Structure of 527681-61-4
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CAS No. : | 527681-61-4 |
Formula : | C9H9NO2 |
M.W : | 163.17 |
SMILES Code : | O=CC1=CC(CCCO2)=C2C=N1 |
MDL No. : | MFCD18802894 |
InChI Key : | DSOLBHZRAGNEPO-UHFFFAOYSA-N |
Pubchem ID : | 56640311 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.78 |
TPSA ? Topological Polar Surface Area: Calculated from |
39.19 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.32 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.01 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.22 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.17 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.37 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.22 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.79 |
Solubility | 2.63 mg/ml ; 0.0161 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.42 |
Solubility | 6.17 mg/ml ; 0.0378 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.53 |
Solubility | 0.477 mg/ml ; 0.00292 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) |
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 |
-6.58 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 |
1.0 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) |
2.0 |
* 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 |
---|---|---|
64% | With methanol; polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; at 20℃; | Example 37 (4R)-4-({4-[(3,4-Dihydro-2/7-pyrano[2,3-c]pyridin-6-ylmethyL)amino|- l-piperidinyl}methyl)-3-fluoro-4,5-dihydro-7/7-pyrrolo[3,24-rfe]-l,5-naphthyridin- 7-one hydrochloride(4i?)-4-[(4-amino-l-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,l-^e]-l,5- naphthyridin-7-one Enantiomer 1 (200 mg, 0.66 mmol) and 3,4-dihydro-2//-pyrano[2,3- phiyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (107 mg, 0.66 mmol) were dissolved in methanol (30ml) and acetic acid (3ml). The solution was treated with (polystyry]methyl)trimethylammonium cyanoborohydride(Novabiochem) (4.1 mmol/g, 0.9g) , and the mixture stirred at room temperature overnight. The mixture was filtered, and the filtrate evaporated. The residue was subjected to column chromatography on silica gel using a dichloromethane/ 2M methanolic ammonia gradient to provide the free base of the title compound (0.188g,64%).1H NMR delta(CDCl3) 1.45-1.55 (2H, m), 1.85-2.06 (4H, m), 2.11 (IH, dt), 2.24 (IH, dt),2.50-2.63 (2H, m), 2.75-2.88 (4H, m), 2.96 (IH, broad d), 3.85 (2H, s), 4.05-4.20 (IH. m), 4.25-4.35 (2H, m), 4.46-4.50 (2H, m), 6.83 (2H, d, JlOHz), 7.00 (IH, s), 7.88 (IH, d,J 10Hz)1 8.08 (IH, s), 8.32 (IH, s)MS (ES+) m/z 472 (MNa+, 20%), 450 (MH+, 40%), 148 (100%)The free base of the title compound was converted to the hydrochloride by dissolving in dichloromethane and adding 1 equivalent of IM HCl/diethyl ether then evaporating to dryness. MS as that of free base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Example 74 3-Fluoro-4-({(3/.,4S)-4-[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6- ylmethyl)amino]-3-hydroxy-l-piperidinyl}methyl)-4,5-dihydro-7H-pyrrolo[3,2,l- (/e]-l,5-naphthyridin-7-one hydrochlorideA mixture of 4- [(3i?,45)-4-amino-3-hydroxy-l-piperidinyl]methyl}-3-fluoro-4,5- dihydro-7H-pyrrolo[3,2, 1-Je]-1, 5-naphthyridin-7-one Diastereomer 1 (54mg), 3,4- dihydtauo-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (20.6mg) and 3A molecular sieves in chloroform (ImI) and methanol (ImI) was heated at 65C for 5h, cooled