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CAS No. : | 325775-44-8 | MDL No. : | MFCD01861762 |
Formula : | C9H18N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XSJPKMUFBHSIRA-UHFFFAOYSA-N |
M.W : | 186.25 | Pubchem ID : | 10679125 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.89 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 54.49 |
TPSA : | 55.56 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) : | -7.29 cm/s |
Log Po/w (iLOGP) : | 2.3 |
Log Po/w (XLOGP3) : | 0.2 |
Log Po/w (WLOGP) : | 0.43 |
Log Po/w (MLOGP) : | 0.56 |
Log Po/w (SILICOS-IT) : | 0.12 |
Consensus Log Po/w : | 0.72 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.86 |
Solubility : | 25.9 mg/ml ; 0.139 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.93 |
Solubility : | 22.1 mg/ml ; 0.119 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.76 |
Solubility : | 32.1 mg/ml ; 0.173 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.1 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
18 g | With hydrogenchloride In ethanol; water | To a solution of l-Boc-3-(aminomethyl)-azetidine (15.5 g, 82.9 mmol) in EtOH (250 mL) was slowly added aq. HCl (1.0 M, 83 mL). The solvent was removed in vacuo at 38 °C, providing the hydrochloride salt of the amine as a white solid (18.0 g). |
18 g | With hydrogenchloride In ethanol; water | To a solution of l-Boc-3-(aminomethyl)-azetidine (15.5 g, 82.9 mmol) in EtOH (250 mL) was slowly added aq. HC1 (1.0 M, 83 mL). The solvent was removed in vacuo at 38 °C, providing the hydrochloride salt of the amine as a white solid (18.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step B: N-(Azetidin-3-ylmethyl)propanamide; Propanoic anhydride (286 mg, 2.2 mmol) was added into a solution of <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (200 mg, 1.08 mmol) and triethylamine (1 mL) in CH2Cl2 (20 mL) at r.t. After 2 hr, the reaction mixture was condensed. The residue was dissolved in CH2Cl2 (10 mL) and treated with TFA (10 mL) at r.t. for 1 h. Evaporation of solvents provided the desired product as its TFA salt, which was used in Step A directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step B: N-(Azetidin-3-ylmethyl)cyclopropanecarboxamide; Cyclopropanecarbonyl chloride (315 mg, 3.0 mmol) was added into a solution of <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (372 mg, 2.0 mmol) and triethylamine (1 mL) in CH2Cl2 (20 mL) at r.t. After 2 h, the reaction mixture was condensed. The residue was dissolved in CH2Cl2 (10 mL) and treated with TFA (10 mL) at r.t for 1 hr. Evaporation of solvents provided the desired product as its TFA salt, which was used in Step A directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 0.166667h; | [0183] Following general procedure 10, to a stirred solution of the amine (48) (100 mg, 1 equiv.) and Et3N (0.11 mL, 1.5 equiv.) in CH2Cl2 (5 mL) was added benzoyl bromide (0.07 mL, 1.1 equiv.). The resultant mixture was stirred at rt for 10 minutes. The mixture was then diluted with EtOAc and washed successively with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 50% EtOAc in hexane to 70% EtOAc in hexane) to afford the desired coupled product. The N-Boc group of the coupled product was then converted to the cyanamide (N-CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 50% EtOAc in hexane to 67% EtOAc in hexane) to afford the desired solid N-[(1-cyano-3-azetidinyl)methyl]benzamide (49). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; | [0187] Following general procedure 9, to a stirred solution of the amine (48) (186 mg, 1 equiv.), N-carbobenzyloxy-L-isoleucine (265 mg, 1 equiv.) and EDCI (211 mg, 1.1 equiv.) in CH2Cl2 (5 mL) was added DMAP (61 mg, 0.5 equiv.). The resultant mixture was stirred at rt for 16 h. The mixture was then diluted with EtOAc and washed successively with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 30% EtOAc in hexane to 50% EtOAc in hexane) to afford the desired coupled product. The N-Boc group of the coupled product was then converted to the cyanamide (N-CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 50% EtOAc in hexane) to afford the desired solid benzyl (1S,2S)-1-([(1-cyano-3-azetidinyl)methyl]amino}carbonyl)-2-methylbutylcarbamate (51). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 0 - 20℃; | EXAMPLE 60: N -(3-Hydroxy-3-methylbutyl)-N-(at)[2,4-dichloronhenyll-methyl(at)-azetidine-3-yl- methylamine L-Tartrate; (i) To a solution of 3-aminomethyl-azetidine-l-carboxylic acid tert-butyl ester (300 mg, 1.6 mmol), 2,4-dichlorobenzaldehyde (281 mg, 1.61 mmol) and acetic acid (0.09 mL, 1.61 mmol) in 1,2-dichloroethane (16 mL) at 0 C is added sodium triacetoxy- borohydride (476 mg, 2.25 mmol). The reaction is warmed to ambient temperature and stirred overnight under N2. The reaction mixture is poured on to 2N NaOH (20 mL) and extracted with ethyl acetate (3X). The combined organic extracts are washed with aqueous saturated NaCl, dried (Na2S04), filtered and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 5% EtOH (10% NH40H)/chloroform to yield 360 mg (65%) of 3-[(2,4-dichlorobenzylamino)-methyl]- azetidine-1-carboxylic acid tert-butyl ester. ¹H NMR (400 MHz, CD30D) No.H 7.49-7.47 (2H, m), 7.36-7.34 (1H, m), 4.05-4.01 (2H, m), 3.88 (2H, s), 3.64-3.61 (2H, m), 2.8 (2H, m), 2.78-2.74 (1H, m), 1.46 (9H, s). Mass spectrum (ion spray): m/z = 345.