Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 142253-55-2 | MDL No. : | MFCD01860897 |
Formula : | C9H15NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NCADHSLPNSTDMJ-UHFFFAOYSA-N |
M.W : | 201.22 | Pubchem ID : | 2755981 |
Synonyms : |
1-Boc-azetidine-3-carboxylic acid
|
Chemical Name : | N-Boc-Azetidine-3-carboxylic acid |
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.78 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 53.56 |
TPSA : | 66.84 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.23 cm/s |
Log Po/w (iLOGP) : | 1.91 |
Log Po/w (XLOGP3) : | 0.42 |
Log Po/w (WLOGP) : | 0.56 |
Log Po/w (MLOGP) : | 0.43 |
Log Po/w (SILICOS-IT) : | -0.06 |
Consensus Log Po/w : | 0.65 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.09 |
Solubility : | 16.4 mg/ml ; 0.0816 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.39 |
Solubility : | 8.18 mg/ml ; 0.0407 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.1 |
Solubility : | 162.0 mg/ml ; 0.804 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.12 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
78% | With 1,3-Diiodo-5,5-dimethyl-2,4-imidazolidinedione In 1,2-dichloro-ethane for 3 h; Reflux; Irradiation | EXAMPLE 3; Radical iodo-de-caboxylation induced by TV-iodo amides/V-iodo amideR-COOH *- R-lGeneral procedure[00111] Procedure: A mixture of R-COOH (1 mmol), N-iodo amide (1-4 equiv), and solvent (3-6 mL) was refluxed (Δ) for 1-24 h in the dark (NL) or under irradiation with 500 W tungsten lamp (TL) or under fluorescent room lighting (FL).[00112] Treatment: The reaction mixture was cooled to rt, and washed with aq NaHS03 and NaHC03 to destroy excess of iodination agent and dissolve unreacted carboxylic acid. The organic solution was dried (Na2S04), filtered through short silica or alumina pad and concentrated in vacuo to give iodide R-I. 100113J Purification: Optionally, the iodide R-I was further purified by crystallization (if the iodide is crystalline compound), or rectification (if the iodide is liquid compound). Analytical sample of the product was purified by column chromatography./V-iodoamideAlk-COOH *- Alk-I[00114] A mixture of Alk-COOH (1 mmol), N-iodo amide (1-3 equiv), and solvent (4 mL) was refluxed (Δ) in the dark (NL) or under irradiation with 500 W tungsten lamp (TL), or under fluorescent room lighting (FL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In methanol at 20℃; for 18 h; | Example 4Ethyl 6-(3-[(benzylsuIfonyl)amino]carbonyl}azetidin-l-yl)-5-cyano-2- 30 (difluoromethyl)nicotinate(a) l-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid <n="92"/>91(BoC)2O (25.535 g, 117 mmol) dissolved in MeOH (70 mL) was added dropwise during 20 minutes to a stirred slurry of azetidine-3-carboxylic acid (10.11 g, 100 mmol) and Et3N (27.8 mL, 200 mmol) in MeOH (105 mL) at r.t (mildly exotermic reaction) and the mixture 5 was stirred over night (18 hours). The reaction was evaporated to dryness and THF (120 mL) was added and evapoprated to give crude l-(tert-butoxycarbonyl)azetidine-3- carboxylic acid which was used without further purification in the next step. Yield: 25.89 g (128 percent) 1H NMR (400 MHz, CDCl5) δ 1.43 (9H, s), 3.21-3.34 (IH, m), 4.00-4.13 (4H, m).10 |
100% | With triethylamine In methanol at 20℃; for 18 h; | (a) 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (Boc)2O (25.535 g, 117 mmol) dissolved in MeOH (70 mL) was added dropwise during 20 minutes to a stirred slurry of azetidine-3-carboxylic acid (10.11 g, 100 mmol) and Et3N (27.8 mL, 200 mmol) in MeOH (105 mL) at r.t (mildly exotermic reaction) and the mixture was stirred over night (18 hours). The reaction was evaporated to dryness and THF (120 mL) was added and evapoprated to give crude 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid which was used without further purification in the next step. Yield: 25.89 g (128percent) 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 3.21-3.34 (1H, m), 4.00-4.13 (4H, m). |
