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CAS No. : | 443955-90-6 | MDL No. : | MFCD09907902 |
Formula : | C8H7NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OMWBUWDHEZIMGQ-UHFFFAOYSA-N |
M.W : | 165.15 | Pubchem ID : | 21873668 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With manganese(IV) oxide In dichloromethane for 72 h; | c) 2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde; A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 percent); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | A solution of (2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 percent); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | A solution of (2,3-dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 ml_) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 percent); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | A solution of 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethanol (250 mg, 1.5 mmole) in CH2CI2 (5 ml.) was treated with MnO2 (650 mg, 7.5 mmole). After 3 days the mixture was filtered and the filtrate was concentrated to afford the title compound (150 mg, 61 percent) as a white solid: MS (APCI+) m/e 166 (M + H)+. |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | A solution of (6b) (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61percent). MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | A solution of (b) (250 mg, 1.5 mmol) in dichloromethane (5 ml) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, [61 percent).] MS (APCI+) [M/Z] 166 (MH+). |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | c) 2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde; A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61percent); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | (c) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde; A solution of (2,3Ldihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61percent); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | A solution of (2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 percent); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide In dichloromethane for 72 h; | A solution of (2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 percent): LC/MS (APCI+) m/z 166 (M+H+) |
0.4 g | With Dess-Martin periodane In dichloromethane at 20℃; for 1 h; | To a stirred solution of dess martin periodinane (1.3 g, 2.96mmol) in CH2C12 (8ml), was added dropwise, a solution of compound 9d (0.45 g, 2.7mmol) in CH2C12 (8ml). The reaction was stirred for 1 h at RT. The reaction was quenched with 1.3M NaOH solution (5ml), then with water and extracted with diethyl ether. The ether layers were dried over sodium sulphate and concentrated under reduced pressure to afford the required compound as a mixture (0.4g). Proceeded to the next step with crude. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(q) Title compound; <n="30"/>A solution of 6-[(4-Amino-1-piperidinyl)methyl]-7-fluoro-5,6-diotahydro-3/-/- pyrrolo[1 ,2,3-de]quinoxalin-3-one (75% pure, 85mg, 0.21 mmol) and 2,3- dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d)) (34mg, 0.21 mmol) in chloroform/methanol (1 :1 , 6ml) was heated under reflux for ~24h. After cooling, sodium triacetoxyborohydride (147mg, 0.69 mmol) was added and the mixture was stirred for ~5h at room temperature. The mixture was washed with aqueous sodium bicarbonate and the aqueous phase was extracted three times with 10% methanol/dichloromethane. Combined organic fractions were dried and evaporated. Chromatography on a reverse-phase HPLC system with mass-directed collection (MDAP) (eluent acetonitrile/water/formic acid, with a very small amount of aqueous HCI added to assist dissolution of crude product in 1 :1 DMSO/acetonitrile for injection, monitoring for m/z 452) gave the racemic formate salt (82mg). This was treated with aqueous sodium bicarbonate and extracted three times with 10% methanol/dichloromethane. The extracts were dried and evaporated to give the racemic free base. deltaH (d-4 methanol, 250MHz) 1.44 (2H, m), 1.89 (2H, m), 2.09 (1 H, td ), 2.24 (1 H, td), 2.50 (2H, m), 2.75 (1 H, br d), 2.86 (1 H, dd), 3.00 (1 H, br d), 3.80 (2H, s), 4.02 (1 H, m), 4.28 (2H, m), 4.33 (2H, m), 4.50 (2H, m), 6.83 (1 H,s), 6.97 (1 H, t), 7.68 (1 H1 dd), 8.11 (1 H, s), 8.20 (1 H, s).LC/MS (+ve ion electrospray): m/z 452 [MH+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(c) Title compound; A solution of 6-[(4-amino-1-piperidinyl)methyl]-7-fluoro-6-hydroxy-5,6- dihydro-3/-/-pyrrolo[1 ,2,3-c/e]quinoxalin-3-one, Enantiomer E1 (300mg, 0.942mmol) and 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d)) (125. Omg, 0.757mmol) in anhydrous dichloromethane (5ml) and anhydrous methanol (1 ml) was stirred at room temperature, under argon, for 5 minutes and then treated with sodium triacetoxyborohydride (480. Omg, 2.26mmol) and stirred for 19 hours. The reaction mixture was treated with saturated aqueous NaHCO3 solution (20ml) and 19:1 dichloromethane:methanol (20ml). The layers were separated and the aqueous layer was washed with 19:1 dichloromethane:methanol (2x20ml).The organic extracts were combined, passed through a phase separator and evaporated to a dark orange gum. Purification on a 5Og silica column eluting with a 0 to 30% methanol in dichloromethane, 30 minute gradient gave the product, after evaporation, treatment with anhydrous diethyl ether and evaporation, as pale yellow foam (246.6mg, 56%). MS (+ve ion electrospray) m/z 468(MH+). delta H (CDCI3, 400MHz) 1.46-1.62 (2H, m), 1.93-1.97 (2H, m), 2.35-2.41 (1 H, m), 2.52-2.65 (2H, m), 2.81 (1 H, d), 2.95 (2H, m), 3.35 (I H, d), 3.82 (2H, s), 4.27- 4.45 (6H, m), 6.83 (1 H,s), 6.99-7.04 (1 H, m), 7.77-7.80 (1 H, m), 8.11 (1 H, s) and 8.22 (1 H, s); Example 13A; 6-({4-[{2,3-Dihydro[1 ,4]dioxi?o[2,3-c]pyridin-7- ylmethyl)amino]-1 -piperidinyl}methyl)-7-fluoro-6-hydroxy-5,6-dihydro-3W- pyrrolo[1,2,3-de]quinoxalin-3-one, Enantiomer E2 dihydrochloride; A solution of 6-[(4-amiotano-1-piotaperidiotanyl)methyl]-7-fluoro-6-hydroxy-5,6- dihydro-3H-pyrroloL1 ,2,3-de]quinoxalin-3-one Enantiomer 2 (50mg, 0 157mmol) and 2,3-dihydro[1 ,4]diotaoxiotano[2,3-c]py?dine-7-carbaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d)) (20.8mg, 0 126mmol) in anhydrous dichloromethane (1 ml) and anhydrous methanol (0.2ml) was stirred at room temperature, under argon, for 2 minutes and then treated with sodium triacetoxyborohydride (80mg, 0.377mmol) and stirred for 2 hours. The reaction mixture was treated with saturated aqueous NaHCO3 solution (3ml) and carefully shaken. The layers were separated and the aqueous layer was washed with 19:1 dichloromethane methanol (2x3ml).The organic extracts were combined, passed through a phase separator and evaporated to a dark orange gum. Purification on a 1Og silica column eluted with a 0 to 30% <n="49"/>methanol in dichloromethane, 30 minute gradient gave the product as an orange gum (51 mg( 68%).MS (+ve ion electrospray) m/z 468(MH+).1H NMR (400MHz) delta(CDCI3) 1.45-1.62 (2H1 m), 1.93-1.97 (2H, m), 2.35-2.41 (1 H, m), 2.52-2.65 (2H1 m), 2.81 (1 H, d), 2.95 (2H, m), 3.35 (1 H, d), 3.80 (2H, s), 4.27-4.45 (6H, m), 6.82 (1 H,s), 6.99-7.04 (1 H, m), 7.77-7.80 (1 H, m), 8.11 (1 H, s) and8.22 (1 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | To a solution of 8-[2-(c/s-4-amino-1-hydroxycyclohexyl)ethyl]-6-chloro-2/-/- chromen-2-one hydrochloride (35 mg, 0.10 mmol), sodium bicarbonate (35 mg, 0.42 mmol), and anhydrous sodium sulfate (85 mg, 0.60 mmol) in 1 :1 methanol/CH2CI2 (2 ml.) was added 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (20 mg, 0.1 1 mmol). The solution was allowed to stir at RT for 14 h, then sodium borohydride (4 mg, 0.10 <n="35"/>mmol) was added. The solution was stirred for an additional 1 h then was concentrated under reduced pressure. Flash chromatography on silica gel (90:9:1 CHCI3/MeOH/conc NH4OH) gave the title compound (31 mg, 66 %) as a white solid: 1H NMR (400 MHz, DMSOd6) 5 8.13 (s, 1 H), 7.63 (d, J = 9.6 Hz, 1 H), 7.42-7.25 (m, 2H), 6.85 (m, 1 H), 6.46 (d, J = 8.0 Hz, 1 H), 4.40-4.20 (m, 4H), 3.80 (s, 2H), 2.94-2.78 (m, 2H), 2.75-2.58 (m, 2H), 2.0-1.6 (m, 8H), 1.65-1.30 (m, 3H); MS (ES) m/e 471 , 473 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | (h) Title compoundA mixture of 4-[(4-amino-l-piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,l- </e]-l,5-naphthyridin-7-one (75mg, 0.236mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine- 7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) (39mg, 0.236mmol) and 3A molecular sieves in chloroform (1.5ml) and methanol (1.5ml) was heated at 650C for 3h, cooled and then sodium triacetoxyborohydride (lOOmg, 0.472mmol) was added. The reaction was stirred at room temperature for 18h, filtered through kieselguhr and evaporated. The residue was treated with aqueous sodium bicarbonate solution and a 4:1 dichloromethane :methanol mixture. The aqueous phase was extracted twice with a 4:1 dichloromethane: methanol mixture and then the combined organic phases were dried and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a dichloromethane, methanol and aqueous ammonia gradient to provide the free base of the title compound (0.087g, 79%).]eta NMR delta(CDCl3) 1.35-1.5 (2H, m), 1.8-2.0 (2H, m), 2.11 (IH, dt), 2.28 (IH, dt), 2.40- 2.60 (2H, m), 2.73 (IH, broad d), 2.95-3.05 (2H, m), 3.80 (2H, s), 3.95-4.05 (IH. m), 4.25-4.35 (4H, m), 4.42 (IH, dd, J 13 and 9 Hz), 4.58 (IH, dd, J 13 and 4Hz), 6.83 (IH, s), 6.87 (IH, d, J 10Hz), 7.88 (IH, d, J 10Hz), 8.11 (IH, s), 8.38 (IH, s) MS (ES+) m/z 468 (MH+, 40%), 150 (100%)The free base of the title compound was converted to the hydrochloride by dissolving in dichloromethane/methanol 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 |
---|---|---|