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In methanol; water; at 20℃; for 20h; | Step 1 1-(t-butoxycarbonyl)-3-(dimethylaminomethyl)azetidine To a solution of 920 mg of 1-(t-butoxycarbonyl)-3-(aminomethyl)azetidine in 18 ml of methanol, 5.66 ml of acetic acid, 4.12 g of a 37% aqueous formaldehyde solution and 3.14 g of sodium triacetoxyborohydride were added in turn, followed by stirring at room temperature for 20 hours. The reaction solution was alkalified by adding an aqueous saturated sodium hydrogen carbonate solution, subjected to extraction with ethyl acetate three times. The organic layers were combined, washed with water and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 673 mg of the objective compound as a colorless oily product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With triethylamine; In N,N-dimethyl-formamide; for 18h; | a) 1 ,1 -Dimethylethyl 3-[([(phenylmethyl)oxy]carbonyl}amino)methyl]-1 - azetidinecarboxylate To a solution of 1 ,1 -dimethylethyl 3-(aminomethyl)-1 -azetidinecarboxylate (5.0 g, 26.84 mmole) in DMF (40 mL) was added triethylamine (4.9 ml_, 34.9 mmole) and Cbz- succinamide (8.7 g, 34.9 mmole). After 18 hours, the reaction solution was concentrated under vacuum and redissolved in EtOAc (250 mL). The organic solution was washed with H2O (2 x 150 mL), brine (100 mL) and dried over Na2SC>4 and concentrated. The remaining residue was purified on silica (hexanes/EtOAc, 1 :1) to give the title compound (5.5 g, 64%) as a light yellow oil: LC-MS (ES) m/e 321 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; for 2h;Heating / reflux; | a. tert-Butyl 3-((5-nitro-1-oxoisoquinolin-2(1H)-yl)methyl)azetidine-1-carboxylate Into a round bottom flask was combined 5-nitro-isochromen-1-one (0.5 g, 0.002 mol), <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (0.975 g, 0.00523 mol), methanol (15 mL, 0.37 mol), and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature. LC-MS showed that the starting material was completely consumed. Volatiles were removed and the resulting oil was purified by silica-gel twice in a methanol:methylene chloride (0-10%) gradient and in a EtoAc:Hexane(30-80%). A light yellow solid was obtained (0.56 g). m/z=360.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Example 38A tert-butyl 3-((5-tert-butyl-2-iminothiazol-3(2H)-yl)methyl)azetidine-1-carboxylate A mixture of 3,3-dimethylbutanal (3.7 mL, 30 mmol), <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (Astatech, 5 g, 27 mmol), and 8 g of 4 A molecular sieves (8-12 mesh beads) in acetonitrile (50 mL) was stirred at ambient temperature for 72 h. The material was filtered through Celite with acetonitrile (additional 25 mL) then potassium thiocyanate (3.5 g, 35 mmol) was added and the mixture was warmed to 50 C. Iodine (6.81 g, 26.8 mmol) was added and the mixture stirred at 50 C. for 16 h then was cooled to ambient temperature. The mixture was stirred with 75 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with 3*10 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (6.3 g, 19 mmol, 72% yield) which was carried on without further purification. MS (DCI/NH3) m/z 326 (M+H)+. | |
Example 1A tert-butyl 3-((5-tert-butyl-2-iminothiazol-3(2H)-yl)methyl)azetidine-1-carboxylate A mixture of 3,3-dimethylbutanal (3.71 mL, 29.5 mmol), <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (Astatech, 5 g, 26.8 mmol), and 8 g of 4 A molecular sieves (8-12 mesh beads) in acetonitrile (50 mL) was stirred at ambient temperature for 72 h. The material was filtered through Celite with acetonitrile (additional 25 mL) then potassium thiocyanate (3.47 g, 35.7 mmol) was added and the mixture was warmed to 50 C. Iodine (6.81 g, 26.8 mmol) was added and the mixture stirred at 50 C. for 16 h then was cooled to ambient temperature. The mixture was stirred with 75 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with 3*10 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (6.3 g, 19.4 mmol, 72% yield) which was carried on without further purification. MS (DCI/NH3) m/z 326 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; for 1h; | Example 91 3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-methyl}-azetidine-1-carboxylic acid tert- butyl ester (I-91) To a mixture of 0.097 g (0.15 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0634 g (0.17 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 3 mL of dichloromethane, 0.13 mL of triethylamine was added followed by 0.0317 g (0.17 mmole) of <strong>[325775-44-8]3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester</strong>. After 1 hour, 4 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluding with hexanes-ethyl acetate (gradient, 100:0-0:100) to give 0.0714 g of 3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (I-91). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In acetonitrile; at 100℃; for 0.5h;Inert atmosphere; Sealed tube; microwave irradiation; | 11. 1 -(3-[(5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1,6-dihydropyrrolo[3l,2l:5,6]pyrido[3,4- b]indol-3(2H)-yl]methyl}azetidin-1 -yl)ethanone; Step 1 : tert-Butyl 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-5-(3-fluoro-4-methoxybenzyl)-2- methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indole-6(1 H)-carboxylate.; tert-Butyl 1-(3-fluoro-4- methoxybenzyl)-4-(prop-2-en-1-yl)-3-[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A9) (500 mg) is dissolved in acetonitrile (2 ml), then cesium carbonate (547 mg), palladium(ll) acetate (19 mg), (+/-)-2,2-bis(diphenylphosphino)-1 ,1 -binaphthalene (79 mg), and 3- aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (316 mg) are added under argon. The mixture is heated in a sealed vial at 1000C for 30 min under microwave irradiation. After cooling to room temperature, the content of the vial is diluted with methanol, filtered over Celite, washed with methanol. The combined filtrates are loaded onto Isolute SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH3 solution in MeOH. The filtrate is concentrated in vacuo to afford crude tert-butyl 3- [1 -(tert-butoxycarbonyl)azetidin-3-yl]methyl}-5-(3-fluoro^4-methoxybenzyl)-2-methyl-2,3- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indole-6(1 H)-carboxylate, that is used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 2h; | Step B: N-(Azetidin-3-ylmethyl)cyclopropanecarboxamideCyclopropanecarbonyl chloride (315 mg, 3.0 mmol) was added into a solution of tert-butyl 3-(aminomethyl)azetidine-1-carboxylat (372 mg, 2.0 mmol) and triethylamine (1 mL) in CH2Cl2 (20 mL) at r.t. After 2 h, the reaction mixture was condensed. The residue was dissolved in CH2Cl2 (10 mL) and treated with TFA (10 mL) at r.t for 1 hr. Evaporation of solvents provided the desired product as its TFA salt, which was used in Step A directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 2h; | Step B: N-(Azetidin-3-ylmethyl)propanamidePropanoic anhydride (286 mg, 2.2 mmol) was added into a solution of tert-butyl 3-(aminomethyl)azetidine-1-carboxylat (200 mg, 1.08 mmol) and triethylamine (1 mL) in CH2Cl2 (20 mL) at r.t. After 2 hr, the reaction mixture was condensed. The residue was dissolved in CH2Cl2 (10 mL) and treated with TFA (10 mL) at r.t. for 1 h. Evaporation of solvents provided the desired product as its TFA salt, which was used in Step A directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | ) 1,1-dimethylethyl 3-[3-(4-bromo-2-fluorophenyl)-4H-l,2,4-triazol-4-yl]methyl}-l- azetidinecarboxylateA solution of 4-bromo-2-fluorobenzohydrazide (200 mg, 0.742 mmol) in CH2CI2 (2 mL) and N,N-dimethylformamide dimethylacetal (200 mu, 1.494 mmol) was stirred at 50 C for 30 min. The reaction mixture was concentrated in vacuo, and to the residue was added N-Boc-4-methylamineazetidine (138 mg, 0.742 mmol) and THF (2.0 mL). The reaction was stirred at 100 C overnight and then concentrated in vacuo. Purification of the residue by flash chromatography (0-10% MeOH/EtOAc) afforded the title compound (120 mg, 36%). MS(ES)+ m/e 411.1, 413.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In tetrahydrofuran; at 100℃;Inert atmosphere; | ) 1,1 -dimethylethyl 3 - { [3 -(4-bromophenyl)-4H- 1 ,2,4-triazol-4-yl]methyl} - 1 - azetidinecarboxylateA'-[(4-Bromophenyl)carbonyl]-N,N-dimethylhydrazonoformamide (0.1 g, 0.37 mmol) and 1,1 -dimethylethyl 3 -(aminomethyl)-l -azetidinecarboxylate (70 mg, 0.376 mmol) were combined in a flask, purged with nitrogen, and stirred at 100 C for 1 h. THF (1.0 mL) was then added and the reaction mixture was stirred at 100 C overnight. Analysis by LCMS indicated the reaction had proceed to -80% completion. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (0-10%MeOH/EtOAc) to provide the title compound (100 mg, 62%). MS(ES)+ m/e 393.0, 394.8 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 120 - 150℃; for 1.33333h;Microwave irradiation; | 300 mg (1.1 mmol) of the compound from Example 23 are initially charged in 6 ml of ethanol. 408 mg (2.2 mmol) of <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> are added, and the mixture is reacted initially for 40 min at 120 C. and then for another 40 min at 150 C. in a single-mode microwave oven (CEM Explorer). The solid is then filtered off, washed twice with methanol and discarded, and the wash solutions are combined with the mother liquor. These are concentrated on a rotary evaporator, and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). The product-containing fractions are combined and concentrated on a rotary evaporator, which gives 354 mg of a residue which, according to LC-MS and 1H-NMR, corresponds to the title compound in a purity of about 50% and is reacted further as such. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18 g | With hydrogenchloride; In ethanol; water; | To a solution of l-Boc-3-(aminomethyl)-azetidine (15.5 g, 82.9 mmol) in EtOH (250 mL) was slowly added aq. HCl (1.0 M, 83 mL). The solvent was removed in vacuo at 38 °C, providing the hydrochloride salt of the amine as a white solid (18.0 g). |
