Structure of 6000-50-6
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Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
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CAS No. : | 6000-50-6 |
Formula : | C7H10Cl2N2 |
M.W : | 193.07 |
SMILES Code : | C1(CNC2)=C2C=CN=C1.[H]Cl.[H]Cl |
MDL No. : | MFCD15144657 |
InChI Key : | GXQCGPVEDZFCGW-UHFFFAOYSA-N |
Pubchem ID : | 18953644 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.29 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 52.7 |
TPSA ? Topological Polar Surface Area: Calculated from | 24.92 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.39 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.6 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 0.87 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 1.79 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.13 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.32 |
Solubility | 0.932 mg/ml ; 0.00483 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -1.52 |
Solubility | 5.87 mg/ml ; 0.0304 mol/l |
Class? Solubility class: Log S scale | Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -2.58 |
Solubility | 0.51 mg/ml ; 0.00264 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) | Yes |
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) | Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -6.49 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) | 1.52 |
* 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 |
---|---|---|
With hydrogenchloride; In acetone; | d) 2,3-Dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride 10.4 g (51 mmol) of ethyl 2,3-dihydro-1H-pyrrolo-[3,4-c]pyridine-2-carboxylate are refluxed for 15 hours together with 100 ml of concentrated hydrochloric acid. The batch is evaporated, and the crystalline residue is stirred with acetone. The product is filtered off with suction and dried in the air. Yield: 9.8 g (100percent of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g | Step 8. tert-Butyl S)-1-[^[1H.2H.3H-pyrrolof3.4-c]pyridin-2- yl]carbonyl)amino]methyl]-6-azaspiro[2.51octane-6-carboxylate. A solution of tert- butyl (1 S)-l -(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (5 g, 20.80 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (4.4 g, 21.83 mmol, 105 equiv) and D1PEA (10 mL) in THF (200 mL) was stirred overnight at rt. 1 H,2H,3H-Pyrrolof3,4- c]pyndine dihydrochloride (44 g, 2279 mmol, 9.24 equiv) was then added and the reaction mixture was stirred overnight at rt The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (20/1 ) to give 2.3 g of tert-butyl (lS)-l-[[([lH,2H,3H-pyrrolo[3,4- c]pyndin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate as a light yellow solid TLC: DCM MeOH =10:1, R, = 0.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; | A mixture ofN-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (100 mg, 0.41 mmol), <strong>[6000-50-6]2,3-dihydro-1H-pyrrolo[3,4-c]pyridine dihydrogen chloride</strong> (102 mg, 0.53 mmol), diisopropylethylamine (0.74 mL, 1.22 mmol) in DMF (0.81 mL) was stirred at 110 °C overnight. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The organic layer was concentrated and purified by chromatography with 0-20percent MeOH in DCM to provide the title compound (13 mg, 10percent) as a slightly yellow solid. ?H NMR (300 MHz, DMSO-d6) oe 12.95 (s, 1H), 9.29 (s, 1H), 8.69 (s, 1H), 8.52 (d, J = 5.0 F{z, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, J= 5.7 F{z, 1H), 7.61?7.46 (m, 3H), 6.11 (d, J= 5.8 F{z, 1H), 4.88 (s, 4H). MS (ES+) m?e 330 (M+H). |
10% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; | Example 195 N-(2-(lH-pyrrolo[3,4-c]pyridin-2(3H)-yl)pyrimidin-4-yl)-lH-indazol-5-amine A mixture of N-(2-chloropyrimidin-4-yl)-lH-indazol-5 -amine (100 mg, 0.41 mmol), 2,3-dihydro-lH-pyrrolo[3,4-c]pyridine dihydrogen chloride (102 mg, 0.53 mmol), diisopropylethylamine (0.74 mL, 1.22 mmol) in DMF (0.81 mL) was stirred at 110 °C overnight. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The organic layer was concentrated and purified by chromatography with 0-20percent MeOH in DCM to provide the title compound (13 mg, 10percent>) as a slightly yellow solid. 1H NMR (300 MHz, DMSO-de) delta 12.95 (s, 1H), 9.29 (s, 1H), 8.69 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, J = 5.7 Hz, 1H), 7.61 - 7.46 (m, 3H), 6.11 (d, J = 5.8 Hz, 1H), 4.88 (s, 4H). MS (ES+) m/e 330 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; In dichloromethane; at 20℃; for 2h; | A solution of 2,3-dihydro-lH-pyrrolo[3,4-c]pyridine dihydrochloride (1.0 g, 5.2 mmol) and Et N (1.1 g, 10.9 mmol) in DCM (50 mL) was treated with slow addition of Boc20 (1.2 g, 5.5 mmol). The mixture was stirred at room temperature for 2h, concentrated in rotary evaporator and the residue was purified by column chromatography over silicagel (petroleum ether/EtOAc = 1/1) to give tert-butyl lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (0.9 g, 78 percent yield). ESI- LCMS (m/z): 221.1 found for [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a solution of SM-1 (1.08 g, 5.0 mmol), TEA (3.03 g, 30.0 mmol) in DCM (20 mL) was added triphosgene (1.49 g, 5.0 mmol) under ice bath. The solution was warmed to room temperature and stirred for 1 h. TEA (2.02 g, 20.0 mmol) and SM-0 (965 mg, 5.0 mmol) was then added. The resulting solution was heated at 50 °C for 1 h. After cooling to room temperature, the solution was diluted with DCM. The resultant was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1~ 30 : 1) to give 130-1 (900 mg, 50 percent) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | To a solution of 102-1 (215 mg, 1.0 mmol), trimethylamine (TEA; 810 mg, 8.0 mmol) in dichloromethane (DCM; 10 mL) was added triphosgene (330 mg, 1.1 mmol) at ice bath. The mixture as warmed to room temperature and stirred for 3 h. TEA (202 mg, 2.0 mmol) and SM0 (230 mg, 1.2 mmol) was then added. The resulting solution was heated at 50 °C for 2 h. The mixture was cooled and diluted with DCM. The resultant was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 35 : 1) to give 102-2 (140 mg, 39 percent) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | To a solution of 103-2 (220 mg, 1.0 mmol), TEA (810 mg, 8.0 mmol) in DCM (10 mL) was added triphosgene (330 mg, 1.1 mmol) under ice bath. The solution was warmed to room temperature and stirred for 3 hrs. TEA (202 mg, 2.0 mmol) and SM-0 (230 mg, 1.2 mmol) was then added. The resulting solution was heated at 50 0 C for 2 h. The mixture was cooled and diluted with DCM. The resultant was washed with brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1~ 30 : 1) to give 103-3 (120 mg, 33 percent) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of Intermediate 97 (289 mg, 1.01 minol, 1 .00 eq) in DCM (12 mL) was treated with 8 mL of an aqueous buffer solution (pH 7). The 2-phase system was stirred for 10 min at roomtemperature. Subsequently 4-nitrophenyl chloroformate (243 mg, 1.21 minol, 1.20 eq) was added and the mixture was stirred at 40 00 for 12 h. The organic layer was separated, dried over Na2504 and the volume was reduced. To this solution a mixture of 2,3-dihydro-I H-pyrrolo[3,4- c]pyridine dihydrochloride (233 mg, 1.21 minol, 1.20 eq) and 3.00 eq DIPEA in DCM II4Owas added. The reaction mixture was stirred over night at room temperature. The reaction mixturewas diluted with DCM and three times extracted with IM aqueous NaOH. The organic layer was dried over Na2504 and the solvent was removed under reduced pressure. After trituration with diethyl ether 275 mg of the desired product were obtained (63percent).1H-NMR (500MHz, DMSO-d6): 6 [ppm] = 1.05 (d, 3H), 1.47 - 1.59 (m, 2H), 1.86 (qd, IH), 2.09(qd, I H), 2.33 (d, I H), 2.72 (dd, I H), 3.35 - 3.48 (m, 3H), 3.86 - 4.02 (m, 2H), 4.75 (tt, I H), 4.83(br d, 4H), 7.44 (d, I H), 7.68 (d, 2H), 7.74 - 7.80 (m, 2H), 8.51 (d, I H), 8.58 - 8.68 (m, 2H).UPLC-MS (Method 2): R = 0.70 min. MS (ESipos): mz [M÷H] 434.Optical rotation (Method 5): [a] = 3Q50 (c = 1.00, DMSO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of Intermediate 103 (4.07 g, 10.5 minol) in THE (45 mL) was added at r.t. 4- nitrophenylchloroformate (2.11 g, 10.5 