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CAS No. : | 217806-26-3 | MDL No. : | MFCD09839423 |
Formula : | C8H17ClN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VLOLOLUAVFGUTD-UHFFFAOYSA-N |
M.W : | 208.69 | Pubchem ID : | 22101213 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.88 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 56.65 |
TPSA : | 50.36 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.76 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.14 |
Log Po/w (WLOGP) : | 0.9 |
Log Po/w (MLOGP) : | 0.56 |
Log Po/w (SILICOS-IT) : | 0.26 |
Consensus Log Po/w : | 0.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.59 |
Solubility : | 5.39 mg/ml ; 0.0258 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.79 |
Solubility : | 3.37 mg/ml ; 0.0162 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.48 |
Solubility : | 6.94 mg/ml ; 0.0333 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.08 |
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 |
---|---|---|
48% | Stage #1: With acetic acid; triethylamine In methanol at 24℃; for 0.5 h; Stage #2: With sodium cyanoborohydride In methanol at 24℃; for 12 h; |
A mixture of tert-butyl azetidin-3-ylcarbamate hydrochloride (200 mg, 0.96 mmol), benzaldehyde (203 mg, 1.92 mmol), triethylamine (0.133 mL, 0.96 mmol) and acetic acid (115 mg, 1.92 mmol) in methanol (10 mL) was stirred at 24 °C for 30 min. Then NaBH3CN (181 mg, 2.88 mmol) was added to the mixture. The resulting mixture was stirred at 24 °C for 12 h and concentrated under reduced pressure to give the crude product, which was purified by column to give tert-butyl 1-benzylazetidin-3-ylcarbamate (120 mg, 48percent yield). LCMS (m/z): 262.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; SULFAMIDE; In 1,4-dioxane; for 48h;Heating / reflux; | i) tert-Bvtyl [l-(aminosulfonyl)azetidin-3-yl]carbamate; A solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (prepared according to J.Antibiot. 1986, 39, 1243-1256, 0.755 g), Proton-Sponge (0.85g) and sulfamide (0.42 g) indioxane (23ml) was heated at reflux for 48h. The residue was partitioned between EkO andEtOAc, and the aqueous layer then extracted with further EtOAc (x4). The combined organicextracts were washed quickly with 2M aqueous hydrochloric acid (x3) then with saturatedaqueous sodium bicarbonate, H^O and saturated aqueous sodium chloride, dried with sodiumsulfate, filtered and evaporated to afford the subtitle compound as a pale brown powder.Yield: 0.44 g.H NMR: 6 (300 MHz, DMSO) 1.38 (s, 9H), 3.55 (t, 2H), 3.82 (t, 2H), 4.09 - 4.18 (m, 1H),6.87 (s, 2H), 7.53 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69%; 11% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 70℃; for 72h;Inert atmosphere; | Example 84: [4-(3-Amino-azetidin-1-yl)-pyhmidin-2-yl]-butyl-amine. --> [1-(2-Chloro-py?rnidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester To a flask containing 2,4-dichloropyrimidine (1.6 g, 10.7 mmol) and N, N- diisopropylethylamine (3.5 mL, 20.1 mmol) in /-PrOH (40 ml_) was added <strong>[217806-26-3]azetidin-3-yl-carbamic acid tert-butyl ester monohydrochloride</strong> (2.1 g. 12.2 mmol). The reaction mixture was heated to 70 0C for 72 h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by flash chromatography on SiO2 (100% hexane increasing gradient to 60% EtOAc-Hexane) to yield two isomeric products. The minor upper Rf product was obtained as a white solid (326 mg, 1 1 %), and the desired major lower Rf product was also obtained as a white solid (2.1 g, 69%). [1-(2-Butylamino-pyhmidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester. To a solution of [1-(2-chloro-pyhmidin-4-yl)-azetidin-3-yl]-carbamic acid tert- butyl ester (250 mg, 0.778 mmol) in /-PrOH (3.0 mL) was added butylamine (600 mul_, 6.0 mmol). The reaction mixture was heated to 95 0C in a sealed tube for 36-48 h followed by cooling to room temperature. The reaction mixture was then concentrated and the crude residue purified by flash chromatography on SiO2 using (100% EtOAc increasing the gradient gradually to 5% 2M NH3-MeOH) to yield the desired product (260 mg, 92%). [4-(3-Amino-azetidin-1-yl)-pyhmidin-2-yl]-butyl-amine. To a solution of [1-(2- butylamino-pyhmidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester (250 mg, 0.778 mmol) in formic acid (4 mL) was added 6N HCI (300 muL). The reaction mixture was stirred at room temperature for 15-30 minutes. Then, MeOH (10 mL) was added and stirred for 10 minutes. The contents were then concentrated and the crude residue purified by flash chromatography on SiO2 using an increasing gradient of (0 to 10% NH3/MeOH in CH2CI2) to yield the desired product (225 mg, 98%) as the free base. MS (ESI): mass calcd. for CnH19N5, 221.3 m/z found, 222.2 [M+H]+. 1H NMR (CD3OD): 7.61 (d, J= 7.3, 1 H), 5.99 (d, J = 7.1 , 1 H), 4.6-4.7 (m, 2H), 4.28-4.48 (m, 3H), 3.40 (bs, 1 H), 1.54-1.62 (m, 2H), 1.31-1 .41 (m, 2H), 0.90 (t, J = 7.4, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 137To a solution of intermediate 118 (10.0 mg, 0.02 mmol) in MeOH (400 mu) was added <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (20.3 mg, 0.10 mmol) and triethylamine (28.0 mu, 0.20 mmol) at room temperature, and the reaction mixture was heated to 70 C. After 2 h, the reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. 