,3-j] [1] azacyclododecin-10-yl)amino)-2- azaspiro [3.3] heptane-2-carboxylat To a stirred suspension of (E)-10-amino-l-methoxy-3-methyl-5,6,15, 16- tetrahydrobenzo[c]pyrido[4,3-j][l]azacyclododecin-14(9H)-one (200 mg, 0.593 mmol) and <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (250 mg, 1.185 mmol) in DCE (6 mL) was added AcOH (0.034 mL, 0.593 mmol). The suspension was stirred for 1 h at room temperature, then Na(OAc)3BH (251 mg, 1.185 mmol) was added in one portion and the reaction was stirred overnight at room temperature. AcOH (0.170 mL, 2.96 mmol), acetaldehyde (0.167 mL, 2.96 mmol), Na(OAc)3BH (377 mg, 1.778 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into aqueous NaHC03 (50 mL) then extracted with DCM (3 x 50 mL). The combined organics were washed with brine (30 mL), dried over Na2S04, filtered, concentrated and the residue was purified by flash column chromatography (0-50percent EtOAc in hexanes, 24 g column) to afford (E)-tert-butyl 6-(ethyl( l-methoxy-3 -methyl- 14-oxo- 5,6,9,14, 15,16-hexahydrobenzo[c]pyrido[4,3-j][l]azacyclododecin-10-yl)amino)-2- azaspiro[3.3]heptane-2-carboxylate (210 mg, 0.375 mmol, 63.2 percent yield) as a white solid. LC-MS(ES) m/z = 561.5 [M+H]+ (minor), 505.4 (major).
tert-butyl 6-benzyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
In tetrahydrofuran; diethyl ether; at 20℃; for 3h;
Step 4: Preparation of tert-butyl 6-benzyl-6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate [0220] Benzyl magnesium chloride solution (8.75 mL, 8.75 mmol, 1 M in diethyl ether) was added drop wise to a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2- carboxylate (0.37 g, 1.75 mmol) in tetrahydrofuran (10 mL) at 0 °C and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was cooled, quenched with saturated ammonium chloride solution and extracted with ethyl acetate (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The crude material was purified by combiflash purifier using 30percent ethyl acetate in hexane to afford the title compound tert-butyl 6-benzyl-6-hydroxy-2- azaspiro[3.3]heptane-2-carboxylate (0.35 g, 69 percent yield) as a white solid. Calculated M+H: 304.40; Found M+H: 204.1 (M-boc).
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1h;
Step 1: 2-Azaspiro[3. 3]heptan-6-oneTo a 25 mL round-bottomed flask was added tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2- carboxylate (600 mg, 2.84 mmol) and 4M HCI in dioxane (lOmI) to give a colorless solution.The reaction was stirred at room temperature for 1 hour. A thick white suspension formed. The crude reaction was filtered under reduced pressure to afford a white solid which was used without further purification;
2-Boc-6-oxo-2-azaspiro[3.3]heptane (0.65 g, 3.08 mmol) was added portionwise tohydrogen chloride (4 M dioxane solution, 3.10 mL, 12.40 mmol). After 24 h, thereaction was concentrated in vacuo and the residual solid dissolved in a mixture ofEt3N (0.86 mL, 6.15 mmol) and DCM (13.5 mL). On completion of dissolution thesolution was immediately cooled to 0 00 then ethyl chloroformate (0.32 mL, 3.38mmol) was added dropwise. After 18 h, the mixture was poured into DCM (50 mL) andNaHCO3 solution (50 mL) and extracted (2 x 50 mL). The organic layers were combined, washed with brine (10 mL), then dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 tim, 60 A, 50 mL per mm, gradient5 1 to 10percent MeOH in DCM]) to provide ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, Intermediate 2, as a colourless oil which solidified to needles on standing (0.17 g, 30percent).
