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CAS No. : | 236406-39-6 | MDL No. : | MFCD09608078 |
Formula : | C13H24N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MGHFVXFMQGQAKJ-UHFFFAOYSA-N |
M.W : | 240.34 | Pubchem ID : | 23282900 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-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 |
---|---|---|
47% | To a solution of 2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (150 mg, 0.6 mmol) in acetonitrile (5.0 mL) were added 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (160 mg, 0.5 mmol) and NaHCO3 (300 mg, 3.6 mmol) and the mixture was refluxed overnight. The reaction mixture was cooled to 0 C., quenched with 0.5 N aq HCl (5 mL) and partitioned between dichloromethane and water. The combined organic layer was dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue was purified with preparative thin layer chromatography (50% ethyl acetate in hexanes) to give the desired product (150 mg, 47%) as a yellow solid. ESI MS m/z 528 (M+H+); 1H NMR (400 MHz, CDCl3) delta 9.25 (d, J=10.8 Hz, 1H), 8.18 (s, 1H), 4.38 (q, J=7.6 Hz, 2H), 3.77-3.72 (m, 2H), 3.53-3.51 (m, 2H), 3.49-3.43 (m, 4H), 2.58 (s, 3H), 2.18-2.14 (m, 1H), 1.91 (t, J=7.2 Hz, 2H), 1.64-1.61 (m, 4H), 1.45 (s, 9H), 1.42 (t, J=7.6 Hz, 3H), 0.96-0.91 (m, 2H), 0.62-0.58 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In tetrahydrofuran; water; at 0 - 20℃; for 1h; | To a solution of 3-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (3 g, 11.8 mmol) in THF (65 mL) was added BH3.THF (1 N in THF, 35 mL) at 0 C. and stirred for 5 minutes. The reaction mixture was heated to reflux overnight and then cooled to 0 C. The mixture was quenched with methanol (30 mL) and evaporated in vacuo. The residue was dissolved in THF (50 mL) and 1 N aq HCl (50 mL) was added to it. The mixture was stirred at room temperature for one hour, cooled to 0 C. and basified with 3 N aq NaOH. The aqueous phase was extracted with dichloromethane twice. The combined organic layer was dried over MgSO4, filtered and evaporated under reduced pressure to give the desired amine (2.8 g, 100%), which was used for next step without further purification. 1H NMR (400 MHz, CD3OD) delta 3.48-3.35 (m, 4H), 3.06 (t, J=6.8 Hz, 2H), 2.80 (s, 2H), 1.73 (t, J=6.8 Hz, 2H), 1.53-1.50 (m, 4H), 1.44 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; benzaldehyde; acetic acid; In tetrahydrofuran; water; | Step 6. Synthesis of 2-benzyl-8-t-butoxycarbonyl-2,8-diazaspiro[4.5]decane To a solution of 10 mg of 8-t-butoxycarbonyl-2,8-diazaspiro[4.5]decane in 1 ml of tetrahydrofuran, 0.01 ml of acetic acid, 0.02 ml of benzaldehyde and 30 mg of sodium triacetoxyborohydride were added successively at room temperature, followed by stirring for 2 hours at the same temperature. The reaction mixture was diluted with ethyl acetate and, after successive washing with a saturated aqueous solution of sodium hydrogen-carbonate, water and brine, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 9 mg of the title compound was obtained by purifying the resulting residue by preparative thin-layer chromatography [Kieselgel60F254, Art 5744 (Merck); chloroform/methanol=15/1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 5. Synthesis of 8-t-butoxycarbonyl-2,8-diazaspiro[4.5]decane The title compound was prepared by procedures similar to Steps 4 and 5 for Example 13 and Step 4 for Example 24, using N-t-butoxycarbonyl-4-(2-hydroxyethyl)-4-hydroxymethylpiperidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With palladium 10% on activated carbon; ammonium formate; In methanol; at 20℃; for 1h;Reflux; Inert atmosphere; | Step b To a solution of ferf-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (from step a, 0.78g, 2.36 mmol) in MeOH (25 mL), ammonium formate (0.9 g, 14.3 mmol) and 10% Pd/C (0.3 g) were added at RT and the mixture was stirred at reflux for 1 h. The mixture was cooled down to RT, filtered through a pad of celite washing with MeOH and the solution concentrated to dryness. The crude material was loaded on a SCX cartridge washing with MeOH and eluting with NH32M in MeOH, affording ferf-butyl 2,8- diazaspiro[4.5]decane-8-carboxylate (p58, 0.56 g, y= 67%).Eta NMR (CHLOROFORM-d): delta ppm 3.33 - 3.50 (m, 4 H), 3.21 (t, 2 H), 2.94 (s, 2 H), 1.80 (t, 2 H), 1.58 (t, 4 H), 1.49 (s, 9 H) |
With hydrogen;palladium(II) hydroxide/carbon; In methanol; under 4395.87 Torr; | Preparation of compound 6 mixture of compound 5 (82 g), 20% Pd(OH)2/C (15 g) and methanol (1 L) was stirred inder 85 Psi of H2 overnight. The mixture was filtered to remove catalyst. Another 16 g of EPO <DP n="89"/>20% Pd(OH)2/C was added and the mixture was stirred under 85 Psi of H2 until the reaction was complete. The mixture was filtered and the filtrate was concentrated to give 59 g of crude product, which was purified by chromatography (CH2Cl2, then 5% NH3 H2OZMeOH) to give compound 6 (30-45 g). 1H NMR (CD4O, HCl salt) delta: 3.58 - 3.35 (m, 6 H), 3.13 (s, 2 H), 1.96 (t, 2 H), 1.59 (t, 4 H), 1.45 (9 H). | |
