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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
1-N-Boc-3-Azetidinecarboxylic acid is a protected azetidine-3-carboxylic acid derivative with the amino group protected by tert-butoxycarbonyl (Boc), used for the synthesis of antibody-drug conjugates (ADCs) and protein degraders (PROTACs).
Synonyms: 1-Boc-azetidine-3-carboxylic acid
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CAS No. : | 142253-55-2 |
Formula : | C9H15NO4 |
M.W : | 201.22 |
SMILES Code : | O=C(C1CN(C(OC(C)(C)C)=O)C1)O |
Synonyms : |
1-Boc-azetidine-3-carboxylic acid
|
MDL No. : | MFCD01860897 |
InChI Key : | NCADHSLPNSTDMJ-UHFFFAOYSA-N |
Pubchem ID : | 2755981 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
81% | Stage #1: With triethylamine; isobutyl chloroformate In tetrahydrofuran at -20 - -10℃; for 0.25 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at -20 - 20℃; for 1 h; |
1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (4.96 g, 24.65 mmol) and TEA (5.84 ml, 42.0 mmol) were dissolved in THF (60 ml) and cooled to -20°C. Isobutyl chloroformate (4.8 ml, 37.0 mmol) was added slowly and the reaction mixture stirred at ^10°C for 15 min. 28percent aqueous ammonia (7.46 ml, 394 mmol) was added and the mixture allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with sat. NaHC<(aq) and extracted with DCM (3 x 100 ml). The combined organic extracts were dried (Na2S04), filtered and evaporated in vacuo. Purification by flash chromatography using a gradient elution of 20-100percent EtOAc / heptane followed by 1-4percent MeOH / EtOAc afforded the title compound (3.99 g, 81 percent) as a white solid. 1 H-NMR (CDCI3, 250 MHz): d[ppm]= 5.47 (s, 2H), 4.22 - 4.01 (m, 4H), 3.34 - 3.15 (m, 1 H), 1 .46 (s, 9H) HPLCMS (Method A): [m/z]: 222.95 [M+Na]+ |
63% | With ammonium acetate; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; | To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (from Activate Scientific. 0.25 g, 1.2 mmol), ammonium acetate (0.14 g, 1.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.71 g, 1.9 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (0.43 mL, 2.5 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1percent ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.156 g, 63percent). LCMS calculated for C9H16N2O3Na (M+Na)+: m/z=223.1. Found: 223.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (22.3 g, 0.111 mol) in THF (250 mL), 1,3-dicyclohexylcarbodiimide (24.4 g, 0.150 mol) was added portion-wise. The reaction mixture was stirred at room temperature for 1.5 h before addition of a suspension of N,O-dimethylhydroxylamine hydrochloride (15.0 g, 0.154 mol) in a mixture of acetonitrile (300 mL) and triethylamine (22.6 mL, 0.162 mol). The resulting mixture was stirred at room temperature for 24 h, and then the reaction was concentrated in vacuo. The residue was taken up in water (300 mL) and EtOAc (800 mL), the organic layer was separated, washed with a 5% aqueous citric acid solution (2*200 mL), water (2*150 mL), and saturated aqueous sodium chloride solution (2*150 mL), and then dried over magnesium sulfate. Filtration and removal of solvent gave C55 as a light yellow oil. Yield: 28.15 g, 0.12 mol, 100%. 1H NMR (400 MHz, CDCl3) δ 4.12-4.09 (m, 2H), 4.03-3.99 (m, 2H), 3.64-3.56 (m, 1H), 3.63 (s, 3H), 3.17 (s, 3H), 1.40 (s, 9H). | |