tert-butyl 6-(4-methylpiperazin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
a3.1) tert-butyl 6-(4-methylpiperazin-l-yl)-2-azaspiro[3.3]heptane-2-carboxylate 1-Methylpiperazin (4.73 mmol, 0.47 g) and concentrated acetic acid (0.5 mL) were added to a solution of <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (4.73 mmol, 1.0 g) in EtOH (15 mL). It was stirred for lh and NaCNBH3 (5.68 mmol, 0.36 g) was added portionswise, and the reaction mixture was further stirred over night at rt. The mixture was poured onto cold 5percent aq. K2CO3 (15 mL) and extracted three-times with ethyl acetate (15 mL); the organic phases were combined, washed with water three-times (15 mL), dried on Na2S04, filtered and evaporated in vacuo. It was passed through a silicagel column [eluent: l .)EtOAc:MeOH 17:3 and 2.) CH2Cl2:MeOH 1 : 1]. Yield: 1.1 g (78percent). ESI-MS: [M+H+] = 296.2
tert-butyl 6-methylidene-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
tert-Butyl N-(2-[3-[([2-fluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]phenyl]methyl)carbamoyl]-1,2,4-oxadiazol-5-yl]propan-2-yl)carbamate In a 25-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, sodium hydride (60percent in oil, 12.50 mg, 0.52 mmol, 1.10 equiv) was suspended in tetrahydrofuran (5 ml), to which was added a solution of methyltriphenylphosphanium bromide (507.3 mg, 1.42 mmol, 3.0 equiv) in DMSO (2 ml) dropwise at 0° C. The mixture was warmed up to room temperature and stirred for 2 h. Then a solution of <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (100 mg, 0.47 mmol, 1.00 equiv) in tetrahydrofuran (2 ml) was added at room temperature. The resulting mixture was stirred for another 16 h at room temperature. When the reaction was done, it was quenched by the addition of 10 mL water and the mixture was extracted with ethyl acetate (3*10 ml). The organic layers were combined, dried over sodium sulfate and concentrated under reduce pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (5percent to 20percent gradient) to afford tert-butyl 6-methylidene-2-azaspiro[3.3]heptane-2-carboxylate (50 mg, 50percent) as yellow solid.
tert-butyl 7-oxo-6-oxa-2-azaspiro[3.4]octane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With alpha-D-glucopyranose; glucose dehydrogenase (GDH-105); Baeyere-Villiger monooxygenase P3-C07; oxygen; NADPH; In methanol; aq. phosphate buffer; at 30℃; for 24h;pH 9.0;Enzymatic reaction;
General procedure: In a typical experiment carried out in 1.5 mL tubes (total volume of 500 muL), the substrate 1a-j, m-v (10 mM) was dissolved in methanol (5 muL, 1percent v/v) and KPi buffer (100 mM, pH 9.0, 482 muL), containing glucose (20 mM), glucose dehydrogenase (GDH-105, 10 U, from stock solution of 1.275 U/muL), NADPH (0.2 mM, from a 20 mM stock solution) and the corresponding Baeyere-Villiger monooxygenase (2 mg). The mixture was shaken at 250 rpm at 30 °C for 24 h. The reaction was stopped by extracting with diethyl ether (2x400 muL) and centrifugedat 13,000 rpm in order to separate both phases and pellet the suspended protein. The organic phases were combined, dried over anhydrous sodium sulfate and analyzed by GC in order to determine the conversion values. Then, the solvent in GC samples was evaporated with a continuous flow of nitrogen, the residue redissolved in a mixture of hexane:ethanol 90:10 and the new sample filtered and analyzed by HPLC, leading to the measurement of the enantiomeric excess of the lactones. Control experiments in the absence of enzyme were performed for all substrates, not observing any reaction product after similar periods of time (Tables S1-S19).
tert-butyl 7-oxo-6-oxa-2-azaspiro[3.4]octane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 20h;
General procedure: To an ice-cooled solution of the corresponding cyclobutanone 1b?t (0.25 mmol) in dichloromethane (1.0 mL), m-chloroperbenzoic acid (MCPBA, 88 mg, 0.50 mmol) was added, and the resulting mixture stirred for 20 h at room temperature. Then, more dichloromethane was added (5 mL) and the solution washed repeatedly with a saturated aqueous solution of sodium bicarbonate (6×5 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. Purification by column chromatography on silica gel (10?30percent EtOAc/hexane) afforded lactones 2b?t in 38?99percent yield (83percent for 2b; 72percent for 2c; 99percent for 2d; 85percent for 2e; 86percent for 2f; 88percent for 2g; 44percent for 2h; 96percent for 2i; 77percent for 2m; see below for 2j?l,n?t).
ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
2-Boc-6-oxo-2-azaspiro[3.3]heptane (0.65 g, 3.08 mmol) was added portionwise to 4.0M HCI in 1 ,4-dioxane (3.1 ml, 12 mmol). After 24 h, the reaction was concentrated in vacuo and the residual solid dissolved in a mixture of NEt3 (0.86 ml, 6.15 mmol) and DCM (13.5 ml). On completion of dissolution the solution was immediately cooled to 0 °C, then ethyl chloroformate (0.32 ml, 3.38 mmol) was added dropwise. After 18 h, the mixture was poured into DCM (50 ml) and NaHC03 solution (50 ml) and extracted (2 chi 50 ml). The organic layers were combined, washed with brine (10 ml), then dried over MgS04. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63muetaiota, 6thetaAlpha, 50 mL per min, gradient 1 percent to 10percent MeOH in DCM]) to provide ethyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate as a colourless oil which solidified to needles on standing (0.17 g, 30percent).
(trans)-2-((E)-1-phenylbut-1-en-2-yl)cyclopropanamine hydrochloride[ No CAS ]
tert-butyl 6-(((trans)-2-((E)-1-phenylbut-1-en-2-yl)cyclopropyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; for 0.5h;
To (trans)-2-((E)-l-phenylbut-l-en-2-yl)cyclopropanamine hydrochloride (177 mg, 794 muiotaetaomicron) and <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (167 mg, 794 muiotaetaomicron) in 1,2-DCE (8 mL) and sodium triacetoxyborohydride (350 mg, 1.66 mmol). After 30 min, the reaction was quenched with K2CO3, and extracted with DCM (2X50 mL). The organic phase was concentrated to afford crude tert-butyl 6-(((trans)-2-((E)-l-phenylbut-l-en- 2-yl)cyclopropyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (303 mg, 792 muiotaetaomicron). LCMS m/z 383 [M+H+].
(1RS,2SR)-2-((E)-1-phenylbut-1-en-2-yl)cyclopropan-1-amine (S)-2-hydroxy-2-phenylacetate[ No CAS ]
tert-butyl 6-(((1RS,2SR)-2-((E)-1-phenylbut-1-en-2-yl)cyclopropyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.35 g
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; for 0.5h;
To {1R,2S or iS,2tf)-2-((E)- l-phenylbut- l-en-2-yl)cyclopropanamine (S)-2- hydroxy-2-phenylacetate (6.82 g, 20.1 mmol) (single stereoisomer) and tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (4.25 g, 20.1 mmol) in 1,2-DCE (100 mL) was added sodium triacetoxyborohydride (8.98 g, 42.4 mmol). After 30 min. the reaction was quenched with K2CO3 (aq.) and extracted with DCM (2X150 mL). The organic phase was concentrated and the crude residue was purified via column chromatography (40g column, 5percent to 100percent EtOAc:hexanes)to afford tert-butyl 6-(((lR,2S or iS,2tf)-2-((E)- l-phenylbut- l-en-2- yl)cyclopropyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (single stereoisomer) (1.35 g, mmol). LCMS M/Z: 383.7 (M+H).
With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 19h;
Preparation of intermediate EH To a solution of tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1181816-12-5], 1 g, 4.73 mmol) in dry DCM (50 mL) at 0 °C was added DAST (1.86 mL, 14.2 mmol), then the mixture was warmed to room temperature and stirred for 16 h. Additional DAST (0.62 mL, 1 eq., 4.73 mmol) was added, then the mixture was stirred at room temperature for 3 h. The mixture was quenched with sat. NaHC03, then stirred for 10 min. The layers were separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgS04, filtered off and evaporated to dryness to give 1.02 g of intermediate EH as a yellow solid (76percent).
Preparation of intermediate AS TFA (1.6 mL, 21 mmol) was added to a solution of tert-butyl 6-oxo-2-azaspiro[3.3] heptane-2-carboxylate (CAS [1181816-12-5], 0.3 g, 1.4 mmol) in dichloromethane (9.8 mL) and the mixture was stirred at room temperature for 18h. The reaction mixture was evaporated under vacuum, and coevaporated twice with toluene to afford 320 mg of Intermediate AS as a colorless oil (100percent).