0.56 g | With palladium 10% on activated carbon; ammonium formate; In methanol; for 1h;Reflux; | To a solution of tert-butyl 2-benzyl-2,8-diazaspiro[4.5]decane-8-carboxylate (from step a, 0.78 g, 2.36 mmol) in MeOH (25 mL), ammonium formate (0.9 g, 14.3 mmol) and 10% Pd/c (0.3 g) were added at RT and the mixture was stirred at reflux for 1 h. The mixture was cooled, filtered through a pad of celite washing with MeOH and the solution was concentrated to dryness. The crude material was loaded on a scx cartridge, washing with MeOH and eluting with NH3 2M in MeOH, affording tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (p160, 0.56 g).1H NMR (CHLOROFORM-d): 6 ppm 3.33 - 3.50 (m, 4 H), 3.21 (t, 2 H), 2.94 (s, 2 H), 1.80 (t, 2 H), 1.58 (t, 4 H), 1.49 (s, 9 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; for 5h; | EXAMPLE 11; 6-(2-acetyl-2,8-diazaspiro[4.5]dec-8-yl)-N-(2-amino-5-(2-thienyl)phenyl]-nicotinamide; A mixture of <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (500 mg, 1.81 mmol) and NEt3 (1.00 mL, 7.19 mmol) in 5 mL of CH2Cl2 was treated with Ac2O and stirred for 5 h. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3, dried (Na2SO4), filtered and concentrated. The oily residue was dissolved in 1 mL of TFA and 3 mL of CH2Cl2, stirred for 1 h and concentrated. Excess TFA was azeotropically removed with methanol. The oily was dissolved in 2 mL DMSO, treated with NEt3 (0.500 mL, 3.59 mmol) and chloronicotinamide F (200 mg, 0.466 mmol), stirred at 90 C for 18 h and partitioned between EtOAc and sat'd NaHCO3. The organic layer was dried (Na2SO4), concentrated and the residue purified by chromatography on SiO2 (MeOH/EtOAc, 0% to 50%). The intermediate was next stirred in 1 mL of TFA and 3 mL of CH2Cl2 for 2 h, concentrated, poured into CH2Cl2/methanol and washed with 2 N NaOH, dried (Na2SO4) and concentrated providing the title compound: 1H NMR (600 MHz, DMSO-d6) delta 9.47 (s, 1 H), 8.72 (s, 1 H), 8.05 (m, 1 H), 7.43 (s, 1 H), 7.33 (d, J=4.7 Hz, 1 H) 7.26 (d, J=8.2 Hz, 1 H), 7.22 (d, J=2.9Hz, 1 H), 7.02 (t, J=4.1 Hz, 1 H), 6.90 (dd, J=8.8, 4.7 Hz, 1 H), 6.78 (d, J=8.2 Hz, 1 H), 5.11 (s, 2 H), 3.72 (m, 2 H), 3.62 (m, 1 H), 3.57 (m, 1 H), 3.48 (t, J=7.0 Hz, 1 H), 3.33 (m, 2 H), 3.20 (s, 1 H), 1.91 (s, 3 H), 1.82 (t, J=7.0 Hz, 1 H), 1.73 (t, J=7.0 Hz, 1 H), 1.50 (m, 4 H); MS (EI) [M+H]+ cal'd 476.1, obs'd 476.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 0.666667h; | EXAMPLE 32; N-(4-[(4-Aminobiphenyl-3-yl)amino]carbonyl}phenyl)-2,8-diazaspiro[4.5]decane-2-carboxamide; To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL dichloromethane was added <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (60 mg, 0.275 mmol) slowly over a period of 10 minutes. The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl (3-aminobiphenyl-4-yl)carbamate (78.2 mg, 0.275 mmol) was then added, followed by the addition of diisopropylethylamine (48 muL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Argonaut MP-Carbonate scavenging resin (285 mg, 0.825 mmol) was then added and stirred overnight at room temperature. The mixture was then filtered from scavenging resin and concentrated. Added dichloromethane (1 mL) and stirred, then treated with trifluoroacetic acid (1 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [M+H]+470.2, obs'd 470.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | EXAMPLE 31; N-(4-Aminobiphenyl-3-yl)-4-(2,8-diazaspiro[4,5]dec-2-ylcarbonyl)benzamide; To a solution of stirring terephthaloyl chloride (338 mg, 1.664 mmol) in 20 mL dichloromethane was added tert-butyl (3-aminobiphenyl-4-yl)carbamate (473 mg, 1.664 mmol) slowly over a period of 10 minutes, followed by the addition of diisopropylethylamine (290 muL, 1.664 mmol). The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl 1,8-diazaspiro[4,5]decane-1-carboxylate (400 mg, 1.664 mmol) was then added, followed by the addition of diisopropylethylamine (290 muL, 1.664 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. The reaction mixture became cloudy. Argonaut MP-Carbonate scavenging resin (1.72 g, 4.992 mmol) was then added and stirred overnight at room temperature. The mixture was then fully dissolved by adding 20 mL dimethylformamide, filtered from scavenging resin, and concentrated. Added dichloromethane (4 mL) and stirred to form suspension, then treated with trifluoroacetic acid (4 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-70-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [M+H]+ 455.2, obs'd 455.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium t-butanolate;palladium diacetate; 2,2'-bis(diphenylphosphino)biphenyl; at 100℃; | A mixture of intermediate compound 1-1 (7.80 g, 0.022 mol), 2,8- diazaspiro[4.5]decane-8-carboxylic acid, 1,1-dimethylethyl ester (6 g, 0.025 mol), Pd(OAc)2 (0.25 g, 0.0011 mol), BINAP (1.12 g, 0.0018 mol) and 1BuONa (2.4 g, 0.025 mol) was stirred overnight under N2 atmosphere in an oil bath at 100 0C. Subsequently the reaction mixture was cooled to room temperature and was filtered over Dicalite. The filter was washed with toluene (200 ml). The filtrate was evaporated and yielded 6 g of <n="48"/>crude residue. The filter was also washed with hot DCM (300 ml). The solvent was evaporated, yielding 12 g of a white solid. The combined residues were crystallized from CH3CN. 8.3 g of a BOC-protected compound was obtained (73 %). This BOC- protected compound (8.3 g, 0.016 mol) was suspended in 2-propanol (200 ml). Then HCl/2-propanol (50 ml; 6 N) was added and a solution was obtained. This solution was heated and a precipitate occurred. The mixture was refluxed for 3 hours after which it was cooled on an ice-bath. The product was filtered off. Yield: 8.0 g of compound 1-15 (99 %; . 2HCl . 