100% | Preparation 84 tert-Butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate; Carbonyldiimidazole (24.4 g, 0.150 mol) was added in portions to a solution of 1-(tert- butoxycarbonyl)azetidine-3-carboxylic acid (Preparation 83, 22.3 g, 0.11 1 mol) in tetrahydrofuran (25OmL). The mixture was stirred at room temperature for 1.5 hours. A suspension of Λ/,O-dimethylhydroxylamine hydrochloride (15.O g, 0.154 mol) in a mixture of acetonitrile (30OmL) and triethylamine (22. mL, 0.162 mol) was added. The resulting mixture was stirred at room temperature for 24 hours. The solvents were evaporated and water (30OmL) and ethyl acetate (80OmL) were added to the residue. The organic layer was separated, washed with a 5% aqueous citric acid (40OmL), water (30OmL) and brine (30OmL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a pale yellow oil (28.15 g, 100%).1H NMR (400 MHz, CDCI3): δ = 4.12-4.09 (m, 2H), 4.03-3.99 (m, 2H), 3.64-3.56 (m, 1 H), 3.63 (s, 3H), 3.17 (s, 3H), 1.40 (s, 9H) ppm. | |
100% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of l-tert-butoxycarbonylazetidine-3-carboxylic acid (1.0 g) in DMF (25 mL) were added Ν,O dimethylhydroxylamine hydrochloride (0.51 g), HATU (2.3 g), and DIPEA (2.6 mL). After stirring for 1 hour at room temperature, the reaction mixture was diluted with brine and extracted with EtOAc twice. The combined organic layer was washed with brine twice, dried over MgS04, and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (25-55% EtOAc in /hexane) to give the title compound (1.3 g, quant.) as colorless oil. MS (ESI) m/z 267 [M+l]. RT = 0.771 min. LCMS condition B. |
99% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | DMF (40 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.89 g, 29.8 mmol), EDC (5.55 g, 29.8 mmol), HOBt (3.36 g, 24.9 mmol) and DIPEA (9.82 mL, 54.7 mmol). The reaction was stirred at room temperature for 20 h. The reaction was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (150 mL) and brine (150 mL), dried over MgSO4 and concentrated under vacuum to afford 4 as a clear colorless oil (6.06 g, 99%); Η-nmr (400 MHz, CDCI3) δ 4.21-4.11 (m, 2H), 4.05 (t, J= 8.0 Hz, 2H), 3.66 (s, 3H), 3.68-3.59 (m, IH), 3.21 (s, 3H), 1.44 (s, 9H); m/z 189.1 [M-1Bu]. |
99% | To a solution of 1-(te/-bυtoxycarbonyl)azetidine-3-carboxylic acid (2.00 g, 9.94 mmol) in THF (50 mL) was added EDCI (2.10 g, 10.93 mmol), HOBt (1.48 g, 10.93 mmol), and /V,/V-diisopropylethylamine (5.19 mL, 29.82 mmol). The mixture was stirred at rt for 15 min. Λ/,Odimethylhydroxylamine hydrochloride (1.16 g, 11.93 mmol) was added and stirring continued for 64 h. The crude reaction was purified via ISCO chromatography using 3:1 ethyl/hexanes to afford 2.4 g (99%) of the desired product, which was used without further characterization. | |
99% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere; | 1-Boc-azetidine-3-carboxylic acid (5 g; 24.9 mmol) and N,O-dimethylhydroxylaminehydrochloride (3.64 g; 37.3 mmol) were placed in a round bottom flask under N2. DCM(75 mL) was added, followed by EDCI.HC1 (7.15 g; 37.3 mmol), DMAP (155 mg; 1.27mmol) and DIPEA (6.5 mL, 37.4 mmol). The reaction mixture was stirred at RT for 16h and diluted with DCM (100 mL). The organic layer was washed with aqueous 1M HC1 (2 x 50 mL), sat. NaHCO3 solution (50 mL), and brine (50 mL). The organic phasewas decanted, dried over MgSO4, filtered, and evaporated to dryness yielding 6.04 g(99%) of intermediate 73. |
98% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | A mixture of 298 (1.8 g, 9 mmol), N,O-dimethylhydroxylamine hydrochloride (2.6 g, 27 mmol), EDCI (5 g, 27 mmol), HOBt (0.1 g, 1 mmol), and DIPEA (12.5 mL, 72 mmol) in DMF (30 mL) was stirred at 20C overnight. The reaction was then concentrated to half volume in vacuo, poured onto water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water and brine, dried (Na2SO4), and concentrated to give 299 as a clear oil (2.1 g, 98%). |