and then sodium triacetoxyborohydride (53mg) <n="86"/>was added. The general procedure of Example 72 was then followed to obtain the free base of the title compound (41mg, 70%).1H NMR delta(CDCl3) 1.5-2.0 (m including exchangeables), 1.99-2.06 (2H, m), 2.15-2.25(IH, m), 2.45 (IH, d, J 10.8Hz), 2.57-2.66 (2H, m), 2.77 (2H, t, J 6.4Hz), 2.8-2.9(2H, m),2.93 (IH, dd, J 12.4 and 5.2Hz), 3.84 (2H, s), 3.86 (IH, broad s), 4.05-4.15 (IH. m), 4.22(2H, t, J 5.2Hz), 4.43 (IH, dd, J 13 and 4Hz), 4.52 (IH, dd, J 13 and 9Hz), 6.83 (IH, d, J10Hz), 7.00 (IH, s), 7.89 (IH, d, J 10Hz), 8.08 (IH, s), 8.33 (IH, d, J 1.2Hz)MS (ES+) m/z 466 (MH+, 100%)The free base of the title compound was converted to the hydrochloride by dissolving in dichloromethane and adding 1 equivalent of IM HC 1/di ethyl ether then evaporating to dryness. MS as that of free base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | (c) Title compound; A mixture of l-[2-(4-amino-l-piperidinyl)ethyl]-7-fluoro-l,5-naphthyridin-2(lH)- one dihydrochloride (145mg, 0.399 mmol) in chloroform (5ml) and MeOH (0.1ml) was treated with triethylamine (llmul, 1.162mmol) and stirred for 0.25h before addition of <strong>[527681-61-4]3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde</strong> (for a synthesis see WO2004058144, Example 126(e)) (59mg, 0.363mmol). The reaction was stirred for 0.5h before addition OfNaBH(OAc)3 (231mg, 1.089mmol). The reaction was stirred for 0.5h before addition of sat. aq NaHCO3 (50ml). The reaction was then extracted with 20% MeOH in DCM (3 x 200ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (132mg, 76%). MS (ES+) m/z 438 (MH+). <n="45"/>1R NMR (250MHz) 6(CDCl3) 1.39-1.58 (2H, m), 1.88-2.09 (4H, m), 2.11-2.28 (2H, m), 2.50-2.72 (3H, m), 2.72-2.82 (2H, t), 2.92-3.03 (2H,m), 3.82(2H, s), 4.21(2H, t), 4.33 (2H, t)6.86 (IH, d, J 10Hz), 6.99(1H, s), 7.58 (IH, dd, J 10.5, 2Hz), 7.90 (IH, d, J 10Hz), 8.08 (IH, s), 8.42 (IH, d J 2.5Hz). | |
To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride and 61 mg of <strong>[527681-61-4]3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carbaldehyde</strong> in 2.5 mL of methanol, 62 mg of sodium cyanoborohydride, 0.14 g of a 28% sodium methoxide/methanol solution and 86 muL of acetic acid were added, and the mixture was stirred at room temperature for 1 hour 50 minutes. Thereto were added ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution, and a 2 mol/L aqueous sodium hydroxide solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol = 10:1. The resultant residue was dissolved in 1 mL of methanol and 1 mL of and ethyl acetate, and thereto was added 0.5 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution at room temperature. The solvent was distilled off under reduced pressure, diethyl ether was added the resultant residue, and the solid was filtered off to obtain 0.11 g of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride as a light yellow solid. 1H-NMR (D2O) delta: 2.00-2.12 (4H, m), 2.50-2.59 (2H, m), 2.93 (2H, t, J = 6.3 Hz), 3.22-3.32 (2H, m), 3.60-3.75 (1H, m), 3.63 (2H, t, J = 5.9 Hz), 3.95-4.06 (2H, m), 4.33-4.36 (2H, m), 4.44 (2H, s), 4.72-4.92 (2H, m), 6.99 (1H, d, J = 9.9 Hz), 7.52 (1H, s), 7.95 (1H, dd, J = 10.3, 2.1 Hz), 8.10 (1H, d, J = 9.9 Hz), 8.20 (1H, s), 8.57 (1H, d, J = 2.1 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(a) Title compound; A mixture of l-[2-(4-amino-l-piperidinyl)ethyl]-7-(methyloxy)-l,5-naphthyridin- 2(lH)-one