4N HCI in dioxane solution (1.00 mL, 4 mmol) was added to the crude residue and the reaction mixture was stirred at room temperature. After 6 h, the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by preparatory HPLC (5-100% MeCN/H20, 0.1% trifluoroacetic acid modifier) to afford compound 137 (8.9 mg, 68%) as a white solid trifluoroacetate salt. NMR (CD3OD, 400MHz): delta 8.77 (br s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.8, 2.4Hz, 1H), 7.44 (d, J= 2.4 Hz, 1H), 6.30 (s, 1H), 6.12 (d, J- 4.2 Hz, 1H), 5.06-4.89 (m, 2H), 4.71(br d, J = 8.5 Hz, 2H), 4.38-4.27 (m, 1H), 3.28-3.23 (m, 1H), 2.98 (s, 3H), 2.81 (t, J = 12.5 Hz,1H), 2.33 (s, 3H), 2.14-2.01 (m, 1H), 1.82-1.63 (m, 2H), 1.38-1.28 (m, 1H), 1.10 (br q, J = 13.3Hz, 1H), 0.71 (d, J= 6.3 Hz, 3H).LCMS (ESI) mlz 532.43 [M + H]+, tR = 1.95 min.HPLC tR (min), purity %: 3.61, 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; acetonitrile; at 20℃; for 18h; | Intermediate 111<strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (62.3 mg, 0.30 mmol) and sodium bicarbonate (50.3 mg, 0.60 mmol) were added to a solution of intermediate 56 (150 mg, 0.30 mmol) in acetonitrile (0.85 mL) and water (0.85 mL) and the reaction mixture was stirred at room temperature. After 18 h, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL), was dried over Na2S04, and was concentrated under reduced pressure. The crude residue was purified via Si02 column chromatography (12 g Si02 Combiflash HP Gold Column, 0-100% ethyl acetate/hexanes) to afford intermediate 111 (166.8 mg, 87%) as a light yellow solid.LCMS (ESI) mlz 638.12 [M + H]+, tR = 2.99 min.HPLC tR (min), purity %: 5.61, 89%.Rf = 0.65 (75% EtOAc/hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With triethylamine; In methanol; at 70℃; for 18h; | To a solution of intermediate 111 (25.0 mg, 0.05 mmol) in MeOH (1.00 mL) was added <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (104.0 mg, 0.5 mmol) and triethylamine (139 muEpsilon, 1.00 mmol) at room temperature, and the reaction mixture was heated to 70 C. After 18 h, the reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The crude residue was purified by preparatory HPLC (5-100% MeCN/H20, 0.1%) trifluoroacetic acid modifier) to afford intermediate 113 (5.0 mg, 13 %) as a white solid. LCMS (ESI) mlz 774.31 [M + H]+, tR = 2.43 min.HPLC tR (min), purity %: 4.48, 99%.Rf= 0.56 (EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 142To a solution of intermediate 123 (20.0 mg, 35.0 muetaiotaomicron) in MeOH (700 mu.) was added <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (73.7 mg, 0.35 mmol) and triethylamine (98.0 mu,, 0.70 mmol) at room temperature, and the reaction mixture was heated to 70 C. After 2 h, the reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by preparatory HPLC (5-100% MeCN/¾0, 0.1% trifluoroacetic acid modifier). 4N HCI in dioxane solution (1.00 mL, 4 mmol) was added and the reaction mixture was stirred at room temperature. After 4.5 h, the reaction mixture was concentrated under reduced pressure to afford compound 142 (9.5 mg, 43%) as a white solid hydrochloric acid salt..H NMR (CD3OD, 400MHz): delta 7.58-7.33 (m, 3H), 6.30 (br s, 1H), 6.03 (d, J = 4.8 Hz, 1H), 5.41 (br s, 1H), 4.55-4.32 (m, 5H), 4.11-3.85 (m, 8H), 3.04 (s, 3H), 2.84 (t, J = 12.2 Hz, 1H),2.41 (d, J = 13.5 Hz, 1H), 2.22 (br s, 1H), 2.09 (t, J = 12.5 Hz, 1H), 1.75 (d, J = 11.6 Hz, 1H),1.46-1.07 (m, 2H), 0.76 (d, J= 6.3 Hz, 3H).LCMS (ESI) mlz 603.40 [M + H]+, tR = 1.89 min.HPLC tR (min), purity %: 3.05, 93%.Rf = 0.50 (10% methanol/CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In dichloromethane; at 20℃;Inert atmosphere; | Step 2: preparation of compound 15-4: To a mixture of compound 15-2 (210 mg, 1.06 mmol) and Et3N (310 mg, 3.0 mmol) in DCM (5 mL), compound 15-3 (200 mg, 0.958 mmol) was added at r.t. After the mixture was stirred at r.t. o.n., water was added to the mixture and it was extracted with DCM. Organic layer was combined and washed with brine. After solvent was removed, the residue was purified by column chromatography to give a white solid (280 mg, 84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | Step 1: preparation of compound 18-2: To a solution of compound 1 (500 mg, 2.4 mmol) in DCM (2 mL) and TEA (900 mg, 8.72 mmol ) was added MsCl (500 mg, 4.36 mmol) dropwise at 0C. After the mixture was stirred at r.t. for 2 h, it was concentrated to give the crude product, which was used directly (550 mg, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
480 mg | With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; | Step 1: preparation of compound 21-3: Compound 21-1 (425 mg, 3.0 mmol) was added dropwise to the solution of i-BuOH (222 mg, 3.0 mmol) in DCM (5.0 mL) at 0 C. After the mixture was stirred at 0 C for 30 mins, a solution of compound 21-2 (689 mg, 3.3 mmol) and Et3N (708 mg, 7.0 mmol) in DCM (3.0 mL) was added dropwise at 0 C. The mixture was warmed to rt and stirred at r.t. for another hour. Water was added to the mixture and it was extracted with DCM, the organic layer was combined and washed with brine, dried over Na2S04, filtered. Solvent was evaporated to give an off-white solid (480 mg, 46%). NMR (400MHz, CDCL) delta 4.41 (br, 1H), 4.28 (m, 2H), 3.99 (m, 2H), 1.49 (s, 9H), 1.42 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere; | Step 1: preparation of compound 26-2: To a solution of compound 1 (2 g, 9.6 mmol) in DCM (30 mL) and Et3N (3.53 g, 28.8 mmol) at rt was added 2 dropwise at r.t. After the mixture was stirred at r.t. for 1 h, it was concentrated to give the crude product, which was used directly (2 g, 97%). | |