95% | With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24 h; | Example 90 Ethyl 6-{3-[(benzyIsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-[(2-oxopyrrolidin-l- yl)methyl]nicotinate(a) l-(toer^Butoxycarbonyl)azetidine-3-carboxylic acidDi-tert-buyldicarbonate (18 g, 83 mmol) was added to a solution of 3-azetidinecarboxylic acid (7.6 g, 75 mmol) in THF (150 mL), water (75 mL) and IM NaOH (75 mL), the reaction mixture was stirred at rt for 24 h. The organic solvent was concentrated in vacuo and the water was made acidic by addition of 4 M HCl (pH 1). The water phase was extracted with EtOAc and the combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo to give l-(te7t-butoxycarbonyl)azetidine-3-carboxylic acid as a white solid. Yield: 14.4 g (95percent). <n="177"/>1H-NMR (400 MHz, DMSO-J6) δ 1.36 (9H, s), 3.27-3.36 (IH, m), 3.80-3.87 (2H, m), 3.93-4.02 (2H, m), 12.64 (IH, s). |
90% | With triethylamine In 1,4-dioxane; water at 4 - 20℃; for 24 h; | A mixture of 297 (1 g, 10 mmol) in 1 :1 water-dioxane (50 mL) was treated with Et3N (4 mL, 13 mmol) and BOC2O (2.8 g, 13 mmol) at 4°C and allowed to warm to 20°C for one day. The solvent was then removed in vacuo. The residue was taken up in 1 :1 water-ethyl acetate and the organic layer was discarded. The aqueous layer was acidified with 1 N aqueous HCl and extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried (Na2SO4), and concentrated to give 298 as a white solid (1.8 g, 90percent). |
80% | With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 17.5 h; | At a temperature of 0 °C, di-ferf-butyl dicarbonate (24.0 g, 110 mmol) was added portionwise to a solution of azetidine-3-carboxylic acid (9.4 g, 93 mol) and triethylamine (28 ml, 200 mmol) in THF (200 ml) and water (200 ml). After completed addition (30 min), the reaction mixture was stirred for 17 h at room temperature. The yellow solution was diluted with ethyl acetate (200 ml) and a pH value of 5 was adjusted by addition of 6 N hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 ml). The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The residue was dried in vacuo and the title compound was obtained in 85 percent purity (18 g of a colourless solid, 80 percent yield). |
73% | With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24 h; | 60 mL of THF and 60 mL of 0.5 M NaOH aqueous solution were added to azetidin-3-carboxylic acid (3 g, 30mmol). Di-tert-butyl dicarbonate (6.8 g, 31.1 mmol) was slowly added thereto, and the mixture was stirred at roomtemperature for 24 hours. The reaction solution was concentrated under reduced pressure. The reaction solution wasadjusted to pH 4 by the addition of water and HCl aqueous solution, and extracted with EtOAc. The organic layer wasdried with MgSO4 to obtain the title compound (4.5 g, 73 percent).1H-NMR (CDCl3) δ 4.12 (4H, m), 3.38 (1H, m), 1.44 (9H, s) |
70% | With potassium hydroxide In tetrahydrofuran; water at 20℃; for 16 h; | Step 1: Azetidine-l,3-dicarboxylic acid mono-tert-butyl esterDi-tert-buyldicarbonate (2.5 g, 11.88 mmol) was added to a stirred solution of 3- azetidinecarboxylic acid (1.0 g, 9.9 mmol) in a mixture of THF / water (12 mL : 2 mL) and 1 M KOH (1 mL) at room temperature. The reaction mixture was stirred for 16 hours and then concentrated to dryness. The crude was partitioned between an aqueous solution of IN NaOH (10 mL) and diethyl ether (50 mL). The ether layer was discarded and the aqueous layer was acidified with a 3M aqueous solution of KHS04 untill pH = 2 and extracted with diethyl ether (3 x 100 ml). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (1.4 g, 70percent).*H NMR (400 MHz, DMSO-d6) δ (ppm) : 12.64 (s, 1 H), 4.02-3.93 (m, 2H), 3.87-3.80 (m, 2H), 3.36-3.27 (m, 1 H), 1.36 (s, 9H). |