With zirconium(IV) chloride; orthoformic acid triethyl ester; In dichloromethane; at 20℃; for 5h;Inert atmosphere;
Preparation of intermediate DE A solution of 2-Boc-2-azaspiro[3.3]heptan-6-one (CAS [1181816-12-5], 0.5 g, 2.37 mmol), 1,3-propanediol (0.26 mL, 3.55 mmol), ethylorthoformate (0.39 mL, 2.37 mmol) and zirconium chloride (0.028 g, 0.118 mmol) in anhydrous DCM (10 mL) was stirred under N2 for 2 h at room temperature. After 2h, 0.25 eq of ethylorthoformate (0.099 mL, 0.59 mmol) and 0.5 eq. of 1,3-propanediol (0.09 mL, 1.18 mmo 1) were added After 5 h: the reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL). The organic phase was washed with water, dried over MgS04, filtered and evaporated to dryness to give 0.633 g of intermediate DE as a colorless oil.
With potassium fluoride; 2-fluoropyridine; silver trifluoromethanesulfonate; Selectfluor; In tetrahydrofuran; ethyl acetate; at 20℃; for 72h;Inert atmosphere;
Preparation of intermediate DI A suspension of silver triflate (3.6 g, 14.1 mmol), Selectfluor® (2.49 g, 7.03 mmol), potassium fluoride (1.09 g, 18.8 mmol) and 6-oxo-2-azaspiro[3.3]heptane-2-carbo- xylate (CAS [1147557-97-8], 1.00 g, 4.69 mmol) was purged with N2. Then, EtOAc (24 mL), 2-fluoropyridine (1.21 mL, 14.1 mmol) and trifluoromethyltrimethylsilane 2M in THF (7.03 mL, 14.1 mmol) were added, the mixture was purged again and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was then filtered on Celite® and evaporated to dryness. The crude product was purified by preparative LC (irregular silica, 15-40 muiotaeta, 50 g, Merck, dry loading (Celite®), mobile phase gradient: Heptane/EtOAc from 90/10 to 50/50) to give 0.64 g of intermediate DI as a white crystals (49percent).
tert-butyl 6-((2-aminophenyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 1.16667h;Inert atmosphere;
To 1 ,2-phenylenediamine (1,54 g, 14,2 mmol) in methanol (50 mL) under a nitrogen atmosphere were <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (1 .00 g, 4,73 mmol), acetic acid (0,38 mL, 6,64 mmol) and sodium cyanoborohydride (447 mg, 7,11 mmol) successively added. The resulting mixture was stirred at room temperature for 1 h 10 mm and was then concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous phase was extracted with fresh ethyl acetate. The organic extracts were passed through a phase separator and concentrated under reduced pressure. The afforded residue was purified by flash chromatography using a gradient of 0-100 percent ethyl acetate in heptane. The desired fractions were pooled and concentrated under reduced pressure and the residue was further purified by flash chromatography using first isocratic elution with dichloromethane (2 CV) then isocratic elution with 5 percent methanol in dichloromethane (6 CV). The desired fractions were pooled and concentrated under reduced pressure to give the title compound and a byproduct (957 mg, 57percent), which was used as such in next step without further purification.MS (ES+) m/z 304 [M+H], (ES-) m/z 362 [M+OAc].