(b) Title compoundA mixture of 4-[(4-amino-l -piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,l- de]-l,5-naphthyridin-7-one Enantiomer 1 (500mg) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) (260mg) in chloroform (10ml)/methanol (10ml) with 3A molecular sieves under argon was left overnight and then heated at 650C for 4 hours. After cooling, the mixture was treated with sodium triacetoxyborohydride (665mg), stirred overnight and workup completed according to the general method of Example 2(h) to give free base of the title compound (626mg containing 3% dichloromethane by weight, 82%). 1H NMR a(CDCIs) 1.35-1.55 (2H, m), 1.8-2.0 (2H, m), 2.11 (IH, dt), 2.28 (IH, dt), 2.4-2.6 (2H, m), 2.72 (IH, br d), 2.95-3.1 (2H, m), 3.80 (2H, s), 3.95-4.05 (IH. m), 4.25-4.35 <n="42"/>(4H, m), 4.35-4.45 (IH, m), 4.55-4.65 (IH, m), 6.83 (IH, s), 6.87 (IH, d, J 10Hz), 7.88(IH, d, J 10Hz), 8.10 (IH, s), 8.38 (IH, s)MS (ES+) m/z 468 (MH+, 30%), 150 (100%)The free base of the title compound was converted to the hydrochloride by dissolving in chloroform and adding 1 equivalent of IM HCl/di ethyl ether, then evaporating to dryness. MS as that of free base.Example 25 3-Chloro-4-({4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)ammo]-lphiiperidinyl}methyl)-4,5-dihydro-7//-pyrrolol3,2,l-rfe]-l,5- naphthyridin-7-one Enantiomer 2 hydrochlorideThe free base of the title compound was prepared from 4-[(4-amino-l- piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-rhoyrrolo[3,2,l -de]-] , 5-naphthyridin-7-one Enantiomer 2 and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) according to the general method of Example 24(b) in 84% yield. 1H NMR delta(CDCl3) 1.35-1.55 (2H, m), 1.8-2.0 (2H, m), 2.11 (IH, dt), 2.28 (IH, dt), 2.4-2.6 (2H, m), 2.72 (IH, br d), 2.95-3.1 (2H, m), 3.80 (2H, s), 3.95-4.05 (IH. m), 4.25-4.35(4H, m), 4.35-4.45 (IH, m), 4.55-4.65 (IH, m), 6.83 (IH, s), 6.87 (IH, d, J 10Hz), 7.88(IH, d, J 10Hz), 8.10 (IH, s), 8.38 (IH, s)MS (ES+) m/z 468 (MH+, 30%), 150 (100%)The free base of the title compound was converted to the hydrochloride by dissolving in chloroform 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 |
---|---|---|
(b) Title compoundA mixture of 4-[(4-amino-l -piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,l- de]-l,5-naphthyridin-7-one Enantiomer 1 (500mg) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) (260mg) in chloroform (10ml)/methanol (10ml) with 3A molecular sieves under argon was left overnight and then heated at 650C for 4 hours. After cooling, the mixture was treated with sodium triacetoxyborohydride (665mg), stirred overnight and workup completed according to the general method of Example 2(h) to give free base of the title compound (626mg containing 3% dichloromethane by weight, 82%). 1H NMR a(CDCIs) 1.35-1.55 (2H, m), 1.8-2.0 (2H, m), 2.11 (IH, dt), 2.28 (IH, dt), 2.4-2.6 (2H, m), 2.72 (IH, br d), 2.95-3.1 (2H, m), 3.80 (2H, s), 3.95-4.05 (IH. m), 4.25-4.35 <n="42"/>(4H, m), 4.35-4.45 (IH, m), 4.55-4.65 (IH, m), 6.83 (IH, s), 6.87 (IH, d, J 10Hz), 7.88(IH, d, J 10Hz), 8.10 (IH, s), 8.38 (IH, s)MS (ES+) m/z 468 (MH+, 30%), 150 (100%)The free base of the title compound was converted to the hydrochloride by dissolving in chloroform and adding 1 equivalent of IM HCl/di ethyl ether, then evaporating to dryness. MS as that of free base.Example 25 3-Chloro-4-({4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)ammo]-lphiiperidinyl}methyl)-4,5-dihydro-7//-pyrrolol3,2,l-rfe]-l,5- naphthyridin-7-one Enantiomer 2 hydrochlorideThe free base of the title compound was prepared from 4-[(4-amino-l- piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-rhoyrrolo[3,2,l -de]-] , 5-naphthyridin-7-one Enantiomer 2 and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) according to the general method of Example 24(b) in 84% yield. 1H NMR delta(CDCl3) 1.35-1.55 (2H, m), 1.8-2.0 (2H, m), 2.11 (IH, dt), 2.28 (IH, dt), 2.4-2.6 (2H, m), 2.72 (IH, br d), 2.95-3.1 (2H, m), 3.80 (2H, s), 3.95-4.05 (IH. m), 4.25-4.35(4H, m), 4.35-4.45 (IH, m), 4.55-4.65 (IH, m), 6.83 (IH, s), 6.87 (IH, d, J 10Hz), 7.88(IH, d, J 10Hz), 8.10 (IH, s), 8.38 (IH, s)MS (ES+) m/z 468 (MH+, 30%), 150 (100%)The free base of the title compound was converted to the hydrochloride by dissolving in chloroform 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 |
---|---|---|
Example 49 4-[(c/s-3-[(2,3-Dihydro[l,4]dioxino[2,3-cJpyridm-7- ylmethy])amino]methyl}-4-hydroxy-l-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7//- pyrrolo[3,2,l-^l-l,5-naphthyridin-7-o?e <n="66"/>A mixture of 4- [c-3-(aminomethyl)-4-hydroxy-l-piperidiny]]inethyl}-3-fluoro-4,5- dihydro-7H-pyrrolo[3,2,l-(/e]-l,5-naphthyridin-7-one (40mg, 0.12mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) (20mg, 0.12mmol) and 3A molecular sieves in chloroform (3ml) and methanol (3ml) was heated at 8O0C for 2h, cooled and then sodium triacetoxyborohydride (64mg, 0.30mmol) was added. The reaction was stirred at room temperature for 18h and then the solids were filtered off and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a dichloromethane and methanol gradient (0-20% methanol/dichloromethane) to provide the 33mg of impure compound. MDAP purification provided 14mg of the formate salt and subsequent solid phase, ion exchange (SCX) treatment afforded lOmg of the title compound. MS (ES+) m/z 482 (MH+, 50%), 241 (100%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Example 72 4-({(3lambda,4S)-4-[(2,3-dihydro|l,4]dioxmo[2,3-c]pyridiii-7- ylmethyl)amino]0-hydroxy-l-piperidinyl}methy])-3-fluoro-4,5-dihydro-7//- pyrrolo[3,2,l-</e]-l,5-n drochlorideA mixture of 4- [(3/?,4£)-4-amino-3-hydroxy-l -piperidinyl] methyl} -3-fluoro-4,5- dihydro-7//-pyrrolo[3,2, 1-Je]-1, 5-naphthyridin-7-one Diastereomer 1 (50mg, 0.157mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) (26mg, 0.157mmol) and 3A molecular sieves in chloroform (ImI) and methanol (ImI) was heated at 65C for 5h, cooled and then sodium triacetoxyborohydride (66.5mg, 0.314mmol) was added. The reaction was stirred at room temperature for 18h, filtered through kieselguhr and evaporated. The residue was treated with aqueous sodium bicarbonate solution and a 4:1 dichloromethane: methanol mixture, shaken and separated. The aqueous phase was extracted with a 4:1 dichloromethane:methanol mixture and then the combined organic phases were dried and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel with dichloromethane/methanol/0,88 ammonia 95:5:0.5 to provide the free base of the title compound (24mg, 33%).1H NMR 5(CDCl3) 1.5-2.0 (m including exchangeables), 2.15-2.25 (IH, m), 2.45 (IH, d, J 11.6Hz), 2.55-2.65 (2H, m), 2.8-3.0(3H, m), 3.84 (3H, s), 4.05-4.15 (IH. m), 4.25-4.35 (4H, m), 4.42 (IH, dd, J 13 and 5Hz), 4.52 (IH, dd, J 13 and 9Hz), 6.81-6.85 (2H, m), 7.89 (IH, d, J 10Hz), 8.11 (IH, s), 8.33 (IH, d, J 1.6Hz) MS (ES+) m/z 468 (MH+, 100%) <n="85"/>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 |
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(g) Title compounds; A solution of (5R/S)-5-[(4-amino-l-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7H- pyrrolo[3,2,l-de]-l,5-naphthyridin-7-one (66 mg, 0.22 mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (36 mg, 0.22 mmol) in chloroform/methanol (2.5 ml/0.25 ml) was treated with sodium triacetoxyborohydride (140 mg, 6.6 mmol) and stirred under argon for 2 hours. The mixture was treated with saturated aqueous sodium bicarbonate solution (5 ml) and 10% methanol in DCM (5 ml) and the phases separated. The aqueous phase was further extracted with 10% methanol in dichloromethane (3 x 5 ml). The combined organic extracts were dried (sodium sulphate) and evaporated affording a yellow oil. Chromatography eluting with 0-30% methanol in DCM afforded the free bases of the title compounds (54 mg, 55%). deltaH (CD3OD, 250 MHz) 1.20-1.50 (2H, m), 1.75-1.95 (2H, m), 2.10-2.30 (2H, m), 2.42- 2.60 (IH, m), 2.60-2.75 (2H, m), 3.00-3.15 (2H, m), 3.50-3.70 (2H, m), 3.80 (2H, s), 4.25-4.40 (4H, m), 5.10-5.20 (IH, m), 6.75 (IH, d), 6.95 (IH, s), 7.95 (IH, d), 8.00 (IH, s), 8.40 (IH, s) MS (+ve ion electrospray) m/z 452 (MH+). <n="35"/>This material was converted to the corresponding dihydrochloride salt (54 mg). Chromatography of a portion (14 mg) of this material on a Chiralpak AS-H column eluting with 85:15:0.1 acetonitrile:methanol:isopropylamine afforded 4.8 mg of each of the separate free bases of the title compounds (Rt Enantiomer 1, 4.6 minutes, Rt Enantiomer 2, 8.7 minutes). Each free base was then converted to the separate title compounds with one equivalent of hydrochloric acid. |
Yield | Reaction Conditions | Operation in experiment |
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(b) Title compound A solution of (6R/S)-6-(4-amino-l-piperidinyl)-8-fluoro-6,7-dihydro-3H,5H- pyrido[l,2,3-de]quinoxalin-3-one (0.1 Og, 0.33 mmol) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (55 mg, 0.33 mmol) in dry 1 :1 chloroform/methanol (10 ml) was heated under reflux with 3A molecular sieves overnight. After cooling, sodium triacetoxyborohydride (0.28g, 1.32 mmol) was added and the mixture was stirred at room temperature for 8h, then allowed to stand overnight. Aqueous sodium bicarbonate was added to basify, and the phases were separated. The aqueous phase was extracted three times with 10% methanol/dichloromethane, and the organic fractions were dried and evaporated. Chromatography on silica, eluting with 0-20% methanol/dichloromethane, gave the free base (131mg, 88%). deltaH (CDCl3, 250MHz) 1.44 (2H, m), 1.92 (2H, m), 2.39 (2H, m), 2.53 ( IH, m), 2.70-3.10 (4H, complex m), 3.22 (IH, d), 3.63 (IH, dd), 3.81 (2H, s), 4.30 (4H, m), 4.65 (IH, d), 6.82 (lH,s), 7.05 (IH, t), 7.70 (IH, dd), 8.11 (IH, s), 8.23 (IH, s). LC-MS (+ve ion electrospray): m/z 452 [MH+]The free base (31mg) in dichloromethane/methanol was treated with excess 0.4M hydrogen chloride in 1,4-dioxane (0.34mL), and the solvent was evaporated to give the title dihydrochloride salt (35mg). The racemic material (100 mg) was partially resolved on Chiralpak IA using acetonitrile:THF:isopropylamine. The enriched second eluting enantiomer (E2) was then further resolved on Chiralpak IA using <n="57"/>CH3thetaH:CH3CN:isopropanol:isopropylamine to give 28 mg of free base which was converted to the mono hydrochoride salt (30 mg ) with 1 equivalent of hydrochloric acid. |