100% | With triethylamine In tetrahydrofuran; water; ethyl acetate | EXAMPLE 37 N-Boc-3-Azetidinecarboxylic Acid 46 A solution of 3-Azetidinecarboxylic acid (45) (250 mg, 2.47 mmol) in 5 mL of THF and 5 mL of H2O was cooled in an ice-water bath and NEt3 (689 μL) was added with stirring. Stirring and cooling were continued while di-tert-butyl dicarbonate (570 mg, 1.05 eq.) was introduced. The mixture was warmed to room temperature and stirred overnight. 20 mL of Ethyl acetate and 10 mL of H2O were added to mixture. The aqueous layer was extracted with ethyl acetate (2*20 mL). The extracts were combined and washed with aqueous potassium carbonate (sat., 2*10 mL), aqueous HCl (5percent, 2*10 mL), brine (10 mL), and dried over anhydrous sodium sulfate, and filtered. Removal of solvents gave 46 as a white solid 0.50 g (100percent). |
100% | With triethylamine In tetrahydrofuran; water; ethyl acetate | EXAMPLE 37 N-Boc-3-Azetidinecarboxylic acid 46 A solution of 3-Azetidinecarboxylic acid (45) (250 mg, 2.47 mmol) in 5 mL of THF and 5 mL of H2O was cooled in an ice-water bath and NEt3 (689 μL) was added with stirring. Stirring and cooling were continued while di-tert-butyl dicarbonate (570 mg, 1.05 eq.) was introduced. The mixture was warmed to room temperature and stirred overnight. 20 mL of Ethyl acetate and 10 mL of H2O were added to mixture. The aqueous layer was extracted with ethyl acetate (2*20 mL). The extracts were combined and washed with aqueous potassium carbonate (sat., 2*10 mL), aqueous HCl (5percent, 2*10 mL), brine (10 mL), and dried over anhydrous sodium sulfate, and filtered. Removal of solvents gave 46 as a white solid 0.50 g (100percent) |
9.9 g | With triethylamine In tetrahydrofuran; water at 20℃; for 17 h; | The title compound (D25) (9.9 g) was prepared according to the experimental procedure described in Description 18 starting from 3-azetidine carboxylic acid (5 g, 49.45 mmol, available from Aldrich 391131) (1.5 g, 4.72 mmol). Reaction time: 17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide In methanol; water for 4 h; Reflux | To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate 22 (3.7 g, 0.0202 mol, 1 equiv.) in MeOH (35 mL) was added a solution of NaOH (4.03 g, 0.101 mol,5 equiv.) in H2O (35 mL) and refluxed until the reaction was complete by TLC (ca. 4 h). The resulting reactionmixture was cooled to rt and concentrated to remove the MeOH. The mixture was neutralized with 10 percent aq.citric acid (200 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed withbrine (50 mL), dried over Na2SO4, and concentrated to give the desired product 23 (3.72 g, 92percent). PhysicalState: white solid (mp 106–107 oC); 1H NMR (500 MHz, CDCl3): δ 4.13 (d, J 7.5 Hz, 4H), 3.41 – 3.35 (m, 1H), 1.44(s, 9H); 13C NMR (126 MHz, CDCl3): δ 177.4, 155.3, 80.3, 51.8 (br, 2C), 32.0, 28.5 (3C); HRMS (ESI-TOF): calc’dfor C9H14NO4 [M-H] 200.0928; found 200.0923. |
80.8% | Stage #1: With water; sodium hydroxide In methanol for 5 h; Reflux Stage #2: With citric acid In water |
Preparation 831 -(tert-ButoxycarbonvDazetidine-S-carboxylic acid; A solution of sodium hydroxide (27.5 g) in water (30OmL) was added to solution of tert-butyl 3- cyanoazetidine-1-carboxylate (Preparation 82, 25.1 g, 0.138 mol) in methanol (30OmL). The mixture was heated at reflux for 5 hours. The methanol was evaporated and the residuary aqueous solution was neutralized with 10percent citric acid and extracted with dichloromethane (2.1 L). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white crystalline solid (22.3 g, 80.8percent). 1H NMR (400 MHz, DMSO-d6): δ = 4.01-3.97 (m, 2H), 3.87-3.84 (m, 2H), 3.36-3.28 (m, 1 H), 1.37 (s, 9H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine In dichloromethane at 20℃; for 18 h; | To a stirred solution of azetidine-3-carboxylic acid hydrochloride salt (1.Og, 7.27 mmol) in DCM (35 mL) is added di-tert-butyl dicarbonate (1.74 g, 8.0 mmol) followed by triethylamine (2.2 mL, 16 mmol). Stirring is continued at room temperature for 18 h.Solvent is removed under reduced pressure. The residue is redissolved in EtOAc (50 mL), washed with saturated aqueous potassium hydrogen sulphate (10 mL) followed by water (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 1.0 g (58percent) of l-(tert-butoxycarbonyl)azetidine-3-carboxylic acid. mJz = 146[M++H-tBu], 187 [M++H-tBu +MeCN]. |
