Structure of 89830-98-8
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CAS No. : | 89830-98-8 |
Formula : | C6H8N2 |
M.W : | 108.14 |
SMILES Code : | C1(C2CC2)=CN=CN1 |
MDL No. : | MFCD18711516 |
InChI Key : | BNFGUBCFRVUHJH-UHFFFAOYSA-N |
Pubchem ID : | 19031522 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 31.05 |
TPSA ? Topological Polar Surface Area: Calculated from |
28.68 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.03 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.64 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.22 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.32 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.07 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.31 |
Solubility | 5.29 mg/ml ; 0.049 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.82 |
Solubility | 16.5 mg/ml ; 0.152 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.77 |
Solubility | 1.84 mg/ml ; 0.0171 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.51 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.76 |
* 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 |
---|---|---|
93.7% | In 1,2-dimethoxyethane; at 110℃; for 15h; | The compound 2-bromo-1-cyclopropylethanone (12.0 g, 74.1 mmol) and formamidine acetate (23.1 g, 222.3 mmol) were dissolved in 100 mL of ethylene glycol and reacted at 110 C for 15 hours. After the reaction was completed, 500 mL of water was added, and the mixture was washed three times with dichloromethane (500 mL×3), then the aqueous phase was adjusted to pH 8 with a 1 M aqueous NaOH solution, and the aqueous phase was extracted twice with dichloromethane (500 mL×2), organic phase was dried and concentrated to give the desired product 7.5g, yield 93.7%. |
In ethylene glycol; at 135℃; | A mixture of 2-bromo-l-cyclopropylethanone (1.63 g, 10.0 mmol) and formimidamide acetate (5.24 g, 50.0 mmol) in ethylene glycol (50 mL) was heated at 135deg;C overnight. After cooling, the mixture was diluted with water (50 mL), and extracted several times with ether. The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the crude product which was directly used in next step reaction without further purification. LCMS: (M+H)+= 109.3. | |
With ammonia; at -78 - 20℃;Sealed tube; | A. Preparation of 4-cyclopropyl-1H-imidazole Ammonia (~75 mL) was condensed into a pressure vessel containing formamidine acetate (60 g, 0.58 mol) and a stir bar at -78 C. 2-bromo-1-cyclopropyl-ethanone (10.2 g, 0.063 mol) was added dropwise and the pressure vessel was sealed and warmed to room temperature and stirred for 12 hours. The reaction mixture was then cooled to -78 C. before being carefully opened. The cooling bath was removed and the ammonia was allowed to evaporate. The residue was dissolved in 100 mL of water and 20 mL saturated sodium bicarbonate solution, and then solid sodium chloride was added until the solution was saturated. This mixture was extracted with ethyl acetate (4*100 mL) and the organic phase was dried with sodium sulfate before being evaporated to yield 4-cyclopropyl-1H-imidazole as a yellow oil (70-80% purity, 5.3 g, 78% yield, M+1=109.1) which was used without further purification. Reverse-phase HPLC (0.1% HCl H2O, MeCN) of the crude compound gave an analytically pure sample (1.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃;Inert atmosphere; Microwaves; | A mixture of 3-bromo-5-(trifluoromethyl)aniline (0.48 g, 2.0 mmol), 4-cyclopropyl-lH- imidazole (0.26g, 2.4 mmol), K2CO3 (0.35g, 2.5 mmol), CuI (57 mg, 0.30 mmol), and 8- hydroxyquinoline (44 mg, 0.30 mmol) in dry DMSO (2 mL) in a microwave tube was cooled to -78deg;C, and degassed by vacuum and refilled with N2 for three times. The mixture was heated at1200C overnight. The mixture was cooled to 40-500C and 14percent aq. NH4OH was added. The mixture was stirred at 40-500C for 1 h. After cooling, the mixture was diluted with water, and extracted with ethyl acetate (3x15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (5percent MeOH in CH2Cl2) to afford the crude product (0.41 g). LCMS: (M+H)+= 268.