0.8 H2O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); CyJohnPhos; In toluene; at 20 - 100℃; for 2h; | Example 50 tert-butyl 2-[4-(2-[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2,8-diazaspiro[4.5]decane-8-carboxylate Under an argon atmosphere, an anhydrous toluene (1 mL) solution of trisdibenzylideneacetone dipalladium (21 mg), biphenyl-2-yl(dicyclohexyl)phosphine (32 mg) and tert-butoxy potassium (306 mg) was stirred at room temperature for one hour. To this solution, an anhydrous toluene (2 mL) solution of the compound (714 mg) obtained in Example 49 and <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (594 mg) was added. The reaction solution was stirred at 100C for one hour. The reaction solution was cooled to room temperature, and then water (10 mL) was added. The aqueous layer was filtered through Celite (trade name). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=98:2?77:23) to obtain the title compound (683 mg) having the following physical properties. TLC: Rf 0.24(n-hexane:ethyl acetate=19:1); NMR(CDCl3):delta 7.07 (d, J=8.4Hz, 2H), 6.48 (d, J=8.4Hz, 2H), 3.73 (t, J=6.9Hz, 2H), 3.49 (m, 2H), 3.36 (m, 4H), 3.14 (s, 2H), 2.73 (t, J=6.9Hz, 2H), 1.87 (t, J=6.9Hz, 2H), 1.56 (m, 4H), 1.46 (s, 9H), 0.89 (s, 9H), -0.03 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 5: tert-butyl 2-[(2-[({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}rnethyl)(methyl)amino]methyl}-1H-imidazol-1-yl)acetyl]-2,8-diazaspiro[4.5]decane-8-carboxylate To an N,N-dimethylformamide (5 mL) solution of the compound (522 mg) synthesized in Example 4 and <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (346 mg), N,N-diisopropylethylamine (0.38 mL) and N,N,N',N'-tetramethyluroniumhexafluorophosphate (HATU) (674 mg) were added. The reaction solution was stirred at room temperature for one hour. To the reaction solution, an aqeuous sodium hydrogencarbonate solution(20 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, the organic solvent was conentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane : ethyl acetate = 4 : 1 ? 0 : 1) to obtain the title compound (656 mg) having the following physical properties. TLC: Rf 0.13 (dichloromethane : methanol : 28% ammonia water = 90 : 10 : 1); NMR(CDCl3): delta 1.46(s, 9H), 1.54(m, 4H), 1.78(t, J = 7.2 Hz, 1H), 1.89(t, J = 7.2 Hz, 1H), 2.24(s, 3H), 2.86(s, 6H), 3.37(m, 5H), 3.59(m, 3H), 3.73(s, 2H), 3.80(s, 2H), 4.96(s, 2H), 6.88(m, 1H), 6.93(m, 1H), 6.95(m, 1H), 7.23(m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 16h; | Example 19: tert-butyl 2-{3-[2-([4-(2-methoxy-2-oxoethyl)benzyl][(1-[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]amino}methyl)-1H-imidazol-1-yl]propyl}-2,8-diazaspiro[4.5]decane-8-carboxylate Under an argon atmosphere, the compound (7.70 g) synthesized in Example 18 was dissolved in acetonitrile (80 mL) and then diisopropylethylamine (5.08 mL) was added. Then, <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (5.26 g) was added, followed by stirring at 60C for 16 hours. To the reaction solution, water (100 mL) was added, followed by extraction twice with ethyl acetate (100 mL). The organic layers were combined, washed with saturated brine and then dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed by filtration and then the filtrate was concentrated. The residue was purified by a preparative medium-pressure liquid chromatograph W-prep 2XY (trade name: manufactured by YAMAZEN CORPORATION, column: main column 3L, inject column L, (n-hexane : ethyl acetate = 80 : 20 ? 0 : 100 ? ethyl acetate : methanol : 28% ammonia water = 100 : 0 : 0 ? 80 : 20 : 2), preparative mode GR) to obtain the title compound (5.48 g) having the following physical properties. TLC: Rf 0.66 (ethyl acetate : methanol : 28% ammonia water = 90 : 10 : 2); NMR(CDCl3): delta 0.06(s, 9H), 0.75(t, J = 8.1Hz, 2H), 1.35-1.80(m, 8H), 1.45(s, 9H), 2.11(t, J = 6.9Hz, 2H), 2.24(s, 2H), 2.43(t, J = 6.9Hz, 2H), 3.18(t, J = 8.1Hz, 2H), 3.22-3.50(m, 4H), 3.59(s, 2H), 3.61(s, 2H), 3.66(s, 2H), 3.67(s, 3H), 3.72(t, J = 6.6Hz, 2H), 3.75(s, 2H), 4.97(s, 2H), 6.84(d, J = 0.9Hz, 1H), 6.90-7.00(m, 3H), 7.14-7.22(m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With sodium tris(acetoxy)borohydride; acetic acid; at 20℃; for 16h; | Method S: tert-butyl 2-isopropyl-2,8-diazaspiro[4.5]decane-8-carboxylate A solution of <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (1.5 g, 6.25 mmol) (prepared following the procedure described in the literature: US20060019985), sodium triacetoxy borohydride (2.1 g, 10 mmol) and acetic acid (2 drops) in acetone (20 ml) was stirred at room temperature for 16 hours. The reaction mixture was hydrolyzed with a saturated aqueous solution of sodium bicarbonate (20 ml) and the compound was extracted with ethyl acetate (3*50 ml). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography to afford the desired compound (150 mg, 8% yield). 