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% | at -78 - 20℃; for 2.5 h; Inert atmosphere | To a stirring solutionof BH3/THF (285 ml)at -78°C was added 1-(tert butoxycarbonyl)azetidine-3-carboxylic acid (22.53 g, 112 mmol) in portions under a N2atmosphere, and the reaction was stirredfor 30 min. The reaction was then warmedto rt and stirred for 2 hr. The reaction mixturewas poured into ice (500 ml), and extractedwith EA (3 x300 ml). The combinedorganic layers were washed with brine (3 x 100 ml), dried (Na2S04), and filtered. The filtrate was concentrated under reduced pressureto yield compound1.2 as 5 clear oil (20.9 g, 100percent). MS: m/z calcd for C9H17N03 187.1, found [M-H] 186.1. |
98% | Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0℃; for 4 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 20℃; for 0.5 h; |
Borane dimethyl sulfide complex (4.5 mL, 15.0 mmol) was slowly added to 1-(tertiary butoxycarbonyl)azetidine-3-carboxylic acid (1.0 g, 5.0 mmol) dissolved in a distilled tetrahydrofuran solution (20 mL) at 0° C., and the mixture was stirred at the same temperature for 4 hours. Thereafter, 1N HCl aqueous solution (70 mL) was slowly added at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (3*30 mL), and the organic layer was washed with a saturated sodium chloride solution and distilled water once, respectively and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain the desired compound tertiary butyl 3-(hydroxymethyl)azetidine-1-carboxylate. Yield: 98percent, oily liquid 1H NMR (300 MHz, CDCl3-d3) δ 1.42 (s, 9H, CO2C(CH3)3), 2.70-2.66 (m, 1H, CH(CH2)2), 3.418 (dd, 1H, OH), 3.71-3.65 (m, 4H, CH(CH2)2), 3.99-3.93 (m, 2H, CH2OH). |
98% | Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0℃; for 4 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 20℃; for 0.5 h; |
[0043] Borane dimethyl sulfide complex (4.5 mL, 15.0 mmol) was slowly added to 1-(tertiary butoxycarbonyl)azetidine-3-carboxylic acid (1.0 g, 5.0 mmol) dissolved in a distilled tetrahydrofuran solution (20 mL) at 0°C, and the mixture was stirred at the same temperature for 4 hours. Thereafter, 1N HCl aqueous solution (70 mL) was slowly added at 0°C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (3*30 mL), and the organic layer was washed with a saturated sodium chloride solution and distilled water once, respectively and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain the desired compound tertiary butyl 3-(hydroxymethyl)azetidine-1-carboxylate. Yield: 98percent, oily liquid 1H NMR (300 MHz, CDCl3-d3) δ 1.42 (s, 9H, CO2C(CH3)3), 2.70-2.66 (m, 1H, CH(CH2)2), 3.418 (dd, 1H, OH), 3.71-3.65 (m, 4H, CH(CH2)2), 3.99-3.93 (m, 2H,CH2OH). |
98% | With boron dimethyl-trifluoro sulphide In tetrahydrofuran at 20℃; for 14 h; | To a tetrahydrofuran (100 mL) solution of 1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid (2.0 g, 9.94 mmol), 10M-borane-dimethyl sulfide complex (2.98 mL, 29.8 mmol) was added at room temperature, and the mixture was stirred for 14 hours. The reaction liquor was poured onto ice water (100 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40S, 2percent methanol/ethyl acetate), to obtain the title compound (1.83 g, 98percent) as an oily matter. NMR(CDCl3)δ:1.44(9H,s),2.63-2.76(1H,m),3.69(2H,dd,J=8 .4,5.2Hz),3.79(2H,d,J=4.6Hz),4.00(2H,t,J=8.5Hz). |
90% | Stage #1: With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 18.4167 h; Reflux Stage #2: With methanol In tetrahydrofuran at 20℃; |
