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CAS No. : | 198989-07-0 | MDL No. : | MFCD06411671 |
Formula : | C10H18N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UXAWXZDXVOYLII-UHFFFAOYSA-N |
M.W : | 198.26 | Pubchem ID : | 2760898 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.9 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 61.2 |
TPSA : | 41.57 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) : | -7.0 cm/s |
Log Po/w (iLOGP) : | 2.46 |
Log Po/w (XLOGP3) : | 0.72 |
Log Po/w (WLOGP) : | 0.21 |
Log Po/w (MLOGP) : | 0.86 |
Log Po/w (SILICOS-IT) : | 0.39 |
Consensus Log Po/w : | 0.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.32 |
Solubility : | 9.38 mg/ml ; 0.0473 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.17 |
Solubility : | 13.4 mg/ml ; 0.0674 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.09 |
Solubility : | 16.0 mg/ml ; 0.0809 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.65 |
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 |
---|---|---|
200 mg | With triethylamine In methanol at -30 - 25℃; | Di-tert-butyldicarbonate (0.38 g, 0.38 mL, 1.7 mmol) was added dropwise for 10 minutes to a cold (-30° C.) stirred solution of 2,5-diazabicyclo[2.2.1]heptanedihydrobromide (1 g, 3.8 mmol) and triethylamine (776 mg, 1.07 mL, 7.6 mmol) in MeOH (30 mL). The reaction mixture was stirred at 25° C. for 12-16 h. The reaction mixture was concentrated under reduced pressure; diluted with water and filtered. The filtrate was extracted with DCM; the organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 200 mg of the title compound as a white solid. MS (ESI): m/z 199.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 15h; | A mixture of 3-bromo-l-chlorobenzene (191 mg, 1.0 mmol), 2,5- diazabicyclo [2.2.1]heptane-2-carboxylic acid tert-butyl ester (240 mg, 1.2 mmol), sodium tert-butoxide (135 mg, 1.4 mmol), Pd2 (dba)3 mg, 0.03 mmol), and BINAP (56 mg, 0.09 mmol) in toluene (3 mL) was heated to 110 C for 15 h. After cooling to room temperature, the mixture was filtered through celite, and the filter cake was rinsed with ethyl acetate. The solvents were removed in vacuo. Column chromatography on silica (hexanes: ethyl acetate 4: 1) of the residue afforded 5-(3-chlorophenyl)-2,5- diazabicyclo [2.2.1]heptane-2-carboxylic acid tert-butyl ester (240 mg, 78% yield) as a yellow solid. ¹H NMR (400 MHz, CDC13, mixture of rotamers) 8 7.10 (q, 1H), 6.65 (d, 1H), 6.50 (m, 1H), 6.40 (d, 1H), 4.62 (s, 0.5H), 4.48 (s, 0.5H), 3.53 (m, 1H), 3.47-3.67 (m, 2H), 3.20-3.08 (dd, 1H), 1.98-1.91 (m, 2H), 1.45 (s, 4.5H), 1.41 (s, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7-CHLORO-2-FURAN-2-YL- [1, 2, 4] triazolo[1, 5-c] PYRIMIDIN-5-YLAMINE (0. 5 mmol ; see US patent 6, 222, 035 B1) was dissolved in 4 mL of DMSO along 2 mmol of 2, 5-diaza- bicyclo [2. 2. 1] heptane-2-carboxylic acid tert-butyl ester (Aldrich-Sigma, St. Louis, MO) and 0. 6 mmol of CsF. The reaction mixture was stirred at 120C for 18 hours. It was then diluted with EtOAc, washed with water and brine, dried with NA2S04, and concentrated. The resulting residue was dissolved in 4 mL of 25% TFA in CHUCK and allowed to stand at room temperature for 18 hours. It was then concentrated to afford the TFA salt OF 7- (2, 5-diaza-bicyclo [2. 2. 1] hept-2-yl)-2-furan-2-yl- [1, 2, 4] triazolo [1, 5- C] PYRIMIDIN-5-YLAMINE. This material was dissolved in 3 mL of CH2C12 along with 0. 6 mmol of 2, 6-difluorobenzaldehyde and 1 mmol of sodium triacetoxyborohydride. The resulting reaction mixture was concentrated and purified by preparative HPLC to afford the title COMPOUND. 1H NMR (400 Hz, DMSO-d6) 8 7. 80 (d, J= 1. 0 Hz, 1H), 7. 00 (d, J = 3. 6 Hz, 1H), 7. 2-7. 4 (m, 3 H), 6. 60 (dd, J= 3. 6, 1. 0 Hz, 1H), 5. 7 (s, 1 H), 4. 80 (brs, 2H), 2. 4-3. 6 (m, 8H). MS m/z : 424 [M + H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; | Step A: tert-Butyl 5-isopropyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate The title compound was prepared from <strong>[198989-07-0]ter<strong>[198989-07-0]t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate</strong></strong> and using acetone as described in EXAMPLE AAA1, Step A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; In tetrahydrofuran; sodium bicarbonate; | 2-tBoc-5-diphenylmethyl-2,5-diazabicyclo[2.2.1]heptane (145) Triethylamine (0.8 g) and 1.55 g of diphenylmethyl chloride are added to a solution of 1.5 g of 2-tBoc-2,5-diazabicyclo[2.2.1]heptane in anhydrous THF and refluxed with stirring for 4 hours. The THF was then evaporated off, taken up in 50 mL of saturated sodium hydrogen carbonate solution and extracted 3 times with 30 mL of ether. Evaporation resulted in 2.2 g of yellowish crystals of 145 (78% of the theoretical yield). 