18 g | With hydrogenchloride; In ethanol; water; | To a solution of l-Boc-3-(aminomethyl)-azetidine (15.5 g, 82.9 mmol) in EtOH (250 mL) was slowly added aq. HC1 (1.0 M, 83 mL). The solvent was removed in vacuo at 38 °C, providing the hydrochloride salt of the amine as a white solid (18.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In acetonitrile; at 80℃; | Into a 20-mL round-bottom flask, was placed l-fluoro-2-nitrobenzene (197.4 mg, 1.40 mmol, 1.00 equiv), tert-butyl 3-(aminomethyl)azetidine-l-carboxylate (260.4 mg, 1.40 mmol, 1.00 equiv), potassium carbonate (386.4 mg, 2.80 mmol, 2.00 equiv) and MeCN (10 mL). The resulting solution was stirred overnight at 80 C. The resulting mixture was concentrated under vacuum and then diluted with 10 mL of water. The resulting solution was extracted with ethyl acetate and the organic layers combined, washed with brine and then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30: 1 to 5: 1). This resulted in 400 mg (93%) of tert-butyl 3- [[(2-nitrophenyl)amino]methyl]-azetidine-l-carboxylate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With triethylamine; In dichloromethane; at 0 - 20℃; for 48h; | 7-Bromo-2,3-dichloropyrido[2,3-b]pyrazine (100.0 mg, 0.56 mmol) was dissolved in DCM (5.6 mL), and <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (104.1 mg, 0.56 mmol) and TEA (0.23 mL, 1.68 mmol) were slowly added thereto at 0 C. The reaction mixture was stirred at room temperature for 48 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (n-Hex:EtOAc=70:30) on silica. The fractions containing the product were collected and concentrated to obtain yellow solid compound of tert-butyl 3-(((7-bromo-2-chloropyrido[2,3-b]pyrazin-3-yl)amino)methyl)azetidine-1-carboxylate (72.0 mg, 30%). [1288] LCMS ESI (+): 428 (M+1) [1289] 1H-NMR (400 MHz, DMSO-d6); ?: 8.85 (d, 1H, J=2.4 Hz), 8.48 (d, 1H, J=2.4 Hz), 8.20 (t, 1H, J=5.6 Hz), 3.90 (m, 2H), 3.70 (m, 4H), 2.92 (m, 1H), 1.38 (s, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
128 mg | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 11.5h; | Preparation Example 340 A mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (350 mg), <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (266 mg), potassium carbonate (154 mg), and N-methylpyrrolidone (7 mL) was reacted at 100 C. for 11.5 hours. To the mixture were added ethyl acetate and water, followed by liquid separation. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain tert-butyl 3-([5-carbamoyl-3-ethyl-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}methyl)azetidine-1-carboxylate (128 mg) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; In dichloromethane; for 16h; | Step 1: tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (1.10 g, 5.91 mmol) was dissolved in dichloromethane (50 mL), and thereafter, 4-nitrophenyl chloroformate (1.19 g, 5.91 mmol) and pyridine (0.47 g, 5.91 mmol) were added to the obtained solution. The obtained mixture was stirred for 16 hours. Thereafter, the reaction solution was concentrated in vacuo to obtain tert-butyl 3-((((4-nitrophenoxy)carbonyl)amino)methyl)azetidine-1-carboxylate (2.52 g, quant) in the form of a white solid. 1H-NMR (CDCl3) delta: 1.45 (9H, s), 2.80 (1H, m), 3.52 (2H, m), 3.69 (2H, m), 4.06 (2H, m), 7.32 (2H, d, J=9.0 Hz), 8.25 (2H, d, J=9.0 Hz) |
With pyridine; In dichloromethane; for 16h; | tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (1.10 g, 5.91 mmol) was dissolved in methylene chloride (50 mL). Thereafter, 4-nitrophenyl chloroformate (1.19 g, 5.91 mmol) and pyridine (0.47 g, 5.91 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred for 16 hours. Thereafter, the reaction solution was concentrated in vacuo to obtain tert-butyl 3-((((4-nitrophenoxy)carbonyl)amino)methyl)azetidine-1-carboxylate (2.52 g, >100%) in the form of a white solid. 1H-NMR (CDCl3) delta: 1.45 (9H, s), 2.80 (1H, m), 3.52 (2H, m), 3.69 (2H, m), 4.06 (2H, m) 7.32 (2H, d, J = 9.0 Hz), 8.25 (2H, d, J = 9.