To a stirred mixture of 0.56 g (14.91 mmol) sodium borohydride in 10 mL THF was added 1.0 g (4.97 mmol) 1-(te/f-butoxycarbonyl)-3-azetidinecarboxylic acid, and the reaction mixture was cooled to 0 °C. 1.26 g (4.97 mmol) iodine in 5 mL THF was added dropwise over 15 minutes and the reaction was stirred at 0 °C for 10 minutes, then heated under reflux for 18 hours. The mixture was allowed to cool to room temperature, diluted with 80 mL MeOH and stirred until all effervescence ceased. After evaporation of the solvent, 25 mL 20percent (w/w) KOH was added to the residue and the mixture was stirred for 4.5 hours. The mixture was extracted with DCM (3 x 100 mL) and the combined organic layers were dried over MgSO4. After filtration, the solvent was evaporated to give the desired product, which was used for the next step without further purification. Yield: 0.84 g (90percent of theory) C9H17NO3 (M=187.24) predicted: Molecular ion (M+H - CH2=C(CH3)2)+: 132 observed: Molecular ion (M+H -CH2=C(CH3)2)+: 132HPLC-MS: 1.34 minutes (Method A) |
66% | Stage #1: With 4-methyl-morpholine; chloroformic acid ethyl ester In tetrahydrofuran at -10℃; Stage #2: With sodium tetrahydroborate In water at 5 - 20℃; |
Example 3A tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate To a solution of 1-Boc-azetidine-3-carboxylic acid (Astatech, 1.0 g, 4.97 mmol) in tetrahydrofuran (10 mL) at -10° C. was added 4-methylmorpholine (0.55 mL, 5.0 mmol). This mixture was stirred for 1 minute and then ethyl chloroformate (0.47 mL, 4.97 mmol) was added dropwise. The mixture was stirred at -10° C. for 15 min then was filtered through Celite and the filtrate was added dropwise via syringe to a mixture of NaBH4 (0.42 g, 111.2 mmol) in H2O (5 mL) at 5° C. The mixture was allowed to warm to ambient temperature and was stirred vigorously for 3 h. The reaction mixture was quenched with 5 mL saturated, aqueous NH4Cl, the layers were separated and the aqueous layer was extracted with 3*5 mL ethyl acetate. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO2, 30percent hexanes in ethyl acetate) to give the title compound (0.62 g, 3.3 mmol, 66percent yield). MS (DCI/NH3) m/z 188 (M+H)+. |
49% | Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran for 0.166667 h; Cooling with NaCl/ice water Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 20℃; for 1.5 h; Cooling with NaCl/ice water |
A stirred solution of 1-(.pound.-butoxycarbonyl)-3-azetidinecarboxylic acid (0.730 g, 3.63 mmol, Fluka) and 4-methylmorpholine (0.440 ml_, 3.99 mmol) in 7 mL of anhydrous THF was cooled in a NaCI/ice water bath. The solution was treated with isobutyl chloroformate (0.520 mL, 3.99 mmol) by drop-wise addition. A white solid rapidly precipitated from the solution. After stirring the cold suspension for 10 minutes, the solid was removed by vacuum filtration and the filter cake washed with three 2 mL portions of THF. The filtrate was cooled in the NaCI/ice water bath and was then treated with NaBH4 (0.210 g, 5.45 mmol) dissolved in 3 mL of water. Vigorous gas evolution occurred during the addition. The solution was allowed to slowly warm to RT with melting of the ice bath. After 1.5 hours the solution was concentrated to dryness at reduced pressure. The residue was suspended in EtOAc. The resulting mixture was washed with 10percent aqueous citric acid (2x), saturated aqueous NaHC03 (2x), aqueous brine (1x), dried over Na2S04, and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, EtOAc/hexane) to afford 0.33 g (49percent) of f-butyl 3-(hydroxymethyl)-1-azetidinecarboxylate as a transparent viscous oil. 1H NMR (DMSO-cf6): 8 4.74 (t, 1H), 3.79 (brs, 2H), 3.53 (brs, 2H), 3.46 (t, 2H), 2.56 (m, 1H), 1.35 (s, 9H). |
40% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 24 h; Stage #2: With water; ammonium chloride In tetrahydrofuran for 1 h; |