1H-NMR (CDCl3): 7.48-7.11 (10 H, m), 4.81 (H, b), 4.31 (H, d), 3.40 (H, d), 3.18 (H, dd), 2.92 (H, dd), 2.56 (H, d), 1.84 (H, d), 1.72 (H, d), 1.54 (9H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 1 (R,R)-2-(tert-Butyloxycarbonyl)-2,5-diazabicyclo[2.2.1] heptane A mixture of 3.6 g of (R,R) -5-benzyl-2-(tertbutyloxycarbonyl)-2,2-diazabicyclo[2.2.1]heptane, prepared by the procedure of Jordis et al, Synthesis, 1990, 925, and 2.2 g of 10% palladium on carbon in 140 ml of methyl alcohol is hydrogenated in a Parr apparatus at 40 pounds per square inch (psi) for 16 hours. The reaction is filtered through a pad of diatomaceous earth and the filtrate is concentrated in vacuo. The residue is purified by column chromatography (aluminum oxide, 2.5 activity grade; 2% methyl alcohol/methylene chloride) to give 1.14 g of the desired product as pale yellow crystals: mp 62-63 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate; In acetone; at 50℃; for 3h; | To a solution of <strong>[198989-07-0]2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester</strong> (0.10 g, 0.50 mmol) in acetone (2 mL) was added 1 -chloro-3-iodo-propane (0.10 g, 0.50 mmol, 1 eq) and K2CO3 (0.084 g, 0.60 mmol, 1.2 eq). The mixture was heated at 50 0C for 3 h and then cooled to r.t. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. Chromatography on silica gel by eluting with 5% EPO <DP n="38"/>MthetaOH/CH2CI2 gave 0.095 g (69%) of 5-(3-chloro-propyl)-2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a yellowish oil. 1H NMR (300 MHz, CDCI3): delta 4.20 (m, 1 H), 3.58 (m, 2H), 3.46 (m, 2H), 3.12 (m, 1 H), 2.86 (m, 1 H), 2.62 (m, 3H), 1.82 (m, 3H), 1.66 (m, 1 H), 1.41 (s, 9H). By analogy to Preparative Example 8, substituted and/or unsubstituted 1-(3- chloro-propyl)-pyrrolidine and 1 -(3-chloro-propyl)-piperidine groups can be prepared with pyrrolidine and piperidine respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; | Example 825-[2-(2-Chloro-phenyl)-l-methyl-ethyl]-2,5-diaza-bicyclo[2.2.1]heptane-2- carboxylic acid (4-trifluoromethyl-phenyl)-amide (METHOD A)(i) l-Isocyanato-4-trifluoromethyl-benzene (990mg, 5.29mmol) was added to a stirred solution of <strong>[198989-07-0]2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester</strong> (Ig, 5.04mmol) in dichloromethane (DCM) (20ml) and stirred overnight at room temperature. Trifluoroacetic acid (4ml) was added and stirred for 2h. The solution was made basic with 2N sodium hydroxide solution, separated, extracted with DCM and the combined organic extracts dried and evaporated. The residue was loaded onto a flash silica column, eluted with ethyl acetate to remove impurities followed by methanol/DCM (1:9) to elute the product. Evaporation gave 2,5-Diaza- bicyclo[2.2. lJheptane-2-carboxylic acid (4-trifluoromethyl-phenyl)-amide (905mg) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 765-[l-(2-Chloro-phenyl)-ethyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid [4-(4-fluoro-phenoxy)-phenyl]-amide (METHOD B)(i) Titanium tetraisopropoxide (4ml) was added drop wise with stirring to l-(2- chloro-phenyl)-ethanone (1.36ml, 10.5mmol). 2,5-Diaza-bicyclo[2.2.1]heptane-2- carboxylic acid tert-butyl ester (2.01g, lO.lmmol) was added in portions and stirred EPO <DP n="41"/>overnight. The mixture was diluted with ethanol (40ml), sodium borohydride (1.32g) added and stirred for Ih before being poured into DCM and water added with stirring. Filtration, extraction of the aqueous phase, drying and evaporation gave a mixture of diastereoisomers of 5-[l-(2-chloro-phenyl)-ethyl]-2, 5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (3.56g). The individual diastereoisomers were separated by chromatography (silica gel, ethyl acetate/hexane 1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 362-(4-Phenoxy-phenyl)-l-[5-(l-o-tolyl-ethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]- ethanone (METHOD G)(i) 2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (2.07g, 10.4mmol) was added portionwise with stirring to titanium tetraisopropoxide (6.0ml, 20.2mmol). 