1H NMR (CD3OD, 400 MHz) delta 1.33-1.36 (6H, d), 1.45 (9H, s), 1.60-1.65 (4H, m), 1.95-2.05 (2H, m), 3.30-3.40 (2H, m), 3.45-3.55 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1,4-dioxane; at 100℃; for 18h; | Example 18Preparation of Compound 2818A28 Step A - Synthesis of Compound 18B5-Methyl-4,6-dichloropyrimidine (0.068 g, 0.66 mmol), Compound 18A (0.100 g, 0.42 mmol), and K2CO3 (0.115 g, 0.83 mmol} were combined in dioxane (2.0 mL) and the resulting reaction was heated to 100 C and allowed to stir at this temperature for 18 hours. The reaction was then cooled to room temperature and concentrated in vacuo and the residue obtained was purified using preparative TLC to provide Compound 18B as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 2h;Inert atmosphere; Reflux; | Synthesis of the amine unit AMN-02: 3-Pyridin-4-yl-3.8-diazaspirof4.51decane- 8-carboxylic acid tert-butyl ester (Boc-AMN-02); Sodium tertbutanolate (3 eq.) and 4-bromopyridine hydrochlorides (1.2 eq.) were added to a solution of the spiro-amine (1 eq.) in toluene (5 ml / mmol). The reaction mixture was degassed under an argon atmosphere, (+/-) BINAP (0.06 eq.) and Pd(OAc)2 (0.02 eq.) were added and the reaction mixture obtained was refluxed for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and the organic phase was washed successively with water and sat. NaCI solution. After drying over Na2SO4, the organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (5 % methanol in methylene chloride). Yield: 40 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 90℃;Product distribution / selectivity; | Step 1: tert-Butyl 2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate A mixture of <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (10.402 mmol, 1.0 eq.), N-ethyl-diisopropylamine (4.0 eq.) and 4-chloropyridine hydrochloride (3.0 eq.) in 2-propanol (20 ml) was stirred at 90 C. overnight. Ethyl acetate and sat. NaHCO3 solution were added and the aqueous phase was extracted with ethyl acetate a further 4*. The combined organic phases were washed 1* with sat. NaCl solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethyl acetate/ethanol/ammonia (25% aq) 500:100:2). Yield: 45% |
With triethylamine; In isopropyl alcohol; at 80℃; | 1. The reaction was performed under an N2 atmosphere. tert-Butyl 2,8- diazaspiro[4.5]decane-8-carboxylate (869 mg, 3.62 mmol), 4-chloropyridine hydrochloride (1.08 g, 7.20 mmol) and TEA (2.5 ml, 18 mmol) were suspended in isopropanol (10 ml). The mixture was heated to 8O0C and stirred overnight at 800C. Then the solvent was removed in a rotary evaporator. The residue was taken up in DCM and concentrated to small volume again. This process was repeated twice more. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98 : 2). The product obtained still contained impurities and was used in the next stage in that condition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 4h;Inert atmosphere; Heating; Reflux;Product distribution / selectivity; | Synthesis of amine (AMN CC-26): 2-Pyridin-4-yl-<strong>[236406-39-6]2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester</strong> (AMN_CC-26) BINAP (293 mg, 0.47 mmol) and Pd(OAc)2 (317 mg, 1.4 mmol) was added to a mixture of <strong>[236406-39-6]2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester</strong> (5.66 g, 23.6 mmol), 4-bromopyridine HCl (4.58 g; 23.6 mmol) and sodium tert-butylate (6.8 g, 70.8 mmol) in toluene and the reaction mixture was degassed under argon for 20 minutes and heated under reflux for 4 h. The mixture was then diluted with ethyl acetate, stirred for 15 minutes and filtered over Celite. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 53% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 50℃; for 4h;Inert atmosphere; | Under an argon atmosphere, the brominated compound (8.72 g) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (8.39 g) were dissolved in acetone (100 mL). Subsequently, potassium carbonate (8.04 g) was added, followed by stirring at 50C for 4 hours. After completion of the reaction, water (50 mL) was added, followed by extraction twice with ethyl acetate (100 mL). The organic layers were combined, washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate by filtration, the filtrate was concentrated to obtain a compound (9.49 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of the benzyl alcohol (starting material 2, 1 mmol) in dichloromethane (5 ml) was added Nu,Nu'-carbonyldiimidazole (1.05 mmol) at room temperature. The mixture was stirred for 3 h at ambient temperature, followed by addition of the spirocyclic amine (starting material 1, 1 mmol) and triethylamine (1 mmol). Then after 18 h the reaction mixture was partitioned between dichloromethane and brine. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel, using a heptane/ethyl acetate gradient, producing the benzyl carbamate intermediate as a colorless oil. | ||
To a solution of the benzyl alcohol (starting material 2, 1 mmol) in dichloromethane (5 ml) was added N,N?-carbonyldiimidazole (1.05 mmol) at room temperature. The mixture was stirred for 3 h at ambient temperature, followed by addition of the spirocyclic amine (starting material 1, 1 mmol) and triethylamine (1 mmol). Then after 18 h the reaction mixture was partitioned between dichloromethane and brine. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel, using a heptane/ethyl acetate gradient, producing the benzyl carbamate intermediate as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With dmap; oxygen; copper diacetate; triethylamine; In dichloromethane; at 20℃; for 3h;Molecular sieve; | To a solution of intermediate I-i 3a (445 mg, 1 .25 mmol) in anhydrous DCM(50 mL) was added R-29a: <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong>(200 mg, 0.833 mmol), Cu(OAc)2 (181 mg, 1.0 mmol), DMAP (22 mg, 0.167 mmol), Et3N (337 mg, 3.332 mmol) and 4A MS (0.8 g), then the mixture was stirred at room temperature for 3 hrs under 02 atmosphere. After LC-MS showed the starting material was consumed completely, then added water,filtered, the mixture was extracted with DCM, the organic layer was washed with brine, dried over anhydrous Na2504, concentrated to give the crude compound which was purified by Prep-TLC ( PE/ EtOAc = 1 .5:1 ) to give the pure intermediate I-131a (60 mg, 13% yield) as a yellow solid. ESI-MS (Mi-i):551 calc. for C30H42N604: 550.