minol). After heating to 6000 for 3 h the reaction mixture was concentrated under reduced pressure and the residue taken up in dichloromethane(40 mL). To the solution was added at r.t. N,N-diisopropylamine (4.28 mL, 24.6 minol) and 2,3- dihydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride (1.53 g, 7.93 minol). After stirring for 20 h at this temperature further N,N-diisopropylamine (1 .50 mL) and THE (25 mL) was added. After 30 min stirring at r.t. the reaction mixture was heated to 60°C. After cooling to r.t. the reaction mixture was poured on water and aq. I N NaOH was added. After separation of the organicphase the aqueous phase was extracted 2 x with dichloromethane and the combined organic extracts were washed with brine and filtered through a phase separator filter. After removal of the solvent the crude product was purified by comumn chromatography (silica gel, ethyl acetate/ethanol gradient) to give the title compound (1.72 g, 75percent purity, 2.54 minol, 32percent).LC-MS (Method 6): Rt = 1.27 min; MS (ESIpos): m/z = 508 [M÷H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solution Intermediate 106 (500 mg, 1.34 minol) in THE (15 mL) was added at r.t. 4- nitrophenylchloroformate (270 mg, 1.34 minol) and the mixture stirred for 14 h at that temperature. After concentrating the mixture under reduced pressure the residue was taken upin dichloromethane (40 mL) and N,N-diisopropylethyl amine (0.78 mL, 4.4 minol) and 2,3- dihydro-1 H-pyrrolo[3,4-c]pyridine dihydrochloride (274 mg, 1 .42 minol) were added. The reaction mixture was heated to 6000 for 4h and then poured on water. After basification of the mixture with I N aqueous sodium hydroxide solution the mixture was extracted with dichloromethane (2x). The combined organic extracts were washed with brine and filtered through a phaseseparator filter. The residue on the filter was dried at 50°C under vacuum to give the titlecompound (446 mg, 1.03 minol, 72percent).1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 8.77 (s, IH), 8.71 (s, IH), 8.65 (d, IH), 7.76-7.64 (m,5H), 4.95-4.86 (m, 4H), 3.80 (br t, 2H), 3.60 (t, 2H), 2.84 (s, 2H), 1.09 (s, 6H).LC-MS (Method 6): Rt = 0.79 min; MS (ESIpos): mz = 408 [M÷H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a solution of Intermediate 108 (200 mg, 0.51 minol) in THE (5 mL) was added at r.t. 4- nitrophenylchloroformate (103 mg, 0.51 minol) and the mixture was heated to 6000 for 3 h. After cooling to r.t. the mixture was concentrated under reduced pressure and taken up indichloromethane (5 mL). To this mixture was added at r.t. N,N-diisopropylethylamine (0.27 mL,1.56 minol) and 2,3-dihydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride (97.0 mg, 0.50 minol) and the mixture stirred for 20 h at that temperature. After that more N,N-diisopropylethylamine (1.5 mL) and THE (25 mL) was added and the mixture was stirred for 30 min at r.t. and then heated to 60°C. After cooling to r.t. the mixture was poured on water, basified with aqueous I N NaOHand extracted with dichloromethane (2 x). The combined organic extracts were washed with brine and filtered through a silicone filter. Removal of the solvent gave the crude product which was purified by column chromatography (silica gel, hexane/ethyl acetate gradient) to give the title compound (183 mg, 0.34 minol, 68percent).1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 8.62 (s, IH), 8.59 (s, IH), 8.51 (d, IH), 7.82 (ddd, 4H),7.54-7.48 (m, 2H), 7.45 (d, I H), 7.41-7.37 (m, 2H), 4.82 (br d, 4H), 4.04-3.98 (m, 2H), 3.91-3.86 (m, 2H), 2.73 (s, 2H), 0.98 (s, 6H).LC-MS (Method 1): R = 0.90 min; MS (ESIpos): mz = 537 [M÷H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a solution of Intermediate 9, 60 mg (0.22 minol), and 4-dimethylaminopyridine, 32 mg (0.26 minol), in tetrahydrofuran, 25 mL, was added N,N-disuccinimidyl carbonate, 67.9 mg, (0.26 minol). The reaction was stirred for 1 hour then triethylamine, 0.092 mL (0.66 minol), and 2,3-dihydro-IH-pyrrolo[3,4-c]pyridine hydrochloride (6000-50-6), 41.3 mg (0.26 minol), was added and the reaction was left to stir at