1-o-Tolyl-ethanone (1.37ml, 10.4mmol) was added and the reaction mixture stirred for 6h. Ethanol (50ml) was added followed by sodium borohydride (1.22g) and the mixture stirred overnight at room temperature. The resulting suspension was poured in to stirred DCM (500ml) and water (50ml) added. The organic layer was separated and the aqueous phase extracted with DCM. The organic layers were filtered through celite, dried and evaporated giving a mixture of diastereoisomers of 5-(l-o-Tolyl-ethyl)-2,5-diaza-bicyclo [2.2.1] 'heptane-2-carboxylic acid tert-butylamide. The individual diastereoisomers were separated by column chromatography (silica gel, ethyl acetate/DCM) giving the higher R? isomer (0.73g) and the lower Rp isomer (1.76g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.2% | With triethylamine; at 0 - 20℃; for 2.5 - 3.5h; | Trifluoroacetic anhydride (0.9 mL, 6.55 mmol) was added dropwise to a solution o tert- butyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 5.04 mmol) and triethylamine (2.2 mL, 15.1 mmol) in dichloromethane (5 mL) at 0 0C over a period of 30 minutes. The mixture was stirred at room temperature for about 2-3 hours and then <n="41"/>partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane, the combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title product (1.30 g, % yield : 87.2%) 1H NMR (400 MHz, MeOH- dA): delta 1.47 (s, 9H), 1.90-2.10 (m, 2H), 3.32-3.50 (m, 3H), 3.60-3.80(m, IH), 4.58 (brs, IH), 4.82 (brs, IH);[ESI-MS (m/z): 295 (M++l)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate;palladium diacetate; johnphos; In toluene; at 50℃; | To a mixture containing 2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert- butyl ester (100 mg, 0.5 mmol), 3-fluoro-phenylbromide (103.8 mg, 0.6 mmol), Pd(AcO) (8 mg, 0.03 mmol), 2-(di-f-butylphosphino)biphenyl (20 mg, 0.07 mmol) and sodium f-butoxide (100 mg, 1 mmol) in toluene (3 ml_) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (60 mg, 41 % yield for two steps) as TFA salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium phosphate; copper(l) iodide; 1,1'-bi-2-naphthol; In N,N-dimethyl-formamide; at 80 - 90℃; | Production Example 652-(4-{2-[4-(2,5-diazabicyclo[2.2.1]hept-2- yl) phenyl] ethyl}phenyl) acetohydrazide trihydrochloride step 1 [0195] [0196]A mixture of 1, 4-diiodobenzene (9.98 g, 30.3 mmol) , tert- butyl 2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (2.0 g, 10.1 mmol), copper (I) iodide (434 mg, 3.03 mmol), l,l'-bi-2- naphthol (867 mg, 3.03 mg) , tripotassium phosphate (5.14 g, 24.2 mmol) and anhydrous N,N-dimethylformamide (50 ml) was stirred at 80C for 2 days. 1, 4-Diiodobenzene (3.33 g, 10.1 mmol) was added, and the mixture was stirred at 9O0C overnight. After cooling to room temperature, the mixture was filtered through Celite, and the insoluble material was washed with ethyl acetate. The filtrate and washing solution were combined, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate :hexane = 80:20) to give tert-butyl 5- (4-iodophenyl) - 2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (1.34 g, yield <n="88"/>33%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Step 1 Synthesis of 5-{2-[(5-Phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-<strong>[198989-07-0]2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester</strong> DIPEA (286 mg, 0.38 mL, 2.2 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (136 mg, 0.55 mmol) (prepared according to a procedure similar to that described in Synthesis Procedure 4, Steps 1-3 and 5-6) in DMF (3 mL). HOBT (74.8 mg, 0.55 mmol) and EDCI (193 mg, 1.0 mmol) were then added at room temperature. After 2 minutes, <strong>[198989-07-0]2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester</strong> (100 mg, 0.5 mmol) (Aldrich, St., MO) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (using 60-120 silica gel and 80% ethyl acetate in hexane as eluent) to afford 110 mg (51%) of 5-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-<strong>[198989-07-0]2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester</strong>. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 15h; | tert-Butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5 g, 25.214 mmol) and pyridine-4-carbaldehyde (2.97 g, 27.74 mmol) were introduced into dichloromethane (650 ml), mixed with sodium triacetoxyboron hydride (10.6 g, 50.43 mmol) and glacial acetic acid (0.14 ml, 2.521 mmol) and the reaction mixture was stirred at room temperature for 15 h. The mixture was then hydrolysed with saturated sodium hydrogen carbonate solution, the phases were separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel; dichloromethane/methanol). Yield: 5.8 g, 79% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 2h; | S odium triacetoxyborohydride (118 mg, 0.556 mmol) was added portionwise over 5 minutes to a mixture of 3-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanone (Intermediate BG, 150 mg, 0.371 mmol), <strong>[198989-07-0]N-Boc-2,5-diazabicyclo[2.2.1]heptane</strong> (90 mg, 0.445 mmol), acetic acid (0.021 ml, 0.371 mmol) and 1 ,2-dichloroethane (2 ml) at room temperature. After stirring for 2 hours at room temperature the reaction mixture was diluted with water, extracted 2X with DCM, the combined organic layers dried over sodium sulphate and evaporated to give the title compound as a clear yellow glass. HPLC/MS tR 0.96 min, M+H 587.4 (Method X). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 4h; | a) iert-Butyl 5-(3-bromoimidazo[1 ,2-b]pyridazin-6-yI)-2,5diazabicyclo[2.2.1]heptane-2- carboxylate3-Bromo-6-chloroimidazo[1 ,2-b]pyridazine (586 mg, 2.53 mmol) was dissolved in NMP (5 mL) and 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid 1 ,1-dimethylethyl ester (1.0 g, 5.05 mmol) was added followed by DIPEA (1.04 mL, 6.31 mmol). The reaction mixture was heated to 30C for 4 h. The solution was cooled down and diluted with DCM, then washed twice with water and twice with brine. The solution was dried over magnesium sulphate and solvents evaporated. Purification by column chromatography on silica gel (10- 00% EtOAc/petroleum ether) gave a brown oil. This was dissolved in ethyl acetate, washed four more times with brine, dried over magnesium sulphate and the solvents evaporated to give a brown solid (486 mg, 49%); H NMR (400 MHz, CDCI3) delta ppm 7.67 (d, J=9.6 Hz, 1 H), 7.67 (d, J=9.6 Hz, 1 H), 7.52 (s, 1 H), 6.54 (d, J=9.6 Hz, 1 H), 4.49-4.84 (m, 2H), 3.43-3.67 (m, 4H), 1.94-2.07 (m, 2H), 1.48 (s, 9H); m/z (ES+APCIf: 394/396 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.166 g | With sodium t-butanolate; at 80℃; for 1h;Inert atmosphere; | 6-{4-[5-(teri-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl}-5-ethyl-2-oxo-l,2- dihydropyridine-3-carboxylic acid (Cpd 137)Methyl 6-(4-bromophenyl)-5-ethyl-2-oxo-l,2-dihydropyridine-3-carboxylate (0.106 mg, 0.31 mmol), Pd-catalyst (7.3 mg, 5 mol%) and t-BuONa (0.072 g, 0.75 mmol) were mixed under Argon in a heat-gun dried vial. Anhydrous toluene (1.0 mL) was added to the mixture followed by <strong>[198989-07-0]ter<strong>[198989-07-0]t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate</strong></strong> (0.19 g, 0.95 mmol).The reaction was heated under Argon at 80 C for 1 hr until complete consumption of the starting material was observed. The mixture was cooled to room temperature and the reaction was quenched with HCl (1M, 5 mL). The product was extracted with DCM (3x7 mL), followed by drying of the organic phase over Na2S04. The solvents were concentrated and the resulting residue (0.166 g) was taken used in the step without further purification.The residue obtained above (0.166 g) was heated in THF (2 mL) with a LiOH solution (1M aqueous, 1.0 mL, 1.0 mmol) at 50 C for 4 h. The reaction mixture was cooled to room temperature and acidified with 1 M HCl to pH~2. The product was extracted with DCM, then the organic phase was dried over Na2S04 and the solvent concentrated. The resulting residue was purified by preparative HPLC to provide (S,S)-6-(4-(5-(tert-butoxycarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl)phenyl)-5-ethyl-2-oxo-l,2-dihydropyridine-3-carboxylic acid(0.0444 g, 32%) as a yellow solid.XH NMR (500 MHz, CHCl3-i/) delta ppm 1.22 (t, J=7.6 Hz, 3H) 1.37 - 1.51 (m, 9 H) 1.90 - 2.09 (m, 2H) 2.64 (q, J=7.6 Hz, 2H) 3.17 - 3.38 (m, IH) 3.39 - 3.56 (m, 2H) 3.62 (dd, J=15.9, 8.7 Hz, IH) 4.47 - 4.76 (m, 2H) 6.66 (d, J=8.2 Hz, 2H) 7.37 (d, J=8.6 Hz, 2H) 8.51 (s, IH) 12.50 (br. s., IH) 13.81 (br. s., IH). LC-MS 437.7 [M-H]", 440.0 [M+H]+, RT 1.27 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | To a solution of 3-(6-bromo-quinazolin-4-yl)-benzoic acid (310 mg, 0.942 mmol) in 8 mL of DMF was added HBTU (429 mg, 1.130 mmol) and DIPEA (0.3455 mL, 1 .98 mmol). The reaction mixture was stirred at rt for 20min. Tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (373 mg, 1 .884 mmol) and DIPEA (0.3455 mL, 1 .98 mmol) were added at rt and the reaction mixture was stirred for 10min at rt. The reaction was quenched with a saturated aqueous solution of NaHC03, extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered and evaporated under vacuum. Purification by flash chromatography on silica gel (Heptane/EtOAc, 80/20 to 0/100) gave the title compound (400.4 mg, >99% purity, 83% yield). MS: 51 1 .3 [M+1 ]+ , Rt (3) = 2.19 min. | |