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; | StepA: tert-butyl-2-[6-(methylsulfonyl)pyridazin-3-yll-2,8-diazaspiro[4.Sldecane-8-carboxylate:A solution of <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (0.2 g, 0.8 mmol) and 3-chloro-6-(methylsulfonyl)pyridazine (0.2 g, 0.8 mmol) in DMF (15 mL) were treated with TEA (0.1mL, 0.8 mmol). The resulting solution was heated to 150C for 10 mm in a microwave reactor.The solution was diluted with brine and extracted with EtOAc. The EtOAc layer was removeddried over MgSO4, filtered and concentrated giving rise to an oil. The oil was purified on an MPLC (10-50% EtOAc:hexanes) to yield the title compound. LCMS: m/z 397.14 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; for 12h;Reflux; | Step A: tert-butyl 2-(5 -(methylsulfonyl)thiazol-2-yl)-2,8-diazaspiro [4.5 ldecane-8-carboxylate: Astirred solution of 2-bromo-5-(methylsulfonyl)-1,3-thiazole (0.20 g, 0.83 mmol), <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (0.20 g, 0.83 mmol), Pd2dba3 (0.038 g, 0.042 mmol), 5- Phos (0.068 g, 0.17 mmol), and Cs2CO3 (0.81 g, 2.5 mmol) in 1,4-Dioxane (5 mL) were heated to reflux for 12 hours. The solution was diluted with H20 and stirred vigorously. The organic layer was removed, dried over MgSO4, filtered and concentrated giving rise to an oil. The oilwas purified using a 25 g Biotage SNAP cartridge (7-60% EtOAc:hexanes) to give title compound. LCMS: m/z 424 (M + Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 150℃; for 0.25h;Sealed tube; | Step A: tert-butyl 2-(5-cyanopyridin-2-yl)- 1 -oxo-2,7-diazaspiro[3 .Slnonane-7-carboxylate: To a5 mL microwave tube charged with tert-butyl 1-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate(commercially available from several vendors, for example WuXi AppTec Co., Ltd, catalog WX100003, 350 mg, 1.5 mmol) and a stir bar was added 6-chloronicotinonitrile (400 mg, 2.9mmol), K2C03 (300 mg, 2.2 mmol), and DMF (2 mL). The tube was sealed and heated to 150 C for 15 mm. The crude reaction was diluted with EtOAc, washed with water and brine. The organic phase was collected, dried over Na2SO4, filtered and concentrated. The resulting oil was purified by MPLC with hexane and EtOAc.6-(2,8-diazaspiro [4.5] decan-2-yl)pyridazine-3 -carbonitrile was prepared using an analogous procedure to that used for the preparation of INTERMEDIATE 26 (6-(1-Oxo-2,7- diazaspiro [3.5 ]nonan-2-yl)nicotinonitrile) starting from from tert-butyl 2,8- diazaspiro[4.5]decane-8-carboxylate (commercially available from many vendors, for example AstaTech, Inc. catalog 11097) and 6-chloropyridazine-3-carbonitrile and using DIEA as thebase (3 equivalents). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 130℃; for 0.75h;Microwave irradiation; | Step A: tert-Butyl 2-(5-cyanopyridin-2-yl)-2,8-diazaspiro[4.Sldecane-8-carboxylate: To asolution of <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (commercially available frommultiple vendors, for example AstaTech, Inc. catalog 11097; 0.15 g, 0.6 mmol) in DMF (10 mL) was added 6-chloropyridine-3-carbonitrile (0.9 g, 0.6 mmol) followed by Hunig?s base (0.2 mL, 1.2 mmol). The resulting solution was heated in a microwave reactor to 130C for 45 mm. Upon completion of the reaction as judged by TLC and LC/MS analysis, the solution was dilutedwith H20, extracted with EtOAc, washed with brine(3x), dried over Mg504, filtered, concentrated to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; | Step A: tert-butyl-2-(5-bromopyrimidin-2-yl)-2,8-diazaspiro[4.Sldecane-8-carboxylate: Asolution of <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (commercially available from multiple vendors, for example AstaTech, Inc. catalog 11097; 2 g, 8.0 mmol) and 5-bromo-2- chloropyrimidine (1.7 g, 9.2 mmol) in DMF (15 mL) were treated with Hunig?s base (4.4 mL, 25 mmol). The resulting solution was heated to 150C for 10 mm in a microwave reactor. The solution was diluted with brine and extracted with EtOAc. The EtOAc layer was removed, driedover MgSO4, filtered, and concentrated. The crude product was purified using a 340 g Biotage SNAP cartridge (0-100% EtOAc) to yield the title compound. LCMS: m/z 298.99 (M+HBOC) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In tetrahydrofuran; for 2h;Reflux; | Step A: tert-butyl 2- [6-(Methylsulfonyl)pyridin-3 -yll-2,8-diazaspiro [4.5 ldecane-8-carboxvlate:A stirred solution of 5-bromo-2-(methylsulfonyl)pyridine (0.1 g, 0.5 mmol), tert-butyl 2,8- diazaspiro [4.5] decane-8-carboxylate (commercially available from multiple vendors, for example AstaTech, Inc. catalog 11097; 0.1 g, 0.4 mmol), Pd2dba3 (0.02 g, 0.02 mmol), 5-Phos (0.03 g, 0.08 mmol), and Cs2CO3 (0.4 g, 1.2 mmol) in THF (20 mL) were heated to reflux for 12h. The solution was diluted with H20 and stirred vigorously. The organic layer was removed,dried over MgSO4, filtered and concentrated giving rise to an oil. The oil was purified using a 25 g Biotage SNAP cartridge (7-60% EtOAc:hexanes) giving rise to title compound. LCMS: m/z 396.20 