1.85 g | With triethylamine; In dichloromethane; at 0℃; for 1h; | To a stirred solution of <strong>[217806-26-3]3-Boc-aminoazetidine hydrochloride</strong> (2.0 g, 9.58mmol) and triethylamine (4.01 mL, 28.75 mmol) in DCM (40 mL) was added acetyl chloride (1.02 mL, 14.38 mmol) slowly at 0 C and the resulting mixture was stirred at 0 C for 1 hr. The resulting reaction mixture was diluted with DCM (20 mL), then washed with H20 (10 mL) and brine (10 mL) successively. The organic phase was dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by the flash column (eluting with PE/EA=5/1, v:v) to afford tert-butyl N-(1-acetylazetidin-3-yl)carbamate (1.85 g) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; | Cesium carbonate (4.68 g, 14.4 mmol), 2-chloroquinoline (0.782 g, 4.8 mmol) and <strong>[217806-26-3]tert-butyl azetidin-3-yl-carbamate hydrochloride</strong> (1.0 g, 4.8 mmol) were dissolved in dry dimethylformamide (15 mL) and the resulting mixture was heated at 120 C. overnight. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2*50 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), then dried over sodium sulfate. The organic was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 40% ethyl acetate in petroleum ether) to give tert-butyl (1-(quinolin-2-yl)azetidin-3-yl)-carbamate (1.14 g, 3.84 mmol, 80% yield) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[001046] In a 20-mL scintillation vial equipped with a stir bar, 5-amino-3,4- dimethylthieno[2,3-c]pyridazine-6-carboxylic acid (100 mg, 0.448 mmol) and HATU (190 mg, 0.500 mmol) were massed and dissolved in DMF (4 mL). Diisopropylethyl amine (120 mg, 0.930 mmol) was added, and the reaction was allowed to stir at ambient temperature for 5 min. tert-Butyl azetidin-3-ylcarbamate hydrochloric acid salt (100 mg, 0.481 mmol) in DMF (2 mL) was then added, and the reaction was monitored by LCMS, which confirmed complete consumption of the starting material after 30 min. The reaction was diluted into DCM/H20 (20 mL, 1: 1), and the organic layer was separated. The aqueous layer was extracted with DCM (2 x 10 mL), and the combined organic fractions were dried over MgS04, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using a 12-gram ISCO column and eluting with 0 to 10% MeOH/DCM to afford tert-butyl (l-(5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6- carbonyl)azetidin-3-yl)carbamate (LCMS: RT = 0.517 min, m/z = 378 [M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 1h; | [001084] In an oven-dried 2-dram vial equipped with a stir bar, tert-butyl azetidin-3- ylcarbamate (20 mg, 0.116 mmol) and 2-chlorobenzothiazole (22 mg, 0.131 mmol) were massed and dissolved in DMF (2 mL) at ambient temperature. Sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added and the reaction was allowed to stir at ambient temperature for 1 hr and monitored by LCMS. Upon complete consumption of the starting material, the reaction was quenched with 0 (1 mL). The reaction mixture was diluted into DCM/H20 (20 mL, 1 : 1). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic fractions were dried over MgS04, filtered, and concentrated under reduced pressure to afford tert-butyl (1- (benzo[d]thiazol-2-yl)azetidin-3-yl)carbamate (LCMS: RT = 0.549 min, m/z = 306 [M+H]+). The crude product was carried forward without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | A mixture of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (200 mg, 0.96 mmol), benzaldehyde (203 mg, 1.92 mmol), triethylamine (0.133 mL, 0.96 mmol) and acetic acid (115 mg, 1.92 mmol) in methanol (10 mL) was stirred at 24 C for 30 min. Then NaBH3CN (181 mg, 2.88 mmol) was added to the mixture. The resulting mixture was stirred at 24 C for 12 h and concentrated under reduced pressure to give the crude product, which was purified by column to give tert-butyl 1-benzylazetidin-3-ylcarbamate (120 mg, 48% yield). LCMS (m/z): 262.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | Step 1 (0850) To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95 C. for 3 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes-hexanes:EtOAc 1:1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84% yield) as a white solid. ESIMS found for C12H17ClN4O2 m/z 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | j0671j To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2504, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes-*hexanes:EtOAc 1:1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17C1N402 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) ( 1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous NaaSO/t, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield tert-butyl (l-(6- chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 