Yield | Reaction Conditions | Operation in experiment |
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Examples 24 (5R/S)-5-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]-l-piperidinyl}-3-fluoro-5,6-dihydro-4H,8H-pyrido[3,2,l-rfe]-l,5- naphthyridin-8-one dihydrochlorideA solution of 1,1-dimethylethyl {l-[(5R/S)-3-fiuoro-8-oxo-5,6-dihydro-4H,8H- pvrido[3,2,l-rfe]-l,5-naphthyridin-5-yl]-4-piperidinyl}carbamate (for a preparation see Example l(e)) (35 mg, 0.09 mmol) was dissolved in dichloromethane and trifluoroacetic acid (1 ml/1 ml) and stirred for 1 hour then evaporated . The residue was dissolved in dichloromethane/methanol and treated with MP-carbonate resin until a moistened pH paper indicated pH 8.. The mixture was filtered, washing with methanol and evaporated affording an oil. Analysis indicated a 4:1 mixture of the anticipated (5R/S)-5-(4-amino-l- piperidinyl)-3-fluoro-5,6-dihydro-4H,8H-pyrido[3,2,l-c?e]-l,5-naphthyridin-8-one and 3- fluoro-6H,8H-pyrido[3,2, 1-Je]-1, 5-naphthyridin-8-one. This material was dissolved in chloroform/methanol (1 ml/0.1 ml) and treated with 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) orWO03/087098, Example 19(d)) (14 mg, 0.09 mmol) and sodium triacetoxyborohydride (55 mg, 0.3 mmol). After 2 hours the mixture was added to a silica column and chromato graphed eluting with 0-30% methanol in dichloromethane affording the monoacetate salt of the free base of the title compound as an oil (30 mg). deltaH (CD3OD, 250 MHz) 1.50-1.70 (2H, m), 1.95 (3H, s), 2.10-2.30 (2H, m), 2.35-2.50 (2H, m), 3.05-3.25 (4H, m), 4.05-4.20 (3H, m), 4.25-4.40 (7H, m), 6.85 (IH, d), 7.00 (IH, s), 7.95 (IH, d), 8.10 (IH, s), 8.45 (IH, s)This material was treated with excess hydrochloric acid in methanol and evaporated to afford the dihydrochloride salt (ca 30 mg). MS (+ve ion electrospray) m/z 452 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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(b) Title compounds; A solution of 5-[(4-amino-l-piperidinyl)methyl]-3-(methyloxy)-4,5-dihydro-7H- pyrrolo[3,2,l-de]-l,5-naphthyridin-7-one (170 mg) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (89 mg) in dichloromethane/methanol (10 ml/2 ml) was treated with sodium triacetoxyborohydride (343 mg, 0.52 mmol) and stirred for 20 hours then treated with saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase further extracted three times with 10% methanol in dichloromethane. The combined extracts were washed with brine, dried and evaporated. Chromatography eluting with 0-30% methanol in dichloromethane afforded the free base of the title compounds as a yellow gum (121 mg). The free base (20 mg) was dissolved in chloroform (0.33 ml) and treated with IM hydrochloric acid in ether (0.5 ml) followed by ether (1 ml). Removal of solvent gave the product (23 mg).1H NMR (400MHz) delta (CDCl3) 1.30-1.45 (2H, m), 1.75-1.95 (2H, m), 2.18 (IH, t), 2.25 (IH, t), 2.50 (2H, m), 2.65 (IH, d), 3.05 (IH, d), 3.15 (IH, dd), 3.45 (IH, dd), 3.55 (IH, dd), 3.80 (2H, s), 4.08 (3H, s) , 4.30 (2H, m), 4.38 (2H, m), 5.05 (IH, m), 6.68 (IH, d), 6.80 (IH, s), 7.82 (IH, d), 8.10 (IH, s), 8.22 (IH, s), MS (ES+) m/z 464 (MH+).Chromatography of a portion (78 mg) of this material (free base) on a Chiralpak AS-H column eluting with a water/acetonitrile gradient (1% isopropylamine present) <n="61"/>afforded separate enantiomers (Rt Enantiomer 1, 2.4 minutes, alphaD +133 (c = 0.5 in methanol), Rt Enantiomer 2, 3.9 minutes, alphaD -143 (c = 0.9 in methanol)). Each material was then converted to the separate title compounds with one equivalent of hydrochloric acid (25 mg El and 28 mg E2). |
Yield | Reaction Conditions | Operation in experiment |
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54% | (f) Title compound; A solution of 4-[(4-amino-l -piperidinyl)methyl]-7-oxo-4,5-dihydro-7H- pyrrolo[3,2,l-rfe]-l,5-naphthyridine-3-carbonitrile (41mg, 0.113 mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (22mg, 0.113mmol)(for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) in 1 :1 methanolxhloroform (2 ml) with 3A molecular sieves was heated at 650C for 4 hours, cooled in ice and treated with sodium triacetoxyborohydride (56 mg, 0.266 mmol) and stirred overnight. The reaction was then partitioned between water and 20% methanohDCM, and the aqueous phase extracted twice more with 20% methanol:DCM. The combined organic phases were dried, evaporated and purified by MDAP (Mass Directed Auto Purification), evaporated and triturated with diethyl ether to afford the desired compound (40 mg; 54%).1H NMR (400MHz) delta(mixture of CD3OD:CDC13) 1.69 (m, 2H), 2.05 (m, 2H), 2.30 (m, 2H), 2.60 (m, IH), 2.80 (m, IH), 3.0 (m, IH), 3.15 (m, 2H), 3.72 (m, 2H), 4.12(s, 2H) , 4.48 (m, 4H), 5.12 (m, IH), 7.01 (m, 2H), 8.02 (d, IH), 8.30 (s, IH), 8.41 (br s, 2H), 8.71 (s, IH) MS (ES+) m/z 459(MH+). |
Yield | Reaction Conditions | Operation in experiment |
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8-{2-[(3lambda)-3-(Aminomethyl)-l-pyrrolidinyl]ethyl}-7-chloro-l-methyl-l,5- naphthyridin-2(lH)-one (ca. 0.13 mmol) was dissolved in methanol (3 mL) and chloroform (3 mL), and acetic acid (5 drops) and treated with sodium acetate (43 mg), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (21 mg), and 3A molecular sieves then stirred at room temperature 2 hours. Sodium cyanoborohydride ( 27 mg) was added and the mixture stirred at room temperature overnight. Aqueous sodium carbonate was added and the mixture was extracted with 10% methanol- dichloromethane, dried (sodium sulfate), and evaporated. The crude product was then subjected to mass directed autoprep purification (M 469; eluent : acetonitrile-water- formic acid) then converted to the dihydrochloride by treatment of a solution in methanol with 4M HCl/1 ,4-dioxane and precipitation with ether to give the title compound (32 mg). . LC/MS (+ve ion electrospray): m/z 470 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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4-[2-(4-Amino-l-piperidinyl)ethyl]-5-methyl-6-oxo-5,6-dihydro-l,5- naphthyridine-3-carbonitrile hydrochloride (0.115 g, 0.37 mmol) was reacted with 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (0.55 g, 0.33 mmol) in methanol (5 ml) and chloroform (5 ml) with sodium acetate (0.122 g, 1.48 mmol) and acetic acid (16 drops) for 3 hours at room temperature in the presence of 3A molecular sieves. Sodium cyanoborohydride (0.075 g, 1.19 mmol) was added and the mixture stirred overnight. After being basified with sodium carbonate solution the reaction was extracted with 10% methanol in DCM. The extracts were dried and evaporated. The residue was chromatographed on silica eluting with 5-20% methanol in DCM to give the free base.1H NMR (CDCl3) delta 8.66 (s, IH), 8.10 (s, IH), 7.87 (d, IH), 7.01 (d, IH), 6.81 (s, IH), 4.37-4.25 (m, 4H), 3.84 (s, 3H), 3.81 (s, 2H), 3.50 (t, 2H), 2.93- 2.84 (m, 2H), 2.58-2.45 (m, IH), 2.24-2.12 (m, 2H), 1.93-1.84 (m, 2H), 1.49-1.33 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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4-{2-[(3lambda,45)-4-Amino-3-hydroxy-l-piperidinyl]ethyl}-5-methyl-6-oxo-5,6- dihydro-l,5-naphthyridine-3-carbonitrile hydrochloride (0.08 g, 0.21 mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (0.034 g, 0.21 mmol) in chloroform (1 ml), methanol (1 ml) and acetic acid (10 drops) with sodium acetate (70 mg, 0.82 mmol) and 3 A molecular sieves were stirred for 2 hours. Sodium cyanoborohydride (70 mg, 1.11 mmol) was added and the mixture stirred at room temperature overnight. The mixture was basified and extracted with 10% methanol in chloroform. The extracts were dried and evaporated, then chromatographed on silica gel eluting with 0-10% methanol in DCM to give the free base (11 mg). 1H NMR (CDCl3) delta 8.68 (s, IH), 7.90 (d, IH), 7.59 (d, IH), 7.02 (d, IH), 6.96 (d, IH), 3.86 (s, 2H), 3.83 (s, 3H), 3.60- 3.34 (m, 5H), 3.12- 2.85 (m, 2H), 2.74-2.20 (m, 7H), 1.85-1.62 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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A mixture of 8-[2-(4-amino-l-piperidinyl)ethyl]-7-fluoro-l-methyl-2(lH)- quinolinone hydrochloride (36 mg), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098 Example 19(d)) (15 mg), sodium acetate (0.05 g) and acetic acid (3 drops) in 1 :1 dichloromethane/methanol (8 mL) was stirred with 3A molecular sieves for 5h. (Polystyrylmethyl)trimethylammonium cyanoborohydride was added and the mixture was stirred over a weekend. The mixture was filtered, basified with sodium carbonate solution and extracted with 10% methanol/dichloromethane three times. The organic <n="59"/>fractions were dried and evaporated. Chromatography on silica, eluting with 0-20% methanol/dichloromethane, gave the free base of the title compound (20 mg).1H NMR (250MHz, CDCl3) 68.08 (IH, s), 7.61 (IH, d), 7.40 (IH, dd), 6.99 (IH, dd),6.84 (IH, s), 6.63 (IH, d), 4.34 (2H, m), 4.28 (2H, m), 3.84 (3H, s), 3.79 (2H, s), 3.23(2H, m), 3.01 (2H, m), 2.65 (2H, m), 2.55 (IH, m), 2.16 (2H, m), 1.95 (2H, m), 1.53 (2H, m).MS (+ve ion electrospray) m/z 453 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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51% | (e) Title compound; A mixture of 4-[2-(4-amino- 1 -piperidinyl)ethyl] -6-(methyloxy)- 1 ,2,4- benzotriazin-3(4H)-one dihydrochloride (42mg, 0.112 mmol) in chloroform (2ml) and MeOH (0.1ml) was treated with triethylamine (50mul, 0.358mmol) and stirred for 0.25h before addition of 2,3-dihydro[l,4]dioxino[2,3-c]rhoyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (18mg, 0.112mmol). The reaction was stirred for 0.5h before addition OfNaBH(OAc)3 (71mg, 0.336mmol). The reaction was stirred for Ih before addition of sat. aq NaHCO3 (10ml). 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 (26mg, 51 %). MS (ES+) m/z 453 (MH+).1H NMR (400MHz) 6(CDCl3) 1.55-1.63 (2H, m), 1.99-2.02 (2H, m), 2.27-2.32 (2H, m),2.67-2.72 (3H, m), 3.02-3.11 (2H, m), 3.87 (2H,m), 4.02 (3H, s), 4.27-4.36 (6H, m), 6.86 (2H, br s), 7.00 (IH, dd, J 9, 2Hz), 8.09 (IH, s), 8.29 (IH, d J 9Hz). |