83% | To a solution of 3-(6-bromo-quinazolin-4-yl)-benzoic acid (310 mg, 0.942 mmol) in 8 mL of D F was added HBTU (429 mg, 1.130 mmol) and DIPEA (0.3455 mL, 1.98 mmol). The reaction mixture was stirred at rt for 20min. Tert-butyl 2,5-diazabicyclo[2.2.1 ]heptane-2- carboxylate (373 mg, 1.884 mmol) and DIPEA (0.3455 mL, 1.98 mmol) were added at rt and the reaction mixture was stirred for 10min at rt. The reaction was quenched with a saturated aqueous solution of NaHC03, extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered and evaporated under vacuum. Purification by flash chromatography on silica gel (Heptane/EtOAc, 80/20 to 0/100) gave the title compound (400.4 mg, >99% purity, 83% yield). MS: 511.3 [M+1]+ , Rt (3,) = 2.19 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.5% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 55℃; for 3h; | General procedure: To a solution of Intermediate 4 (1 g, 5.37 mmol) in 1,4-dioxane (7 mL) was added DIPEA (1.32 mL, 8.046 mmol), followed by tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (1.17 g, 5.90 mmol). The reaction mixture was heated at 55C for 3 h. The reaction mixture was then concentrated, and diluted with DCM. The organic layer was washed with water and 5% aqueous acetic acid solution, then concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH: DCM 2%) to afford the title compound (1 g, 55.5%). LCMS (ES+) 349.1 (M+H)+, RT 1.70 minutes (method 1). |
55.5% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 55℃; for 3h; | Intermediate 95 tert-Butyl 5-(5-aminothiazolo[5,4-d]pyrimidin-7-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [0316] To a solution of Intermediate 4 (1 g, 5.37 mmol) in 1,4-dioxane (7 mL) was added DIPEA (1.32 mL, 8.046 mmol), followed by <strong>[198989-07-0]ter<strong>[198989-07-0]t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate</strong></strong> (1.17 g, 5.90 mmol). The reaction mixture was heated at 55 C. for 3 h. The reaction mixture was then concentrated, and diluted with DCM. The organic layer was washed with water and 5% aqueous acetic acid solution, then concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH: DCM 2%) to afford the title compound (1 g, 55.5%). LCMS (ES+) 349.1 (M+H)+, RT 1.70 minutes (method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | With triethylamine; In methanol; at -30 - 25℃; | Di-tert-butyldicarbonate (0.38 g, 0.38 mL, 1.7 mmol) was added dropwise for 10 minutes to a cold (-30 C.) stirred solution of 2,5-diazabicyclo[2.2.1]heptanedihydrobromide (1 g, 3.8 mmol) and triethylamine (776 mg, 1.07 mL, 7.6 mmol) in MeOH (30 mL). The reaction mixture was stirred at 25 C. for 12-16 h. The reaction mixture was concentrated under reduced pressure; diluted with water and filtered. The filtrate was extracted with DCM; the organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 200 mg of the title compound as a white solid. MS (ESI): m/z 199.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; at 20 - 70℃;Inert atmosphere; | General procedure: ferf-Butyl 5-((( ?)-1-(1 H-benzo[ ]imidazol-2-yl)-2-(4-methoxyphenyl)ethyl)carbamoyl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate: Following general procedure A, starting from (f?)-3-(4-methoxybenzyl)-2,3-dihydro-1 /-/- benzo[d]imidazo[1 ,5-a]imidazol-1-one and using te/f-butyl 2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate: LC-MS-conditions 07: tR = 0.70 min; [M+H]+ = 492.27. General procedure A: Urea formation: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a 0.1 M suspension of the suitably substituted 2,3-dihydro-1 /-/- benzo[d]imidazo[1 ,5-a]imidazol-1-one derivative (1.0 eq.) in AcCN or THF was treated at rt with DIPEA (1.25 to 4.0 eq.) followed by the amine (1.0 to 1.50 eq.) and the reaction mixture was stirred at 70 C until completion. Water and EA were added to the cooled reaction mixture. The org. layer was dried over MgS04, filtered, and the solvent was removed under reduced pressure. Purification of the residue by preparative HPLC gave the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 3A (1S,4S)-tert-butyl 5-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoline-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate The product from Example 1D (800 mg, 2.39 mmol) was subjected to the conditions described in Example 2, substituting (1S,4S)-<strong>[198989-07-0]ter<strong>[198989-07-0]t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate</strong></strong> for 3-aminotetrahydrothiophene 1,1-dioxide hydrochloride to give the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium hexamethyldisilazane; In tetrahydrofuran; 1,4-dioxane; at 60℃;Inert atmosphere; | To a solution of 6b (150 mg, 