dihydrochloride (174mg, 0.466 mmol) in chloroform (5ml) and MeOH (0.1ml) was treated with triethylamine (205mul, 1.484mmol) and stirred for 0.25h before addition of <strong>[527681-61-4]3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde</strong> (for a synthesis see WO2004058144, Example 126(e)) (69mg, 0.424mmol). The reaction was stirred for 0.5h before addition OfNaBH(OAc)3 (270mg, 1.272mmol). The reaction was stirred for 0.5h before addition of sat. aq NaHCO3 (50ml). The reaction was then extracted with 20% MeOH in DCM (3 x 200ml). The combined organic phases were dried, evaporated and <n="60"/>the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (157mg, 75%). MS (ES+) m/z 450(MH+).1H NMR (250MHz) delta(CDCl3) 1.37-1.58 (2H, m), 1.82-2.10 (4H, m), 2.11-2.29 (2H, m), 2.40-2.82 (5H, m), 3.80 (2H, m), 3.78 (2H, s), 3.98 (3H, s), 4.19-4.23(m, 2H), 4.35- 4.41(m, 2H), 6.73 (IH, d, J 10Hz), 6.97 (IH, s), 7.27 (IH, s), 7.82 (IH, d, J 10Hz), 8.08 (IH, s), 8.28 (IH, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Example 5 (4R)-4-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6- ylmethyl)amino]-l-piperidinyl}methyl)-3-fluoro-4-hydroxy-4,5-dihydro-7£T- pyrrolo[3,2,l-<fe]-l,5-naphthyridin-7-one (E2 enantiomer series) hydrochlorideA solution of (4R)-4-[(4-amino-l-piperidinyl)methyl]-3-fluoro-4-hydroxy-4,5- dihydro-7H-pyrrolo[3,2,l-Je]-l,5-naphthyridin-7-one (E2 enantiomer) (49 mg, 0.154 <n="36"/>mmol) and <strong>[527681-61-4]3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde</strong> (for a synthesis, see WO2004058144, Example 126(e)) (25 mg, 0.154 mmol) in dichloromethane/methanol (2 ml/0.2 ml) was treated with sodium triacetoxyborohydride (65 mg, 0.31 mmol). After 1 hour the mixture was evaporated and the residue chromatographed on silica eluting with 0-20% methanol in ' dichloromethane. The partially purified material was rechromatographed in a similar manner affording the monoacetate salt of the free base of the title compound (16mg, 18%).6H (CDCl3, 400 MHz) 1.50-1.70 (2H, m), 1.90-2.10 (7H, m), 2.40 (IH, t), 2.55 (IH, t), 2.65 (IH, m), 2.75 (2H, t), 2.85 (IH, d), 3.00 (2H, m), 3.28 (IH, d), 3.85 (2H, s), 4.20 (2H, m), 4.35 (IH, d), 4.40 (IH, d), 6.82 (IH, d), 6.98 (IH, s), 7.90 (IH, d), 8.06 (IH, s), 8.36 (IH, s). MS (+ve ion electrospray) m/z 466 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Example 13 (4R/S)-3-Chloro-4-({4-[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6- ylmethyl)amino]-l-piperidinyl}methyl)-4-hydroxy-4,5-dihydro-7H-pyrrolo[3,2,l- «fe]-l,5-naphthyridin-7-one dihydrochlorideA solution of (4i?/jS)-4-[(4-amino-l-piperidinyl)methyl]-3-chloro-4-hydroxy- 4,5-dihydro-7H-pyrrolo[3,2,l-de]-l,5-naphthyridin-7-one (50 mg, 0.15 mmol) and <strong>[527681-61-4]3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde</strong> (for a synthesis, see WO2004058144, Example 126(e)) (25 mg, 0.15 mmol) in chloroform/methanol (2 ml/2 ml) was stirred at room temperature for 2 hours then treated with sodium triacetoxyborohydride (96 mg, 0.45 mmol). After 2 hours the reaction mixture was evaporated and the residue chromatographed on silica eluting with 0-20% methanol in dichloromethane affording the monoacetate salt of the free base of the title compound (70 mg, 88%). deltaH (CDCl3, 400 MHz) 1.58 (IH, m), 1.70 (IH, m), 1.85-2.05 (7H, m), 2.38 (IH, t), 2.55 (IH, t), 2.70-2.80 (3H, m), 2.85 (IH, d), 2.90 (IH, d), 3.05 (IH, d), 3.45 (IH, d), 3.90 (2H, s), 4.20 (2H, t), 4.35 (IH, d), 4.50 (IH, d), 6.86 (IH, d), 7.02 (IH, s), 7.90 (IH, d), 8.05 (IH, s), 8.40 (IH, s). MS (+ve ion electrospray) m/z 482 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Example 10; (lR)-l-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]- l-piperidinyl}methyl)-l,2-dihydro-4H,9H-imidazo[l,2,3-//]-l,8-naphthyridine-4,9- dione hydrochloride; A suspension of (R)- 1 -[(4-amino- 1 -piperidinyl)methyl]- 1 ,2-dihydro-4eta,9eta- imidazo[l,2,3-ij]-l,8-naphthyridine-4,9-dione (for a preparation see Example 5(j)) (51 mg, 0.14 mmol) in chloroform:methanol (9:1, 3 ml) at rt under argon was treated with triethylamine (0.06ml) and stirred at rt for 10 min. The solution was then treated with 1,3- dihydrofuro[3,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144,Example 126(e)) (21mg, 0.133mmol) and stirred for a further 2h. The solution was then treated with NaBH(OAc)3 (87mg) and stirred at rt for 2h. The reaction was then treated with saturated aqueous NaHCO (10ml) and extracted with 20% methanol/DCM (3 x 50ml). The combined organic extracts were dried (MgSO ), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a light brown solid (20mg, 32%) MS (ES+) m/z 448 (MH+). deltaH (CDCl3, 400MHz) 1.15-1.49 (2H, m), 1.61-1.95 (2H, m), 1.99-2.09 (2H, m) 2.20-2.38 (IH, m), 2.45-2.85 (6H, m), 2.92-3.02(1H, m), 3.05-3.15 (IH, m), 3.78 (2H, s), 4.20 (2H, t), 4.30-4.42 (IH, m), 4.52-4.61 (IH, m), 4.95-5.05 (IH, m), 6.23-6.32 (2H, m), 7.00 (IH, s), 7.47-7.50 (2H, m), 8.07 (IH, s).The free base in DCM was treated with one equivalent IM HCl in diethyl ether and then evaporated to give the title monohydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Example 37; (lR)-l-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]- l-piperidinyl}methyl)-l,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride; A suspension of (li?)-l-[(4-amino-l-piperidinyl)methyl]-l,2-dihydro-3eta,8eta- 2a,5,8a-triazaacenaphthylene-3,8-dione dihydro chloride (for a preparation see Example 13(k) or 15(d)) (50 mg, 0.100 mmol) in chloroform (4 ml) and methanol (0.200 ml) at room temperature under nitrogen was treated with triethylamine (0.042 ml, 0.301 mmol) and stirred for 0.25h (the suspension turned into a solution). 3,4-Dihydro-2H-pyrano[2,3- c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (16.35 mg, 0.100 mmol) was then added and the reaction was stirred at room temperature for 0.5h. Sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was then added and the reaction was stirred at room temperature. After 3h there was still some starting material so 30 mg of sodium triacetoxyborohydride were added. After Ih a saturated aqueous solution of sodium bicarbonate (25mL) was added followed by 20% methanol/DCM (25mL) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% methanol/DCM (2x25mL). The combined organiclayers were dried on sodium sulphate, filtered and evaporated to afford 60mg of crude product. The crude product was purified by silica chromatography (0- 20%MeOH/DCM) to afford the free base of the title compound as a yellow solid (39mg, 87%).1H NMR deltaH CDCl3, (400MHz) 1.25-1.45 (m, 2H), 1.78-2.08 (m, 4H), 2.22-2.38 (m, 2H), 2.45-2.60 (m, IH), 2.62 (d, IH), 2.67-2.80 (m, 3H), 2.93 (d, IH), 3.05-3.14 (m, IH), 3.78 (s, 2H), 4.15-4.25 (m, 2H), 4.30-4.45 (m, IH), 4.50-4.60 (m, IH), 4.95-5.05 (m, IH), 6.33 (d, IH), 6.96 (s, IH), 7.75(s, IH), 7.87 (s, IH), 8.07 (s, IH). MS (ES+) m/z 449 (MH+).The free base of the title compound was dissolved