Yield | Reaction Conditions | Operation in experiment |
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55% | Example 15A l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-l- piperidinyl}ethyl)-2-ox hydrochloride; A suspension of l-[2-(4-amino-l-piperidinyl)ethyl]-2-oxo-l,2-dihydro-7- quinolinecarbonitrile (300mg, 1.Olmmol) and 2,3-dihydro[ 1 ,4]dioxino[2,3-c]pvridine-7- carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (167mg, 1. Olmmol) in chloroform (1OmL), methanol (15mL) and DMF (2OmL) was stirred at rt for 30 min then NaBH(OAc)3 (642mg, 3.03mmol) was added. The reaction was stirred at rt overnight. The solvents were removed and residue dried in vacuo. The residue was subjected to column chromatography on silica gel eluting with 0- 20% methanol-DCM to afford the free base of the title compound (247mg, 55%). MS (ES+) m/z 446(MH+).1H NMR (400MHz) 6(CDCl3) 1.55(m, 2H), 1.97(d, 2H), 2.23(t, 2H), 2.6-2.7 (m, 3H), 3.04(d, 2H), 3.37 (bs, IH), 3.85 (s, 2H), 4.20-4.35 (m, 4H), 4.41 (m, 2H), 6.81 (d, IH), 6.85 (s, IH), 7.46 (dd, IH), 7.64 (d, IH), 7.69 (d, IH), 7.80, (s, IH), 8.10 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
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48% | (h) Title compound; l-[2-(4-amino-l-piperidinyl)ethyl]-8-ethyl-7-fluoro-l,5-naphthyridin-2(lH)-one (0.056g, 0.184mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (0.030g, 0.184mmol) was dissolved in CHCl3 (ImI) and MeOH (0. ImI) at rt under argon. NaBH(OAc)3 (0.117g, 0.552mmol) was then added and the reaction was allowed to stir at rt for 16h. After which it was purified by chromatography on silica gel (1Og) using a 0- 30% MeOH in DCM gradient to give the free base of the title compound as a yellow oil (0.04 Ig, 48%). MS (ES+) m/z 468 (MH+).1H NMR (250MHz) 5(MeOD) 1.38 (3H, t), 1.51-1.67 (2H, m), 2.03-2.10 (2H, m), 2.18- 2.27 (2H, m), 2.65-2.85 (2H, m), 3.00-3.21 (5H, m), 4.18 (2H,s), 4.30-4.41(4H, m), 4.55 (2H, t), 6.84(1H, d), 6.99 (IH, s), 7.93 (IH, d), 8.13 (IH, s), 8.45 (IH, s). |
Yield | Reaction Conditions | Operation in experiment |
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96% | (i) Title compound; 10-[2-(4-amino- 1 -piperidinyl)ethyl]-2,3-dihydro[ 1 ,4]dioxino[2,3-A]quinolin-9(10H)-one (lOOmg; 0.304mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (50mg; 0.304mmol) were dissolved in a 5:1 mixture of chloroform andMeOH (5ml:lml) and stirred at rt for 2.5h. More 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (lOmg; 0.031mmol) was added to the reaction and stirred for 20 mins.This was then treated with NaBH(OAc)3 (20mg; 0.092mmol) and stirred for 30 mins.More 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (lOmg; 0.031mmol) was added to the reaction and stirred for 15 mins. This was then treated with NaBH(OAc)3(20mg; 0.092mmol) and stirred for 15 mins. The solvents were then removed and the crude residues purified by column chromatography on silica gel using a 0-20% 2MNH3:MeOH/DCM gradient. Fractions containing the desired were concentrated to afford the free base of the title compound. (140mg; 96%). deltaH CDCl3, (400MHz) 1.49 (m, 2H), 1.8-2.6 (m, 8H), 2.76 (m, 2H), 3.04 (d, 2H), 3.81 (s,2H), 4..2-4.4 (m, 8H), 4.71 (m, 2H), 6.51 (d, IH), 6.78 (d, IH), 6.83(s, IH), 7.01 (d, IH),7.49 (d, IH), 8.1 (s, IH).MS (ES+) m/z 479 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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92% | (k) Title compound; A solution of 5-[2-(4-amino-l-piperidinyl)ethyl]-6-oxo-5,6-dihydro-l,5- naphthyridine-3-carbonitrile (44mg, 0.148mmol) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (24.5mg, 0.148mmol) and 3A molecular sieves in chloroform (ImI) and MeOH (ImI) was heated at 65 C for 5h, cooled and then NaBH(OAc)3 (63mg, 0.30mmol) was added. The reaction was stirred at rt for 18h, filtered through Celite and evaporated. The residue was treated with sat. aq NaHCO3 solution and a 4:1 DCM:MeOH mixture. The aqueous phase was extracted twice with a 4: 1 DCM:MeOH mixture and then the combined organic phases were dried and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a DCM, MeOH and aqueous ammonia gradient to provide the free base of the title compound (0.06 Ig, 92%). MS (ES+) m/z 447(MH+). 1H NMR (400MHz) 5(CDCl3) 1.35-1.58 (2H, m), 1.85-1.95 (2H, m), 2.12-2.22 (2H, m), 2.45-2.56 (IH, m), 2.62-2.68 (2H, t), 2.90-2.96 (2H, m), 3.80 (2H, s), 4.26-4.35(m, 6H), 6.68 (IH, s), 7.05 (IH, d, J 10Hz), 7.94 (IH, d, J 10Hz), 8.10 (2H, s), 8.72 (IH, s). | |
To a solution of 32 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-cyano-(1,5-naphthyridin)-2(1H)-one and 16 mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde in 5 mL of chloroform, 9 muL of acetic acid was added, and the mixture was stirred at room temperature overnight. To the reaction mixture, 34 mg of sodium triacetoxyborohydride was added, and the mixture was stirred for 9 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of chloroform to obtain 39 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-cyano-1,5-naphthyridin-2(1H)-one as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
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89% | (g) Title compound; l-[2-(4-Amino-l-piperidinyl)ethyl]-5,7-difluoro-2(lH)-quinolinone (150mg; 0.49mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (80mg; 0.49mmol) were dissolved in a 5:1 mixture of chloroform and MeOH (5ml:lml) and stirred at rt for Ih. This was then treated with NaBH(OAc)3 (310mg; 1.47mmol) and stirred for a further 2h under the same conditions. The solvents were then removed from the reaction and the crude residues purified by column chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient. Fractions containing the desired product were concentrated to afford the free base of the title compound (200mg; 89%) however this was shown to be impure so was further purified by MDAP to afford the title compound (30mg; 14%) directly as the diformate salt. MS (ES+) m/z 457 (MH+). deltaH MeOD, (400MHz) 1.74 (m, 2H), 2.17 (d, 2H), 2.37 (m, 2H), 2.83 (t, 2H), 3.19 (m, IH), 3.25-3.40 (m, 2H), 4.21 (d, 2H), 4.35(m, 2H), 4.38 (m, 2H), 4.49 (t, 2H), 6.66 (d, IH), 6.96-7.02 (m, 2H), 7.29 (d, IH), 8.05(d, IH), 8.13 (s, IH), 8.28 (bs, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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57% | h) Title compound; A solution of 4-[2-(4-amino-l-piperidinyl)ethyl]-6-(methyloxy)pyrido[2,3- &]pyrazin-3(4H)-one (150mg, 0.494 mmoles) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or <n="89"/>WO03/087098, Example 19(d)) (82mg, 0.496 mmoles) in anhydrous DCM (10 ml) and anhydrous MeOH (1 ml) was stirred at rt for 5 minutes. Sodium triacetoxyborohydride (316 mg, 1.49 mmoles) was added and the mixture was stirred, under argon, for 18h, treated with sat. aq. NaHCO3 solution (5 ml) and 10:1 DCM:MeOH (10ml). The layers were separated and the aqueous layer was washed with 10: 1 DCM:MeOH (5 ml). The organic extracts were combined, washed with brine, passed through a hydrophobic frit and evaporated to an orange gum. Purification on a 20 g silica column eluted with a 0% to 30% DCM/MeOH gradient elution gave the free base of the title compound as a colourless gum (128mg, 57%). MS (ES+) m/z 453 (MH+).1H NMR 5(CDCl3) 1.44 (2H, m). 1.90 (2H, m), 2.18 (2H, m), 2.58 (IH, m), 2.74 (2H, m), 3.04 (2H, m), 3.81 (2H, s), 4.03 (3H, s), 4.27 (2H, m), 4.32 (2H, m), 4.58 (2H, t, J= 7.2 Hz), 6.73 ( IH, d, J = 8.4 Hz), 6.82 (IH, s), 8.01 (IH, d, J = 8.4 Hz), 8.09 (IH, s), 8.15 (IH, s). |
Yield | Reaction Conditions | Operation in experiment |
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(c) Title compound; 1 - {2-[(3i?,45)-4-Amino-3-hydroxy-l -piperidinyl]ethyl} -7-fluoro-l ,5- naphthyridin-2(lH)-one dihydrochloride (lOOmg, 0.2637mmol) was stirred in 9:1 v:v chloroform:MeOeta (5ml) at rt under argon and triethylamine (129mul, 3.5eq.) was added. The mixture was stirred at rt for 10 mins, then 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (44mg, 0.264 mmol) was added and the mixture was stirred at rt for Ih before being treated with sodium triacetoxyborohydride (168mg) added in one portion. The mixture was then stirred at rt over the weekend. Saturated aqueous sodium hydrogen cabonate (2ml) was then added and the organic phase was diluted with DCM to bring the total volume to ca. 20ml. The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2x20ml). The combined DCM extracts were evaporated under reduced pressure and purified by MDAP to give the free base of the title compound as an off-white foam (66mg).1H NMR delta (400MHz, CDCl3): 8.44 (IH, d, J 2Hz), 8.34 (IH, s), 8.11 (IH, s), 7.91 (IH, d, J 10Hz), 7.54 (IH, dd, J 8Hz, 2Hz), 6.89-6.86 (2H, m), 4.53-4.44 (IH, m), 4.36-4.20 <n="95"/>(5H, m), 4.12 (IH, s), 4.08 (2H, s), 3.32-3.28 (IH, m), 3.03-2.99 (2H, m), 2.80-2.71 (2H, m), 2.39 (IH, d, J 1 IHz), 2.32-2.25 (IH, m), 1.95-1.84 (2H, m). MS (ES+) m/z 456 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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(c) Title compound 1 - {2-[(35',4i?)