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; acetonitrile; | Example 12Preparation of 4-Alkyl Substituted ImidazolesA. Preparation of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> Ammonia (75 mL) was condensed into a pressure vessel containing formamidine acetate (60 g, 0.58 mol) and a stir bar at -78° C. 2-bromo-1-cyclopropyl-ethanone (10.2 g, 0.063 mol) was added dropwise and the pressure vessel was sealed and warmed to room temperature and stirred for 12 hours. The reaction mixture was then cooled to -78° C. before being carefully opened. The cooling bath was removed and the ammonia was allowed to evaporate. The residue was dissolved in 100 mL of water and 20 mL saturated sodium bicarbonate solution, and then solid sodium chloride was added until the solution was saturated. This mixture was extracted with ethyl acetate (4.x.100 mL) and the organic phase was dried with sodium sulfate before being evaporated to yield <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> as a yellow oil (70-80percent purity, 5.3 g, 78percent yield, M+1=109.1) which was used without further purification. Reverse-phase HPLC (0.1percent HCl H2O, MeCN) of the crude compound gave an analytically pure sample (1.0 g). 1H NMR of HCl salt (DMSO) d 8.96 (s, 1H), 7.38 (s, 1H), 1.96 (m, 1H), 0.97 (m, 2H), 0.79 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With 8-quinolinol; caesium carbonate; In propyl cyanide; at 100℃; for 16h; | A suspension 4-bromo-N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide (63 mg, 0.16 mmol), <strong>[89830-98-8]4-cyclopropyl imidazole</strong> (35 mg, 0.24 mmol), Cu2O (1.2 mg, 0.0081 mmol), 4,7-dimethoxy-1,10-phenanthroline (5.9 mg, 0.024 mmol, (or 8-hydroxy-quinoline may be used as the ligand with comparable results), cesium carbonate (116 mg, 0.36 mmol), and PEG-3350 (32 mg) in butyronitrile (1 mL) was heated at 100° C. for 16 hours. The solvent was removed and the residue was purified by reverse-phase HPLC to 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide as a white powder (9.2 mg, 0.377 mmol, 13percent yield). C21H19N7OS. 418.2 (M+1). 1H NMR (DMSO) delta 11.42 (s, 1H), 8.77 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.37 (d, J=2 Hz, 1H), 8.33 (d, J=2 Hz, 1H), 8.04 (d, J=1 Hz, 1H), 7.97 (dd, J=2, 5 Hz, 1H), 7.85 (s, 1H), 3.55-3.59 (m, 1H), 1.85-1.88 (m, 1H), 1.22-1.26 (m, 2H), 1.11-1.13 (m, 2H), 0.82-0.86 (m, 2H), 0.72-0.75 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | A mixture of 4-fluoropicolinic acid (400 mg, 2.84 mmol) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (322 mg, 2.98 mmol) were dissolved in N,N-dimethylformamide, and N-methylmorpholine (0.36 ml, 3.28 mmol) was added. The reaction was warmed to 35° C., and stirred for 20 hours. The solvent was then removed under reduced pressure to afford a viscous oily residue. This residue was dissolved in 1N hydrochloric acid (5 mL), and the aqueous layer was extracted with ethyl acetate (2*5 mL). The aqueous layer was concentrated under reduced pressure to afford a yellow solid. To this residue was added 5 mL of acetonitrile/methanol (20:1) and the mixture was sonicated to afford a fine suspension of solids.The solids were collected by filtration, washed several times with acetonitrile, and dried on the filter funnel.The yellow solids were collected to afford 520 mg (69percent yield) of 4-(4-cyclopropyl-1H-imidazol-1-yl)picolinic acid as the hydrochloride salt. M+1=230.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With caesium carbonate; In propyl cyanide; at 105℃; for 2h; | Step 2-Preparation of a Compound of Formula (19A) in which R is Hydrogen, X2 is CH, X3 is S, X4 is CH, X5 is N, and Y is 4-(4-cyclopropyl-1H-imidazol-1-yl)To a solution of methyl 4-(4-fluoropicolinamido)thiophene-2-carboxylate (400 mg, 1.4 mmol) in butyronitrile (5 mL), was added <strong>[89830-98-8]4-cyclopropyl imidazole</strong> (310 mg, 2.9 mmol), and caesium carbonate (840 mg, 2.6 mmol) and the reaction was heated to 105° C. for 2 hours.The reaction was filtered and the solids were washed with acetonitrile, methylene chloride, and the filtrate was evaporated under reduced pressure.The residue was suspended in acetonitrile, and the solids were collected by filtration to provide 384 mg (73percent) of methyl 4-(4-(4-cyclopropyl-1H-imidazol-1-yl)picolinamido)thiophene-2-carboxylate. M+1=369.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 8-quinolinol; caesium carbonate;copper(I) oxide; In butyronitile; at 120℃; for 16h;Inert atmosphere; | A suspension of isopropyl 5-iodo-2-methoxybenzoate (1.52 g, 4.75 mmol), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (0.777 g, 7.13 mmol), copper(I) oxide (0.067 g, 0.047 mmol), 8-hydroxyquinoline (0.103 g, 0.71 mmol), cesium carbonate (2.41 g, 7.41 mmol), PEG-3350 (1.18 g) and butyronitile (60 ml) was placed in a sealed tube, which was flushed with nitrogen and heated at 120° C. for 16 hours.The solvent was removed under reduced pressure, and the residue was purified by reversed phase HPLC to provide isopropyl 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-methoxybenzoate. (0.720 g, 2.4 mmol).51percent yield. 