room temperature for 18 hours. Water was added and the mixture was extracted with dichloromethane. The combined organics were dried over solid sodium sulfate and concentrated under vacuum. Purification by flash chromatography on silica gel 60 (eluent: ethyl acetate-heptane 0:1, 1:1, 1:0 and methanol-ethyl acetate 1:9) gave thedesired product, 62.8 mg (68percent).1H NMR (300 MHz, CDCI3): 6 [ppm] = 1.16 (d, 3H), 1.57-2.00 (m, 8H), 2.46 (d, IH), 2.64 (dd, IH), 3.27 (m, IH), 4.90 (d, 4H), 5.21 (m, IH), 6.40 (s, IH), 7.30 (d, IH), 7.52 (d, 2H), 7.76 (d, 2H), 8.58 (d, IH), 8.63 (s, IH).UPLC-MS (Method 4): R 1.93 min., 100percent. MS (ESIpos): mz[M+H]418. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | A solution of 100mg of Intermediate 11(0.35 minol, 1.00 eq) in DMF (10 mL) was treated with108 mg of N,N?-disuccinimidyl carbonate (0.42 minol, 1.20 eq) and 51.4 mg of 4-dimethylaminopyridine (0.42 minol, 1.20 eq) and was left over night at room temperature. Asuspension of 81 .2 mg of 2,3-dihydro-1 H-pyrrolo[3,4-c]pyridine dihydrochloride (0.42 minol, 1 .20eq) and 667 pL of triethylamine (4.78 minol, 3.60 eq) in DMF (5 mL) was added. The reactionmixture was left for 3 days at room temperature. The mixture was poured into water. The aqueous phase was three times extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2504 and the solved was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC to yield the desired productExample 11(30 mg, 20percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.09 (d, 3H), 2.40-2.47 (m, IH), 2.79-2.87 (m, IH),3.42-3.54 (m, IH), 4.26-4.38 (m, IH), 4.37-4.37 (m, IH), 4.80-4.83 (m, 4H), 7.41 -7.47 (m, I H), 7.65 - 7.72 (m, 2H), 7.72 - 7.79 (m, 2H), 8.50 (d, I H), 8.61 (s, I H), 8.66 (s, I H).U PLC-MS (Method 2): R= 0.81 min; MS (ESipos): mz [M÷H] 432. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | A solution of 177 mg of Intermediate 14 (0.31 minol, 50percent purity 1.00 eq) in DMF (19 mL) wastreated with 94.7 mg of N,N?-disuccinimidyl carbonate (0.37 minol, 1.20 eq) and 45.2 mg, of 4-dimethylaminopyridine (0.37 minol, 1.20 eq). The mixture was left over night at room temperature. A suspension of 71.4 mg of 2,3-dihydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride (0.37 minol, 1.20 eq) and 155 pL of triethylamine (1.11 minol, 3.60 eq) on DMF (3 mL) wasadded. The reaction mixture was stirred 3 days at room temperature. The mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The aqueous and the organic phase were evaporated under reduced pressure. Both residues were purified by preparative HPLC to yield in total 15.0mg of the desired product Example 21(0.03 minol, 11percent).1H-NMR (400MHz, DMSO-d6): oe [ppm]= 1.05 (d, 3H), 1.49- 1.61 (m, 2H), 1.80- 1.93 (m, IH),2.02 - 2.16 (m, I H), 2.29 - 2.37 (m, I H), 2.68 - 2.76 (m, I H), 3.88 - 3.99 (m, 2H), 4.70 - 4.80 (m,IH), 4.91 (d, 4H), 7.64 - 7.71 (m, 3H), 7.74 - 7.79 (m, 2H), 8.64 (d, IH), 8.72 (s, IH), 8.76 (s,I H). Three protons are not visible.U PLC-MS (Method 2): R 0.71 min; MS (ESIpos): mz [M÷H] 434. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | A solution of 100 mg of Intermediate 23(0.36 minol, 1.00 eq) in DMF (11 mL) was treated with110 mg of N,N?-disuccinimidyl carbonate (0.43 minol, 1.20 eq) and 53.4 mg of 4-dimethylaminopyrdine (0.44 minol, 1.20 eq). The mixture was stirred over night at roomtemperature. A solution of 82.9 mg of 2,3-dihydro-1 H-pyrrolo[3,4-c]pyridine dihydrochloride (0.43minol, 1 .20 eq) and 2.99 mL of triethylamine (21.47 minol, 30 eq) in DMF (2 mL) was added. The mixture was stirred over night. THE was removed from under reduced pressure. The remaining solution was poured into water. The solid was removed by filtration, the filtrate was taken to dryness and the residue was purified by preparative reverse phase HPLC to yield 35.0mg of the desired product (21percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07 (d, 3H), 2.17 (s, 6H), 2.22-2.36 (m, IH), 2.40-2.48 (m, 2H), 2.64 - 2.70 (m, I H), 3.37 - 3.44 (m, I H), 3.59 - 3.75 (m, I H), 3.91 - 4.08 (m, I H),4.83 (d, 4H), 7.44 (d, IH), 7.63 - 7.71 (m, 2H), 7.71 - 7.79 (m, 2H), 8.50 (d, IH), 8.65 (s, IH),8.61 (s, IH).UPLC-MS (Method 1): R0.83 min; MS (ESIpos): mz[M+H]426. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | A solution of 100mg of Intermediate 24 (0.36 minol, 1.00 eq) in DMF (11 mL) was treated with112 mg of N,N?-disuccinimidyl carbonate (0.44 minol, 1.20 eq) and 53.4 mg of 4-dimethylaminopyrdine (0.44 minol, 1.20 eq). The mixture was stirred over night at roomtemperature. A solution of 84.4 mg of 2,3-dihydro-1 H-pyrrolo[3,4-c]pyridine dihydrochloride (0.44minol, 1 .20 eq) and 3.05 mL of triethylamine (21.87 minol, 30 eq) in DMF (2 mL) was added. The mixture was stirred over night. THE was removed from under reduced pressure. The remaining solution was poured into water. The solid was removed by filtration, the filtrate was taken to dryness and the residue was purified by preparative reverse phase HPLC to yield 20.0mg of the desired product (13percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07 (d, 3H), 2.17 (s, 6H), 2.22-2.36 (m, IH), 2.40-2.48 (m, 2H), 2.64 - 2.70 (m, I H), 3.37 - 3.44 (m, I H), 3.59 - 3.75 (m, I H), 3.91 - 4.08 (m, I H),4.83 (d, 4H), 7.44 (d, IH), 7.63 - 7.71 (m, 2H), 7.71 - 7.79 (m, 2H), 8.50 (d, IH), 8.65 (s, IH),8.61 (s, IH).UPLC-MS (Method 1): R0.47 min; MS (ESIpos): mz[M+2H]421 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | A solution of 200 mg of Intermediate 25 (0.56 minol, 1.00 eq) in DMF (8 mL) was treated with171 mg of N,N?-disuccinimidyl carbonate (0.67 minol, 1.20 eq) and 82.0 mg of 4- dimethylaminopyrdine (0.67 minol, 1.20 eq). The mixture was stirred for 3 days at room temperature. A suspension of 129 mg of 2,3-dihydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride (0.67 minol, 1.20 eq) and 279 pL of triethylamine (2.00 minol, 3.6 eq) in DMF (2 mL) was added. The mixture was stirred over night. The resulting suspension was filtered, the solid was removedand the filtrate was taken to dryness. The residue was purified by reverse phase preparative HPLC to yield 34.0mg of the desired product (12percent).1H-NMR (400MHz, DMSO-d6): oe [ppm]= 1.04 (d, 3H), 2.30 -2.40 (m, IH), 2.75 -2.86 (m, IH),3.38-3.48 (m, IH), 4.78 -4.87 (m, 5H), 4.99 (s, IH), 7.00- 7.22 (m, 3H), 7.34 -7.40 (m, 2H),7.44 (d, I H), 7.62 - 7.68 (m, 2H), 7.69 - 7.75 (m, 2H), 8.50 (d, I H), 8.63 (d, 2H).UPLC-MS (Method 2): Rt0.92 min; MS (ESIpos): mz [M÷H] 506. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.5% | A solution of 100.0 mg of 4-(4-aminophenyl)-2-methylphthalazin-1(2H)-one (by S. Demirayak etal. in Eur. J. Med. Chem. 2004, 39, 1089?1095, 0.42 minol, 1.00 eq) in DMF (12 mL) wastreated with 129.6mg of N,N?-disuccinimidyl carbonate (0.51 minol, 1.20 eq) and 61.8mg of 4-dimethylaminopyridine (0.51 minol, 1.20 eq). The mixture was left of night at room temperature.A suspension of 97.7 mg of 2,3-dihydro-1 H-pyrrolo[3,4-c]pyridine dihydrochloride (0.51 minol,1.20 eq) and 1.76 mL of triethylamine (12.79 minol, 30 eq) in DMF (2 mL) was added and themixture was again stirred over night. The suspension was filtered, the filtrate was taken to dryness and the residue was purified by preparative reverse phase HPLC to obtain 2.5 mg of the desired material (1.5percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 4.86 (d, 4H), 7.39 - 7.60 (m, 3H), 7.76 (d, 3H), 7.83 -8.00 (m, 2H), 8.24-8.40 (m, IH), 8.52 (d, IH), 8.67 (s, IH), 8.63 (s, IH), 12.80 (s, IH).UPLC-MS (Method 2): R0.80 min; MS (ESIpos): mz [M÷H] 384. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | A solution of 150 mg of Intermediate 34 (0.47 minol, 1.00 eq) in DMF (5 mL) was treated with145 mg of N,N?-disuccinimidyl carbonate (0.57 minol, 1.20 eq) and 181 mg of 4-dimethylaminopyrdine (0.57 minol, 1.20 eq). The mixture was stirred over night at roomtemperature. A suspension of 109 mg of 2,3-dihhydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride(0.57 minol, 1.20 eq) and 2.00 mL of triethylamine in DMF (2 mL) was added. The mixture was stirred for 3 days. The solid was removed by filtration, the filtrate was taken to dryness and the residue was purified by preparative reverse phase HPLC to yield 24.2 mg of the desired product(11percent).1H-NMR(400MHz, DMSO-d6): oe [ppm]= 1.09-1.13 (m, 3H), 2.30 (dd, IH), 2.35 -2.45 (m, 4H),2.65-2.75 (m, IH), 3.36-3.43 (m, 4H), 3.50 (t, 4H), 3.59-3.68 (m, IH), 4.12 (dt, IH), 4.82 (d,4H), 7.44 (d, I H), 7.64 - 7.69 (m, 2H), 7.71 - 7.77 (m, I H), 8.50 (d, I H), 8.63 (d, 2H).UPLC-MS (Method 2): R = 0.49 min; MS (ESIpos): mz [M÷H] 463. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A solution of 108 mg of Intermediate 4 (0.50 minol, 1.00 eq) in THE (18 mL) was treated with154 mg N,N?-disuccinimidyl carbonate (0.60 minol, 1.20 eq) and 73.3 mg of 4-dimethylaminopyrindine. The reaction mixture was stirred at room temperature over night. Asuspension of 116mg 2,3-dihydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride (0.6 minol, 1.20 eq)and 251 pL of triethylamine (1.80 minol, 3.60 eq) was added. The reaction mixture was stirred at room temperature and additionally 250 pL triethylamine were added. After stirring for 3 days the precipitate was filtered off and discarded. The filtrate was taken to dryness. The remaining residue was purified by preparative reverse phase HPLC to provide 150 mg of the desiredproduct Example 4 (83percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07 (d, 3H), 2.30 (dd, IH), 2.65-2.75 (m, IH), 3.32(s, 3H), 4.83 (d, 4H), 7.41 -7.46 (m, IH), 7.64-7.69 (m, 2H), 7.71 -7.76 (m, 2H), 8.14 (s, IH),8.50 (d, I H), 8.62 (d, 2H). One proton under the water protons.LC-MS (Method 2): R = 0.62 min; MS (ESIpos): mz = 364 [M÷H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | To a solution of Intermediate 83 45 mg (0.21 minol) in acetonitrile, 6mL, was added N,Ndisuccinimidyl carbonate, 63.38 mg (0.25 minol). The reaction was stirred at room temperature for 18 hours in a sealed tube. To a suspension of 2,3-dihydro-IH-pyrrolo[3,4-c]pyridinehydrochloride, 32 mg (0.21 minol) in acetonitrile, I mL, was added triethylamine, 0.057 mL (0.41 minol), the slurry was transferred to the tube and the reaction was left to stir at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organics were dried over solid sodium sulfate and concentrated under vacuum.Purification by MDAP (Eluent: Acetonitrile: 0.1percent NH4OH 5:90, 40:60) gave 102.4, 15.9 mg (21percent) as a white solid.1H NMR (300 MHz, CDCI3): 6 [ppm] = 1.23 (d, 3H), 2.50 (d, IH), 2.70 (dd, IH), 3.27 (m, IH),3.47 (s, 3H), 4.92 (d, 4H), 7.32 (m, IH), 8.14 (m, IH), 8.22 (m, IH), 8.58-8.64 (m, 3H).UPLC-MS (Method 4): R= 1.31min., 99percent ES (ESIpos) [M÷H] 365. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A solution of 500 mg of Intermediate 6 (2.30 minol, 1.00 eq) in THE (60 mL) was treated with707 mg of N,N?-disuccinimidyl carbonate (2.76 minol, 1.20 eq) and 338 mg of 4-dimethylaminopyridine (2.76 minol, 1.20 eq). The mixture was stirred for 3 days at roomtemperature. A suspension of 533 mg 2,3-dihydro-IH-pyrrolo[3,4-c] pyrimidine dihydrochloride(2.76 minol, 1.20 eq) and 1.16 mL of triethylamine (8.29 minol, 3.60 eq) in DMF (3 mL) wasadded. Additionally 5 mL of DMF were added to the mixture and it was stirred again over night at room temperature. The precipitate was filtered off and discarded. The filtrate was poured into water. The resulting suspension was stirred over night, the precipitate collected by filtration, washed with water and dried to provide the desired product Example 5 (732 mg, 83percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07 (d, 3H), 2.30 (dd, IH), 2.70 (dd, IH), 3.35-3.45 (m, I H), 4.82 (d, 4H), 7.44 (d, I H), 7.63 - 7.70 (m, 2H), 7.71 - 7.76 (m, 2H), 8.50 (d, I H), 8.62 (d,I H). The methyl group is under the water protons.LC-MS (Method 2): R = 0.60 min; MS (ESIpos): mz = 364 [M÷H].Optical rotation (Method 5): [a] = + 35750 (c = 1.00, DMSO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | To a solution of 6-(4-aminophenyl)-5-isopropyl-2-methyl-4, 5-dihydropyridazin-3(2H )-one Intermediate 91, 50 mg (0.20 minol) and 4-dimethylaminopyridine, 30 mg (0.25 minol) in tetrahydrofuran, 5 mL, N,N-disuccinimidyl carbonate, 63 mg (0.25 minol) was added. After 2 