84% | With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 17h; | A solution of 1-boc-azetidine-3-carboxylic acid (5.00 g, 24.8 mmol, and CDI (4.23 g, 26.1 mmol) in dichloromethane (100 mL) was stirred at room temperature for 1 hour, then N,O-dimethylhydroxylamine hydrochloride (4.0 g, 29.8 mmol) was added and stirring continued at room temperature for 16 hours. The resulting suspension was washed with water (3×30 mL), sat. aq. NaHCO3 (3×30 mL), and brine (3×30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (87a, 5.1 g, 84% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.14 (br s, 2H), 4.05 (t, J=8.6 Hz, 2H), 3.66 (s, 3H), 3.65 (m, 1H), 3.20 (s, 3H), 1.43 (s, 9H). |
83% | With triethylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 16h; | Example 232: 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzvϖ- azetidine.; Step A: Preparation of 3-(Methoxy-methyl-carbamoyl)-azetidine-1 - carboxylic acid tert-butyl ester.; To a solution of azetidine-1 ,3-dicarboxylic acid mono-tert-butyl ester (3.5 g, 17 mmol) in DMF (50 ml_) was added O1N- dimethyl-hydroxylamine hydrochloride (3.4 g, 34 mmol), thethylamine (9.6 mL, 69 mmol), HATU (13.4 g, 34.6 mmol) and DCM (125 mL). After stirring for 16 h, saturated NaHCO3 solution and ethyl acetate were added. The aqueous portion was extracted three times with ethyl acetate. The combined organic fractions were dried (Na2SO4) and concentrated and the crude product was purified using RP HPLC (basic conditions) to provide the title compound (3.5 g, 83%) MS (ESI): mass calcd. for CnH2ON2O4, 244.1 ; m/z found, 189.1 [M-t- Bu]+. 1H NMR (CDCI3): 4.14-4.03 (m, 2H), 4.05 (t, J = 8.7 Hz, 2H), 3.66 (s, 3H), 3.63-3.59 (m, 1 H), 3.21 (s, 1 H), 1.43 (s, 9H). |
80% | With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a stirred solution of l-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.0 g, 14.9 mmol, CAS 142253-55-2) in DMF (45 mL) at room temperature was added N,0-dimethyl hydroxylamine hydrochloride (1.75 g, 17.9 mmol), HBTU (8.48 g, 22.4 mmol) and iV-methyl morpholine (6.56 mL, 59.6 mmol). After 16 hours, the reaction mixture was poured into a 1: 1 mixture of water and saturated NH4C1 and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHC03 and brine, dried (Na2S04) and concentrated in vacuo to afford the title compound (2.9 g, 80%) as a colorless oil. MS (ISP): 189.1 ([M- C4H8+H]+). |
77% | With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h; | Intermediate 24: tert-Butvl 3- {r methoxy( methyl) amino 1 carbonyl } azetidine-l-carboxylate; To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (H. Itani et al, Biorg. Med. Chem. Lett. 12 (5), 757-762,2002) (0.5 g, 2.48 mmol) and bis (2-oxo-3- oxazolidinyl) phosphinic chloride (0.633 g, 2.48 mmol) in DMF (4 mL) was added N,O- dimethylhydroxylamine hydrochloride (339 mg, 3.48 mmol), followed by diisopropylethyl amine (1.3 mL, 7.45 mmol). The exothermic reaction was allowed to cool to room temperature and was stirred for 2 hours. Excess base was removed under reduced pressure, the residue was diluted with ethyl acetate (100 mL), washed with potassium phosphate buffer (1M, pH 7,2x 100 mL) and with water (2x 100 mL) and dried over sodium sulfate. Chromatography on silica gel with hexanes/ acetone (3:1) gave 470 mg (77%) of the product as a colourless solid. MS (ESP): 267.23 (MNa+) for C11H20N2O4 'H-NMR (DMSO-d(at) 5: 1.36 (s, 9H); 3.10 (s, 3H); 3.61 (s, 3H); 3.68 (m, 1H); 3.83-4.00 (m, 4H). |
76% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; for 16h; | A solution of R-1 (50 g, 250 mmol) and HATU (104 g, 270 mmol) in CH2C12 (8000 mL) is treated with TEA (135 mL, 1000 mmol). The mixture is stirred for 16 h then washed with saturated aqueous ammonium chloride and filtered through a phase separator. The organics are collected and volatiles are removed in vacuo to afford a crude residue that is purified by flans chromatography (Si02, 12% EtOAc in heptane to 100%EtOAc) to afford 1-1 (46 g, 76%) m/z 245.1 [M+H]. |
72% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 25℃; for 16h;Inert atmosphere; | A mixture of l-Boc-azetidine-3-carboxylic acid (50 g, 248 mmol), triethylamine (69.3 mL, 497 mmol), 1 -hydroxybenzotriazole (33.5 g, 248 mmol) and EDC1 (47.6 g, 248 mmol) and (9, /V-dimcthyl hydroxy laminc HC1 (24.24 g, 248.5 mmol) in DMF (1000 mL) was stirred at 25 C for 16 h. The mixture was concentrated in vacuo to give a residue, which was neutralized by HC1 (1M) to pH = 7 and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with NaHCO, (2 x sat.aq. 200 mL), dried over Na2S04 and concentrated in vacuo to give tert- butyl 3- (1025) [methoxy(methyl)carbamoyl]azetidine-l-carboxylate (55 g, 72%) as colorless oil; LC-MS: 189.1 [M-56+H]+. |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 6h; | To a solution of 980 mg (4.87 mmol) of boc-azetidine-3-carboxylic acid, 951 mg (9.75 mmol) OF N, O- dimethylhydroxylamine hydrochloride, 329 mg (2.435 mmol) of HOBT and 1.87g (9.75 mmol) of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride in 30 mL of CH2CL2 was added 2.54 mL (44.61 mmol) of N, N-diisopropylethylamine at 0 oC and it was stirred for 6h at rt. Then the reaction mixture was poured into 100 mL of ether and washed with 20 mL of aq NAHC03. The organic layer was dried over Na2S04 and concentrated. to afford the title compound. 1NMR (CDC13) 8 1.46 (s, 9H), 3.23 (s, 3H), 3.62 (m, 1H), 3.68 (s, 3H), 4.07 (M, 2H), 4.09 (m, 2H). | |
EXAMPLE 6; 1 - [5 -fluoro-2-(methylsulfonyl)benzoyl] -3 -( 1 -methyl- 1 - { [3 - (trifluoromethyl)phenyl] sulfonyl } ethyl)azetidineStep 1 : tert-butyl 3-[methoxy(methyl)amino]carbonyl}azetidine-l-carboxylateTo a 100 ml round bottom flask was added l-(fert-butoxycarbonyl)azetidine-3- carboxylic acid (3.75 g, 18.6 mmol) and 20 ml tetrahydrofuran, followed by CDI (3.63 g, 22.4 mmol). Vigorous gas evolution was observed. After gas evolution stopped, the reaction mixture was stirred at room temperature for additional 30 minutes. Methoxy(methyl)ammonium chloride (2.55 g, 26.1 mmol) was added, followed by diisopropylethyl amine (6.5 ml, 37.3 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was diluted with 120 ml ether and washed with 60 ml saturated NH4Cl. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column, eluted with 1 :2 to 3:2 ethyl acetate/hexane to give 3.6 g desired product was colorless oil. <n="54"/>1H-NMR (CDCl3): 54.17 (m, 2H), 4.08 (t, J = 8.7 Hz, 2H), 3.69 (s, 3H), 3.5 (b, IH), 3.24 (s, 3H), 1.47 (s, 9H). | ||
With triethylamine; HATU; at 20℃; for 19h; | EXAMPLE 8; F5-(2- 13 - [2-(Trifluoromethyl)benzovnazetidin- 1 -vU - 1 ,3 -thiazol-5 -yl)-2//-tetrazol-2-yllacetic acid; Step 1 : ferf -Butyl 3 - { [methoxy (methyl)amino] carbonyl ) azetidine- 1 -carboxylate; To a solution of l-(/er/-butoxycarbonyl)azetidine-3-carboxylic acid (3.78 g, 18.8 mmol), N, 0-dimethylhydroxylamine hydrochloride (2.75 g, 28.2 mmol), and Et3N (7.85 mL, 56.4 mmol) was added HATU (7.86 g, 20.7 mmol). The resulting mixture was stirred at room temperature for 19 h. A second portion of HATU (4.5 g, 11.8 mmol) was added and the reaction was stirred at room temperature for 19 h. The mixture was poured into a 250 mL separatory funnel containing water (150 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 20% EtOAc in hexanes to 70% EtOAc in hexanes as a gradient, to afford the title compound as a colorless oil. | |