301 (M+1).Step 3-Preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-methoxybenzoic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | NaCN (360 mg; 7.35 mmol) was added to a suspension of cyclopropane- carboxaldehyde (5 g; 71 .3 mmol) and tosylmethyl-isocyanide (13.7 g; 69.9 mmol) in EtOH (200 mL). The resulting mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure and the residue was washed with a mixture of heptane/ether (1 :1 ). The beige dried powder was stirred in NH3/MeOH 7N (480 mL; 3.36 mol) and the mixture was stirred at 100°C in steel bomb for 16 h. The mixture was cooled to RT and the solvant was evaporated under reduced pressure. iPr20 was added to the residue and the solid was filtered. The filtrate was evaporated to dryness and the crude was purified by preparative LC on (Irregular SiOH 20-45??? 1000g DAVISIL). Mobile phase (0.5percent NH4OH, 94percent DCM, 6percent MeOH). The pure fraction was collected and evaporated to give 4.9 g of intermediate J-1 a as a brown oil (65percent yield). 1 H NMR (DMSO-de, 400MHz) : ? (ppm) 8.60 (br. s., 1 H), 7.58 (s, 1 H), 6.76 (s, 1 H), 1 .85 (m, 1 H), 0.86 (m, 2H), 0.71 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BuLi (1.6M in hexane)(1 1 mL; 17.6 mmol) was added to a solution of J-1 b (3.5 g; 14.7 mmol) in THF (60 mL) at -50°C. The mixture was stirred at the sametemperature for 30 min and DMF (1 .7 mL; 22 mmol) was added. The mixture was warmed slowly to RT in 1 h and NH2OH,HCI (970 mg; 29.4 mmol) was added and the mixture was stirred at RT for 16h. Water was added and the product was extracted with DCM (3 times), washed with brine, dried over MgS04 and the solvent was removed under reduced pressure to give 4.1 g (quantitative yield) of the mixture of isomers K-1 as yellow oil.HPLC Rt (min) = 5.30, 5.41 and 5.90 ; MS M+ (H+): 282 (method V2002V2002) K-1 ( 3.1 g; 1 1 mmol) was dissolved in DCM (18 mL) and pyridine (19 mL) at RT. The mixture was cooled to 0°C and TFAA (4.6 mL; 33 mmol) was added. The mixture was stirred at RT for 24h. The solvent was removed under reduced pressure and the residue was dissolved in AcOEt. The organic layer was washed with water and brine, dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 15-40??? 90g merck, mobile phase Heptane/DCM 30/70 to DCM 100percent) to give 2.14 g of intermediate J-1 (73percent) as a mixture of two isomers.HPLC Rt (min) = 6.51 ; MS M+ (H+): 264 (method V2002V2002) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BuLi (1.6M in hexane)(1 1 mL; 17.6 mmol) was added to a solution of J-1 b (3.5 g; 14.7 mmol) in THF (60 mL) at -50°C. The mixture was stirred at the sametemperature for 30 min and DMF (1 .7 mL; 22 mmol) was added. The mixture was warmed slowly to RT in 1 h and NH2OH,HCI (970 mg; 29.4 mmol) was added and the mixture was stirred at RT for 16h. Water was added and the product was extracted with DCM (3 times), washed with brine, dried over MgS04 and the solvent was removed under reduced pressure to give 4.1 g (quantitative yield) of the mixture of isomers K-1 as yellow oil.HPLC Rt (min) = 5.30, 5.41 and 5.90 ; MS M+ (H+): 282 (method V2002V2002) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
120 mg | J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012) EtONa (904 mg; 13.3 mmol) was added to a solution of 2-cyano-imidazole 1-1 (0.7 g; 2.66 mmol) and intermediate C-1 (736 mg; 2.66 mmol) in EtOH (30 ml_). The mixture was stirred at 90°C for 16 h. The solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 45g Merck, mobile phase 97/3/0.1 to 95/5/0.5) to give 0.51 g of the SEM-protected ethoxy intermediate as a lightly yellow solid (38percent yield).HPLC Rt (min) = 7.45 ; MS M+ (H+): 506 method (v2003v2002) NaF (170 mg; 4.05 mmol) was added to a solution of SEM-protected ethoxy intermediate (0.41 g; 0.81 1 mmol) in THF (28 ml_), HCI (37percent in H20) (28 mL) and MeOH (10 mL). The mixture was stirred at 40°C for 16h. The mixture was cooled to RT and a 10percent solution of K2C03 was added until the pH of the solution was basic. The aqueous layer was saturated with K2C03 powder and the product was extracted with DCM/MeOH (5percent) (3 times). The combined organic layers were dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 15-40??"