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; | Example 123 6-Benzyl-N-(3-hydroxypropyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide trifluoroacetate salt To a suspension of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.01 g, 0.04 mmol, from Example 100, Step 3) in N,N-dimethylformamide (1.0 mL) was added N,N-diisopropylethylamine (0.024 mL, 0.13 mmol), followed by the addition of HATU (0.0257 g, 0.0675 mmol) and 3-amino-1-propanol (0.010 g, 0.13 mmol, Aldrich). When the reaction was complete, the reaction mixture was diluted with MeCN and the product was purified by preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA). Yield: (8 mg, 40%). Example 124 N-(Azetidin-3-ylmethyl)-6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide bis(trifluoroacetate) salt The title compound was prepared according to the methods of Example 123, using <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (0.025 g, 0.13 mmol, Astatech) in the coupling step. After completing an aqueous workup, the Boc protecting group was removed from the product by stirring with 1:1 TFA:DCM for 1 hour. Solvents were evaporated in vacuo. The final purification was performed according to the methods of Example 123. Yield: (6 mg, 20%). 1H NMR (500 MHz, d6-DMSO) delta 8.92 (t, J=5.8 Hz, 1H), 8.65 (br d, 2H), 7.98 (d, J=9.8 Hz, 1H), 7.77 (s, 1H), 7.60 (d, J=9.8 Hz, 1H), 7.31-7.26 (m, 2H), 7.26-7.20 (m, 1H), 7.14-7.03 (m, 2H), 6.05 (s, 2H), 4.02-3.89 (m, 2H), 3.83-3.72 (m, 2H), 3.51 (t, J=6.3 Hz, 2H), 3.07-2.98 (m, 1H), 2.97 (s, 3H); LCMS (M+H)+: 375.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 127 6-(3-Chlorobenzyl)-N-(3-hydroxypropyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide trifluoroacetate salt To a suspension of 6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.004 g, 0.01 mmol, from Example 99, Step 4) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.014 mL, 0.078 mmol), followed by the addition of HATU (0.010 g, 0.026 mmol). After 1 minute, 3-amino-1-propanol (5.9 mg, 0.078 mmol, Aldrich) was added to the reaction mixture. The reaction mixture was diluted with MeCN and purified by preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA). Yield: (4.8 mg, 70%). 10860] The title compound was prepared as in Example127, using tert-butyl 3-(aminomethyl)azetidine-i -carboxylate (14 mg, 0.078 mmol, Astatech). Afier the coupling step/was complete, the crude reaction mixture was diluted with water and the product was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude residue was dissolved in 1:1 mixture of TFA:DCM and the resultant reaction mixture was stirred for 1 hour until the Hoc group was removed. The title product was purified according to the methods of Example 127.Yield: (5.4 mg, 60%).j0861] ?H NMR (500 MHz, d5-DMSO) oe 8.93 (t, J=5.8 Hz, 1H), 8.63 (br s, 2H), 7.95 (d, J=9.9 Hz, 1H), 7.79 (s, 1H), 7.60 (d, J=9.8 Hz, 1H), 7.37-7.26 (m, 2H), 7.19 (s, 1H), 7.09-6.97 (m, 1H), 6.03 (s, 2H), 4.03-3.92 (m, 2H), 3.83-3.73 (m, 2H), 3.52 (t, J=6.3 Hz, 2H), 3.07-2.98 (m, 1H), 2.96 (s, 3H); ECMS (M+H): 409.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; N,N-dimethyl-formamide; at 0 - 20℃; for 3h; | Step 3: Tert-butyl 3-((((2-(((2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)amino)methyl)azetidine-1-carboxylate To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (150 mg, 0.21 mmol) in DCE (4 ml) at 0 C. was added <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (78 mg, 0.420 mmol), sodium triacetoxyborohydride (66.7 mg, 0.315 mmol), and DMF (0.4 mL). After stirring at rt for 3 h, the reaction mixture was quenched with saturated NaHCO3 (aq) and diluted with 10% EtOH/DCM (40 mL). The organic layer was separated, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was used as such in the following step. LCMS: Rt=0.55 min, m/z=885.5 (M+1). Method 2m_acidic. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.089 g | 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 25℃; for 2h; | The solution of compound 6 (0.1 g, 0.33 mmol) in DMF(3 mL) was added DIEA (0.086 g, 0.66 mmol), compound 14 (0.074 g, 0.4 mmol) and HATU (0.15 g, 0.4 mmol). The mixture was stirred at 25 C for 2 hrs and purified by pre-HPLC to give compound 15 (0.089 g, 57%). TFA (1 mL) in DCM (10 mL) was added to compound 15 (0.089 g, 0.19 mmol). The mixture was stirred at 25 C for 3 hrs and the mixture was concentrated to give compound 16 (0.13 g, crude). The solution of compound 9 (0.13 g, 0.35 mmol) in DCM (2 mL) was added DIEA (0.09 g, 0.66 mmol), benzoyl chloride (0.049 g, 0.35 mmol) was added dropwise to the above solution at 0 C. The mixture was stirred at 25 C for 2 hrs and purified by pre-HPLC to give SC14 (0.031 g, 19%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 6-(4-cyanophenyl)-5-(4-methylphenyl)imidazo[1,2-a]pyrazine-8-carboxylic acid (8.0 g, 0.022 mmol) and <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (8.41 g, 0.0452 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (16 muL, 0.094 mmol), followed by N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (8.6 g, 0.022 mmol). The resulting mixture was stirred at room temperature for 1 h then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was used in the next step without further purification. LC-MS calculated for C30H31N6O3 (M+H)+: m/z=523.2. found 523.