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In tetrahydrofuran; for 12h;Reflux; | Step A: tert-butyl 2- [6-methyl-S -(methylsulfonyl)pyridin-2-yll -2, 8-diazaspiro [4.51 decane-8- carboxylate: A stirred solution of 6-fluoro-2-methyl-3-(methylsulfonyl)pyridine (0.3 g, 1.3 mmol), tert-butyl 2,8-diazaspiro[4.S]decane-8-carboxylate (0.3 g, 1.3 mmol), Pd2dba3 (0.06 g,0.06 mmol), S-Phos (0.1 g, 0.25 mmol), and Cs2CO3 (1.2 g, 3.7 mmol) in THF (10 mL) were heated to reflux for 12 h. The solution was diluted with H20 and stirred vigorously. The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude product was purified using a SO g Biotage SNAP cartridge (7-80% EtOAc:hexanes) to give the title compound. LCMS: m/z410.18 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere; Sealed tube; | Step B: tert-butyl 2-15 -(methylsulfonyl)- 1,3 ,4-thiadiazol-2-yll-2, 8-diazaspiro [4.51 decane-8- carboxylate: To a microwave vial was added <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (59 mg, 0.25 mmol), 2-bromo-5 -(methylsulfonyl)- 1,3 ,4-thiadiazole (60 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.0 12 mmol), 2-dicyclohexylphosphino- 2?,4?,6?-triisopropylbiphenyl (18 mg, 0.037 mmol), and potassium phosphate tribasic (104 mg,0.49 mmol). The vial was sealed and vacuum purged with nitrogen three times. Anhydrous dioxane (5 mL, 0.05M) was then added and degassed with nitrogen for 15 minutes. The reaction mixture was then heated to 100 C for 15 hours, cooled, filtered over a CELITE pad, and concentrated in vacuo. The crude residue was purified via MPLC (0-100% EtOAc/hexanes gradient) to afford title compound. LCMS: m/z 403 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 135℃; for 1h; | Step A: (R)-tert-butyl 2-(2-hydroxy-2-(4-methyl- 1 -oxo- 1,3 -dihydroisobenzofuran-5 -yl)ethyl)2, 8-diazaspiro [4.51 decane-8-carboxylate: A mixture of tert-butyl 2, 8-diazaspiro [4.5] decane-8- carboxylate (150 mg, 0.62 mmol) and (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-i(3H)-one(120 mg, 0.62 mmol) in EtOH (2 mL) was heated to 135 C in a microwave reactor for 1 hour. The solvent was removed, and the residue was purified by silica gel flash chromatography. LCMS: m/z 431 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 1.5h; | Step A: tert-butyl 2-(5-nitropyridin-2-yl)-2,8-diazaspiro[4.5ldecane-8-carboxylate: A mixture of <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (commercially available from multiple vendors, for example AstaTech, Inc. catalog 11097; 150 mg, 0.62 mmol), 2-bromo-5- nitropyridine (86 mg, 0.62 mmol), and DIEA (0.22 mL, 1.2 mmol) in NMP (0.2 mL) was heated to 130 C for 1.5 hours. The reaction was diluted with water, extracted with EtOAc. The organiclayer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography. LCMS: m/z 263 (M - Boc + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; | 1-bromo-4,5-difluoro-2-(3-fluorophenoxy)benzene (p7, 131 mg, 0.433 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), BINAP (13.5 mg, 0.022 mmol) and sodium t-butoxide (58.3 mg, 0.606 mmol) were added to a solution of <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (plGO, 110 mg, 0.433 mmol) in Toluene (1 mL) and the mixture was stirred at 100 c overnight. Then the mixture was cooled down to RT, diluted with EtOAc, dried and concentrated. crude material was purified by Fc on silica gel (eluent: cHex tocHex/EtOAc 85/15) to obtain tert-butyl 2-[4,5-difluoro-2-(3-fluorophenoxy)phenyl]-2,8- diazaspiro[4.5]decane-8-carboxylate (plGl, 45 mg, y= 23%) as orange oil.MS (ES) (m/z): 463.3 [M÷H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 mg | With potassium carbonate; In acetonitrile; at 80℃;Inert atmosphere; | Step a <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (p58, 0.1 g, 0.416 mmol) and l-(chloro-(4- fluorophenyl)methyl)-4-fluorobenzene (0.109 mL, 0.457 mmol) were dissolved in Acetonitrile and K2C03(115 mg) was added. The mixture was heated to 80 C overnight. DCM and water were added and the two phases separated. The aqueous one was extracted with DCM. The combined organic phases were concentrated to dryness. The residue was purified by FC on silica gel (eluent: DCM to DCM/MeOH 90/10) affording ieri-butyl 2-[bis(4-fluorophenyl)methyl]-2,8-diazaspiro[4.5]decane-8-carboxylate (70 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
150 mg | With potassium carbonate; In acetonitrile; for 18h;Reflux; Inert atmosphere; | Step a 1-chloro-4-[chloro(4-chlorophenyl)methyl]benzene (217 mg, 0.799 mmol) was added to a stirred mixture of ferf-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (p58, 160 mg, 0.666 mmol) and K2C03(230 mg,1.665 mmol) in Acetonitrile (6 mL). The mixture was stirred for 18 hrs at reflux. The solution was filtered using EtOAc and evaporated. The crude material was purified by FC on silica gel (eluent: EtOAc to EtOAc/MeOH 90/10) affording ferf-butyl 2-[bis(4-chlorophenyl)methyl]-2,8- diazaspiro[4.5]decane-8-carboxylate (150 mg) as colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Intermediate 15: tert-mty 3-[[4-[(2-aminophenyl)methoxy]phenyl]methyl]-3,8- diazaspiro[4.5]decane-8-carboxylate tert-butyl 3-ff 4-f (2-nitrophenyl)methoxy] phenyl] methyl] -3.8-diazaspiro [ 4.5Jdecane-8-carboxylate 0.119 g (0.495 mmol) of <strong>[236406-39-6]tert-butyl 3,8-diazaspiro[4.5]decane-8-carboxylate</strong> (Fluorochem, cat. no. 091348) and 0.140 g (0.544 mmol) of 4-[(2-nitrophenyl)methoxy]benzaldehyde (Vitas-M Lab, cat. no. BBL024967) were dissolved in 6 mL of dry THF. After 30 min of stirring, the reaction mixture was treated with 0.276 g (1.236 mmol) of NaBH(OAc)3 and stirred overnight. The reaction was quenched with 10 mL of saturated aqueous NaHCC . The aqueous phase was extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SC>4, filtered and evaporated to afford a residue, which was purified by column chromatography (eluent hexane/acetone, from 0% to 15% acetone) providing 0.217 g (91%) of tert-butyl 3-[[4-[(2- nitrophenyl)methoxy]phenyl]methyl]-3,8-diazaspiro[4.5]decane-8-carboxylate as yellow oil. JH NMR (DMSO-de) delta (ppm): 8.15-8.07 (m, 1 H), 7.82-7.74 (m, 2 H), 7.66-7.57 (m, 1 H), 7.29-7.13 (m, 2 H), 6.99-6.89 (m, 2 H), 5.42 (s, 2 H), 3.45 (s, 2 H), 3.31-3.25 (m, 2 H), 3.23-3.12 (m, 2 H), 2.46 (t, J= 6.8 Hz, 2 H), 2.29 (s, 2 H), 1.55 (t, J=6.8 Hz, 2 H), 1.43-1.34 (m, 13 H). MS (ESI): m/z: 482 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 95℃;Sealed tube; | A microwave vial was charged with a magnetic stir bar, tert-butyl 2, 8-diazaspiro [4.5] decane-8-carboxylate (commercially available from multiple vendors, 120 mg, 0.499 mmol) , 5-iodo-3-methoxy-1, 2, 4-thiadiazole (133 mg, 0.549 mmol) , tribasic potassium phosphate (212 mg, 0.999 mmol) , Pd2 (dba) 3 (22.9 mg, 0.025 mmol) , and XPhos (47.6 mg, 0.100 mmol) . The vial was sealed, degassed, and filled with dioxane (3.3 mL) . The reaction mixture was heated at 95 overnight, filtered and rinsed with DCM. The filtrate was concentrated and the crude product was purified by silica gel column chromatography (0-10MeOH/DCM) to give the title compound. LC-MS 355 [M+1] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 10h; | Compound 5-fluoro-1 - (2-methoxy-2-oxo-ethyl) - 2-methyl -1H-indole-3-carboxylic acid (170 mg, 0 . 64mmol), 2,8-diaza-spiro [4.5] decane-8-carboxylic acid T-butyl ester (155 mg, 0 . 64mmol), 1-ethyl-3 - (3-dimethylamino-propyl) carbodiimide hydrochloride (184 mg, 0 . 96mmol) and N-hydroxy-7-azabenzene and triazazole (130 mg, 0 . 96mmol) dissolved in dichloromethane (10 ml) in, 0 C to this solution under the conditions of adding dropwisely N, N-diisopropyl ethylamine (0.35 ml, 1 . 92mmol), stirring the mixture at room temperature for 10h, and washing with water (10 ml × 3), the organic phase is dried with anhydrous sodium sulfate, removal of solvent, concentrate under column separation (V (petroleum ether)/ V (ethyl acetate) =1/1) to obtain 163 mg white solid, yield: 52%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.7% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); In toluene; at 85℃; for 16h;Inert atmosphere; | Under nitrogen atmosphere, to the two 100mL round bottom flask were sequentially added iodobenzene (1.63g, 8.0mmol), 2,8- diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (1.92g, 8.0mmol ), BINAP (1.0g, 1.6mmol), Pd (dba)2(920mg, 1.6mmol), cesium carbonate (5.2g, 16 mmol) and toluene (50mL), the mixture was heated to 85 stirred for 16 hours.Cooled to room temperature, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, the crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 20/1), to give a yellow oil (700mg, 27.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tert-Butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (1.3 g, 5.42 mmol), 6-chloro- [l,2,4]triazolo[4,3-P]pyridazine (1.25 g, 8.11 mmol), diisopropylethylamine (2.74 ml, 15.6 mmol) and N,N-dimethylacetamide (8 ml) were mixed in a 40 mL vial. The mixture was heated at 80C for 16 hours. The solvent was then removed in Genavac to dryness to give the crude product, which was dissolved in 1,4-dioxanes (4 mL) and 4M HC1 in 1,4-dioxanes (8 mL). The mixture was stirred for 3 hours at rt. The solvent was then removed to give a solid. Diethyl ether (10 mL) and ethyl acetate (10 mL) was added and the mixture was sonicated for 2 minutes. The solid was then filtered and dried under vacuum to give 6-(2,8-diazaspiro[4.5]decan-2-yl)- [l,2,4]triazolo[4,3-P]pyridazine as hydrochloric acid salt, which was used in the next step without further purification. LC-MS (IE, m/z): 259 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃; for 1h;Inert atmosphere; Microwave irradiation; Sealed tube; | tert-Butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (0.150 g, 0.624 mmol), 6- chlorotetrazolo[l,5-P]pyridazine (0.097 g, 0.624 mmol), Huning's base (0.327 mL, 1.87 mmol) and 1,4-dioxane (2.0 mL) was charged to a microwave tube. The solution was degassed and filled with nitrogen (3X), then sealed and heated in a microwave reactor to 120C for 1 h. The reaction was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by prep TLC (5% MeOH:DCM) to give the title compound. 