?, mobile phase DCM/MeOH/NH3aq 95/5/0.5 to 90/10/0.5) to give 120 mg of compound 1 as a white powder (43percent yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012) EtONa (904 mg; 13.3 mmol) was added to a solution of 2-cyano-imidazole 1-1 (0.7 g; 2.66 mmol) and intermediate C-1 (736 mg; 2.66 mmol) in EtOH (30 ml_). The mixture was stirred at 90°C for 16 h. The solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 45g Merck, mobile phase 97/3/0.1 to 95/5/0.5) to give 0.51 g of the SEM-protected ethoxy intermediate as a lightly yellow solid (38percent yield).HPLC Rt (min) = 7.45 ; MS M+ (H+): 506 method (v2003v2002) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.48 g | Step 1: 9-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 95-1-1 To a stirred solution of 9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.0 g, 6.51 mmol) in 1,2-dichloroethane (65 mL) was added POCl3 (1.21 mL, 13.02 mmol) at RT and the resulting suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and the solvent was evaporated under reduced pressure. The residue was dried under high vacuo at RT. The resulting crude chloro intermediate was dissolved in 1,2-dichloroethane (50 mL), a solution of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (2.11 g, 19.53 mmol) in 1,2-dichloroethane (15 mL) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1percent MeOH in DCM for 5 min, then from 1percent MeOH in DCM to 4percent MeOH in DCM in 25 min, 4percent MeOH in DCM for 5 min) to yield 1.72 g of a redbrown foam. A second flash-column chromatography over silicagel was done (Biotage Isolera Four, eluent: 20percent AcOEt in DCM for 3 min, then from 20percent AcOEt in DCM to 80percent AcOEt in DCM in 25 min, followed by 80percent AcOEt in DCM for 10 min) to yield the title compound as a yellow solid (1.48 g). UPLC-MS: MS 397.1/399.1 (M+H+); UPLC rt 1.00 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11 mg | Step 1: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 107-1 A mixture of 9-iodo-1-methyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (30 mg, 81 mumol) in DCE (2 mL) is treated with POCl3 (15 muL, 0.16 mmol) and heated to 100° C. for 3 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (2 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (31 mg, 0.28 mmol) and pyridine (20 muL, 0.24 mmol) were then added. The mixture was heated to 100° C. for 4.5 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Filtration through a pad of SiO2 (AcOEt) afforded a brown solid that was purified by SFC (column: Diol 5 mum, 250*30 mm, 60A, Princeton; eluent: 13percent MeOH/CO2 for 1 min, then from 13percent MeOH/CO2 to 18percent MeOH/CO2 in 6 min; then from 18percent MeOH/CO2 to 50percent MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (11 mg) as a white powder. UPLC-MS: MS 459.0 (M+H+); UPLC rt 0.98 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42 mg | Step 4: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(isoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one A solution of 9-(isoxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (90 mg, 0.31 mmol) in DCE (4 mL) was treated with POCl3 (57 muL, 0.61 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (4 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (50 mg, 0.46 mmol) and pyridine (74 muL, 0.91 mmol) were then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, cHex/AcOEt 100:0 to 0:100 and DCm/MeOH 99:1 to 90:10) afforded the title compound (42 mg) as a pale red solid. UPLC-MS: MS 386.2 (M+H+); UPLC rt 0.85 min. 1H NMR (400 MHz, CHLOROFORM-d): delta ppm 0.67-0.79 (m, 2H); 0.80-0.91 (m, 2H); 1.80-1.91 (m, 1H); 3.17 (t, J=6.06 Hz, 2H); 3.90 (t, J=6.19 Hz, 2H); 4.37 (s, 2H); 6.47 (s, 1H); 6.63 (s, 1H); 7.18 (s, 1H); 7.50 (t, J=7.83 Hz, 1H); 7.70-7.83 (m, 2H); 7.88 (s, 1H); 8.38 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42 mg | Step 4: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one A mixture of 9-(2-methyloxazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (140 mg, 0.45 mmol) in DCE (10 mL) was treated with POCl3 (84 muL, 0.91 mmol) and heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto cold H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (59 mg, 0.54 mmol) and pyridine (110 muL, 1.36 mmol) were then added. The mixture was heated to 100° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 mum, 250*30 mm, 60A, Princeton; eluent: 10percent MeOH/CO2 for 1 min, then from 10percent MeOH/CO2 to 15percent MeOH/CO2 in 6 