4-1-methyl-1H-imidazol-2-yl-piperidine hydrochloride[ No CAS ]
C20H32N4O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4-(1-Methyl-1H-imidazol-2-yl-piperidine hydrochloride (0.303 g, 1.50 mmol) and 2-Boc-6-oxo-2-azaspiro[3.3]heptane (0.317 g, 1.50 mmol) were suspended in DCM (10 mL) at rt and triethylamine (0.42 mL, 3.0 mmol) was added. The reaction mixture wasstirred at rt for 1 h, acetic acid (0.26 mL, 4.50 mmol) added stirred for 3 h. STAB (0.80 g, 3.75 mmol) was added and the reaction mixture was stirred overnight under nitrogen. The reaction mixture was quenched with the addition of sat. aqueous NaHCO3 (15 mL) extracted with DCM (4 x 30 mL) and the solvents removed in vacuo. The residue was dissolved in DCM (15 mL), 4 M hydrogen chloride in dioxane (1.88 ml, 7.50 mmol) was added and the reaction mixture was stirred at rt for 18 h. The volatiles were then removed in vacuo and the residue dissolved in DCM (15 mL) andtriethylamine (2.10 mL, 15.0 mmol). Ethyl chloroformate (214 pL, 2.25 mmol) was added dropwise and the solution stirred at rt for 18 h. The mixture was then poured into NaHCO3(aq) (40 ml) and DCM (40 ml), extracted with DCM (3 x 50 ml), and the combined DCM extracts washed concentrated in vacuo. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25g, 40-63tim, 60 A, 50 mL per mm, gradient 1percent to 10percent MeOH in DCM]). The residue wasfurther purified by preparative reversed phase HPLC (Phenomenex Gemini-NX 5 im018 11OA Axia column, 100 x 30 mm, eluting with 20 to 55percent MeCN/Solvent B over14.4 mm at 30 mL/min [where solvent B is 0.2percent of (28percent NH3/H20) in H20] andcollecting fractions by monitoring at 205 nm) to give ethyl 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin- 1 -yl]-2-azaspiro[3. 3]heptane-2-carboxylate, Exam pie 1-2 (60 mg, 12percent),as a colourless solid.
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)sulfonyl)benzamide[ No CAS ]
6-(4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester[ No CAS ]
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(2-azaspiro[3.3]heptan-6-yloxy)3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide[ No CAS ]
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-N-(3-nitro-4-((2-(tetrahydro-2H-pyran-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)phenylsulfonyl)benzamide[ No CAS ]
2-phenylcyclopropan-1-amine hydrochloride[ No CAS ]
[ 407-25-0 ]
tert-butyl 6-(2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetamido)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
To a stirred solution of 2-phenylcyclopropan-l -amine hydrochloride (XXVIII, 0.2 g, 1.17mmol) and <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (0.3 g, 1.41 mmol) in DCE (6 mL) was added sodium triacetoxyborohydride (0.89 g, 4.20mmol) and stirred at room temperature for 0.5 h. Methanol (1 mL) was added and then followed by addition of ethylacetate (10 mL) and I potassium carbonate solutionand the stirring was continued for 30 min.. The organic layer was separated and washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to get the crude. The crude product was diluted with dry dichloromethane (5 mL) and cooled to 0° C. Triethylamine (0.5 mL, 3.51 mmol)and trifluoroacetic anhydride (0.25 mL, 1.70 mmol) were added to it. The reaction mixture was stirred for 30 min. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to get crude which was purified by column chromatography using ethylacetate-hexane gradient to afford the titled product as an brown colour liquid (LX, 0.2 g, 40 percent). LC-MS m/z calcd for C22H27F3N2O3, 424.2; found 425.2 [M+H]+.
tert-butyl 6-(2-methoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.9 g
In toluene; at 20℃; for 19h;Inert atmosphere; Reflux;
To a stirred of 6-Oxo-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.00 g; 9.47 mmol; 1.0 eq.) in toluene (30 mL), were added methyl (triphenylphosphoranylidene)acetate (3.48 g; 10.41 mmol; 1.1 eq). The resulting suspension was stirred for 3 hours at reflux and left to stir over 16 hours at room temperature. The suspension was filtered and the solid washed with MTBE (2 X 10 mL). The filtrate was concentratted to dryness and purified by flash chromatography (silica gel, EtOAc-heptane 10/90) to afford (1.9 g) tert-butyl 6-(2-methoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylateas a colourless oil.MS(ES+) m/z 168(M-Boc+H+).
(2S,5R)-2-((2-(tert-butyloxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylsulfuric acid tetra(n-butyl)ammonium salt[ No CAS ]
tetra(n-butyl)ammonium (2R,5R)-2-((2-(tert-butoxylcarbonyl)-2-azaspiro[3.3]heptan-6-yl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylsulfate[ No CAS ]
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