-4-Amino-3-hydroxy- 1 -piperidinyl]ethyl} -7-fluoro- 1 ,5- naphthyridin-2(lH)-one dihydrochloride (247mg, 0.6513mmol) was stirred in 9:1 v:v chlorofornr.MeOeta (10ml) at rt under argon and triethylamine (318muL, 3.5eq.) was added. The mixture was stirred at rt for 10 mins., then 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carboxaldehyde (108mg, for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) was added and the mixture was stirred at rt for 2 hours before being treated with sodium triacetoxyborohydride (414mg) added in one portion. The mixture was then stirred at rt overnight. Saturated aqueous sodium hydrogen cabonate (5ml) was then added and the organic phase was diluted with DCM to bring the total volume to ca. 100ml. The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2x50ml). The combined DCM extracts were evaporated under reduced pressure and purified by MDAP to give the free base of the title compound as a white foam (130mg). <n="117"/>NMR delta (400MHz, CDCl3): 8.44 (IH, d, J 2Hz), 8.34 (IH, s), 8.11 (IH, s), 7.91 (IH, d, J 10Hz), 7.54 (IH, dd, J 8Hz, 2Hz), 6.89-6.86 (2H, m), 4.53-4.44 (IH, m), 4.36-4.20 (5H, m), 4.12 (IH, s), 4.08 (2H, s), 3.32-3.28 (IH, m), 3.03-2.99 (2H, m), 2.80-2.71 (2H, m), 2.39 (IH, d, J 1 IHz), 2.32-2.25 (IH, m), 1.95-1.84 (2H, m). MS (ES+) m/z 456 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 2 mL of dichloromethane solution containing 80 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 41 mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 14 muL of acetic acid were added at room temperature, 78 mg of sodium triacetoxyborohydride was added under ice-cooling, and stirred at room temperature for 1 hour. To the reaction mixture, water, chloroform and aqueous saturated sodium hydrogen carbonate solution were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform : methanol=20 : 1], to give 65 mg of ethyl 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate as a yellow oil. 1H-NMR (CDCl3) delta: 1.18 (3H, t, J=7.2 Hz), 1.47-1.58 (2H, m), 1.64-1.70 (4H, m), 2.08-2.18 (4H, m), 2.66-2.74 (2H, m), 3.46 (2H, s), 3.91 (3H, s), 4.10 (2H, q, J=7.2 Hz), 4.16-4.22 (2H, m), 4.24-4.36 (4H, m), 6.52 (1H, d, J=9.5 Hz), 6.72 (1H, d, J=2.4 Hz), 6.81 (1H, dd, J=8.6, 2.4 Hz), 6.88 (1H, s), 7.46 (1H, d, J=8.6 Hz), 7.58 (1H, d, J=9.5 Hz), 8.10 (1H, d, J=9.5 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 1.5 mL of dichloromethane solution containing 6.0 mg of 1-(2-(4-aminocyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one, 10 mg of molecular sieves 3A, 3.4 mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 1.6 muL of acetic acid were added at room temperature, and stirred at the same temperature for 1.5 hours. To the reaction mixture, 6.0 mg of sodium triacetoxyborohydride was added, and stirred at the same temperature for 1.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[eluent; chloroform : methanol=10 : 1], to give 5.5 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)cyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a yellow oil. 1H-NMR (CDCl3) delta: 1.00-1.74 (7H, m), 1.80-2.10 (4H, m), 2.41 (3H, s), 2.46-2.81 (1H, m), 3.65 (2H, s), 3.91 (3H, s), 4.20-4.35 (6H, m), 6.43 (1H, s), 6.77-6.85 (3H, m), 7.62 (1H, d, J=8.8 Hz), 8.10 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium tris(acetoxy)borohydride; In DMF (N,N-dimethyl-formamide); for 5h; | A solution of amine (18c) (0.6g, 2 mmol) and aldehyde [(C)] (0.33g, 2 mmol) in DMF (10 ml) was treated with sodium triacetoxyborohydride (1. [28G,] 6 mmol). After 5 hours the mixture was treated with 5M aqueous hydrochloric acid dropwise until no further effervescence was observed and then basified with half-saturated aqueous sodium bicarbonate solution (-100 ml). The resulting precipitate was filtered, washed with water and dried in vacuo. The crude product was chromatographed on silica eluting with 2-10% methanol in dichloromethane affording the free base of the title compound as a white solid (0.58g, 64%). 1H [NMR 8 (CDC13)] 8.75 [(1H,] m), 8.10 [(1H,] s), 8. 00 [(1H,] d), 7.45 (2H, m), 7.30 [(1H,] d), 6.82 [(1H,] s), 4.30 (4H, m), 3.85 (2H, s), 2.75 (3H, s), 2. 80 [(1H,] m), 2.20-1. 85 (6H, m), 1.60 (2H, m). MS (+ve ion electrospray) m/z 449 (MH+). This material was converted into the dihydrochloride salt by the method of Example (1) affording the title compound as a white solid (0. [61G).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.5% | With sodium tris(acetoxy)borohydride; In DMF (N,N-dimethyl-formamide); for 26h; | A mixture of amine (25c) (0.24 mg, 0.75 mmol) and aldehyde (35c) (0.12 mg, 0.75 mmol) in DMF (7 ml) was treated with sodium triacetoxyborohydride (0.21g, 1 mmol). After [18] hours the mixture was treated with more sodium triacetoxyborohydride (0.3g) and stirred for a further 8 hours. The reaction mixture was diluted to 20 mL with water and an equal volume of saturated aqueous sodium bicarbonate solution was added. After cooling down to [4C] for 1 hour, the precipitate formed was filtered, washed with water and dried in vacuo. The crude product was chromatographed on silica eluting with 2-10% methanol in dichloromethane affording the free base of the title compound as a white solid [(160MG,] 47. [5%).] [1H NMR 6 (CDCL3)] 8. [80-8.] 75 [(2H,] m), 8.1 [(1H,] s), 7.80-7. 70 (2H, m), 6.79 [(1H,] s), 4.33-4. 24 (4H, m), 3. 84 (2H, s), 2.77 (3H, s), 2.65 [(1H,] m), 2.10 (2H, m), 2.00-1. 80 (4H, m), 1.65 (2H, m). MS (+ve ion electrospray) m/z 450 (MH+). This material, as a solution in chloroform/methanol, was treated with an excess [OF 4M] [HC1] in dioxan and evaporated to dryness. The solid was triturated under ether, filtered and dried under vacuum to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | c) 2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde; A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 %); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | A solution of (2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 %); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | A solution of (2,3-dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 ml_) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 %); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | A solution of 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethanol (250 mg, 1.5 mmole) in CH2CI2 (5 ml.) was treated with MnO2 (650 mg, 7.5 mmole). After 3 days the mixture was filtered and the filtrate was concentrated to afford the title compound (150 mg, 61 %) as a white solid: MS (APCI+) m/e 166 (M + H)+. |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | A solution of (6b) (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61%). MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | A solution of (b) (250 mg, 1.5 mmol) in dichloromethane (5 ml) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, [61 %).] MS (APCI+) [M/Z] 166 (MH+). |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | c) 2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde; A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61%); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | (c) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde; A solution of (2,3Ldihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61%); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | A solution of (2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 %); MS (APCI+) m/z 166 (MH+). |
61% | With manganese(IV) oxide; In dichloromethane; for 72h; | A solution of (2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61 %): LC/MS (APCI+) m/z 166 (M+H+) |
With manganese(IV) oxide; In dichloromethane; at 20℃; for 13h; | Alcohol (19c) (98mg, 0. 587mmol) was dissolved in dichloromethane (lOmL) and manganese dioxide (152mg, 1. 76mmol) was added. The slurry was stirred at room temperature for 3 hours and then another batch of manganese dioxide (152mg, 1. 76mmol) added. After 10 hours further stirring at room temperature the oxidant was removed by filtration through Celite and the solvent removed under reduced pressure to provide the desired product which was used without further purification. MS (APCI+) m/z 166 (MH+). | |
With manganese(IV) oxide; In tetrahydrofuran; at 20 - 70℃; | Example 11 To a solution of 111 g of (2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-yl)methanol in 1110 mL of tetrahydrofuran, 164 g of manganese dioxide was added, the mixture was stirred for 5 hours at 70C and stirred overnight at room temperature. The reaction mixture was subjected to celite filtration and the filter residue was washed with 500 mL of tetrahydrofuran. The filtrate and the wash liquid were combined to evaporate the solvent under reduced pressure. The obtained residue was recrystallized from 750 mL of 2-propanol to give 53.5 g of 2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-carbaldehyde as a light yellow solid. 1H-NMR(CDCl3)delta value: 4.38(4H,s),7.51(1H,s),8.31(1H,s),9.92(1H,s) | |
30d) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehydeTo a solution of oxalyl chloride (2.2 ml) in dichloromethane (22ml) cooled to -78C was added dropwise a solution of DMSO (2.2ml) in dichloromethane (22 ml). The reaction mixture was stirredfor 15 minutes, and then a solution of alcohol (30c) (1.49 g) indichloromethane (16 ml) was added. After stirring for 1 hour atthis temperature, a solution of triethylamine (8.7 ml) indichloromethane (11 ml) was added. The reaction was stirred for20 minutes, then warmed to 0C and stirred for 30 minutes. Waterwas added and the layers were separated. The aqueous layer wasextracted twice with dichloromethane. The combined organiclayers were dried over magnesium sulfate, filtered andevaporated. The residue was purified by flash chromatography(silica gel, dichloromethane/methanol 19:1) to give the desiredproduct (1.36 g).XH NMR (300 MHz, CDC13) : 8: 9.91 (s, 1H) , 8.24 (s, 1H) , 7.45 (s,1H), 4.33 (s, 4H) | ||
To a solution of oxalyl chloride (2.2 ml) in dichloromethane (22 ml), a solution of dimethyl sulfoxide (DMSO) (2.2 ml) in dichloromethane (22 ml) was added thereto in drops at -78 C. and stirred for 15 minutes. Subsequently, a solution of the alcohol (5c) (1.49 g) in dichloromethane (16 ml) was added, stirred for 1 hour and then, a solution of triethylamine (8.7 ml) in dichloromethane (11 ml) was added thereto. After 20 minutes, the reaction mixture was heated to 0 C. and stirred for 30 minutes. Thereafter, water was added, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, dichloromethane:methanol: 19:1) and resulted in the desired product (1.36 g).1H NMR (300 MHz, CDCl3): delta: 9.91 (s, 1H), 8.24 (s, 1H), 7.45 (s, 1H), 4.33 (s, 4H) | ||