min; then from 15percent MeOH/CO2 to 50percent MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (42 mg) as beige powder. UPLC-MS: MS 400.2 (M+H+); UPLC rt 0.86 min. 1H NMR (400 MHz, CHLOROFORM-d): delta ppm 0.61-0.82 (m, 2H); 0.82-0.91 (m, 2H); 1.78-1.96 (m, 1H); 2.56 (s, 3H); 3.16 (t, J=6.02 Hz, 2H); 3.89 (t, J=6.15 Hz, 2H); 4.37 (br. s., 2H); 6.62 (s, 1H); 7.19 (d, J=1.25 Hz, 1H); 7.38-7.48 (m, 1H); 7.63-7.70 (m, 2H); 7.78 (dd, J=7.65, 1.13 Hz, 1H); 7.89 (d, J=1.26 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7 mg | Step 2: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one A mixture of 9-(oxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (180 mg, 0.61 mmol) in DCE (10 mL) was treated with POCl3 (114 muL, 1.22 mmol) and heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto cold H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (79 mg, 0.73 mmol) and pyridine (148 muL, 1.83 mmol) were then added. The mixture was heated to 100° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 mum, 250*30 mm, 60A, Princeton; eluent: 9percent MeOH/CO2 for 1 min, then from 9percent MeOH/CO2 to 14percent MeOH/CO2 in 6 min; then from 14percent MeOH/CO2 to 50percent MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (7 mg) as pale brown solid. UPLC-MS: MS 386.1 (M+H+); UPLC rt 0.79 min. 1H NMR (400 MHz, CHLOROFORM-d): delta ppm 0.78 (m, 2H); 0.81-0.87 (m, 2H); 1.79-1.93 (m, 1H); 3.14 (t, J=6.02 Hz, 2H); 3.94 (t, J=6.15 Hz, 2H); 4.38 (br. s., 2H); 6.66 (s, 1H); 7.20 (s, 1H); 7.30 (s, 1H); 7.42-7.60 (m, 1H); 7.77 (d, J=7.78 Hz, 1H); 7.74 (d, J=8.03 Hz, 1H); 7.90 (s, 1H); 8.03 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
116 mg | Step 2: methyl 2-(4-cyclopropyl-1H-imidazol-1-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate A solution of methyl 2,5-dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate (225 mg, 0.79 mmol) in DCE (20 mL) was treated with POCl3 (0.37 mL, 3.93 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, and then concentrated in vacuo, and dried azeotropically with toluene. The residue obtained was taken up in DCE (40 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (261 mg, 2.41 mmol) were added. The mixture was heated to to 100° C. for 1 h and then allowed to cool to RT, diluted with DCM and washed with a saturated aq, solution of NaHCO3. The org. layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/MeOH 100:0 to 90:10) and crystallization in Et2O/petroleum ether gave the title compound (116 mg). UPLC-MS: MS 377.2 (M+H+); UPLC rt 0.88 min. 1H NMR (600 MHz, DMSO-d6): delta ppm 0.54-0.73 (m, 2H); 0.73-0.88 (m, 2H); 1.74-1.89 (m, 1H); 3.25 (br s, 2H); 3.67-3.82 (m, 2H); 3.88 (s, 3H); 4.25 (br s, 2H); 7.13 (s, 1H); 7.44 (s, 1H); 7.48-7.57 (m, 1H); 7.96 (d, J=7.65 Hz, 1H); 8.09 (s, 1H); 8.19 (d, J=7.91, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21 mg | Step 2: 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2H-1,2,3-triazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one To a stirred solution of 9-(2H-1,2,3-triazol-2-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (97 mg, 0.328 mmol) in 1,2-dichloroethane (3 mL) was added POCl3 (0.061 mL, 0.657 mmol) at rt and the resulting suspension was stirred at 100° C. for 35 min. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and the solvent was evaporated under reduced pressure. The residue was dried under high vacuo at rt. The resulting crude chloro intermediate was dissolved in 1,2-dichloroethane (3 mL), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (107 mg, 0.985 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: pure DCM for 3 min, then from 0percent MeOH in DCM to 5percent MeOH in DCM in 14 min, 5percent MeOH in DCM for 3 min) to yield a yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.48 g | In 1,2-dichloro-ethane; at 100℃; for 2h; | To a stirred solution of 9-bromo-3,4,7,8-tetrahydro- [1 ,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.0 g, 6.51 mmol) in 1 ,2-dichioroethane (65 mL) was added POCI3 (1 .21 mL, 13.02 mmol) at RT and the resulting suspension was stirred at 100°C for 1h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCI3 the residue was taken up in toluene and the solvent was evaporated under reduced pressure. The residue was dried under high vacuo at RT. The resulting crude chloro intermediate was dissolved in 1 ,2-dichloroethane (50 mL), a solution of 4-cyclopropyl-lH-imidazole (2.11 g, 19.53 mmol) in 1 ,2-dichloroethane (15 mL) was added and the