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 80℃; for 168h;Inert atmosphere; | Intermediate 271: (S)-tert-butyl 3-(((4-(((1-(cyclopentyloxy)-4-methyl-1-oxopentan-2- yl)amino)methyl)-2-nitrophenyl)amino)methyl)azetidine-1-carboxylate A round bottom flask was charged with (S)-cyclopentyl 2-((4-fluoro-3-nitrobenzyl)amino)-4- methylpentanoate (for a preparation see Intermediate 137, 230 mg, 0.653 mmol), acetonitrile (10 mL), potassium carbonate (180 mg, 1.305 mmol) and tert-butyl 3-(aminomethyl)azetidine-1- carboxylate (146 mg, 0.783 mmol). An air condensor was fitted and the mixture warmed to 80C under a blanket of nitrogen for 1 week. The mixture was diluted with water and ethyl acetate, the layers mixed and separated before the organics were washed with brine. The organics were passed through a hydrophobic frit and concentrated in vacuo to give an orange oil. The oil was loaded in dichloromethane and purified by Biotage SP4 SNAP 25g silica (Si) using a gradient of 0-40% ethyl acetate-cyclohexane over 15 CV. The appropriate fractions were combined and evaporated in vacuo to give the title compound (355 mg, 0.684 mmol, 105 % yield) as an orange oil. LCMS (System A): tRET = 1.07 min; MH+ 519. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 1h; | tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (75 mg, 0.40 mmol, 1.1 eq) [325775-44-8] is added at room temperature to a stirred solution of 3-[(2-bromo-4-chloro-phenyl)methoxy]-5-chloro-benzaldehyde (120 mg, 0.33 mmol, 1.0 eq) in 1,2-dichloroethane (10 mL), followed by one drop of acetic acid and sodium triacetoxyborohydride (212 mg, 1.00 mmol, 3.0 eq). After 1 hour stirring at room temperature, the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel; ethyl acetate) to afford tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-chloro- phenyl]methylamino]methyl]azetidine-1-carboxylate as a light yellow oil (150 mg, 85% yield). MS m/z (+ESI): 528.9, 531.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 70℃; | Step 1: preparation of tert-butyl 3-(((2-chloro-thieno[3,2-d]pyrimidin-4-yl)amino) methyl)azetidine-1-carboxylate (0248) (0249) 2,4-Dichloro-thieno[3,2-d]pyrimidine (205 mg, 1 mmol) and <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (186 mg, 1 mmol) were dissolved in tetrahydrofuran (5 mL), followed by the addition of N,N-diisopropylethylamine (258 mg, 2 mmol). The reaction solution was reacted at 70C overnight, and then concentrated. The residue was added with water (20 mL), and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 5 : 1) to give a white solid (340 mg). Yield: 96.0%. MS (ESI, m/z): [M+H]+: 355.1; 1H-NMR (300 MHz, CDCl3): 7.76 (d, 1H, J = 5.4 Hz), 7.37 (d, 1H, J = 5.4 Hz), 5.49 (s, 1H), 4.05-4.09 (m, 2H), 3.87-3.91 (m, 2H), 3.71-3.75 (m, 2H), 2.94 (m, 1H), 1.44 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.5% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;Reflux; | Step 1: preparation of tert-butyl 3-(((2-chloro-furo[3,2-d]pyrimidin-4-yl)amino) methyl)azetidine-1-carboxylate (0257) (0258) 2,4-Dichloro-furo[3,2-d]pyrimidine (189 mg, 1 mmol) and <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (186 mg, 1 mmol) were dissolved in tetrahydrofuran (20 mL), followed by the addition of N,N-diisopropylethylamine (258 mg, 2 mmol). The reaction solution was reacted under reflux overnight, then cooled to room temperature, and concentrated. The residue was added with water (20 mL), and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 6 : 1), to give a white solid (283 mg). Yield: 83.5%. MS (ESI, m/z): [M+H]+: 339.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.2% | With N-ethyl-N,N-diisopropylamine; In methanol; at 18 - 25℃; for 3h;Reflux; | Step 1: preparation of tert-butyl 3-(((2-chloro-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)methyl)azetidine-1-carboxylate (0266) (0267) 2,4-Dichloro-5H-pyrrolo[3,2-d]pyrimidine (360 mg, 1.92 mmol) and <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (374 mg, 2.01 mmol) were dissolved in methanol (20 mL), followed by the addition of N,N-diisopropylethylamine (667 muL, 3.83 mmol) under stirring at room temperature. The reaction solution was refluxed for 3 hours, and then concentrated, re-dissolved in dichloromethane (50 mL), washed with water (30 mL) and concentrated to give a white solid (350 mg). Yield: 51.2%. MS (ESI, m/z): [M+H]+: 338.