0.4 g | With Dess-Martin periodane; In dichloromethane; at 20℃; for 1h; | To a stirred solution of dess martin periodinane (1.3 g, 2.96mmol) in CH2C12 (8ml), was added dropwise, a solution of compound 9d (0.45 g, 2.7mmol) in CH2C12 (8ml). The reaction was stirred for 1 h at RT. The reaction was quenched with 1.3M NaOH solution (5ml), then with water and extracted with diethyl ether. The ether layers were dried over sodium sulphate and concentrated under reduced pressure to afford the required compound as a mixture (0.4g). Proceeded to the next step with crude. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In ethanol; at 20℃; for 2h; | To a stirred solution of 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (1.0 g, 6. 1 mmole) in EtOH (20 ML) at RT was added NaBH4 (0. 23 g, 6. 1 mmole). After 2H, H2O (2 ML) was added and the reaction solution concentrated in vacuo. The remaining solid was passed through a small pad of silica (CH2Cl2/MeOH, 9: 1) to give a white solid that was used directly. To a stirred solution of 2, 3-dihydro [1,4] dioxino [2,3-c] PYRIDIN-7-YLMETHANOL (0.77 g, 4.61 MMOLE) in CH2CI2 (20 mL) at 0 C was added PBR3 (0.52 mL, 5.53 mmole). After 24h, The reaction solution was poured onto 10% aqueous NaHCO3, extracted with EtOAc, and the organic layer washed with H2O. The organic layer was dried over NA2SO4 and concentrated in vacuo. The remaining solid was passed through a small pad of silica (EtOAc) to give a white solid (0.97 g, 92%) that was used directly. LC-MS (ES) m/e 230 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In DMF (N,N-dimethyl-formamide); at 20℃; | The amine (7e) (0.53 g) and aldehyde (6c) (0.25 g) were dissolved in DMF (16 mL) and sodium triacetoxyborohydride (0.96 g) added and the solution was stirred overnight at room temperature. The reaction mixture was quenched with 2N HCI, basified with sodium bicarbonate solution, and extracted with methanol-DCM to afford the free base of the title compound (0.25g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of l-tert-butyl 2-methyl (2.pound.,4R)-4-aminopyrrolidine-l,2-dicarboxylate (3 g) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (2.15 g) in methanol (50 mL) with 3 A molecular sieves powder (0.58 g) was heated at 80 °C for 1 hour. The solution was chilled with an ice bath and NaCNBH3 (1.0 g) was added. After stirring at room temperature overnight, the reaction was concentrated. The residue was dissolved in ethylacetate, washed with NaHCO3 (sat'd soin) and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography using an ISCO yielding 2.5 g. EPO <DP n="75"/>ES (M+H)+= 394. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of { (3R,6R)-6-[2-(3-fluoro-6-methoxy-l,5-naphthyridin-4-yl)ethyl]tetrahydro- 2H-pyran-3-yl} amine (Intermediate 1, crude, approximately 0.089 mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (15 mg, 0.09 mmol) in dry chloroform/ methanol (5 mL, 1:1) were heated over 3 A molecular sieves at 70 C for 3 hours. The reaction mixture was cooled to 0 C, sodium triacetoxy borohydride (58 mg, 0.272 mmol) was added and the resulting mixture was stirred at room temperature over night. The reaction mixture was acidified with conccentrated HCl to pEta of approximately 1, and was filtered and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (20 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL), and the phases were separated. The aqueous phase was back extracted twice with dichloromethane (2x 20 mL) and the combined organic phases were dried over anhydrous sodium sulfate. Chromatography on silica gel with dichloromethane/ methanol (15:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound as a slightly yellow film. The free base was taken up in dichloromethane (0.5 mL), isopropanol (2 mL) was added, followed by addition of IM HCl in ether (50 muL). The resulting mixture was concentrated to dryness. Precipitation from dichloromethane (0.5 mL) with hexanes (2 mL) gave 14 mg (32% yield) of the hydrochloride salt of the product as a colorless solid.1H-NMR (DMSO-de) : delta 1.20-4.50 (m, 18H); 4.03 (s, 3H); 7.12 (s, IH); 7.23 (d, IH); 8.19 (s, IH); 8.27 (d, IH); 8.77 (s, IH); 9.14 (brs, 2H). MS (ESP): 455.23 (MH+) for C24H27FN4O4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 1-tert-butyl 2-methyl (2S,5R)-5-aminopiperidine-l,2-dicarboxylate (1.60 g) in methanol (40 mL) were added 3 A molecular sieves powder (0.17 g) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (1.16 g). After heating at reflux for 2 hours, the reaction was cooled with an ice bath before adding NaCNBH3 (0.47 g). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated. This residue was purified by flash chromatography using a FlashMaster with methylenechloride to methylenechloride/methanol (10:1) as eluants to give 1.26 g of the title compound.ES (MH-H)+= 408. |
Yield | Reaction Conditions | Operation in experiment |
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Example 1 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l- yl}ethyl)-7-methoxyquinolin-2(lH)-oneA solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-methoxyquinolin-2(lH)-one (Intermediate 1, crude, 60 mg, 0.20 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heated over 3 A molecular sieves at 7O0C for 3 hours. The reaction mixture was cooled to O0C, and sodium triacetoxy borohydride (127 mg, 0.6 mmol) was added. The EPO <DP n="52"/>resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 mum membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to a pH of 10 with IM aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2x 20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (8:1 to 4:1) gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of IM HCl in ether (0.3 mL). The colorless precipitate was collected by filtration and gave 50 mg (48%) of the bis-hydrochloride salt of the product, mp 2430C. MS TES): 451.14 (MH+) for C25H30N4O41H-NMR (DMSO-d^ delta (ppm): 2.00-3.80 (m, HH); 3.96 (s, 3H); 4.20-4.45 (m, 6H); 4.68 (m, 2H); 6.45 (d, IH); 6.93 (d, IH); 7.18 (s, IH); 7.30 (s, IH); 7.68 (d, IH); 7.88 (d, IH); 8.25 (s, IH); 9.74 (brs, 2H); 11.18 (brs, IH). |
Yield | Reaction Conditions | Operation in experiment |
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Example 2 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l- yl}ethyl)-7-methoxyquinolin-4(lH)-oneA solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-methoxyquinolin-4(lH)-one (Intermediate 8, 60 mg, 0.20 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/ methanol (5 mL, 1:1) was heated over 3 A molecular sieves at 7O0C for 3 hours. The reaction mixture was cooled to O0C, and sodium triacetoxyborohydride (127 mg, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was then filtered through a 0.45 mum membrane, acidified with cone. HCl to pEta 1 and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pEta of the aqueous phase was adjusted to pEtalO with IM aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2x 20 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol EPO <DP n="56"/>(4:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of IM HCl in ether (0.45 mL). The colorless precipitate was collected by filtration and gave 84 mg (81% yield) of the bis-hydrochloride salt of the product, mp 26O0C.MS (ES): 451.21 (MH+) for C25H30N4O41H-NMR (DMSO-(U delta: 2.00-3.80 (m, 1 IH); 4.07 (s, 3H); 4.30-4.46 (m, 6H); 5.06 (m, 2H); 6.83 (d, IH); 7.28 (d, IH); 7.45-7.58 (m, 2H); 8.22 (d, IH); 8.37 (s, IH); 8.61 (d, IH); 9.94 (brs, 2H); 11.90 (brs, IH). |
Yield | Reaction Conditions | Operation in experiment |
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82% | Example 3; Methyl l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]piperidin-l-yl}ethyl)-6-methoxy-lH-indole-2-carboxylate A solution of methyl l-[2-(4-aminopiperidin-l-yl)ethyl]-6-methoxy-lH-indole-2- carboxylate (Intermediate 12, 200 mg, 0.60 mmol) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (WO 2004/058144) (100 mg, 0.60 mmol) in dry chloroform/ methanol (10 mL, 1:1) was heated over 3 A molecular sieves at 7O0C for 3 hours. The reaction mixture was cooled to O0C, sodium triacetoxy borohydride (384 mg, 1.8 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a 0.45 mum membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (150 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), the aqueous phase back extracted once with dichloromethane (70 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/ methanol (5:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound, 239 mg (82% yield), as a colorless solid, mp 13O0C.MS (ESY 481.15 (MH+) for C26H32N4O51H-NMR CDMSO-d^ delta: 1.10-1.25 (m, 2H); 1.70 (m, 2H); 1.96 (t, 2H); 2.12 (m, IH); 2.30 (m, 2H); 2.79 (m, 2H); 3.62 (s, 2H); 3.80 (s, 3H); 3.82 (s, 3H); 4.22-4.35 (m, 4H); 4.58 (t, 2H); 6.75 (m, IH); 6.91 (s, IH); 7.01 (s, IH); 7.17 (s, IH); 7.52 (d, IH); 7.98 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
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54% | Example 69; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylraethyl)amino]piperidin-l- yl}ethyl)-7-fluoroquinoxalin-2(lH)-oneA mixture of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(lH)-one (Intermediate 140, 85 mg, 0.29 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (49 mg, 0.29 mmol) and molecular sieves 3 A in dry methanol/ chloroform (1:1, 10 mL) was heated to 70 0C for 3 hours. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (190 mg, 0.88 mmol) was added. After 30 minutes, the reaction was filtered through celite, the filtrate was concentrated to dryness, taken up in 15% methanol/ chloroform, and washed with saturated sodium bicarbonate solution. The aqueous phase was reextracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 70 mg (54%) of the title compound as an off-white solid. MS CES): 440 (MH+) for C23H26FN5O31HNMR (DMSO-D6) delta 1.11 - 1.24 (m, 2H); 1.73 (d, 2H); 2.00 (t, 2H); 2.18 (s, IH); 2.25 - 2.38 (m, IH); 2.51 - 2.56 (m, 2H); 2.87 (d, 2H); 3.64 (s, 2H); 4.24 - 4.35 (m, 6H); 6.92 (s, IH); 7.24 (td, IH); 7.52 (dd, IH); 7.87 (dd, IH); 7.99 (s, IH); 8.18 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