mixture was stirred at 100°C for 2h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHC03 solution was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, euent 1 percent MeOH in DCM for 5 min, then from 1percent MeOH in DCM to 4percent MeOH in DCM in 25 min, 4percent MeOH in DCM for 5 min) to yield 1.72 g of a redbrown foam. A second flash-column chromatography over silicagel was done (Biotage Isolera Four, euent: 20percent AcOEt in DCM for 3 min, then from 20percent AcOEt in DCM to 80percent AcOEt in DCM in 25 min, followed by 80percent AcOEt in DCM for 10 min) to yield the title compound as a yellow solid (1.48 g). UPLC-MS: MS 397.1 /399.1 (M+H*); UPLC rt 1.00 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42 mg | With pyridine; In 1,2-dichloro-ethane; at 110℃; for 1h; | A solution of 9-(isoxazol-5-yl)- 3,4,7,8-tetrahydro-[1 ,4]diazepino[7,1-a]isoquinoline-2,5-dione (90 mg, 0.31 mmol) in DCE (4 mL) was treated with POCI3 (57 mu, 0,61 mmol) and the mixture was heated to 100 °C for 1 h. The mixture was then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. phases were then dried over Na2S04, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (4 mL) and 4-cyclopropyl-1 H-imidazole (50 mg, 0.46 mmol) and pyridine (74 , 0.91 mmol) were then added. The mixture was heated to 110 °C for 1 h, and then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. layers were then dried over Na2SO,, filtered and concentrated in vacuo. Purification by flash chromatography (Si02, cHex AcOEt 100:0 to 0:100 and DCm/MeOH 99: 1 to 90:10) afforded the title compound (42 mg) as a pale red solid. UPLC-MS: MS 386.2 (M+H*); UPLC rt 0.85 min. 1H NMR (400 MHz, CHL OROFORM-d) : delta ppm 0.67 - 0.79 (m, 2 H); 0.80 - 0.91 (m, 2 H); 1.80 - 1.91 (m, 1 H); 3.17 (t, J=6.06 Hz, 2 H); 3.90 (t, J=6.19 Hz, 2H); 4.37 (s, 2 H); 6.47 (s, 1 H); 6.63 (s, 1 H); 7.18 (s, 1 H); 7.50 (t, J=7.83 Hz, 1 H); 7.70 - 7.83 (m, 2 H); 7.88 (s, 1 H); 8.38 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11 mg | With pyridine; In 1,2-dichloro-ethane; at 100℃; for 4.5h; | A mixture of 9-iodo-1-methyl-3,4,7,8- tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (30 mg, 81 muGammaetaomicronIota) in DCE (2 mL) is treated with POCI3 (15 mu, 0.16 mmol) and heated to 100 °C for 3 h. The mixture was then allowed to cool to RT, poured onto H20 and extracted with DCM, The org. phases were dried over Na2S0 , filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (2 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (31 mg, 0.28 mmol) and pyridine (20 mu, 0.24 mmol) were then added. The mixture was heated to 100 °C for 4.5 h, and then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. layers were then dried over Na2S04, filtered and concentrated in vacuo. Filtration through a pad of Si02 (AcOEt) afforded a brown solid that was purified by SFC (column: Diol 5 muiotaeta, 250 x 30 mm, 60A, Princeton; euent: 13percent MeOH/C02 for 1 min, then from 13percent MeOH/C02 to 18percent MeOH/C02 in 6 min; then from 18percent MeOH/C02 to 50percent MeOH/C02 in 1 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (11 mg) as a white powder. UPLC-MS: MS 459.0 (M+hf ); UPLC rt 0.98 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In 1,2-dichloro-ethane; at 100℃; for 1h; | General procedure: A mixture of 9-(2-methyloxazol- 4-yl)-3,4,7,8-tetrahydro-[1 ,4]diazepino[7,1-a]isoquinoline-2,5-dione (140 mg, 0.45 mmol) in DCE (10 mL) was treated with POCI3 (84 mu, 0.91 mmol) and heated to 100 °C for 1 h. The mixture was then allowed to cool to RT, poured onto cold H20 and extracted with DCM. The org. phases were dried over Na2SO,, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (59 mg, 0.54 mmol) and pyridine (110 mu, 1.36 mmol) were then added. The mixture was heated to 100 DC for 1 h, and then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. layers were then dried over Na2S04. filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 muetaiota, 250 x 30 mm, 60A, Princeton; eluent: 10percent MeOH/C02 for 1 min, then from 10percent MeOH/C02 to 15percent MeOH/C02 in 6 min; then from 15percent MeOH/C02 to 50percent MeOH/C02 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (42 mg) as beige powder. UPLC-MS: MS 400.2 (M+H+); UPLC rt 0.86 min. 1H NMR (400 MHz, CHLOROFORM- : delta ppm 0.61 - 0.82 (m, 2 H); 0.82 - 0.91 (mr 2 H); 1.78 - 1.96 (m, 1 H); 2.56 (s, 3 H); 3.16 (t, J=6.02 Hz, 2 H); 3.89 (t, J=6.15 Hz, 2 H); 4.37 (br. s., 2 H); 6.62 (s, 1 H); 7.19 (d, J=1.25 Hz, 1 H); 7.38 - 