Lithium aluminium hydride (1 .89 g, 49.7 mmol) was added portionwise to a solution of 1 - (tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.00 g, 24.8 mmol) in THF (75 ml). After a reaction time of 1 d at room temperature, the reaction mixture was quenched with saturated ammonium chloride solution (30 ml), stirred for 1 h, and filtered over a pad of diatomaceous earth. The filter cake was washed with dichloromethane. The phases of the combined filtrates were separated. The aqueous phase was saturated with sodium chloride and extracted with dichloromethane (3 x). The combined organic phases were dried over magnesium sulfate and the solvent was evaporated. The title compound (1.87 g of a pale-yellow oil) was obtained in 40 percent yield. |
27% | Stage #1: With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; Inert atmosphere; Reflux Stage #2: With methanol; water; potassium hydroxide In tetrahydrofuran at 20℃; |
To a stirred suspension of sodium borohydride (1.92 g, 50.6 mmol) in dry THF (20 mL) is added a solution of l-(tert-butoxycarbonyl)azetidine-3-carboxylic acid in dry THF (20 mL) at 0 0C. A solution of iodine (4.71 g, 18.6 mmol) in THF (20 mL) is added dropwise (caution: gas evolution) under N2 atmosphere. The reaction mixture is allowed to warm to room temperature then heated under reflux for 18 h. The resulting white suspension is cooled to room temperature. MeOH is added until the suspension dissolved. The mixture is concentrated under reduced pressure, then quenched with IM aqueous KOH (100 mL) and extracted with DCM (3 x 150 mL). The organic phases are combined, washed with water followed by brine and concentrated under reduced pressure to give 2.13 g (27percent) of tert-butyl 3-(hydroxymethyl)azetidine-l-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With diazomethyl-trimethyl-silane In toluene at 0 - 20℃; for 0.916667 h; | 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 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-/-butyl 3-methyl azetidine-1,3-dicarboxylate (1-2) that was used directly in the next step without being purified (99percent crude yield). |
80% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 18 h; | 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 μ, 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: 80percent). Vppm (400 MHz, CDC13) 4.10 (4H), 3.75 (3H), 3.35 (IH), 1.44 (9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: With sodium hydride In tetrahydrofuran at 10 - 20℃; for 0.5 h; Stage #2: at 15 - 25℃; for 16 h; |
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), 95percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 0 - 20℃; for 0.916667 h; | 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 (99percent crude yield). |
[ 610791-05-4 ]
Methyl 1-Boc-azetidine-3-carboxylate
Similarity: 0.96
[ 1346674-10-9 ]
1-tert-Butyl 3-ethyl azetidine-1,3-dicarboxylate
Similarity: 0.94
[ 177947-96-5 ]
tert-Butyl 3-formylazetidine-1-carboxylate
Similarity: 0.92
[ 486415-29-6 ]
tert-Butyl 3-carbamoylazetidine-1-carboxylate
Similarity: 0.87
[ 534602-47-6 ]
1-(tert-Butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid
Similarity: 0.84
[ 88495-54-9 ]
(S)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid
Similarity: 0.84
[ 183062-96-6 ]
2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid
Similarity: 0.83
[ 1221818-81-0 ]
7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid
Similarity: 0.81
[ 1352882-80-4 ]
2-(tert-Butoxycarbonyl)-2-azaspiro[5.5]undecane-9-carboxylic acid
Similarity: 0.81
[ 610791-05-4 ]
Methyl 1-Boc-azetidine-3-carboxylate
Similarity: 0.96
[ 1346674-10-9 ]
1-tert-Butyl 3-ethyl azetidine-1,3-dicarboxylate
Similarity: 0.94
[ 177947-96-5 ]
tert-Butyl 3-formylazetidine-1-carboxylate
Similarity: 0.92
[ 486415-29-6 ]
tert-Butyl 3-carbamoylazetidine-1-carboxylate
Similarity: 0.87
[ 610791-05-4 ]
Methyl 1-Boc-azetidine-3-carboxylate
Similarity: 0.96
[ 1346674-10-9 ]
1-tert-Butyl 3-ethyl azetidine-1,3-dicarboxylate
Similarity: 0.94
[ 177947-96-5 ]
tert-Butyl 3-formylazetidine-1-carboxylate
Similarity: 0.92
[ 486415-29-6 ]
tert-Butyl 3-carbamoylazetidine-1-carboxylate
Similarity: 0.87