1HNMR (500 MHz, CDCls), delta 8.02(m, 1H), 7.01(m, 1H), 3.65 (s, 3H), 3.28 (m, 2H), 3.53 (m, 4H), 3.39 (m, 2H), 1.63 (m, 4H), 1.38 (s, 9H); LC-MS (IE, m/z): 360 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 95℃; for 1h;Inert atmosphere; Microwave irradiation; | <strong>[236406-39-6]tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (0.200 g, 0.832 mmol), 6- bromo-[l,2,4]triazolo[4,3-a]pyridine (0.181 g, 0.915 mmol), cesium carbonate (0.407 mg, 1.25 mmol), Pd2(dba)3 (0.019 mg, 0.021 mmol), Xantphos (0.036 mg, 0.062 mmol), and 1,4-dioxane (3.0 mL) were charged to a microwave tube. The solution was degassed and filled with nitrogen (3X), then heated to 95C for 1 hour. The reaction was cooled to rt and concentrated in vacuo. The resulting residue was purified by prep TLC (5% MeOH/DCM) to provide tert-butyl 2- ([l,2,4]triazolo[4,3-a]pyridin-6-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate. LC-MS (IE, m/z): 358 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 100℃; for 1h;Sealed tube; Inert atmosphere; Microwave irradiation; | A microwave vial containing tert-butyl diazaspiro[4.5]decane-8-carboxylate (100 mg, 0.416 mmol), 5-bromo-4-methylisobenzofuran- l(3H)-one (94 mg, 0.416 mmol), Pd2(dba)3 (19.05 mg, 0.021 mmol), X-Phos (29.8 mg, 0.062 mmol) and potassium phosphate (177 mg, 0.832 mmol) in dioxane (2.080 mL) was sealed and evacuated and purged with nitrogen before heating to 100C for 1 h. The reaction was cooled, diluted with ethyl acetate, filtered and the filtrates concentrated to give crude material which was purified via MPLC (10-75% EtOAc/hexanes) to afford the title compound. LC/MS: [(M+l)]+ = 387. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 25℃; for 16h; | To a suspension of te/ -butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.832 mmol) in acetonitrile (2 mL) were added 2-fluorobenzoic acid (175 mg, 1.25 mmol), 0-(7- azabenzotriazol-1-yl)-/V,//,A/',//-tetramethyluronium hexafluorophosphate (HATU; 506 mg, 1.33 mmol), and /V,/V-diisopropylethylamine (323 mg, 2.50 mmol). The reaction mixture was stirred at 25 C for 16 hours, whereupon it was concentrated in vacuo. The residue was dissolved in methanol (8 mL), treated with ion exchange resin Amberlyst A26, hydroxide form [3.6 g, pre- washed with methanol (7 mL)], stirred at 25 C for 1 hour, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether), affording the product as a colorless gum. By 1 H NMR analysis, this was judged to be a mixture of rotamers. Yield: 231 mg, 0.637 mmol, 77%. 1 H NMR (400 MHz, CD3OD) delta 7.55-7.46 (m, 1 H), 7.45-7.38 (m, 1 H), 7.32-7.26 (m, 1 H), 7.26-7.18 (m, 1 H), 3.72-3.66 (m, 1 H), 3.56-3.47 (m, 1 H), 3.51 (s, 1 H), 3.46-3.3 (m, 4H), 3.21 (br s, 1 H), [1.94 (dd, J=7.5, 7.3 Hz) and 1.87 (dd, J=7.3, 7.0 Hz), total 2H], 1.66-1.48 (m, 4H), [1.47 (s) and 1.43 (s), total 9H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of fe/f-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (36 mg, 0.15 mmol) in pyridine (0.4 mL) was added to a solution of benzenesulfonyl chloride (39.7 mg, 0.225 mmol) and /V,/V-dimethylpyridin-4-amine (0.25 mg, 2.0 muetaetaomicronIota) in pyridine (0.4 mL), and the reaction mixture was shaken at room temperature for 2 days. The pyridine was removed in vacuo, and the residue was partitioned between half-saturated aqueous sodium bicarbonate solution (1.5 mL) and ethyl acetate (2.4 mL). After the mixture had been vortexed, the organic layer was eluted through a solid phase extraction cartridge (6 mL) charged with sodium sulfate (~1 g); this extraction procedure was repeated twice, and the combined eluents were concentrated in vacuo. The residue was treated with a mixture of 1 ,2-dichloroethane and trifluoroacetic acid (1 : 1 ; 1 mL), shaken at room temperature for 2.5 hours, and concentrated under reduced pressure. The remaining material was dissolved in 1 ,2-dichloroethane (2.4 mL), vortexed, and loaded onto an SCX (strong cation exchanger) solid phase extraction cartridge (Silicycle, 6 mL, 1 g); the vial was rinsed with a mixture of methanol and 1 ,2-dichloroethane (1 :1 ; 2 x 2.4 mL). The cartridge was eluted with methanol (5 mL), followed by a solution of triethylamine in methanol (1 M, 7.5 mL) to elute the deprotected intermediate. Fractions containing the desired material were concentrated in vacuo, and the residue was azeotroped with toluene (2 x 1 mL) to remove trace methanol. The resulting material was dissolved in dichloromethane (0.5 mL). A crude solution of C2 was prepared separately, as follows: Bis(pentafluorophenyl) carbonate (5.8 g, 15 mmol) and triethylamine (41 mL, 290 mmol) were added to a stirring solution of C1 (3.75 g, 15.0 mmol) in tetrahydrofuran (30 mL). Sufficient tetrahydrofuran was added to bring the total volume to 98 mL, and the reaction mixture was stirred at room temperature for 1 hour. A portion of this crude C2 solution (1.0 mL, 0.15 mmol of C2 and 3 mmol of triethylamine) was added to the deprotected amine solution prepared above, and the reaction mixture was shaken at room temperature for 5 days. It was then partitioned between half-saturated aqueous sodium bicarbonate solution (1.5 mL) and ethyl acetate (2.4 mL) and subjected to vortexing. The organic layer was eluted through a solid phase extraction cartridge (6 mL) charged with sodium sulfate (~1 g); this extraction procedure was repeated twice, and the combined eluents were concentrated in vacuo. This material was treated with a mixture of trifluoroacetic acid and 1 ,2-dichloroethane (1 : 1 , 1 mL) and shaken at room temperature for 1 hour, whereupon it was concentrated in vacuo and purified using reversed phase HPLC (Column: Waters Sunfire C18, 5 muetaeta; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 25% to 95% B). Yield: 4.8 mg, 11 muetaetaomicronIota, 7%. Analytical retention time: 2.64 minutes (Analytical HPLC conditions - Column: Waters Atlantis dC18, 4.6 x 50 mm, 5 muetaeta; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2 mL/minute). LCMS m/z 437.1 [M+Hf. |
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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