7.48 (m, 1 H); 7.63 - 7.70 (m, 2 H); 7.78 (dd, J=7.65, .13 Hz, 1 H); 7.89 (d, J=1.26 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7 mg | With pyridine; In 1,2-dichloro-ethane; at 100℃; for 1h; | A mixture of 9-(oxazol-5-yl)-3,4,7,8-tetrahydro-[1 ,4]diazepino[7,1-a]isoquinoline-2,5-dione (180 mg, 0.61 mmol) in DCE (10 mL) was treated with POCI3 (114 muIota_, 1 .22 mmol) and heated to 100 °C for 1 h. The mixture was then allowed to cool to RT, poured onto cold H20 and extracted with DCM. The org. phases were dried over Na2S04, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and 4-cyclopropyH H-imidazole (79 mg, 0.73 mmol) and pyridine (148 muIota_, 1.83 mmol) were then added. The mixture was heated to 100 °C for 1 h, and then allowed to cool to RT, poured onto H20 and extracted with DCM. The org. layers were then dried over filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 mueta, 250 x 30 mm, 60A, Princeton; eluent: 9percent MeOH/C02 for 1 min, then from 9percent MeOH/C02 to 14percent MeOH/C02 in 6 min; then from 14percent MeOH/C02 to 50percent MeOH/C02 in 1 min; flow 100 mL min; UV detection at 220 nm) afforded the title compound (7 mg) as pale brown solid. UPLC-MS: MS 386.1 (M+Hf); UPLC rt 0.79 min. H NMR (400 MHz, CHLOROFORM-d): 8 ppm 0.78 (m, 2 H); 0.81 - 0.87 (m, 2 H); 1.79 - 1.93 (m, 1 H); 3.14 (t, J=6.02 Hz, 2 H); 3.94 (t, J=6.15 Hz, 2 H); 4.38 (br. s., 2 H); 6.66 (s, 1 H); 7.20 (s, 1 H); 7.30 (s, 1 H); 7.42 - 7.60 (m, 1 H); 7.77 (d, J=7.78 Hz, 1 H); 7.74 (d, J=8.03 Hz, 1 H); 7.90 (s, 1 H); 8.03 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
116 mg | In 1,2-dichloro-ethane; at 100℃; for 1h; | A solution of methyl 2,5- dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate (225 mg, 0.79 mmol) in DCE (20 mL) was treated with POCI3 (0.37 mL, 3.93 mmol) and the mixture was heated to 100 °C for 1 h. The mixture was then allowed to cool to RT, and then concentrated in vacuo, and dried azeotropically with toluene. The residue obtained was taken up in DCE (40 mL) and <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (261 mg, 2.41 mmol) were added. The mixture was heated to to 100 °C for 1h and then allowed to cool to RT, diluted with DCM and washed with a saturated aq, solution of NaHC03. The org. layer was dried over Na2S04, filtered and concentrated in vacuo. Purification by flash chromatography (Si02, AcOEt MeOH 100. to 90: 10) and crystallization in Et20/petroleum ether gave the title compound (116 mg). UPLC- MS: MS 377.2 (M+H+); UPLC rt 0.88 min. 1H NMR (600 MHz, DMSO-c/6): delta ppm 0.54-0.73 (m, 2H); 0.73-0.88 (m, 2H); 1.74-1.89 (m, 1 H); 3.25 (br s, 2H); 3.67-3.82 (m, 2H); 3.88 (s, 3H); 4.25 (br s, 2H); 7.13 (s, 1H); 7.44 (s, 1H); 7.48-7.57 (m, 1H); 7.96 (d, J=7.65 Hz, 1H); 8.09 (s, 1H); 8.19 (d, J=7.91 , 1H). |
Yield | Reaction Conditions | Operation in experiment |
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21 mg | In 1,2-dichloro-ethane; at 100℃; for 2h; | To a stirred solution of 9-(2H- 1 ,2,3-triazol-2-y)-3,4,7,8-tetrahydro-[1 ,4]diazepino[7,1-a]isoquinoine-2,5-dione (97 mg, 0.328 mmol) in 1 ,2-dichloroethane (3 mL) was added POCI3 (0.061 mL, 0.657 mmol) at rt and the resulting suspension was stirred at 100°C for 35 min. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCI3 the residue was taken up in toluene and the solvent was evaporated under reduced pressure. The residue was dried under high vacuo at rt. The resulting crude choro intermediate was dissolved in 1 ,2-dichloroethane (3 ml_), 4- cyclopropyl-1 H-imidazole (107 mg, 0.985 mmol) was added and the mixture was stirred at 100°C for 2h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHC03 solution was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: pure DCM for 3 min, then from 0percent MeOH in DCM to 5percent MeOH in DCM in 14 min, 5percent MeOH in DCM for 3 min) to yield a yellow foam. Further purification by SFC (column: 2-Ethylpyridine 5 mutauiota, 250 x 30 mm, 60A, Princeton; eluent: 8percent MeOH/C02 for 1 min, then from 8percent MeOH/C02 to 13percent MeOH/C02 in 6 min ; flow 100 ml_ min ; U V detection at 220 n m) gave the title compound as slightly yellow foam (21 mg). UPLC-MS: MS 386.2 (M+hT); UPLC rt 0.86 min. 1H NMR (400 MHz, DMSO-d6) delta ppm 0.58 - 0.70 (m, 2 H), 0.74 - 0.82 (m, 2 H), 1.74 - 1.86 (m, 1 H), 2.91 (t, J=5.75 Hz, 2 H), 3.75 (t, J=5.