Structure of 215453-53-5
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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| CAS No. : | 215453-53-5 |
| Formula : | C9H7BrN2 |
| M.W : | 223.07 |
| SMILES Code : | BrC1=CC=C2C(=C1)C(=NC=C2)N |
| English Name : | 7-Bromoisoquinolin-1-amine |
| MDL No. : | MFCD07374397 |
| InChI Key : | PLOCDXILPIGHEZ-UHFFFAOYSA-N |
| Pubchem ID : | 22665734 |
| Num. heavy atoms | 12 |
| Num. arom. heavy atoms | 10 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 0 |
| Num. H-bond acceptors | 1.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 53.85 |
| TPSA ? Topological Polar Surface Area: Calculated from |
38.91 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.79 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.59 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.59 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.31 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.4 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.34 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-3.47 |
| Solubility | 0.0753 mg/ml ; 0.000338 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-3.06 |
| Solubility | 0.196 mg/ml ; 0.000879 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.2 |
| Solubility | 0.014 mg/ml ; 0.000063 mol/l |
| Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
| 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 |
-5.82 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 |
0.0 |
| 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) |
1.53 |
* 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 ammonium acetate at 150℃; for 14h; | ||
| Multi-step reaction with 2 steps 1: trichlorophosphate / 3 h / 100 °C / Inert atmosphere 2: ammonium hydroxide; 1-methyl-pyrrolidin-2-one / water / 20 h / 148 °C / Sealed tube |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88.7% | With 1-methyl-pyrrolidin-2-one; ammonium hydroxide In water at 148℃; for 20h; Sealed tube; | |
| 72.42% | With ammonium hydroxide In 1-methyl-pyrrolidin-2-one for 15h; | 1 Example 1. Preparation of N-(l-aminoisoquinolin-7-yl)-N-methylcyanamide (1) To a solution of compound 1.5 (3 g, 12.4 mmol, 1 eq) in NMP (30 mL) was addedNH.HzO (30 mL). The mixture was stirred 150°C for 15 hours. The reaction mixture wasquenched by addition H20 100 mL at 25 °C, and then extracted with EtOAC (100 mL x 3). The combined organic layers were washed with saturated brines (15 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (Si02, Petroleum ether/Ethylacetate=1:1). Compound 1.4 (2.0 g, 9 mmol, 72.42% yield) was obtained as a brown oil. LCMS (ESI): m/z: [M + H] calcd for C9H7N2Br:223; found 223; RT=1.049 mm. |
| Multi-step reaction with 2 steps 1: KOH; PhOH / 2 h / 140 °C 2: NH4OAc / 14 h / 150 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 8 steps 1: pyridine / 1 h / 125 °C 2: n-BuLi / tetrahydrofuran / 0.5 h / -78 °C 3: NaBH4 / tetrahydrofuran; methanol / 0.08 h / 20 °C 4: Et3N / CH2Cl2 / 2 h / 20 °C 5: LiCl / tetrahydrofuran / 16 h / 20 °C 6: EtONa / ethanol; dioxane / 2 h / 80 °C 7: aq. HCl / acetic acid / 16 h / 100 °C 8: 100 percent / SOCl2 / 2 h / 50 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: pyridine / 1 h / 125 °C 2: n-BuLi / tetrahydrofuran / 0.5 h / -78 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 11 steps 1: pyridine / 1 h / 125 °C 2: n-BuLi / tetrahydrofuran / 0.5 h / -78 °C 3: NaBH4 / tetrahydrofuran; methanol / 0.08 h / 20 °C 4: Et3N / CH2Cl2 / 2 h / 20 °C 5: LiCl / tetrahydrofuran / 16 h / 20 °C 6: EtONa / ethanol; dioxane / 2 h / 80 °C 7: aq. HCl / acetic acid / 16 h / 100 °C 8: 100 percent / SOCl2 / 2 h / 50 °C 9: Et3N / CH2Cl2 / 1 h / 0 - 20 °C 10: aq. NaOH / dioxane / 20 °C 11: TBTU / dimethylformamide / 16 h / 20 °C | ||