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.9% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 70℃; | Step 1: preparation of tert-butyl 3-(((2-chloro-thieno[2,3-d]pyrimidin-4-yl)amino) methyl)azetidine-1-carboxylate (0278) (0279) 2,4-Dichloro-thieno[2,3-d]pyrimidine (300 mg, 1.46 mmol) and <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (272 mg, 1.46 mmol) were dissolved in tetrahydrofuran (25 mL), followed by the addition of N,N-diisopropylethylamine (258 mg, 2 mmol). The reaction solution was reacted at 70°C overnight, and then concentrated. The residue was added with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 5) to give a white solid (425 mg). Yield: 81.9percent. MS (ESI, m/z): [M+H]+: 355.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h; | To a solution of N-(1-[6-chloro-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)cyclopropanecarboxamide obtained in Reference Example 15 (30 mg) in DMF (1 mL) were added DIPEA (48 muL) and 3-(aminomethyl)azetidine-1-carboxylic acid tert-butyl (19 mg), and the mixture was stirred at 120 C for 2 h. The reaction solution was diluted with ethyl acetate, separated by adding saturated aqueous sodium bicarbonate solution, and the aqueous layer was further extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give a solid (40 mg). To a solution of the obtained solid (35 mg) in dichloromethane (1 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by silica gel column chromatography to give the title compound (29 mg). MS (m/z): 481 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanesulfonato(2-dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl)(2-amino-1,1?-biphenyl-2-yl) palladium(II); caesium carbonate; In 1,4-dioxane; at 70℃;Inert atmosphere; | To a solution of (R)tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-((3 -chloroisoquinolin-7-yl)oxy)propanoate (1-4,300 mg, 0.685 mmol) in dioxane (5 ml) were added tert-butyl 3-(aminomethyl)azetidine-1- carboxylate (191 mg, 1.03 mmol), 2nd generation Ruphos precatalyst (106 mg, 0.137 mmol) and Cs2CO3 (558 mg, 1.71 mmol). After degassing and refilling with N2, the reaction was heated at 70 C overnight. Then the reaction mixture was diluted with EtOAc, washed with NH4C1, water, and brine. The solvent was removed, and the resulting residue was purified bycolumn chromatography on silica gel (40g), eluting with EtOAc/hexane (40%) to give the title compound. LC-MS [M + Hj: m/z 589.52. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In acetonitrile; at 60℃; for 4h; | tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate [325775-44-8] (620 mg, 3.30 mmol, 1.2 eq) is added at room temperature to a stirred solution of [3-[(2-bromo-4-chlorophenyl)methoxy]-5-(hydroxymethyl)phenyl]methyl methanesulfonate (1.2 g, 2.75 mmol, 1.0 eq) in acetonitrile (20 mL). After 4 hours stirring at 60C, the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel; dichloromethane:methanol, 10: 1, v/v) to afford tert-butyl 3-[[[3-[(2-bromo-4-chlorophenyl)methoxy]-5-(hydroxymethyl)phenyl]methylamino]methyl]azetidine-1-carboxylate as a white foam (700 mg, 48% yield). 'H-NMR (400 MHz, CDC13) delta ppm: 7.60 (s, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.25 (s, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 5.15 (s, 2H), 4.65 (s, 2H), 3.95-4.20 (m, 4H), 3.68 (m, 2H), 3.10 (m, 2H), 2.95 (m, 1H), 1.43 (s, 9H). MS m/z (+ESI): 525.2, 527.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 83 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 13.5h;Inert atmosphere; | To a tube was added <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (186 mg, 182 ).ll,999 ).lmol), bromobenzene (188 mg, 125 ).ll, 1.2 mmol), toluene (4 mL), 2,2'bis(diphenylphosphino)-1,1'-binaphthalene (62 mg, 100 ).lmol), Cs2C03 (651 mg, 2 mmol,) andPd2(dba)3 (46 mg, 50 ).lmol). Then it was bubbled with N2 for 5 mins and heated to 90 C (oilbath) for about 13.5 hours. The reaction mixture was filtered through a layer of celite, and the10 celite was washed with toluene and EA. The filtrate was concentrated to give a brown oil whichwas purified by silica gel column chromatography (eluted with EA/PE=O- 20%- 40%), about83 mg tert-butyl 3-( anilinomethyl)azetidine-1-carboxylate (Compound 4A) was obtained as ayellow oil. MS: calc'd 263 (M+Ht, measured 263 (M+Ht. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In 1,4-dioxane; at 20℃; for 48h;Inert atmosphere; | General procedure: 3-[8-(1-Methyl-1H-indol-6-yl)quinoxalin-6-yl]amino}pyridine-4-carboxylic acid6[11](70 mg; 0.18 mmol; 1 eq.),EDC?HCl(62 mg; 0.32 mmol; 1.8 eq.) andHOBt hydrate(50 mg; 0.32 mmol; 1.8 eq.) were dissolved in dioxane (7 mL) at room temperature. Triethylamine (0.11 mL; 0.88 mmol; 5 eq.) was added followed by methylamine hydrochloride (18 mg; 0.26 mmol; 1.5 eq.), after 30 minutes. After 48 hours of stirring at room temperature under argon, dioxane was evaporatedin vacuoand the residue was vigorously stirred in a 1:1 (v/v, 50 mL) mixture of water and EtOAc. The medium was neutralized with 1M HCl and the phases were separated. The aqueous phase was extracted twice with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentratedin vacuo. The resulting residue waspurified by automated flash