With triethylamine; HATU; at 20℃; for 38h; | Step 1: tert-Butyl 3-[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.78 g, 18.8 mmol), N,O-dimethylhydroxylamine hydrochloride (2.75 g, 28.2 mmol), and Et3N (7.85 mL, 56.4 mmol) was added HATU (7.86 g, 20.7 mmol). The resulting mixture was stirred at room temperature for 19 h. A second portion of HATU (4.5 g, 11.8 mmol) was added and the reaction was stirred at room temperature for 19 h. The mixture was poured into a 250 mL separatory funnel containing water (150 mL) and extracted with EtOAc (2*50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 20% EtOAc in hexanes to 70% EtOAc in hexanes as a gradient, to afford the title compound as a colorless oil. | |
With triethylamine; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 16h; | [0299] To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.15 g, 25.6 mmol)in THF (100 mL) was added DCC (7.11 g, 34.5 mmol), Et3N (5.18 g, 51.2 mmol) andN,Odimethylhydroxylaminehydrochloride (3.44 g, 35.3 mmol), the reaction was stirred at RT forabout 16 hr. Concentrated under reduced pressure to remove solvent, the residue was portionedbetween EA (100 mL) and water (50 mL), the aqueous was further extracted with EA (50 mL x3). The combined organic phases were washed with brine (20 mL), concentrated under reducedpressure to remove solvent, then purified by column chromatography on silica gel (200-300mesh, CH2Cb/MeOH = 2011) to give the crude product ( -8.0 g) as a colorless oil. MS (ESI) m/e[M+23t 266.9, [M-55t 189.0. | |
7.30 g | (1) Synthesis oftert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.00 g) in tetrahydrofuran (62.1 mL), 1,1'-carbonyldiimidazole (6.05 g) was added and the mixture was stirred at room temperature for an hour. To the reaction mixture, a solution of N,O-dimethylhydroxylamine hydrochloride (3.64 g) and triethylamine (4.02 g) in acetonitrile (62.1 mL) was added and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue. Extraction was conducted with ethyl acetate and the combined organic layers were washed with an aqueous solution of 5% citric acid and saturated brine. The washed organic layers were dried over anhydrous sodium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate as a pale yellow oil (7.30 g). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 3.21 (s, 3 H) 3.56 - 3.68 (m, 4 H) 4.00 - 4.09 (m, 2 H) 4.09 - 4.19 (m, 2 H). | |
With triethylamine; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 16h; | To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.15 g, 25.6 mmol) in THF (100 mL),Add DCC (7.11g, 34.5 mmol),Et3N (5.18 g, 51.2 mmol)And N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.3 mmol),The reaction was stirred at room temperature for about 16 hours.Concentration under reduced pressure to remove the solvent, the residue was partitioned between EA (100 mL) and water (50 mL) and the aqueous phase was further extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), concentrated under reduced pressure to remove the solvent, and then purified on a tannin gel column (200-300 mesh CH 2 Cl 2 /MeOH=20/1).The crude