3h; | j0662j To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture wasadded 2,6-dichloropyrazine (LXIII) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes-*hexanes:EtOAc 1:1) to yield tert-butyl (1-(6- chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXIV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17C1N402 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of fert-butyl azetidin-3-ylcarbamate hydrochloride (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) ( 1.428 g, 9.58 mmol) and the reaction was stirred at 95 C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SC filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield fert-butyl (l-(6- chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of fert-butyl azetidin-3-ylcarbamate hydrochloride (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SC filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield fert-butyl (l-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of fert-butyl azetidin-3-ylcarbamate hydrochloride (LXXX) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXXXI) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous NaaSO/t, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield fert-butyl (l-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXXXII) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of tert-butyl azetidin-3 -ylcarbamate hydrochloride (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2504, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes-*hexanes:EtOAc 1:1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C,2H,7C1N402 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of fert-butyl azetidin-3-ylcarbamate hydrochloride (LXXX) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXXXI) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield fert-butyl (l-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXXXII) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 m/z 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | Step 1 [0666] To a solution of fert-butyl azetidin-3-ylcarbamate hydrochloride (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous NaaSO/t, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield fert-butyl (l-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | 0662] To a solution of fert-butyl azetidin-3-ylcarbamate hydrochloride (LXII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIII) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous NaaSO/t, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield fert-butyl (l-(6- chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXIV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of fert-butyl azetidin-3-ylcarbamate hydrochloride (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous NaaSO/t, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1 : 1) to yield fert-butyl (l-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84 % yield) as a white solid. ESIMS found for C12H17CIN4O2 mlz 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | Step 1 To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95 C. for 3 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes-hexanes:EtOAc 1:1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84% yield) as a white solid. ESIMS found for C12H17ClN4O2 m/z 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | Step 1 (0853) To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95 C. for 3 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1:1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXV) (2.2882 g, 8.04 mmol, 84% yield) as a white solid. ESIMS found for C12H17ClN4O2 m/z 285.1 (M+H). |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | Step 1 (0874) To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXXVIII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXXIX) (1.428 g, 9.58 mmol) and the reaction was stirred at 95 C. for 3 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes?hexanes:EtOAc 1:1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXXX) (2.2882 g, 8.04 mmol, 84% yield) as a white solid. ESIMS found for C12H17ClN4O2 m/z 285.1 (M+H). |
83.9% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 95℃; for 3h; | To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (LXIV) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXV) (1.428 g, 9.58 mmol) and the reaction was stirred at 95C for 3 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (40g) (100%) hexanes?hexanes:EtOAc 1 : 1) to yield tert-butyl (1-(6- chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXVI) (2.2882 g, 8.04 mmol, 83.9% yield) as a white solid. ESIMS found for C12H17CIN4O2 m/z 285.