in a small amount of methanol/DCM and treated with leq of IM hydrochloric acid in diethyl ether. The solvents were removed and the solid was dried in the desiccator (in the presence of P2O5) over the weekend to afford the title compound as the mono-HCl salt as a yellow solid (40.6mg, 79%). LCMS was consistent with product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 39; (2R)-2-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]- l-piperidinyl}methyl)-l,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride; <n="94"/>A suspension of (2i?)-2-[(4-amino-l-piperidinyl)methyl]-l,2-dihydro-3H,8H- 2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(J)) (60mg, 0.199 mmol) and <strong>[527681-61-4]3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde</strong> (for a synthesis see WO2004058144, Example 126(e)) (29.2 mg, 0.179 mmol) in chloroform (2 ml) and methanol (0.061 ml) at rt under nitrogen was treated with sodium triacetoxyborohydride (127 mg, 0.597 mmol) and stirred at rt for 30min. The reaction was then treated with saturated aqueous NaHCO3 (10ml) and extracted with 20% methanol/DCM (3 x 20ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and purified using silica chromatography (0-20% MeOH/DCM) to give the free base of the title compound as a light brown solid1H NMR deltaH CDCl3, (400MHz) 1.28-1.40 (m, 2H), 1.78-1.86 (m, 2H), 1.96-2.01 (m, 2H), 2.14-2.34 (m, 2H), 2.45-2.52 (m, IH), 2.62-2.74 (m, 4H), 2.91 (m, IH), 3.07-3.11 (m, IH), 3.74 (s, 2H), 4.16-4.18 (m, 2H), 4.32-4.37 (m, IH), 4.48-4.52 (m, IH), 4.97-5.03 (m, IH), 6.34 (d, IH), 6.93 (s, IH), 7.72 (d, IH), 7.77 (s, IH), 8.03 (s, IH), MS (ES+) m/z 449 (MH+).The free base of the title compound in a small amount of DCM was treated with one equivalent of IM HCl in diethyl ether (0.17ml), evaporated and dried in a dessicator overnight to give the title compound as the mono-HCl salt (57.3 mg, 56.4 % yield). LCMS consistent with product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With manganese(IV) oxide; In chloroform; for 4.83333h;Heating / reflux; | To a solution of 0.25 g of (3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl)methanol in 7.5 mL of chloroform, 0.66 g of manganese dioxide was added, and the mixture was heated under reflux while stirring for 4 hours 50 minutes. The reaction mixture was cooled to room temperature, the insoluble substance was then filtered off, and the solvent was distilled off under reduced pressure to obtain 0.24 g of 3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carbaldehyde as a light yellow oily substance. 1H-NMR (CDCl3) delta: 2.04-2.11 (2H, m), 2.85 (2H, t, J = 6.5 Hz), 4.32 (2H, t, J = 5.1 Hz), 7.72 (1H, s), 8.27 (1H, s), 9.94 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.7% | suspension of (1 /?)-1-[(4-amino-1-piperidinyl)methyl]-6-methyl-1 ,2-dihydro- 4H,9H-imidazo[1 ,2,3-ij]-1 ,8-naphthyridine-4,9-dione dihydrochloride (50mg, 0.135 mmol) in chloroform (4 ml) and methanol (0.200 ml) at room temperature under nitrogen was treated with triethylamine (0.057 ml, 0.406 mmol) and stirred for 0.25h (the suspension turned into a solution). 