product was obtained as a colorless oil (-8.0 g). | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h; | Example 5 1) Synthesis of N-t.butoxycarbonyl-3-(methoxy-methyl-carbamoyl)-azetidine 2 g (10 mmol) of N-t.butoxycarbonyl-azetidine-3-carboxylic acid is dissolved in 20 ml of dimethylformamide under argon. This solution is cooled down to 0 C. using an ice bath and 5.46 g (12.3 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1.4 g (14.3 mmol) of N,O-dimethylhydroxylamine chloride and 6 ml of diisopropylethylamine are added. The reaction mixture is left to return to ambient temperature and is stirred for 18 hours at ambient temperature. The dimethylformamide and diisopropylethylamine are evaporated off under reduced pressure (2 kPa). Purification is carried out by chromatography on silica gel eluding with a heptane/ethyl acetate 50:50 mixture 2.1 g of colourless oil is recovered. TLC: Rf=0.25 (silica gel, eluent: heptane/ethyl acetate 50:50 1H-NMR (CDCl3): δ 1.44 (s, 9H, tBu); 3.22 (s, 3H, -N-C); 3.64 (m, 1H, H3); 3.67 (s, 3H, -O-C); 4.05 and 4.15 (m, 4H, H2 and H2') | |
Carbonyldiimidazole (24.4 g, 150 mmol) was added in portions to a solution of 1-tert-butoxycarbonylazetidine-3-carboxylic acid (23.2 g, 115 mmol) in THF (250 ml) and the mixture was stirred at room temperature for 1.5 h. A suspension of N,O-dimethylhydroxylamine hydrochloride (15.0 g, 154 mmol) in a mixture of acetonitrile (300 ml) and triethylamine (22.0 ml, 162 mmol) was added and the reaction was stirred at room temperature for 24 h. The solvents were evaporated and the residue was partitioned between water (300 ml) and ethyl acetate (800 ml). The organic layer was separated, washed with a 5% aqueous citric acid solution (400 ml), water (300 ml) and brine (300 ml), dried over anhydrous magnesium sulfate, and concentrated in vac- uo to afford the title compound (28.2 g, quant). | ||
With triethylamine; 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 1h; | To a stirred solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (2.00 g, 9.94 mmol) and CDI (1.80 g, 10.9 mmol) in DCM (10 mL) were added Et3N (1.20 g, 11.93 mmol) and N,O-methoxy(methyl)amine hydrochloride (0.90 g, 14.91 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 h. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford tert-butyl 3- [methoxy(methyl)carbamoyl]azetidine-1-carboxylate as a light yellow oil (2.10 g, 78%): LCMS (ESI) calc’d for C11H20N2O4 [M + H - 56]+: 189, found 189; 1H NMR (300 MHz, CD3OD) δ 4.14-3.99 (m, 4H), 3.89-3.76 (m, 1H), 3.72 (s, 3H), 3.22 (s, 3H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In methanol; toluene; at 0 - 20℃; for 0.916667h; | General Procedure 58 1-(t-butoxycarbonyl) azetidine-3-carboxylic acid (1-1)(AXL016917, 1000 mg, 4.97 mmol) was dissolved in MeOH (5 mL)/Toluene (20 mL) and then cooled to 0 C. TMSCHNN (trimethylsilyldiazomethane) (7.45 mmol) was then added drop-wise over 15 minutes with some bubbling observed. The color started clear and slowly turned yellow. The solution was stirred for 10 minutes at 0 C. and then warmed to room temperature over 30 minutes. The solution was then concentrated and pumped on to remove toluene to afford 1.055 g of 1-t-butyl 3-methyl azetidine-1,3-dicarboxylate (-2) that was used directly in the next step without being purified (99% crude yield). |