&7 Hz, 2 H), 4.25 (s, 2 H), 7.22 (s, 1 H), 7.43 (s, 1 H), 7.54 - 7.63 (m, 1 H), 7.76 (d, J=8.80 Hz, 1 H), 8.10 (s, 1 H), 8.14 - 8.21 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With copper(I) oxide; 8-quinolinol; caesium carbonate; at 65℃; for 16h; | A mixture of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (1.95 g, 18.1 mmol), 2-chloro-5-fluoro-4- iodopyridine (3.1 g, 12.0 mmol), Cu20 (105 mg, 0.6 mmol), 8-hydroxyquinoline (353 mg,2.4 mmol), and C52CO3 (11.7 g, 36 mmol) in butyronitrile (100 mL) was stirred at 65C for16 h. After cooling down to room temperature, 100 mL of water was added and the resulting mixture was extracted with EtOAc (100 mL x2). The organic layer was dried over Na2504, filtered, and evaporated. The residue was purified by silica gel column chromatography with PE/EtOAc (3:1) to afford 1.7 g (57%) of 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine as white solid. |
42% | With copper(I) oxide; 8-quinolinol; propyl cyanide; caesium carbonate; at 65℃; for 16h;Inert atmosphere; | A suspension 2-chloro-5-fluoro-4-iodopyridine (1.8 g, 1.00 mmol), <strong>[89830-98-8]4-cyclopropyl imidazole</strong> (982 mg, 9.10 mmol), Cu2O (100 mg, 0.700 mmol), 8-hydroxyquinoline (152 mg, 1.05 mmol), cesium carbonate (4.60 g, 14.0 mmol), and PEG-3350 (1.4 g) in butyronitrile (50 mL) was heated at 65 C. for 16 hours. The reaction mixture was filtered through Celite, concentrated and the residue was partitioned between dichlormethane and water. The layers were separated and the aqueous layer washed twice with dichloromethane. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (15?60% EtOAc in hexanes) to afford 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (702 mg, 42% yield). |
21% | With copper(l) iodide; 2-methyl-8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 90℃;Inert atmosphere; | To a flask were added 2-chloro-5-fluoro-4-iodopyridine (23.0 g, 89.3 mmol), <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (29.0 g, 268 mmol), potassium carbonate (30.8 g, 223 mmol), cuprous iodide (340 mg, 1.79 mmol), 8-hydroxyquinaldine (569 mg, 3.57 mmol) and dimethylsulfoxide (80 mL) under nitrogen. The mixture was heated to 90 C and stirred overnight. The resulting mixture was cooled to rt naturally and quenched with water (100 mL) and then extracted with EtOAc (200 mL x 2). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCMIEtOAc (V/V) = 10/1-5/1) to give the title compound as a yellow solid (4.50 g, 2 1%).?HNIVIR(400MH4 CDCl3)8.40(d,J=2.7H4 1H), 7.92 (s, 1H), 7.38 (d,J= 5.4 H4 1H), 7.11 (s, 1H), 1.96-1.82 (m, 1H), 0.96 - 0.87 (m, 2H), 0.86- 0.80 (m, 2H?). |
With copper(I) oxide; 8-quinolinol; caesium carbonate; at 65℃; for 16h;Inert atmosphere; | Step 1: Preparation of 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine A suspension 2-chloro-5-fluoro-4-iodopyridine (1.8 g, 1.00 mmol), <strong>[89830-98-8]4-cyclopropyl imidazole</strong> (982 mg, 9.10 mmol), Cu2O (100 mg, 0.700 mmol), 8-hydroxyquinoline (152 mg, 1.05 mmol), cesium carbonate (4.60 g, 14.0 mmol), and PEG-3350 (1.4 g) in butyronitrile (50 mL) was heated at 65 C. for 16 hours. The reaction mixture was filtered through Celite, concentrated and the residue was partitioned between dichlormethane and water. The layers were separated and the aqueous layer washed twice with dichloromethane. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (15?60% EtOAc in hexanes) to afford 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine. | |
With copper(I) oxide; 8-quinolinol; caesium carbonate; at 70℃; for 16h;Inert atmosphere; | 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (19a) To a mixture of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (1.4 g, 12.95 mmol) and 2-chloro-5-fluoro-4-iodopyridine (3.50 g, 13.59 mmol) in butyronitrile (210 mL) was added Cu2O (185.25 mg, 1.29 mmol), 8-hydroxyquinoline (281.88 mg, 1.94 mmol), Cs2CO3 (8.44 g, 25.89 mmol) and PEG-3350 (1.09 g, 12.95 mmol) at 20 C. under N2. The mixture was stirred at 20 C. for 10 min, then heated to 70 C. and stirred for 16 hours. LCMS showed one new peak with desired MS. The mixture was cooled to 25 C. and filtered and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and H2O (40 mL) was added, the mixture was extracted with DCM (30 mL*3). The combined organic layers were washed with brine (20 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=100:1 to 30:1) to give 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (19a). 1H NMR (400 MHz, CHLOROFORM-d) delta 8.41 (d, J=2.7 Hz, 1H), 7.90 (s, 1H), 7.37 (d, J=5.4 Hz, 1H), 7.10 (s, 1H), 1.95-1.86 (m, 1H), 0.95-0.89 (m, 2H), 0.87-0.81 (m, 2H). |