0.34 mmol), tert-butyl 2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (109 mg, 0.51 mmol), Pd2(dba)3 (16 mg, 0.017 mmol) and S-Phos (28 mg, 0.068 mmol) in dry 1,4-dioxane (8.5 mL) was added NaHMDS (2 M in THF, 0.6 mL) under a nitrogen atmosphere. The mixture was purged with nitrogen for 5 min, and then heated at 60 C until the completion of the reaction. After cooled to room temperature, the mixture was diluted with DCM (20 mL) and filtered. The filtrate was concentrated in vacuum and purified by chromatograph (CHCl3/MeOH) to give the coupling intermediate as pale yellow solid (103 mg, 59% yield): 1H NMR (400 MHz, CDCl3) delta 11.60-11.40 (m, 1H), 8.52 (d, J = 7.6 Hz, 1H), 8.19 (s, 1H), 7.80-7.64 (m, 1H), 7.50 (d, J = 7.8 Hz, 1H), 6.83 (s, 1H), 4.72-4.54 (m, 1H), 4.53-4.37 (m, 1H), 3.88-3.75 (m, 1H), 3.74-3.21 (m, 3H), 2.85-2.53 (m, 2H), 2.09-1.97 (m, 2H), 1.86 (s, 6H), 1.59-1.40 (m, 9H), 1.23-1.08 (m, 3H). Subsequent deprotection of the intermediate with TFA (100 equiv) in DCM at room temperature afforded compound 7c as a yellow solid (69 mg, 49% yield in two steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere; | To 188 (15.0 mg, 0.039 mmol) in DMF (2 mL) was added a <strong>[198989-07-0]ter<strong>[198989-07-0]t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate</strong></strong> (11.6 mg, 0.0585 mmol) and heated at 90 C for 2 h. Solvent was removed under reduced pressure and to the residue was added CH2C12 (3 mL) followed by TFA (1 mL) dropwise over 5 minutes and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and dried under high vacuum overnight. This residue was taken up into CH3OH (3 mL) and to this was added 37% formaldehyde (40 mu, 15 mg, 0.495 mmol), sodium triacetoxyborohydride (35 mg, 0.165 mmol) and sodium acetate (27 mg, 0.330 mmol) and the reaction was heated at 50 C for 5 h. Solvent was removed under reduced pressure and the residue was purified by preparatory TLC (CH2Cl2:MeOH, 10:1) to afford 16.2 m (91%) of 194. MS (m/z): [M+H]+ 460.18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In acetone; at 60℃; for 48h; | General procedure: Commercial Boc-protectedamine (0.015 mol) was dissolved in acetone (15 ml). Then K2CO3 (0.045mol) and catalytic amount of KI were added followed by dropwise addition of (aryloxy)ethylbromide (0.018 mol). The reaction was refluxed for 48 h. Inorganic residueswere filtered off and organic mixture was concentrated under reduced pressure.The obtained crude product was purified using silica gel with CH2Cl2/MeOH(9/0.7 v/v) as an eluting system. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In acetone; at 60℃; for 48h; | General procedure: Commercial Boc-protectedamine (0.015 mol) was dissolved in acetone (15 ml). Then K2CO3 (0.045mol) and catalytic amount of KI were added followed by dropwise addition of (aryloxy)ethylbromide (0.018 mol). The reaction was refluxed for 48 h. Inorganic residueswere filtered off and organic mixture was concentrated under reduced pressure.The obtained crude product was purified using silica gel with CH2Cl2/MeOH(9/0.7 v/v) as an eluting system. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 23℃; for 16h; | Step 2.4: To a solution of 1?-(5-(4-acetamidopyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3?-indoline]- 6?-carboxylic acid (0.25 g, 0.62 mmol, 1 eq) in DMF (5 mL), the TBTU (0.24 g, 0.747 mmol, 1.2 eq), NMM (0.126 g, 1.25 mmoL, 2 eq) and <strong>[198989-07-0]2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester</strong> (0.123 g, 0.623 mmol, 1 eq) were added at RT. RM was then stirred at RT for 16 h. After completion of reaction,reaction mixture was quenched with ice water (40 mL) and a solid was precipitated out. The solid was filtered off and re-dissolved in EtOAc (50 mL). The EtOAc solution of the desired compound was washed with water (2 x 40 mL), brine (40 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to get the crude product. The crude product was triturated with Et20-hexane (3 x) to afford tert-butyl 5-(1 (5-(4-acetamidopyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3-indolinj-6?