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 18h; | To a chilled solution, 0 C, of tert-butyl azetidin-3-ylcarbamate (183 mg, 0.88 mmol) in DCM (5.00 mL), was added DIEA (0.58 mL, 3.51mmol) followed by 3 -cyano-6-(4-fluorotetrahydro-2H-pyran-4-yl)-2-methoxybenzoyl chloride(Intermediate 23, 261 mg, 0.88 mmol). The reaction mixture was stirred for 18 h at rt. The reaction mixture was then washed with water then brine. The combined organic layers were isolated, dried (Mg504), filtered and concentrated under reduced pressure. The resulting residue was purified (FCC, 5i02, 40-100% EtOAc/Hexanes) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h; | To a cooled solution, 0 C, of tert-butyl azetidin-3- ylcarbamate HC1 salt (217 mg, 1.04 mmol) in DCM was added DIEA (0.36 mL, 2.17 mmol). To the cooled reaction mixture was added a solution of (S)-3-cyano-2-methoxy-6-((1,1,1- trifluoropropan-2-yl)oxy)benzoyl chloride (Intermediate 24) in DCM (4mL) and the reactionmixture was stirred at rt for an additional 3 h. The reaction mixture was washed with sat. aq. NaHCO3. The organic layer was separated, dried (Na2504), filtered, and concentrated under reduced pressure. Purification (FCC, 5i02, 10-90% EtOAc/hexanes) afforded the title compound which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; water; at 135℃; for 2h;Inert atmosphere; Microwave irradiation; | Step 1: Preparation of tert-Butyl (1-(1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)carbamate A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.1 mmol), <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (1.5 g, 7.2 mmol), Pd2(dba)3 (350 mg, 0.38 mmol), X-Phos (467 mg, 1 mmol) and Cs2CO3 (4.9 g, 15 mmol) in 1,4-dioxane/H2O (15 mL/3 mL) was stirred under Ar at 135 C. with microwave for 2 h. After cooling the result mixture was poured into 30 mL water, and water layer was extracted with ethyl acetate (20 mL*3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified with normal phase chromatography (ethyl acetate/heptane) to give tert-butyl (1-(1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)carbamate as a yellow solid (0.4 g, 27% yield): MS (ES) m/z 289 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.2% | A mixture of 1-(4-chlorobenzyl)-1H-pyrazole-4-carbaldehyde (200 mg, 0.9063 mmol), tert-Butyl (azetidin-3-yl)carbamate hydrochloride (377 mg, 1.81 mmol) and acetic acid (54.4 mg, 0.9063 mmol) were dissolved in MeOH (40 ml). After stirred for 2h at r.t., sodium cyanoborohydride (142 mg, 2.26 mmol) was added to the solution. The mixture was stirring over night at r.t.. Then, the solution was concentrated under reduced pressure and the residue purified by flash column chromatography (eluant: DCM : MeOH = 10:1 (600 ml)). To furnish tert-butyl (1-((1-(4-chlorobenzyl)-1H-pyrazol-4- yl)methyl)azetidin-3-yl)carbamate (273 mg, 54.2 %) as colorless oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.7% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 18h;Inert atmosphere; | To a solution of <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (compound 3A, 1.0 g, 4.8 mmol), bromobenzene (750 mg, 4.8 mmol), Cs2CO3 (4.7 g, 14.4 mmol), BINAP (600 mg, 9.6 mmol) in toluene (60 mL) was added Pd2(dba)3 (440 mg, 0.48 mmol) at 90 C under N2 atmosphere. Then the mixture was stirred at the same temperature for 18 hrs. The mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE/EA=5: 1) to give tert-butyl (1-phenylazetidin-3-yl)carbamate (compound 3B, 800 mg, 66.7%) as a yellow solid. MS: calc'd 249 (M+H)+, measured 249 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃;Microwave irradiation; | Tert-butyl (1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)carbamate (X28) To a microwave vial was added 3-Boc aminoazetidine HCl (1 eq), 2-chloro-5-(trifluoromethyl)pyrimidine (1.1 eq), DIEA (3 eq) and DMF (0.5M). The rxn was heated to 100 C. overnight. LCMS confirms complete conversion. To the rxn was added EtOAc: H2O (1:1). The organic layer was separated and washed with water (2*). The water layers were re-extracted with EtOAc (3*). The collected organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified using Biotage system (solid loading, 120G column, 0-40% EtOAc/Hexanes, 25 min run). The desired fractions were concentrated. ES-MS [M+1]+: 319.2. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; | To a microwave vial was added 3-Boc aminoazetidine HC1 (1 eq), 2-chloro-5- (0257) (trifluoromethyl)pyrimidine (1.1 eq), DIEA (3 eq) and DMF (0.5 M). The reaction was heated to 100C overnight. LCMS confirmed complete conversion. To the reaction was added EtOAc: H20 (1 : 1). The organic layer was separated and washed with water (2x). The water layers were re-extracted with EtOAc (3x). The collected organic layers were dried (MgS04), filtered and concentrated in vacuo. The crude material was purified using Biotage system (solid loading, 120G column, 0-40% EtOAc/Hexanes, 25 min run). The desired fractions were concentrated. LCMS (90 second method): Rt=0.902 min; M+H=319.2, >98% 215 and 254 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 85℃; | To terf-butyl azetidin-3-ylcarbamate hydrochloride (500 mg, 2.40 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.84 mL, 4.8 mmol) followed by 2-fluoropyridine (233 mg, 2.40 mmol). The mixture was heated at 85 C for overnight, cooled, diluted with EtOAc, washed with water, and the aqueous extracted with EtOAc. The combined organic layers were washed with water (2X) and brine, dried over MgSC , filtered and concentrated. The residue was purified on silica gel eluting with a 20%-70% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (90 mg, 15%). 