3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, example 5(c)) (22.06 mg, 0.135 mmol) was then added and the reaction was stirred at room temperature for 0.5h.Sodium triacetoxyborohydride (90 mg, 0.406 mmol) was then added and the reaction was stirred at room temperature. After 2h there was still some starting material so 30 mg of sodium triacetoxyborohydride were added. After 1 h sat NaHCO3 (25ml_) was added followed by 20% MeOH/DCM (25ml_) and the aqueous was extracted and then separated from the organic layer. The aqueous was extracted again twice with 20%MeOH/DCM (2x25ml_). Combined organics were dried NaSO4, filtered and evaporated to afford the crude. The crude was purified by silica chromatography (0- 20%MeOH/DCM) to afford 41 mg of desired compound (65.7%) as a pale yellow gum. 1H NMR deltaH CDCI3, (400MHz) 1.30-1.45 (m, 2H), 1.80-1.89 (m, 2H), 1.99-2.05 (m, 2H), 2.15-2.4 (m, 5H), 2.45-2.58 (m, 1 H), 2.62-2.67 (m, 2H), 2.74-2.78 (m, 2H), 2.96 (d, 1 H), 3.05-3.09 (m, 1 H), 3.79 (s, 2H), 4.19-4.22 (m, 2H), 4.28-4.33 (m, 1 H), 4.51-4.55 (m, 1 H), 4.95-5.05 (m, 1 H), 6.15 (s, 1 H), 6.26 (d, 1 H), 6.97 (s, 1 H), 7.56 (d, 1 H), 8.07 (s, 1 H). MS (ES+) m/z 462 (MH+).The compound was dissolved in a small amount of MeOH/DCM and treated with 1eq of a 1 M solution of HCI in diethyl ether. The solvents were removed and the solid was dried in the desiccator (in the presence of P2O5) overnight to afford the mono-HCI salt of the product as a yellow solid (45.9mg, 64.8%). LCMS was consistent with product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | To a solution of <strong>[527681-61-4]3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde</strong> (prepared as described in WO2012012391 , 21 8 mg, 1 .33 mmol) and DIPEA (0.25 mL) in DCM (3 mL), 2-[4-(7-fluoroisoquinolin-1 -yl)piperazin-1 -yl]ethan- 1 -amine trifluoroacetate (1 .6 g, 5.8 mmol) in DCM (5 mL) and 2 drops of AcOH were added. After stirring 10 min NaBH(OAc)3 (446 mg, 2 mmol) was added. The mixture was stirred at room temperature for 4 h then DCM (35 mL) and sat. NaHCO3 (25 mL) were added. The organic phase was separated, washed with sat. NaCI, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, DCM/MeOH 9/1 ) to give A/-[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methyl]-2-[4-(7-fluoro isoquinolin-1 -yl)piperazin-1 -yl]ethan-1 -amine (139 mg, 0.33 mmol, 25% yield). LC-MS (M-H+) = 422.2. 1 H NMR (300MHz ,CHLOROFORM-d) delta = 8.13 (d, J = 5.8 Hz, 1 H), 8.09 (s, 1 H), 7.76 (dd, J = 5.6, 9.0 Hz, 1 H), 7.69 (dd, J = 2.6, 10.2 Hz, 1 H), 7.39 (dt, J = 2.6, 8.6 Hz, 1 H), 7.24 (d, J = 5.8 Hz, 1 H), 7.01 (s, 1 H), 4.21 (t, J = 5.1 Hz, 2 H), 3.87 (s, 2 H), 3.40 (t, J = 4.9 Hz, 4 H), 2.84 (t, J = 6.2 Hz, 2 H), 2.80 - 2.64 (m, 8 H), 2.55 (br. s., 1 H), 2.08 - 1 .95 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | General procedure: To a solution of amine (0.2 mmol) in methanol (2 mL)was added the requisite aldehyde (0.2 mmol) and zinc chloride (2 mg, 0.015 mmol, 0.07 equiv).The mixture was stirred at room temperature for 30 min, followed by addition of sodiumcyanoborohydride (40 mg, 0.6 mmol, 3.0 equiv). The reaction mixture was stirred at roomtemperature overnight and then purified by chromatography on silica gel withdichloromethane/methanol (50:1). On occasion, the product obtained from flash chromatographywas contaminated by a BH3 adduct, seen in the 1H NMR spectrum as four broad peaks from 0.00-0.88 ppm. In these instances, the column-purified material was dissolved in methanol (2 mL) andstirred overnight at ambient temperature with Amberlite IRA743 free base (ca. 100 mg). The puretitle compound was then obtained by removal of the resin by filtration and removal of the solventunder reduced pressure. |
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