| Multi-step reaction with 11 steps 1: pyridine / 1 h / 125 °C 2: n-BuLi / tetrahydrofuran / 0.5 h / -78 °C 3: NaBH4 / tetrahydrofuran; methanol / 0.08 h / 20 °C 4: Et3N / CH2Cl2 / 2 h / 20 °C 5: LiCl / tetrahydrofuran / 16 h / 20 °C 6: EtONa / ethanol; dioxane / 2 h / 80 °C 7: aq. HCl / acetic acid / 16 h / 100 °C 8: 100 percent / Et3N / methanol / 20 °C 9: TBTU / dimethylformamide / 1 h / 20 °C 10: TFA / CH2Cl2 / 1 h / 20 °C 11: Et3N / CH2Cl2 / 1 h / 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 69.32% | With dmap; triethylamine In tetrahydrofuran at 25℃; for 15h; | 1 To a solution of compound 1.4 (1.90 g, 8.52 mmol, 1 eq) in THF (40 mL) wasadded TEA (3.45 g, 34.08 mmol, 4.73 mL, 4 eq) and Boc20 (4.65 g, 21.30 mmol, 4.89 mL,2.50 eq) and DMAP (312.18 mg, 2.56 mmol, 0.30 eq). The mixture was stirred at 25 °C for15 hours. The reaction mixture was quenched by addition H20 50 mL at 25°C and extracted with EtOAc (5OmL x 3). The combined organic layers were washed with saturated brines (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=2: 1). Compound 1.3 (2.50 g, 5.91 mmol, 69.32% yield) wasobtained as a yellow oil. ‘HNMR (400 MHz, methanol-d4) ö ppm 1.16 - 1.49 (m, 21 H) 7.89 (d, J5.77 Hz, 1 H) 7.92 - 8.03 (m, 2 H) 8.10 (s, 1 H) 8.42 (d, J=5.77 Hz, 1 H). LCMS (ESI):m/z: [M + H] calcd for C19H23N2BrO4:423; found 423; RT=0.957 mm. |
| 68% | With dmap In dichloromethane at 20℃; for 16h; | A Step A: bis-tert-Butyl (7-bromoisoquinolin-1-yl)carbamate. In a 1 L round- bottomed flask, DMAP (0.13 g, 1.05 mmol) was added to a suspension of 7- bromoisoquinolin-1-amine (4.7 g, 21 mmol) and di-tert-butyl decarbonate (9.2 g, 42 mmol) in DCM (210 mL). The resulting mixture was stirred at rt for 16 h, the resulting solid was collected filtration, and triturated with ethyl acetate to afford bis-tert-butyl (7- bromoisoquinolin-1-yl)carbamate (6.1 g, 68%) as a colorless solid. MS (ESI): mass calcd. for C19H23BrN2O4, 422.08; m/z found, 421.3, 423.1 [M+H]+.1H NMR (400 MHz, Chloroform-d) d 8.47 (d, J = 5.7 Hz, 1H), 8.15 (s, 1H), 7.84 - 7.73 (m, 2H), 7.65 (dd, J = 5.7, 1.0 Hz, 1H), 1.36 (s, 18H). |
| 64% | With dmap In ethyl acetate; acetonitrile | 17.F Part F. Part F. 1-[Bis(t-butoxycarbonyl)amino]-7-bromoisoquinoline A solution of 740 mg (3.32 mmol) of 1-amino-7-bromoisoquinoline in 50 mL of acetonitrile was treated with 1.4 mL of N,N-diiospropylethylamine and 100 mg of 4-(N,N-dimethylamino)pyridine, followed by 3.0 g (4.1 eq) of di-t-butyldicarbonate, and the reaction was stirred at 40° C. for 1 hr. By HPLC analysis, there was still some starting amino compound that remained, so another 1.0 g of di-t-butyldicarbonate were added, and the reaction was stirred at 40° C. for another 30 min. The reaction mixture was concentrated to give a dark oil, which was subjected to flash column chromatography on silica gel with 20% EtOAc in hexanes to give 736 mg of the desired product as a light yellow solid. Also isolated were 156 mg of product as a somewhat less pure light yellow solid, making the total yield 64%. |
| 64% | With dmap In ethyl acetate; acetonitrile | 40.6 Part 6. Part 6. 1-[Bis(t-butoxycarbonyl)amino]-7-bromoisoquinoline A solution of 740 mg (3.32 mmol) of 1-amino-7-bromoisoquinoline in 50 mL of acetonitrile was treated with 1.4 mL of N,N-diiospropylethylamine and 100 mg of 4-(N,N-dimethylamino)pyridine, followed by 3.0 g (4.1 eq) of di-t-butyldicarbonate, and the reaction was stirred at 40° C. for 1 hr. By HPLC analysis, there was still some starting amino compound that remained, so another 1.0 g of di-t-butyldicarbonate were added, and the reaction was stirred at 40° C. for another 30 min. The reaction mixture was concentrated to give a dark oil, which was subjected to flash column chromatography on silica gel with 20% ethyl acetate in hexanes to give 736 mg of the desired product as a light yellow solid. Also isolated were 156 mg of product as a somewhat less pure fight yellow solid, making the total yield 64%. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: ethyl 3-oxo-3-(4-pyridyl)propanoate; 7-bromoisoquinolin-1-amine With ammonium acetate at 140℃; for 12h; Stage #2: In diphenyl ether-biphenyl eutectic at 210℃; for 8h; Stage #3: oxalic acid | 1 Example 1 (Compound No. 2 of table 1) 10-Bromo-2-pyridin-4-yl-4H-pyrimido[2,1-a]isoquinolin-4-one oxalate (1:1) ; To a mixture of 0.1g (0.38 mmol) of 7-bromoisoquinolin-1-amine (synthesis described in WO9847876) and 0.134g (0.69 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate were added 0.059g (0.77 mmol) of ammonium acetate. The reaction mixture was heated at 140°C for 12 hours. Then 2ml of Dowtherm A were added and the resulting mixture was allowed to stir at 210°C for 8 hours. After cooling, water was added and the resulting solution was acidified using isopropanol hydrochloride 6N. Dowtherm A was extracted using diethyl ether and the aqueous phase was basified by an aqueous solution of sodium hydroxide (30%) and extracted with dichloromethane. The extracts were dried over sodium sulphate and evaporated. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 99/1 to 95/5 to give 0.041g (30%) of the desired compound which was transformed into the oxalate salt in the usual manner to give the pure product as a solid. MP: 244-246°C RMN 1H (DMSO-d6; 200 MHz) δ (ppm) : 9.25 (s, 1H), 8.80 (d, 2H), 8.70 (d, 1H), 8.30 (d, 2H), 8.10 (dd, 1H), 8.00 (dd, 1H), 7.65 (d, 1H), 7.40 (s, 1H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium acetate In 1,4-dioxane at 130℃; Inert atmosphere; | 113A.1 Under an argon atmosphere, 500 mg (2.241 mmol) of 7-bromo-isoquinolin-l -amine [Rewinkel et al., Bioorg. Med. Chem. Lett. 1999, 9, 2837] was dissolved in 4 ml dioxane. Then 660 mg (6.72 mmol) potassium acetate, 146 mg (0.179 mmol) of l,r-bis-(diphenylphosphino)ferrocene- palladium(II) chloride-dichloromethane complex and 626 mg (2.465 mmol) of 4,4,4'4'5,5,5'5'- octamethyl-2,2'-bi-l,3,2-dioxaborolan were added. The reaction mixture was stirred overnight at an oil bath temperature of 1300C. After cooling, dichloromethane was added and it was filtered on kieselguhr. Then it was washed again with ethyl acetate. The filtrate was concentrated in a rotary evaporator at reduced pressure and dried under high vacuum. We obtained 776 mg of 7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-amine [63%, (LC-MS)] as raw product. This was reacted subsequently without further purification. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 7 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / water; 1,4-dioxane / 15 h / Inert atmosphere; Reflux 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 3 h / 0 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; dmap / 70 °C / 2585.81 Torr 4: dmap; triethylamine / dichloromethane / 48 h / 20 °C / Inert atmosphere 5: sodium hydroxide / water; methanol; tetrahydrofuran / 20 °C 6: N-ethyl-N,N-diisopropylamine; HATU / tetrahydrofuran / 20 °C / Inert atmosphere 7: sodium tetrahydroborate / methanol / 1 h / 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 8 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / water; 1,4-dioxane / 15 h / Inert atmosphere; Reflux 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 3 h / 0 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; dmap / 70 °C / 2585.81 Torr 4: dmap; triethylamine / dichloromethane / 48 h / 20 °C / Inert atmosphere 5: sodium hydroxide / water; methanol; tetrahydrofuran / 20 °C 6: N-ethyl-N,N-diisopropylamine; HATU / tetrahydrofuran / 20 °C / Inert atmosphere 7: sodium tetrahydroborate / methanol / 1 h / 20 °C / Inert atmosphere 8: hydrogenchloride / water; tetrahydrofuran / 5 h / 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / water; 1,4-dioxane / 15 h / Inert atmosphere; Reflux 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 3 h / 0 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / water; 1,4-dioxane / 15 h / Inert atmosphere; Reflux 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 3 h / 0 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; dmap / 70 °C / 2585.81 Torr 4: dmap; triethylamine / dichloromethane / 48 h / 20 °C / Inert atmosphere 5: sodium hydroxide / water; methanol; tetrahydrofuran / 20 °C 6: N-ethyl-N,N-diisopropylamine; HATU / tetrahydrofuran / 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / water; 1,4-dioxane / 15 h / Inert atmosphere; Reflux 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 3 h / 0 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; dmap / 70 °C / 2585.81 Torr |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / water; 1,4-dioxane / 15 h / Inert atmosphere; Reflux 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 3 h / 0 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; dmap / 70 °C / 2585.81 Torr 4: dmap; triethylamine / dichloromethane / 48 h / 20 °C / Inert atmosphere |