1 H NMR (400 MHz, CDCI3) delta 1 .49 (s, 9 H), 3.82 (dd, J = 8, 5 Hz, 2 H), 4.38 (t, J = 8 Hz, 2 H), 4.66 (s br, 1 H), 6.33 (d, J = 8 Hz, 1 H), 6.61 -6.70 (m, 1 H), 7.42-7.53 (m, 1 H), 8.18 (d, J = 4 Hz, 1 H); LC-MS (LC-ES) M+H = 250. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 2.5h;Microwave irradiation; | To a microwave reaction vial with terf-butyl azetidin-3-ylcarbamate hydrochloride (209 mg, 1 .00 mmol) in NMP (2 mL) was added 2-chloropyrimidine (1 15 mg, 1 .00 mmol) and N,N- diisopropylethylamine (0.35 mL, 2.0 mmol). The mixture was heated in a microwave (130 C) for 2.5 h, cooled, diluted with water and MeOH, and loaded onto a semi-prep HPLC (NH4OH as modifier) to afford the title compound as a pale yellow solid (147 mg, 59% yield). 1H NMR (400 MHz, CD3OD) delta 1 .45 (s, 9 H), 3.93 (dd, J = 9, 5 Hz, 2 H), 4.36 (t, J = 8 Hz, 2 H), 4.42-4.57 (m, 1 H), 6.67 (t, J = 5 Hz, 1 H), 8.31 (d, J = 5 Hz, 2 H); LC-MS (LC-ES) M+H = 251 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 120℃; for 5h;Microwave irradiation; | To a microwave reaction vial with terf-butyl azetidin-3-ylcarbamate hydrochloride (522 mg, 2.5 mmol) in ethanol (8 mL) was added 2-chloro-5-methylpyridine 1 -oxide (359 mg, 2.5 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.0 mmol). The mixture was heated in a microwave at 120 C for 2 h, cooled, and then another portion (2.5 mmol) of both terf-butyl azetidin-3-ylcarbamate hydrochloride and Nu,Nu-diisopropylethylamine were added. The mixture was heated in a microwave at 125 C for 3 h, cooled, and concentrated. The resulting residue was purified on silica gel eluting with a 0%-40% MeOH-DCM gradient to give the title compound (335 mg, 31 %) as a white solid. 1H NMR (400 MHz, CD3OD) delta 1 .47 (s, 9 H), 2.24 (s, 3 H), 3.67- 3.83 (m, 2 H), 4.00-4.06 (m, 2 H), 4.44-4.54 (m, 1 H), 6.66 (d, J = 9 Hz, 1 H), 7.29-7.38 (m, 1 H), 7.86 (s, 1 H); LC-MS (LC-ES) M+H = 280. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 130℃; for 3h;Microwave irradiation; | To a microwave reaction vial with terf-butyl azetidin-3-ylcarbamate hydrochloride (433 mg, 2.1 mmol) in acetonitrile (10 mL) was added (2-chloropyrimidin-5-yl)methanol (300 mg, 2.1 mmol) and N,N-diisopropylethylamine (1 .8 mL, 10 mmol). The mixture was heated in a microwave at 130 for 3 h, cooled and concentrated. The resulting residue was purified on silica gel eluting with a 30%-100% EtOAc:EtOH (3:1) in hexanes gradient to give the title compound (415 mg, 71 %) as a white solid. 1H NMR (400 MHz, CD3OD) delta 1 .47 (s, 9 H), 3.96 (dd, J = 9, 6 Hz, 2 H), 4.38 (t, J = 8 Hz, 2 H), 4.48 (s, 2 H), 4.48-4.57 (m, 1 H), 8.34 (s, 2 H); LC-MS (LC-ES) M+H = 281 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃; for 5h;Microwave irradiation; | To terf-butyl azetidin-3-ylcarbamate hydrochloride (300 mg, 1 .44 mmol) in acetonitrile (10 mL), 2-chlorothiazole-5-carbonitrile (208 mg, 1 .44 mmol) was added, followed by N,N- diisopropylethylamine (0.75 mL, 4.3 mmol). The mixture was heated in a microwave at 1 10 C for 5 h, then allowed to sit at room temperature for two days as crystals appeared. This solid product was collected by filtration, the filtrate was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure, combined with the previously harvested crystal solid and placed in vacuo to give the title compound as a white solid (90 mg, 22%). 1H NMR (400 MHz, CDCI3) 5 1 .45 (s, 9 H), 4.03-4.07 (m, 2 H), 4.41 -4.49 (m, 2 H), 4.71 (br s, 1 H), 5.05 (br s, 1 H), 7.67 (s, 1 H); LC-MS (LC-ES) M+H-Boc = 181 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 105℃; | (Intermediate 97B) (535 mg, 1 .46 mmol) in DCM (2 mL) was added 4 N HCI in dioxane (3 mL, 12 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed in vacuo to give the title compound as a light tan solid (388 mg, quantitative). 1H NMR (400 MHz, CD3OD) delta 1 .20 (t, J = 7 Hz, 3 H), 3.50-3.64 (m, 6 H), 4.41 -4.49 (m, 1 H), 4.58 (ddd, J = 1 1 , 5, 1 Hz, 2 H), 4.79-4.88 (m, 2 H), 7.61 (d, J = 10 Hz, 1 H), 8.32 (d, J = 10 Hz, 1 H); LC-MS (LC-ES) M+H = 266. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 1h; | To a reaction vial with terf-butyl azetidin-3-ylcarbamate hydrochloride (902 mg, 5.24 mmol) in acetonitrile (15 mL) was added 2-chloropyrazine (600 mg, 5.24 mmol) and N,N- diisopropylethylamine (1 .37 mL, 7.86 mmol). The mixture was heated to 100 C for 1 h, heated to 90 C overnight, cooled, and concentrated. The resulting residue was purified on silica gel eluting with a 5%-20% MeOH in DCM gradient to give the title compound (595 mg, 45%) as a white solid. 1H NMR (400 MHz, CD3OD) delta 1 .47 (s, 9 H), 3.94 (dd, J = 8, 6 Hz, 2 H), 4.38 (t, J = 8 Hz, 2 H), 4.58 (d, J = 6 Hz, 1 H), 7.83 (dd, J = 1 1 , 2 Hz, 2 H), 8.03 (dd, J = 3, 2 Hz, 1 H); LC- MS (LC-ES) M+H = 251 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 3h;Microwave irradiation; | To terf-butyl azetidin-3-ylcarbamate hydrochloride (300 mg, 1 .44 mmol) in acetonitrile (10 ml_), 2-chloropyrimidine-4-carbonitrile (241 mg, 1 .73 mmol) was added, followed by N,N- diisopropylethylamine (0.75 ml_, 4.3 mmol). The mixture was heated in a microwave at 90 C for 3 h, the solvent was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (423 mg, quantitative yield). 