In methanol; hexane; dichloromethane; at 0 - 20℃; for 0.166667h; | Step A; Methyl 1 -tert-Butoxycarbonylazetidine-3 -carboxylate;To a solution of l-tert-butoxycarbonylazetidine-3-carboxylic acid (0.90 g, 4.5 mmol) in methanol (10 mL) and methylene chloride (10 mL) at 00C was added trimethylsilyldiazomethane (2 M in hexane, 4 mL, 7.0 mmol) until a yellow color persisted. The reaction was stirred at room temperature for 10 min, and was concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (400 MHz, CD3OD): delta 4.15 (d, 2H), 3.76 (s, 3H), 3.72 (d, 2H), 1.94 (q, 2H), 1.42 (s, 9H), 0.88(t, 3H). LC-MS: m/e 266 (M + Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol; | (a) 1-tert-Butyl 3-methyI azetidine-l,3-dicarboxylate; 1-(ter^Butoxycarbonyl)azetidine-3-carboxylic acid (2.42 g, 12.0 mmol) was dissolved in MeOH (30 mL) and TM5CHN2 (30.1 ml, 60.1 mmol) was added drop- wise at room temperature (reaction became warm and gas was evolved). TM5CHN2 was added until a persistent yellow color was produced indicating excess reagent. AcOH was added drop- wise to quench the excess TM5CHN2 and then the reaction mixture was concentrated under reduced pressure and azeotroped with toluene (3 x 20 mL) to remove any trace MeOH and AcOH. The crude material was used without any further purification assuming 100 percent yield. 1H NMR (400 MHz, CDCl3): 6 1.44 (9H, s), 3.29-3.39 (1H, m), 3.75 (3H, s), 4.07-4.13 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With diazomethyl-trimethyl-silane; In toluene; at 0 - 20℃; for 0.916667h; | 1-(/-butoxycarbonyl)azetidine-3-carboxylic acid (H)(AXL016917, 1000 mg, 4.97 mmol) was dissolved in MeOH (5 ml_)/Toluene (20 mL) and then cooled to 0C. TMSCHNN (trimethylsilyldiazomethane) (7.45 mmol) was then added drop-wise over 15 minutes with some bubbling observed. The color started clear and slowly turned yellow. The solution was stirred for 10 minutes at 0C and then warmed to room temperature over 30 minutes. The solution was then concentrated and pumped on to remove toluene to afford 1.055 g of 1-/-butyl 3-methyl azetidine-1,3-dicarboxylate (1-2) that was used directly in the next step without being purified (99% crude yield). |
80% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 18h; | Intermediate 10: l-teri-Butyl-3-met oxylate To a solution of l-(fert-butoxycarbonyl)azetidine-3-carboxylic acid (200 mg, 0.99 mmol) in dichloromethane (2 mL) was added N,N'-dicyclohexylcarbodiimide (246 mg, 1.19 mmol), 4- dimethylaminopyridine (12 mg, 0.12 mmol) and methanol (50 mu, 1.23 mmol) and reaction mixture was stirred at room temperature for 18 h. Urea by-product was removed by filtration then filtrate was concentrated under reduced pressure, yielding the product as a colourless oil (170 mg, yield: 80%). Vppm (400 MHz, CDC13) 4.10 (4H), 3.75 (3H), 3.35 (IH), 1.44 (9H). |
With diazomethyl-trimethyl-silane; In diethyl ether; dichloromethane; at 0 - 20℃; for 0.75h; | Example 15 1-tert-butyl 3 -methyl azetidine-l,3-dicarboxylate 119[0148] l-(t-butoxycarbonyl)azetidine-3-carboxylic acid (2.03 g, 10.09 mmol) was dissolved in MeOH (10 ml) and DCM (10 mL) and then cooled to 0 C. A 2M solution of trimethylsilyldiazomethane in ether (7.57 ml, 15.1 mmol) was then added drop-wise over 5 minutes. The solution was stirred for 10 minutes at 0 C and then warmed to room temperature over 30 minutes. The solution was concentrated under reduced pressure to remove volatiles to afford crude 119, which was used directly in the next step without further purification. H NMR: 1.44 (s, 9H), 3.35 (m, 1H), 3.75 (s, 3H), 4.10 (d, 4H, J = 7.