hours at room temperature 2,3-dihydro-1 H-pyrollo[3,4-c]pyridine dihydrochloride, 59 mg (6000- 50-6, 0.31 minol) and triethylamine, 0.29 mL, (2.04 minol) dissolved in N,N dimethylformide (3mL) were added and the mixture was stirred for a further 16 hours. The reaction mixture was diluted with a saturated solution of aminonium chloride and extracted with ethyl acetate. The combined organic layers were dried over solid sodium sulfate, filtered and concentrated undervacuum. The crude compound was purified by reverse phase chromatography (BIOTAGE SP4, 30 g Biotage cartridge) using acetonitrile and water containing 10min aminonium bicarbonate pH 10 buffer (3:97 to 100:0) to give Example 78, 31 mg (42percent) as a colourless solid.1H NMR (400 MHz, CDCI3): 6 [ppm] = 0.89 (m, 6H), 1.96 (m, IH), 2.56 (dd, IH), 2.70 (d, IH),3.04 (m, IH), 3.41 (s, 3H), 4.89 (d, 4H), 6.44 (s, IH), 7.33 (m, IH), 7.51 (d, 2H), 7.73 (d, 2H),8.59 (m, IH), 8.65 (m, IH).UPLC (Method 3): R = 0.61 min., 95percent. MS (ESIpos): mz = [M÷H] 392. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | A solution of 406 mg of Intermediate 7 (2.00 minol, 1.00 eq) in THE (30 mL) was treated with615 mg of N,N?-disuccinimidyl carbonate (2.40 minol, 1.20 eq) and 293 mg of 4-dimethylaminopyridine (2.40 minol, 1 .20 eq). The mixture was stirred for three days at roomtemperature. A suspension of 463 mg of 2,3-dihydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride(2.40 minol, 1.20 eq) and 1.00 mL of triethylamine (7.2Ominol, 3.60 eq) in DMF (2 mL) was added and the resulting suspension as again stirred over night. The mixture was poured into water, the precipitate was collected by filtration and was washed with water to provide after trituration with ethanol 440 mg of the desired product (63percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07 (d, 3H), 2.17-2.26 (m, IH), 2.62-2.71 (m, IH),3.35-3.42 (m, IH), 4.82 (d, 4H), 7.41 -7.46 (m, IH), 7.61 -7.74 (m, 4H), 8.50 (d, IH), 8.61 (d,2H), 10.85 (s, IH).LC-MS (Method 1): R = 0.57 min; MS (ESIpos): mz = 350 [M÷H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | To a solution of Intermediate 47 (400 mg, 1.73 minol, 1.00 eq) in THE (10 mL) was added 4- nitrophenyl chloroformiate (418 mg, 2.08 minol, 1.20 eq) and the mixture was stirred over night at 60 00. The solution was taken to dryness, the residue was resolved in DCM (12 mL) andtreated with DIPEA (0.90 mL, 5.19 minol, 3.00 eq) and 2,3-dihydro-IH-pyrrolo[3,4-C]pyridine dihydrochloride (401 mg, 2.08 minol, 1.20 eq). The resulting mixture was stirred over night at room temperature. The mixture was extracted three times with I M aqueous sodium hydroxide solution, the organic layer was washed with water and dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was triturated with MeOHdiethyl ether toyield the desired product (630 mg, 97percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07- 1.09 (m, 6H), 2.85 (s, 2H), 3.31 (s, 3H), 4.82 (d,4H), 7.44 (d, I H), 7.63 - 7.75 (m, 4H), 8.50 (d, I H), 8.63 (d, 2H).UPLC-MS (Method 2): Rt= 0.69 min; MS (ESIpos): mz [M÷H] 378. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | A solution of 100mg of Intermediate 22 (0.41 minol, 1.00 eq) in DMF (12 mL)was treated with125 mg of N,N?-disuccinimidyl carbonate (0.49 minol, 1.20 eq) and 59.7 mg of 4-dimethylaminopyrdine (0.49 minol, 1.20 eq). The mixture was stirred over night at roomtemperature. A solution of 94.4 mg of 2,3-dihydro-I H-pyrrolo[3,4-c]pyridine dihydrochloride (0.49minol, 1 .20 eq) and 1.70 mL of triethylamine (12.37 minol, 30 eq) in DMF (2 mL) was added.The mixture was stirred over night. THE was removed from under reduced pressure. The remaining solution was poured into water. The solid was removed by filtration, the filtrate was taken to dryness and the residue was purified by preparative reverse phase HPLC to yield 40.3 mg of the desired product (25percent).H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.04 (d, 3H), 1.15 (d, 3H), 1.24 (d, 3H), 2.29 (dd, IH),2.68 (dd, IH), 3.21 - 3.42 (m, IH), 4.83 (d, 4H), 4.90 (quin, IH), 7.44 (d, IH), 7.60 - 7.72 (m,2H), 7.72 - 7.83 (m, 2H), 8.50 (d, I H), 8.62 (d, 2H).UPLC-MS (Method 1): RO.78 min; MS (ESIpos): mz [M÷2H] 393. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 6-(4-aminophenyl)-4-{1-[oxan-2-yl]-1H-indazol-4-yl}pyridazin-3(2H)-one (360 mg, 0.929 mmol) in dichloromethane (34.3 mL) under argon was added pyridine (150 muL, 1.86 mmol), followed by portion wise addition of 4-nitrophenyl carbonochloridate (225 mg 1.12 mmol) over 1 minute, and the reaction mixture stirred at r.t. for 5 hours. To this crude reaction mixture was added N,N-diisopropylethylamine (809 muL, 4.65 mmol), followed by 2,3- dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride (359 mg, 1.86 mmol) under argon and the reaction mixture stirred at r.t. for 5 hours. The reaction mixture was combined with another batch starting from 4-nitrophenyl (4-{6-oxo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]- 1,6-dihydropyridazin-3-yl}phenyl)carbamate (0.852 mmol), and concentrated to give a residue. The crude residue was triturated with water-ethanol and the precipitate collected by filtration, washed with ethyl acetate, diethyl ether and dried to give the desired product, 580 mg (61% combined yield over two steps, 88% purity). (0950) LC-MS (Method 3): Rt = 0.46 min; MS (ESIneg): m/z = 532 [M-H]- 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.57 (s, 2H), 1.75 (s, 1H), 1.94-2.01 (m, 2H), 2.40- 2.42 (m, 1H), 3.70-3.77 (m, 1H), 3.85-3.88 (m, 1H), 4.80 (d, 4H), 5.87-5.89 (m, 1H), 7.41- 7.42 (m, 1H), 7.47-7.52 (m, 2H),7.66- 7.74 (m, 2H),7.80- 7.83 (m, 3H),8.08- 8.10 (m, 2H), 8.48 (d, 1H), 8.59-8.62 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 6-(4-aminophenyl)-4-{1-[(4-methylphenyl)sulfonyl]-1H-indol-5-yl}pyridazin- 3(2H)-one (200 mg, 0.438 mmol) in dichloromethane (16.2 mL) and N,N-dimethylformamide (4.00 mL) was added pyridine (71.0 muL, 0.876 mmol) followed by portion wise addition of 4- nitrophenyl carbonochloridate (106 mg, 0.526 mmol) over 1 minute, and the reaction mixture stirred at r.t. for1 hour. To this reaction mixture was added N,N-diisopropylethylamine (381 muL, 2.19 mmol) followed by <strong>[6000-50-6]2,3-dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride</strong> (169 mg, 0.876 mmol) under argon and the reaction mixture stirred at r.t. for 16 hours. The reaction mixture was combined with another batch (0.219 mmol), and concentrated to give a residue. The crude residue was triturated with water-ethanol and the resulting precipitate collected by filtration, washed with ethyl acetate, diethyl ether and dried to give 246 mg (90% purity,63% combined yield over two steps) of the desired product as pale yellow solid. (0981) LC-MS (Method 5): Rt = 0.85 min; MS (ESIpos): m/z = 603 [M+H]+ (0982) 1H-NMR (400 MHz, DMSO-D6) delta (ppm): 2.29 (s, 3H), 4.80 (d, 4H), 6.90 (s, 1H), 7.37 (d, 2H), 7.53-7.54 (m, 1H), 7.60-7.66 (m, 2H), 7.83-7.97 (m, 5H), 8.10 (s, 2H), 8.24 (s, 1H), 8.53- 8.55 (m, 1H), 8.63-8.65 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
850 mg | To a solution of 6-(4-aminophenyl)-4-(quinolin-7-yl)pyridazin-3(2H)-one, (800 mg, 2.54 mmol), in tetrahydrofuran, 160 mL, was added 4-nitrophenyl carbonochloridate (615 mg, 3.05 mmol). The reaction mixture was heated at 60 C for 5 hours and concentrated under vacuum. The residue was dissolved in N,N-dimethylformamide, 20 mL and added to 2,3- dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride (588 mg, 2.54 mmol) and N,N- diisopropylethylamine, (2.21 mL, 12.7 mmol) in dichloromethane (60 mL) and stirred at r.t. for 16 hours. The precipitate was collected by filtration, washed with water and dried to give the desired product, 850 mg (98% purity, 65% yield over two steps).PRODUCTS: (1029) LC-MS (Method 3): Rt = 0.32 min; MS (ESIpos): m/z = 461 [M+H]+ 1H-NMR (400 MHz, DMSO-D6) delta [ppm]: 4.79-4.81 (m, 4H), 7.41 (d, 1H), 7.54-7.57 (m, 1H), 7.68-7.71 (m, 2H), 7.91-7.93 (m, 2H), 8.03-8.05 (m, 1H), 8.15-8.17 (m, 1H), 8.31 (s, 1H), 8.38-8.40 (m, 1H), 8.46-8.48 (m, 1H), 8.58-8.60 (m, 2H), 8.74 (s, 1H), 8.93-8.94 (m, 1H). |
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