-ylcarbonyl)-2,5-diazabicycle-[2.2.1]heptane-2-carboxylate (0.35 g, 96.9%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 mg | With potassium carbonate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 85℃; for 1h; | Methanesulfonic anhydride (Ms2O) (662 mg, 3.81 mmol) was slowly added to a solution of 5-formyl-1-(2-hydroxyethyl)-4-methyl-1H-indole-2-carbonitrile (290 mg, 1.27 mmol) and DIPEA (1.1 mL) in THF (6.3 mL). After stirring for 10 minutes, the mixture was diluted with saturated bicarbonate solution and stirred for 20 minutes, and the product was filtered off and thoroughly dried.1H NMR (600 MHz, CD3CN): 10.39 (s, 1H), 7.88 (d, 1H, J=8.4Hz), 7.59 (s, 1H), 7,49 (d, 1 H, J=8.4Hz), 4.66 (m, 2H), 4.53 (m, 2H), 2.86 (m, 6H). The mesylated derivative (130 mg, 0.42 mmol) was dissolved in DMF (2 mL) and tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (166 mg, 0.84 mmol) and potassium carbonate (86 mg, 0.63 mmol) were added. The mixture was heated at 85 C for 1 h, cooled down, diluted with water, and extracted with DCM. The crude mixture was purified on silica gel column to produce tert-butyl 5-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)ethyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (10 mg). HR MS (ESI): C23H28N4O3+ H+calculated 409.2234; found 409.2232. |
10 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 1h; | [00170] Methanesulfonic anhydride (Ms2O) (662 mg, 3.81 mmol) was slowly added to a solution of 5-formyl-1-(2-hydroxyethyl)-4-methyl-1H-indole-2-carbonitrile (290 mg, 1.27 mmol) and DIPEA (1.1 mL) in THF (6.3 mL). After stirring for 10 minutes, the mixture was diluted with saturated bicarbonate solution and stirred for 20 minutes, and the product was filtered off and thoroughly dried.1H NMR (600 MHz, CD3CN): 10.39 (s, 1H), 7.88 (d, 1H, J=8.4Hz), 7.59 (s, 1H), 7,49 (d, 1H, J=8.4Hz), 4.66 (m, 2H), 4.53 (m, 2H), 2.86 (m, 6H). The mesylated derivative (130 mg, 0.42 mmol) was dissolved in DMF (2 mL) and tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (166 mg, 0.84 mmol) and potassium carbonate (86 mg, 0.63 mmol) were added. The mixture was heated at 85 C for 1 h, cooled down, diluted with water, and extracted with DCM. The crude fied on silica gel column to produce tert-butyl 5-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)ethyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (10 mg). HR MS (ESI): C23H28N4O3 + H+ calculated 409.2234; found 409.2232. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 24h; | A 100-mE round-bottom flask was charged with ethyl 4-bromobenzoate (500 mg, 2.18 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (226 mg, 0.22 mmol), 2,2?-bis(diphenylphosphino)-l , 1 ?-binaphthyl (261 mg, 0.44 mmol), cesium carbonate (2.14 g, 6.57 mmol), toluene (20 mE) and tert-butyl 2,5-diazabicyclo[2.2. 1]hep- tane-2-carboxylate (521 mg, 2.61 mmol). The resulting solution was stirred for 24 hat 1100 C. The reaction was cooled to room temperature and quenched by the addition of water (20 mE). The resulting solution was extracted with of dichloromethane (4x20 mE). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:1, v/v). The collected fractions were combined and concentrated under vacuum to afford tert-butyl 5-(4-(ethoxycarbonyl)phenyl)-2,5-diaza-bicyclo[2.2. 1 ]heptane-2-carboxylate as a yellow oil (700 mg, 92%). ECMS:(ESI) mlz 347 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With methanesulfonato(2-dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl)(2?-methylamino-1,1?-biphenyl-2-yl)palladium(II); sodium t-butanolate; In 1,4-dioxane; at 100℃; for 12h;Sealed tube; Inert atmosphere; | In a pyrex vial <strong>[198989-07-0]ter<strong>[198989-07-0]t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate</strong></strong> (500 mg, 2.5 mmol), 2-chioropyridine (0.29 mL, 3.0 mmol), sodium tert-butoxide (364 mg, 3.8 mmol) andmethanesulfonato(2-dicyclohexylphosphino-2?,6?-di-i-propoxy- 1,1 ?-biphenyl)(2?-amino- 1,1biphenyl-2-yl)palladium(II) (105 mg, 0.13 mmol) were added. The vial was sealed, evacuated and purged with nitrogen (g) (3 X). Anhydrous dioxane (6 mL) was added and the reaction was heated at 100 C for 12 h. The reaction was cooled to ambient temperature, diluted with Ethyl acetate, filtered through a pad of celite then concentrated to dryness and deposited on to silicagel with aid of methylene chloride. The crude residue was purified by silica gel chromatography(eluting with hexanes ethyl acetate) to provide tert-butyl 5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (603 mg, 87%) as a white solid. LCMS M/Z (M+H)276. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃;Sealed tube; | Step-1: A thick-walled pressure vessel with teflon screwtop and stirbar was charged with methyl-(E)-3-(2-bromophenyl)acrylate (1.00 g, 4.15 mmol, 1.00 equiv), tert-butyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.905 g, 4.56 mmol, 1.10 equiv), cesium carbonate (2.70 g, 8.3 mmol, 2.0 equiv), palladium(II) acetate (65 mg, 0.29 mmol, 0.07 equiv), and xantphos (360 mg, 0.62, 0.14 equiv). The vessel was brought into a glovebox and dry toluene (10 mL) was added. The vessel was sealed, removed from the glovebox and heated at 90 C. overnight. The reaction mixture was then cooled to room temperature and diluted with 50 mL of EtOAc, then washed with 10% K2CO3, 1M HCl, and brine. The organic phase was dried with Na2SO4, the solvent was removed and the brown oil was purified via flash column chromatography on silica gel (40% EtOAc/Hexane, Rf=0.55) to afford a bright yellow solid (1.00 g, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 4h; | General procedure: To a stirred solution of compound 1 (121.0 mg, 1.0mmol) and2a-e (1.0 mmol) in anhydrous DMSO (10 mL) was added anhydrous K2CO3 (165.6 mg, 1.2 mmol). After stirring 4 h at 80 C, the reactionwas poured into ice, the precipitationwas filtrated to obtain 3a-e ina yield of 45%-75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; | A flask was charged with <strong>[89763-93-9]2-fluoro-4-(trifluoromethyl)benzaldehyde</strong> (768 mg, 4.00 mmol, 1.00 equiv), t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (950 mg, 4.80 mmol, 1.20 equiv), DMSO (10 mL), and potassium carbonate (1.66 g, 12.0 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80 C and quenched with water (30 mL). The mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 500 mg (34% yield) of t-butyl 5-(2-formyl-5 -(trifluoromethyl)phenyl)-2, 5 -diazabicyclo[2. 2.1 ]heptane-2- carboxylate as a yellow oil. LCMS (ESI, m/z): 371 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With potassium carbonate; In N,N-dimethyl acetamide; at 60℃; | <strong>[198989-07-0]2,5-diazabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester</strong> (250 mg, 1.26 mmol), 2-(3-((7-(3-chloropropoxy)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (382mg, 0.84mmol), Potassium carbonate (348 mg, 2.52 mmol) was added to dimethyl acetamide (5 mL).The mixture was heated to 60 C and allowed to react overnight. After the reaction of the starting material is completed, it is cooled to room temperature, and the solvent is removed under reduced pressure.The crude product was purified by column chromatography (DCM/CH3OH (v/v) = 20/1).A yellow solid (152 mg, 29%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid; at 20 - 50℃;pH 6-7; | General procedure: To a stirring solution of 16a-d (0.3 mmol) in MeOH (5 mL) wasadded the f 4-fluorobenzaldehyde (0.4 mmol) and NaCNBH3(0.5 mmol) at room temperature. The mixture was adjusted to pH 6-7 by acetic acid, stirred overnight at room temperature, and quenched by 1MNaOH solution (5 mL). The mixture was diluted by H2O (15 mL), and extracted by DCM (10mL x 3). The combined organic layer was washed by brine, dried over anhydrous MgSO4,filtered, and concentrated. The residue was purified over silica gel column (DCM: MeOH = 20 : 1) to yield oils 17a-d (yields, 65-83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
930 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h; | 5-bromo-4-(4-chlorothiophen-2-yl)-thiazole-2-amine (819mg, 2.77mmol), <strong>[198989-07-0]2-tert-butyloxycarbonyl-2,5-diazabicyclo[2.2.1]heptane</strong> (500mg, 2.52mmol) and potassium carbonate (696mg, 5.04mmol) were added to N,N-dimethylformamide (15mL). The mixture was reacted at 90C for 1h. The reaction system was added to water, extracted with ethyl acetate. The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to produce a crude product. The crude product was purified with a silica gel column chromatography to produce the title compound (930mg). ESI-MS (m/z): 413.1 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1.5h; | A solution of <strong>[198989-07-0]ter<strong>[198989-07-0]t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate</strong></strong> (600 mg, 3.03 mmol, 1.00 equiv), 6-chloropyridine-3-carbonitrile (460 mg, 3.32 mmol, 1.10 equiv), potassium carbonate (1.254 g, 17.16 mmol, 3.00 equiv) in DMF (10 mL) was stirred for 1.5 h at 80 C. The resulting solution was quenched with 40 ml water. The solution was extracted with EtOAc (3×40 mL) and the organic layers combined. The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc/hexane (1:1) to afford 770 mg (85%) of the title compound as a yellow solid. LCMS (ESI, m/z): 301.16 [M+H]+ |
Tags: 198989-07-0 synthesis path| 198989-07-0 SDS| 198989-07-0 COA| 198989-07-0 purity| 198989-07-0 application| 198989-07-0 NMR| 198989-07-0 COA| 198989-07-0 structure
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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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