1H NMR (400 MHz, CDCI3) delta 1 .46 (s, 9 H), 3.91 -3.99 (m, 2 H), 4.40- 4.48 (m, 2 H), 4.63 (br s, 1 H), 5.03 (br s, 1 H), 6.81 (d, J = 5 Hz, 1 H), 8.45 (d, J = 5 Hz, 1 H); LC-MS (LC-ES) M+H-Boc = 176. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | To terf-butyl azetidin-3-ylcarbamate hydrochloride (500 mg, 2.40 mmol) in methanol (10 mL), MP-carbonate (3.1 mmol/g) was added. The mixture was stirred for 1 h, filtered and washed with MeOH. To this mixture, 2,4-dichloropyrimidine (428 mg, 2.88 mmol) was added followed by N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The mixture was stirred at room temperature for 2 h, the solvent was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (412 mg, 60%). 1H NMR (400 MHz, CDCI3) delta 1 .45 (s, 9 H), 3.88-4.00 (m, 2 H), 4.33-4.47 (m, 2 H), 4.55- 4.73 (m, 1 H), 4.92-5.10 (m, 1 H), 6.07 (d, J = 6 Hz, 1 H), 8.02 (d, J = 6 Hz, 1 H); LC-MS (LC- ES) M+H = 285, 287 (CI pattern). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | To terf-butyl azetidin-3-ylcarbamate hydrochloride (500 mg, 2.40 mmol) in methanol (10 mL) was added MP-carbonate (3.1 mmol/g). The mixture was stirred for 1 h, filtered and washed with MeOH. To this mixture, 2,4-dichloropyrimidine (428 mg, 2.88 mmol) was added followed by N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The mixture was stirred at room temperature for 2 h, the solvent was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (68 mg, 10%). 1H NMR (400 MHz, CDCI3) delta 1 .46 (s, 9 H), 3.90-3.96 (m, 2 H), 4.42-4.47 (m, 2 H), 4.56- 4.66 (m, 1 H), 4.92-5.01 (m, 1 H), 6.57 (d, J = 5 Hz, 1 H), 8.16 (d, J = 5 Hz, 1 H); LC-MS (LC- ES) M+H = 285, 287 (CI pattern). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 125℃; for 2.5h;Microwave irradiation; | To a microwave reaction vial with terf-butyl azetidin-3-ylcarbamate hydrochloride (732 mg, 3.51 mmol) in acetonitrile (2 mL) was added 2-chloro-5-fluoropyrimidine (465 mg, 3.51 mmol) and N,N-diisopropylethylamine (1 .23 mL, 7.02 mmol). The mixture was heated in a microwave (125 C) for 2.5 h , cooled and some precipitated product collected by filtration. The filtrate was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-50% EtOAc/EtOH (3:1 ) in hexanes gradient. The appropriate fractions were combined , evaporated under reduced pressure and placed in vacuo to give the title compound (620 mg, 65%) as a white solid. 1 H NMR (400 MHz, CD3OD) delta 1 .47 (s, 9 H), 3.89-3.98 (m, 2 H), 4.32-4.39 (m, 2 H), 4.43-4.53 (m, 1 H), 8.31 (s, 2 H); LC-MS (LC-ES) M+H = 269. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 1h;Sealed tube; Microwave irradiation; | A 10 mL snap-cap microwave vessel was charged with a mixture of 2-chloro-6,7- dimethoxyquinazolin-4-amine (100.0 mg, 0.42 mmol), <strong>[217806-26-3]tert-butyl azetidin-3-ylcarbamate hydrochloride</strong> (130.6 mg, 0.63 mmol), N,N-diisopropylethylamine (0.18 mL, 1 .04 mmol) and n-butanol (2 mL). The tube was sealed then subjected to microwave irradiation (120 C / 1 h, ramp time 5 minutes, maximum power 250W). The mixture was cooled and concentrated in vacuo and the resulting residue was subjected to flash column chromatography [silica, 5:95 to 20:80 v/v methanol/ethyl acetate elution] to give, after concentration of the appropriate fractions tert-butyl (1 -(4-amino-6,7- dimethoxyquinazolin-2-yl)azetidin-3-yl)carbamate (Rf = 0.40, 20:80 v/v methanol/ethyl acetate elution). 1H NMR (400 MHz, methanol-d4) delta 7.26 (s, 1 H), 6.79 (s, 1 H), 4.45 (brs, 1 H), 4.33 (t, J = 7.9 Hz, 2H), 3.92 (dd, J = 8.5 and 5.6 Hz, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 1 .45 (s, 9H); (+)-LRESIMS m/z (rel. int.) 376 (100) [M + H]+; vmax 3329, 3215, 2974, 1685, 1640, 1574, 1497, 1465, 1454, 1441 , 1383, 1345, 1241 , 1210, 1 158, 1 103, 1000, 842, 783 cm"1. A solution of tert-butyl (1 -(4-amino-6,7- dimethoxyquinazolin-2-yl)azetidin-3-yl)carbamate obtained above in DCM (2 mL) was treated dropwise with trifluoroacetic acid (0.5 mL) at 0 C. The resulting mixture was stirred at 20 C until the completion conversion (observed by TLC). Solvent was then evaporated to obtain the TFA salt of 2- (3-aminoazetidin-1 -yl)-6,7-dimethoxyquinazolin-4-amine. The product was then dissolved in pyridine (2 mL) and the solution was stirred for 15 min before evaporated and subjected to a short pad silica gel to afford the title compound (Rf = 0.24, 10:90 v/v methanol saturated ammonia/dichloromethane elution) (100.0 mg, 87%). 1H NMR (400 MHz, acetone-d6) delta 9.1 1 (brs, 1 H), 7.39 (s, 1 H), 6.87 (s, 1 H), 6.72 (s, 2H), 4.80 (m, 1 H), 4.37 (t, J = 8.3 Hz, 2H), 4.05 (dd, J = 9.0 and 5.4 Hz, 2H), 3.89 (s, 3H); (+)-LRESIMS m/z (rel. int.) 276 (100) [M + H]+; vmax 3343, 3195, 2957, 1640, 1606, 1558, 1492, 1438, 141 1 , 1376, 1345, 1277, 1237, 1210, 1 128, 1097, 1031 , 997, 839, 785 cm"1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