chromatography (0-100% EtOAc gradient in hexane and continued with 0-10% MeOH gradient in EtOAc)to affordN-methyl-3-[8-(1-methyl-1H-indol-6-yl)quinoxalin-6-yl]amino}pyridine-4-carboxamide11as a yellow powder (62 mg; 0.15 mmol; yield: 83%; LCMS purity: 97%, method B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Into a solution of 3- [3-( { 9-chloro-7-methoxy- 1 H,2H,3H-cyclopenta[b] quinolin-6- yl}oxy)propyl]-3-azabicyclo[3.1.1]heptane(Intermediate 29) (110.00 mg; 0.28 mmol; 1.00 eq.) in 1,4-dioxane (2 ml) was added a solution of <strong>[325775-44-8]tert-butyl 3-(aminomethyl)-1-azetidinecarboxylate</strong> (79.43 mg; 0.43 mmol; 1.50 eq.) in dioxane (1 mL) followed by chloro[2-(dicyclohexylphosphino)-3,6- dimethoxy-T,4?, 6?-triisopropyl- 1,1 ?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos Pd Gi, Methyl t-Butyl Ether Adduct, 22.71 mg; 0.03 mmol; 0.10 eq.) and tBuONa (54.6 mg; 0.57 mmol;2.00 eq.). The resulting mixture was allowed to stir at 125 C for 25 mm, cooled to rt and treated withMeCN. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. Theresidue was subjected to purification on reverse phase preparative HPLC (Prep-C 18, 5 pM SunFirecolumn, 19 x 150 mm, Waters; gradient elution of 5% MeCN in water to 80% MeCN in water over a13 mm period, where both solvents contain 0.1% HC1) to provide tert-butyl 3-([6-(3-{3- azabicyclo[3.1. 1 ]heptan-3-yl }propoxy)-7-methoxy- 1 H,2H,3H-cyclopenta[b] quinolin-9-yl]amino}methyl)azetidine-1-carboxylate dihydrochloride as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 24h; | To a mixture of 4-fluorobenzaldehyde (268 jil, 2.5 mmol) and tert-butyl 3-(amino- methyl)azetidine-1-carboxylate (465.7 mg, 2.5 mmol) in dichloromethane (25 ml) sodium triacetoxyborohydride (795 mg, 3.75 mmol) was added at ambient temperature. After stirring for 24 hours the mixture was treated with sodium hydroxide (1M, 10 ml), separated and extracted with dichioromethane (2 x 10 ml). The organic phase was dried using a phase separator and concentrated. The crude material was purified by column chromatography using silica gel, eluting with 2-5% methanol in dichloromethane to afford the title compound in 61% yield (471 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃; | Compound 82 (305 mg). <strong>[325775-44-8]tert-butyl 3-(aminomethyl)azetidine-1-carboxylate</strong> (86 mg) and diisopropyl amine (0.202 ml) in dioxane (3 ml) were heated to 110 C. After stirring overnight, the reaction was concentrated. Silica gel chromatography (Reveleris, 12 g) eluting with a gradient of 0.5% to 3% methanol/dichloromethane (flow=36 ml/minute) gave the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 16h; | To a solution of 4-[(4-chloro-2,6-difluorophenyl)methylene]piperidine hydrochloride (300 mg; 1.07 mmol) in dioxane (12 mL) were added tris(dibenzylideneacetone)dipalladium (224 mg; 0.21 mmol), 1- Boc-3-(aminomethyl)azetidine (302 mg; 1.61 mmol), CS2CO3 (1057 mg; 3.21 mmol) and X-Phos (206 mg; 0.43 mmol). The reaction mixture was heated to 100 C and stirred for 16 h. After cooling to rt, water and EA were added and the organic layer was separated, dried over MgSO i, filtered and concentrated. The residue was purified by preparative HPLC to afford teri-butyl 3-[[3,5-difluoro-4-(4- piperidylidenemethyl)anilino]methyl]azetidine-l -carboxylate (100 mg) as a brown oil. (1006) MS m/z (+ESI): 394.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In tetrahydrofuran; at 20℃; for 0.0833333h; | Compound 7 (150 mg, 0.4 mmol) and compound 42 (91 mg, 0.6 mmol) were dissolved in 2 mL of THF.Triethylamine (202 mg, 2.0 mmol) was added dropwise at room temperature for 5 minutes, and water (10 mL) was added.Ethyl acetate was extracted twice, dried over anhydrous sodium sulfate, concentrated, and petroleum ether was taken over ethyl acetate (8:1).Compound 43 (192 mg, 95%) was obtained as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; In dichloromethane; at 0℃; for 3h; | tert-Butyl 3-(aminomethyl)azetidine-l-carboxylate (300 mg, 1.0 equiv) and pyridine (1 mL) were combined in DCM (20 mL) at 0C. MsCl (1.1 equiv) was added dropwise. The mixture was stirred at 0C for 3h. The reaction mixture was diluted with DCM (30 mL), washed with 3x30 mL 1N HC1, water, and brine to afford /er/-butyl 3- (0609) (methylsulfonamidomethyl)azetidine-l-carboxylate (390 mg, yield 91%) which was used without further purification. |
Tags: 325775-44-8 synthesis path| 325775-44-8 SDS| 325775-44-8 COA| 325775-44-8 purity| 325775-44-8 application| 325775-44-8 NMR| 325775-44-8 COA| 325775-44-8 structure
[ 1173206-71-7 ]
tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate hydrochloride
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tert-Butyl azetidine-1-carboxylate
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
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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