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Commercially available l-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.50g, 1.0 eq) was dissolved in tetrahyrdofuran (5 ml) then treated with carbonyl diimidazole (0.48g, 1.2 eq) and diisopropylethylamine (0.95ml, 2.2 eq). The reaction stirred for 30 minutes at room temperature then the weinrib amine (0.27 g, 1.1 eq) was added. The reaction continued for 15 hours at room temperature. The reaction was worked up by diluting with saturated NH4C1 aq. (5 ml) then extracted with ethylacetate (2x-10 ml). The organics were pooled and washed with water (2x-10 mL) then brine (lx-10 mL). The organics were dried over Na2S04 and concentrated to give 0.60 g of compound VI (98% yield). 1H-NMR (DMSO-de): δ 4.0-3.8 (m, 4H), 3.8-3.7 (m, 1H), 3.6 (s, 3H), 3.1 (s, 3H); LC/MS m/z calc M+Na 267, obs M+Na 267. | |
78% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; for 2h; | 7-1-1 3-(Methoxymethylcarbamoyl)azetidine-1-tert-butoxycarbonyl; 2 g (9.94 mmol) of i -tert-butoxycarbonyl-S-azetidinecarboxylic acid are dissolved in 8 imL of dichloromethane, and 3.19 g (9.94 mmol) of TBTU and then 4 mL of dimethylformamide are added. 0.97 g (9.94 mmol) of N,O-dimethylhydroxylamine in 1 O mL of dichloromethane and 5.17 mL (29.8 mmol) of diisopropylethylamine are added. After stirring for 2 hours, dichloromethane is added and the medium is washed with saturated NaHCCb solution and then with 5% citric acid solution. The organic phase is dried over MgSO4, filtered and concentrated on a rotary evaporator. The crude product obtained is chromatographed on silica gel (eluent: 7/3 heptane/ethyl acetate). 1 .9 g in the form of a colourless oil are obtained in a yield of 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | the compound 1 (500g, 2.5mol) was dissolved in tetrahydrofuran (8L) was added with stirring NaH (180g, 7.5mol) after 30 minutes at at 10 to 20 , then MeI (710g, 5.0mol ) at 5 to 10 dropwise to the reaction system. The reaction was stirred at 15 to 25 for 16 hours. TLC (petroleum ether / ethyl acetate = 1/1) showed the reaction. The reaction was poured into ice water (8L) in, (4Lx3) and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried, filtered, and concentrated under reduced pressure to give compound 2 (500g), 95% yield. | |
With caesium carbonate; In N,N-dimethyl-formamide; for 10h; | To a solution of l-(feri-butoxycarbonyl)azetidine-3-carboxylic acid (0.30 kg, 1.5 mol) and cesium carbonate (978 g, 3.0 mol) in anhydrous A^N-dimethylacetamide (1.5 L) was added iodomethane (537 g, 3.8 mol) over 10 h. The reaction was filtered through Celite, and the filtrate was extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford a clear yellow oil (303 g, crude, 94% yield). NMR (400 MHz, CDC13): delta 4.09 - 4.07 (m, 4 H), 3.73 (s, 3 H), 3.35 - 3.31 (m, 1 H), 1.42 (s, 9 H). | |
8 g | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; | To a solution of azetidine-l,3-dicarboxylic acid mono-tert-butyl ester (11 g, 54.7 mmol) in DMF (75 mL), were added K2C03(15 g, 109.4 mmol) and CH3I (9.3 g, 65.6 mmol). The reaction mixture was stirred at r.t. for 24 h. TLC showed the reaction was complete. Water was added. The water phase was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous MgS04and concentrated in vacuo to give azetidine- l,3-dicarboxylic acid l-tert-butyl ester 3-methyl ester (8 g) as a white solid. LC-MS (ESI) m/z (M+l): 216. |
Tags: 1-N-Boc-3-Azetidinecarboxylic acid | 1-Boc-azetidine-3-carboxylic acid | Azetidines | Carboxylic Acids | Amides | N-protective Amino Acid | Carbamates | Aliphatic Cyclic Hydrocarbons | Organic Building Blocks | Amino Acids | Heterocyclic Building Blocks | 142253-55-2
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