550 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; | To a solution of tert-butyl azeti din-3 -ylcarbamate hydrochloride (1.15 g, 5.5 mmol) and K2C03(1.4 g, 10 mmol) in DMF (20 mL) was added 3 -bromo-2, 2-dimethylpropanoic acid (1.0 g, 5.5 mmol) dropwise at 0C. The reaction was stirred at room temperature overnight under N2atmosphere. TLC showed the reaction was complete. Water was added and the pH of the water layer adjusted to 5~6, then the water layer was extracted with DCM. Thedichloromethane solution was dried over anhydrous Na2S0 , filtered and concentrated to give crude product. The crude product was purified by column chromatography (silica gel, 1 to -10 % MeOH in DCM) to give 3-(3-((tert-butoxycarbonyl)amino)azetidin-l-yl)-2,2- dimethylpropanoic acid (550 mg) as a white solid. LC-MS (ESI) found: 273 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.24% | With sodium cyanoborohydride; In methanol; at 20℃; for 1h; | To a stirred solution of 2,6-dimethoxy-4-(2-methyl-1 -oxo-1 ,2-dihydro-2,7-naphthyridin-4- yl)benzaldehyde (450.00 mg, 1 .387 mmol, 1 .00 equiv) in MeOH (10.00 ml_) was added NaBFhCN (261 .57 mg, 4.162 mmol, 3.00 equiv), ferf-butyl A/-(azetidin-3-yl)carbamate hydrochloride (347.46 mg, 1 .665 mmol, 1 .20 equiv). The resulting mixture was stirred for 1 hour at room temperature. The residue was purified by Flash column chromatography with EtOAc/PE (0-1 00%) to afford ferf-butyl A/-(1 -[[2,6- dimethoxy-4-(2-methyl-1 -oxo-1 ,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)carbamate (475 mg, 71 .24%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+ = 481 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[217806-26-3]tert-butyl N-(azetidin-3-yl)carbamate hydrochloride</strong> (500 mg, 2.40 mmol) in THF (6 mL) was added CDI (393 mg, 2.42 mmol). The reaction mixture was stirred 16 h at 25C. To the reaction mixture were then added NEt3 (0.33 mL, 2.40 mmol) and 2-(4-chloro-3- fluorophenoxy)acetohydrazide (577 mg, 2.64 mmol) as a solution in THF (4 mL). The reaction mixture was then stirred for an additional 16 h at 25 C. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel colunm chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | [0513] 1-(3-fluoropropyl)azetidin-3-amine ethane-1,2-disulfonate was prepared according to the following reaction scheme:.[0514] Tert-butyl azetidin-3-ylcarbamate hydrochloride (109.7kg, 1.0 eq.) was dissolved in MTBE (793.4kg), and 1-bromo-3-fluoropropane (82.3kg) was added. MTBE (14kg) and water (530kg) were added followed by LiOH?H2O (66.0kg) at 15-25C followed by stirring at 50-60C. After reaction completion, an organic phase was separated and then combined 1,2- ethanedisulfonic acid dihydrate aqueous solution (247.8kg) at 0-5C. The resulting mixture was stirred for 30 min at 15-20C. An aqueous phase was separated, and 1,2-ethanedisulfonic acid dihydrate (56.85kg) was added to the organic phase. The resulting mixture was stirred for 5h at 35-40C until deprotection was complete. MeOH (884.1kg) was then added at 35-40C, and the mixture was stirred for 2h at 35-40C. After cooling to room temperature, the reaction mixture was stirred for 4h. Solid was collected by filtration and rinsed with aq. MeOH. The washed solid was dried at 35-42C under reduced pressure to provide 106.8 kg of 1-(3-fluoropropyl)azetidin-3- amine ethane-1,2-disulfonate (63% yield).1H NMR (400 MHz, DMSO-d6) d 9.92 (s, 0.7H), 9.63 (s, 0.3H), 8.35 (s, 3H), 4.52 (dt, J = 47.1, 5.6 Hz, 2H), 4.43-4.08 (m, 5H), 3.36 (s, 3H), 2.74 (s, 4H), 2.06- 1.77 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h; | To a solution of compound 2a (3.00 g, 13.0 mmol, 1 eq) in DMF (30.0 mL) was added tert-butyl N-(azeti din-3 -yl)carbamate (2.78 g, 13.3 mmol, 1.02 eq , HC1) dicesium;carbonate (8.50 g, 26.0 mmol, 2 eq) and[2-(2-aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane;2-methoxy-2 -methyl-propane (496.0 mg, 652.0 umol, 0.05 eq), the mixture was stirred at 80C for 12 hrs. TLC (Dichloromethane : Methanol = 10 : 1, Rf= 0.28) showed the reaction was complete. The mixture was poured into FLO (100.0 mL) and extracted with EtOAc (50.0 mL x 3). Then the organic phases were washed with brine (200.0 mL) dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography eluted with Petroleum ether : Ethyl acetate = 100/1 ~ 20/1 ~ 10/1-1/1. Give the compound 3a (2.00 g, crude) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.4% | With sodium hydrogencarbonate; In dimethyl sulfoxide; at 70℃; for 16h; | A mixture of Intermediate 1 (11.0 g, 69.3 mmol, 1 eq), Intermediate 2 (21.7 g, 104.0 mmol, 1.5 eq, HC1) and NaHCCb (14.5 g, 173.4 mmol, 6.75 mL, 2.5 eq) in DMSO (100.0 mL) was stirred at 70C for 16 h. TLC (Petroleum ether/Ethyl acetat = 1/1, Rf = 0.24) indicated the starting material was consumed completely. The reaction mixtures were combined, and then diluted with EhO (50.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic layers were washed with LEO (50.0 mL x 5) and brine (20.0 mL ), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 20/1 to 1/1). Intermediate 3 (15.0 g, 50.9 mmol, 73.4% yield) was obtained as a yellow solid. NMR : MeOD Varian_Y_400MHz 8.07 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 6.66 (dd, J = 2.2, 5.7 Hz, 1H), 4.60 (br s, 1H), 4.37 (t, J = 8.2 Hz, 2H), 3.93 (dd, J = 5.6, 8.5 Hz, 2H), 1.45 (s, 9H) |
Tags: 217806-26-3 synthesis path| 217806-26-3 SDS| 217806-26-3 COA| 217806-26-3 purity| 217806-26-3 application| 217806-26-3 NMR| 217806-26-3 COA| 217806-26-3 structure
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H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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