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69% | Example 120 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2- methylpiperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(lH)-oneA solution of l-[2-(4-amino-2-methylpiperidin-l-yl)ethyl]-5,7-difluoroquinolin- 2(lH)-one (Intermediate 213, crude, 220 mg, 0.69 mmol) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (WO 2004/058144) (114 mg, 0.69 mmol) in dry dichloroethane/methanol (4 mL, 4:1) was heated over 3 A molecular sieves at 80 0C for 3 hours. The reaction mixture was cooled to O0C, and sodium triacetoxy borohydride (299 mg, 1.38 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 hours and then was filtered through a 0.45 mum membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (20 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pEta of the aqueous phase was adjusted to pEta~10 with IM aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (4x 20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/niethanol (17:3) gave 195 mg (69%) of the title compound as a white foam.MS (ESP): 471.22 (MH+) for C25H28F2 N4O3 EPO <DP n="175"/>1H NMR (300 MHz, DMSO-dQ delta: 0.82-0.91 (m, 4H); 1.16-1.26 (m, IH); 1.74-1.90 (m, 2H); 2.16-2.25 (m, 2H); 2.34 -2.42 (m, 2H); 2.85-2.95 (m, IH); 3.08 (d, IH, J = 11.5 Hz); 3.76 (s, 2H); 4.27-4.34 (m, 6H); 6.63 (d, IH, J= 9.8 Hz); 6.96 (s, IH); 7.18 -7.32 (m, 2H); 7.94 (d, IH, J = 9.8 Hz); 8.03 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium chlorite; aminosulfonic acid; In water; acetone; at 25℃; for 2h; | To a solution of 2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (780 mg, 4.74 mmol) in acetone-H2O (1 :4, 47 mL) at 250C were added NaCIO2 (575 mg, 6.36 mmol) followed by H2NSO3H (599 mg, 6.17 mmol). After 2h, the solution was concentrated and the residue purified through a plug of silica (10% MeOH in DCM (1% NH4OH)) affording the title compound as an off-white solid (600 mg, 70%): LCMS (ES) m/e 182 (M+H)+; 1H NMR (CD3OD, 400 MHz) delta 8.11 (s, 1 H), 7.57 (s, 1 H), 4.37-4.92 (m, 4H). |
70% | With sodium chlorite; aminosulfonic acid; In water; acetone; at 25℃; for 2h; | To a solution of 2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (780 mg, 4.74 mmol) in acetone-H2O (1 :4, 47 mL) at 25C were added NaCIO2 (575 mg, 6.36 mmol) followed by H2NSO3H (599 mg, 6.17 mmol). After 2h, the solution was concentrated and the residue purified through a plug of silica (10% MeOH in DCM (1 % NH4OH)) affording the title compound as an off-white solid (600 mg, 70%): LC/MS (ES) m/e 182 (Mn-H)+ |
51% | With sodium chlorite; sodium dihydrogenphosphate; In 2-methyl-but-2-ene; water; tert-butyl alcohol; at 20℃; for 19h; | To a solution of 2,3-dihydro-[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (722 mg, 4.37 mmol) in 2-methyl-2-propanol (95 mL) and 2-methyl-2-butene (22 mL) was added dropwise a solution of sodium chlorite (80%, 4.55 g, 40.22 mmol) and sodium dihydrogenphosphate (3.65 g, 26.45 mmol) in water (35 mL). The resulting solution was stirred at rt for 19 h. The volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pEta was adjusted to 3 by addition of N HCl. The aq. layer was extracted with DCM-MeOH 9-1 (25 x 30 mL). The combined extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated in ether and filtered to give the title acid as a white solid (0.405 g, 51% yield). 1H NMR (d6-DMSO) delta: 8.19 (s, 1Eta); 7.50 (s, 1Eta); 4.36 (s, 4Eta). MS (ESI, m/z): 182.3 [M+H+] for C8H7NO4. |
51% | 24.i. 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxylic acidTo a solution of <strong>[443955-90-6]2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde</strong> (722 mg, 4.37 mmol) in 2-methyl-2-propanol (95 mL) and 2-methyl-2-butene (22 mL) was added dropwise a solution of sodium chlorite (80%, 4.55 g, 40.22 mmol) and sodium dihydrogenphosphate (3.65 g, 26.45 mmol) in water (35 mL). The resulting solution was stirred at rt for 19 h. The volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pH was adjusted to 3 by addition of 1N HCl. The aq. layer was extracted with DCM-MeOH 9-1 (25×30 mL). The combined extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated in ether and filtered to give the title acid as a white solid (0.405 g, 51% yield).1H NMR (d6-DMSO) delta: 8.19 (s, 1H); 7.50 (s, 1H); 4.36 (s, 4H).MS (ESI, m/z): 182.3 [M+H+] for C8H7NO4. |
Yield | Reaction Conditions | Operation in experiment |
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71% | (c) Title compounds A mixture of (4i?/S)-4-[(4-amino-l-piperidinyl)methyl]-3,4-difluoro-4,5- dihydro-7H-pyrrolo[3,2,l-Je]-l,5-naphthyridin-7-one dihydrochloride (82 mg, 0.21 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis, see WO2004058144, Example 2(c)) (35 mg, 0.21 mmol), sodium acetate (86 mg, 1.05 mmol) and acetic acid (8 drops) in methanol/chloroform (2.5 ml/2.5 ml) was stirred with 3 A molecular sieves for 1 hour then sodium triacetoxyborohydride (51 mg) was added. After 5 hours saturated aqueous sodium bicarbonate solution was added, then the phases were separated. The aqueous phase was twice extracted with 10% methanol in dichloromethane. The combined organic extracts were dried and evaporated. The residue was chromatographed eluting with 0-10% methanol in dichloromethane affording the racemic free base of the title compounds (70 mg, 71%). deltaH (CDCl3, 250 MHz) 1.40-1.60 (2H, m), 1.70 (IH, m), 2.25-2.45 (2H, m), 2.60 (IH, m), 2.78 (IH, m), 2.95 (IH, d), 3.10 (IH, d), 3.35 (IH, t), 3.80 (2H, s), 4.25-4.35 (4H, m), 4.55 (IH, t), 4.68 (IH, d), 4.80 (IH, t), 6.82 (IH, s), 6.88 (IH, d), 7.90 (IH, d), 8.10 (IH, s), 8.45 (IH, s).MS (+ve ion electrospray) m/z 470 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(h) Title compound Method A A solution of 4-[(4-amino-l-piperidinyl)methyl]-3-fluoro-4-hydroxy-4,5- dihydro-7H-pyrrolo[3,2,l-Je]-l,5-naphthyridin-7-one(5.7g, 18 mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (3.0g, 18 mmol) in dichloromethane/methanol (75 ml/7 ml) was cooled in an ice bath under argon, stirred and treated with sodium triacetoxyborohydride (7.6g, 35.9 mmol). More dichloromethane/methanol (50 ml/5 ml) was added and the mixture stirred at O0C for 1 hour. Saturated aqueous sodium bicarbonate solution (150 ml) and then brine (100 ml) were added. The resulting mixture was extracted with 10 % methanol/dichloromethane (2 x 100 ml) then 20% methanol/dichloromethane (100 ml). The organic extracts were dried over magnesium sulphate and evaporated to give a yellow foam (7.6g). This was chromatographed on silica eluting with 0-25% 2M ammonia in methanol/ethyl acetate affording the free base of the title compound (approx 3:1 4S:4R) (6.8g, 81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Method BA solution of (45)-4- [(4-amino- 1 -piperidinyl)methyl] -3 -fluoro-4-hydroxy-4,5 - dihydro-7H-pyrrolo[3,2,l-cfe]-l,5-naphthyridin-7-one (El enantiomer) (l.Og, 3.14 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (0.52g, 3.14 mmol) in dichloromethane/methanol (13 ml/1 ml) under argon was treated at 00C with sodium triacetoxyborohydride (1.33g, 6.29 mmol). The reaction was then allowed to warm to room temperature and stirred at room temperature for 2.5h. Saturated aqueous sodium bicarbonate solution (20 ml) and then brine (25 ml) were added. The resulting mixture was extracted with 10% methanol/dichloromethane (3 x 20 ml) then 20% methanol/dichloromethane (15 ml) then 10% methanol/dichloromethane (20 ml). The organic extracts were dried with magnesium sulphate and evaporated to give a yellow solid/oil (1.42g). This was chromatographed on silica eluting with 0-10% 2M <n="30"/>ammonia in methanol/dichloromethane affording the free base of the title compound (0.969g, 66%).The reductive alkylation reaction may also be conducted in DMF instead of DCM/methanol. Molecular sieves may be included in the reaction mass.The extraction may be carried out with 10% methanol in chloroform and the product may be purified by precipitation from acetone instead of chromatography on silica.NMR of title compound, free base deltaH (CDCl3, 400 MHz) 1.35-1.55 (2H, m), 1.85-1.95 (2H, m), 2.37 (IH, t), 2.45-2.60 (2H, m), 2.85-2.92 (2H, m), 2.95-3.02 (IH, d), 3.20 (IH, d), 3.75 (2H, s), 4.25-4.29 (2H, m), 4.32-4.35 (2H, m), 4.38-4.42 (2H, m), 6.75-6.80 (2H, m), 7.88 (IH, d), 8.05 (IH, s), 8.35 (IH, s). MS (+ve ion electrospray) m/z 468 (MH+).To amorphous free base of the title compound (361.0mg), tetrahydrofuran (1.5mL) was added. The input material dissolved completely in the solvent. The solution was left undisturbed and within a few minutes, crystals started to appear. The slurry was left undisturbed overnight and the solid was analysed using polarised light microscopy which showed the presence of crystalline material. The solid was filtered, washed with tetrahydrofuran and dried in a vacuum oven overnight at 50C with a slight flow of nitrogen. The weight of the crystalline free base material obtained was about 271.9mg. Melting Onset: 184.70C (measured by DSC).XRPD peaks (values given in degrees two-theta): 9.5 +/- 0.2 (2theta), 12.5 +/- 0.2 (2theta), 13.2 +/- 0.2 (2theta), 14.7 +/- 0.2 (2theta), 17.6 +/- 0.2 (2theta), 19.7 +/- 0.2 (2theta). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Example 2 (^R)-4-({4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]-l-piperidinyl}methyl)-3-fluoro-4-hydroxy-4,5-dihydro-7i- pyrrolo[3,2,l-«fe]-l,5-naphthyridin-7-one (E2 enantiomer series) dihydrochlorideA solution of (4R)-4-[(4-amino-l -piperidinyl)methyl]-3-fluoro-4-hydroxy-4,5- dihydro-7H-pyrrolo[3,2,l-de]-l,5-naphthyridin-7-one (E2 enantiomer) (127 mg, 0.4 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldeliyde (for a synthesis see WO2004058144, Example 2(c)) (66 mg, 0.4 mmol) in chloroform/methanol (1 ml/1 ml) was heated at 65C in the presence of 3 A molecular sieves for 4 hours. The cooled mixture was treated with sodium triacetoxyborohydride (169 mg, 0.8 mmol) and stirred for 16 hours. The mixture was filtered through Kieselguhr, evaporated, then the residue partitioned between 20% methanol in dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was further extracted(twice) with 20% methanol in dichloromethane and the combined extracts were dried and evaporated. This was chromatographed on silica eluting with dichloromethane/methanol/saturated aqueous ammonia (95:5:5) affording the free base of the title compound (144 mg, 77%), showing identical spectroscopic properties to the corresponding El enantiomer (Example 1). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In methanol; dichloromethane; | Example 2 1-({4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, Enantiomer E1 Dihydrochloride The E1 enantiomer free base (63 mg) was prepared from 1-[(4-amino-1-piperidinyl)methyl]-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (enantiomer E1) (64 mg) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde</strong> (35 mg) by the general method of Example 1(1) (chromatographed on silica gel, eluding with 0-20% methanol in dichloromethane), and exhibited the same NMR and MS spectroscopic properties. The free base in methanol, was converted to the dihydrochloride salt by adding an excess of 1M hydrogen chloride in methanol, followed by evaporation to dryness and trituration with ether, to give a solid (61 mg). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In methanol; dichloromethane; | Example 4 1-({(3R,4S)-4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxy-1-piperidinyl}methyl)-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one Diastereomer 2, Dihydrochloride The free base of the title compound (93 mg) was prepared from 1-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1-ij]quinolin-4-one (D2 diastereomer) (122 mg) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde</strong> (for a synthesis see, Example 2(c)) (64 mg) by the general method of Example 3 (chromatographed on silica gel, eluding with 0-30% methanol in dichloromethane), giving material with the same NMR and MS spectroscopic data as Example 3. The free base in methanol, was converted to the dihydrochloride salt by adding an excess of 1M hydrogen chloride in methanol, followed by evaporation to dryness, to give a solid (87 mg). | |
With sodium tris(acetoxy)borohydride; In N,N-dimethyl-formamide; for 24h;Product distribution / selectivity; | (b) Title CompoundA solution of 1-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (222 mg, 0.7 mmol, D1 diastereomer) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde</strong> (for a synthesis see WO2004058144, Example 2(c)) (115 mg, 0.7 mmol) in N,N-dimethylformamide (3 ml) was treated with sodium triacetoxyborohydride (445 mg, 2.1 mmol). After 1 day the mixture was evaporated and the residue worked up and chromatographed in a similar manner to Example 1 (l) affording the free base of the title compound as a colourless oil (202 mg, 62%).deltaH (CDCl3, 250 MHz) 1.70-1.80 (2H, m), 2.20-2.30 (2H, m), 2.50-2.65 (2H, m), 2.70-2.95 (3H, m), 3.00-3.10 (1H, m), 3.85 (2H, s), 3.95-4.05 (1H, m), 4.25-4.35 (4H, m), 4.40-4.55 (2H, m), 6.62 (1H, d), 6.85 (1H, t), 6.85 (1H, s), 7.58 (1H, dd), 7.65 (1H, m), 8.10 (1H, s).This material was converted into the title compound (220 mg) by dissolving in dichloromethane and then adding excess hydrogen chloride in ether in a similar manner to Example 1.MS (+ve ion electrospray) m/z 467 (MH+).; Example 4 1-({(3R,4S)-4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxy-1-piperidinyl}methyl)-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one Diastereomer 2, Dihydrochloride The free base of the title compound (93 mg) was prepared from 1-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (D2 diastereomer) (122 mg) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde</strong> (for a synthesis see WO2004058144, Example 2(c)) (64 mg) by the general method of Example 3 (chromatographed on silica gel, eluting with 0-30% methanol in dichloromethane), giving material with the same NMR and MS spectroscopic data as Example 3.The free base in methanol, was converted to the dihydrochloride salt by adding an excess of 1M hydrogen chloride in methanol, followed by evaporation to dryness, to give a solid (87 mg). |
Yield | Reaction Conditions | Operation in experiment |
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Example 44 1-[(3-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-1-pyrrolidinyl)methyl]-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one Dihydrochloride This was prepared from 1- [3-(aminomethyl)-1-pyrrolidinyl]methyl}-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde</strong> (for a synthesis, see Example 20(e)) by the general method of Example 36. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 3-[(4-aminopiperidin-l-yl)methyl]-10-fiuoro-2,3-dihydro-5H-[l,4]oxazino[2,3,4-z/]quinolin-5-one (Intermediate 1, 30 mg, 0.095 mmol) and 2,3- dihydro[l,4]dioxmo[2,3-c]pyridine-7-carbaldehyde (PCT Pub. No. WO 2004/058144, 15.6 mg, 0.095 mmol) in chloroform : methanol (1:1, 6 mL) was heated over freshly activated 3 A molecular sieves at 7O0C for 2 hours. The reaction mixture was cooled to room temperature, and sodium triacetoxy borohydride (60 mg, 0.28 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 mum membrane and concentrated to dryness under reduced pressure. The mixture was purified by chromatography on silica gel with dichloromethane/ methanol (6:1). Fractions containing product were combined and concentrated to dryness. |
Yield | Reaction Conditions | Operation in experiment |
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26% | A mixture of l-{2-[4-amino-3-fluoropiperidin-l-yl]ethyl}-2-oxo-l,2-dihydroquinoline-7- carbonitrile, trans enantiomer A (Intermediate 67, crude, 150 mg, 0.48 mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (80 mg, 0.48 mmol) in dry methanol/chloroform (1:1, 20 mL) was heated under nitrogen over 3 A molecular sieves for one hour at 70 0C. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (300 mg, 1.43 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to dryness. The crude product was taken up in 15% methanol/chloroform and washed with saturated sodium bicarbonate solution. The aqueous phase was re-extracted once with 15% methanol/chloroform. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel with <n="143"/>a gradient of 0-5% methanol in dichloromethane gave 66 mg (26%) of the free base of the title composition as an oil. This was taken up in 1:1 dichloromethane/diethyl ether (5 mL) and treated with 1.0 M HCl in ether (~2 eq) resulting in a precipitate. This mixture was concentrated to dryness. The resulting solid was reconstituted in water and lyophilized to give 66 mg of the title composition.1H NMR (D7Q) delta ppm: 1.81-1.94 (m, IH); 2.30-2.43 (m, IH); 3.13-3.26 (m, IH); 3.32-3.42(m, IH); 3.42-3.50 (m, IH); 3.53 (t, 2H); 3.57-3.66 (m, IH); 3.79-3.93 (m, IH); 4.11-4.27 (m,2H); 4.38-4.43 (m, 2H); 4.50-4.56 (m, 2H); 4.62-4.75 (m, IH); 4.80-4.88 (m, IH); 4.85 (m,IH) 6.85 (d, IH); 7.25 (s, IH); 7.68 (dd, IH); 7.89 (d, IH); 7.98 (s, IH); 8.03 (d, IH); 8.20 (s,IH).MS (ESP): 464 (MH+) for C25H26FN5O3 |
Yield | Reaction Conditions | Operation in experiment |
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40% | A mixture of l-{2-[(3i?,47?)-4-amino-3-methoxypiperidin-l-yl]ethyl}-2-oxo-l,2- dihydroquinoline-7-carbonitrile (Intermediate 85, 105 mg crude, 0.32 mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (53 mg, 0.32 mmol) in dry methanol/chloroform (1:1, 10 mL) was heated under a nitrogen atmosphere over 3 A molecular sieves for three hours at 70 0C. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (205 mg, 0.97 mmol) was added. The reaction was stirred at room temperature overnight, and then filtered through celite. The filtrate was concentrated to dryness, taken up in 15% methanol in chloroform, and washed with saturated sodium bicarbonate solution. The aqueous phase was re-extracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel <n="147"/>with a gradient of 2-10% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 61 mg (40%) of the free base of the title composition as an oil. This was taken up in 1:1 dichloromethane/diethyl ether (5 mL) and treated with 1.0 M HCl in ether (~2 eq). The resulting precipitate was collected by filtration, reconstituted in water and lyophilized to give 63 mg of the title composition as a solid. MS (ESP): 476 (MH+) for C26H29N5O41H NMR (D7Q) delta ppm: 1.84 - 2.00 (m, IH); 2.37 - 2.49 (m, IH); 2.93 - 3.06 (m, IH); 3.10 - 3.23 (m, IH); 3.33 - 3.44 (m, 4H); 3.53 - 3.80 (m, 4H); 4.19 (d, IH); 4.27 - 4.40 (m, 4H); 4.40 - 4.48 (m, 2H); 4.62 - 4.76 (m, 2H); 6.79 (d, IH); 7.22 (s, IH); 7.62 (dd, IH); 7.83 (d, IH); 7.91 (s, IH); 7.97 (d, IH); 8.14 - 8.20 (m, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | A mixture of l-{2-[(3/?,4S)-4-amino-3-hydroxypiperidin-l-yi]ethyl}-2-oxo-l,2- dihydroquinoline-7-carbonitrile (Intermediate 1, 74 mg, 0.24 mmol) and 2,3- dihydro[l,4]dioxino[2,3-phiyridine-7-carbaldehyde (WO 2004/058144) (39 mg, 0.24 mmol) was heated over freshly activated 3 A molecular sieves at 700C for 3 hours. The reaction mixture was cooled to room temperature, and sodium triacetoxy borohydride (150 mg, 0.75 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 mum membrane and concentrated to dryness under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (8:1 to 4:1). Fractions containing product were pooled and concentrated to dryness. The residue was taken up in dichloromethane/ diethyl ether (1:2, 10 mL) and HCl in diethyl ether (2M, -0.15 mL) was added. The mixture was concentrated to dryness under reduced pressure, codistilled two times with dichloromethane (2x 15 mL) and titurated from ether to give the title composition as a colorless solid, 91 mg (72%), mp >210C. MS (ESP): 462 (MH+) for C25H27N5O4 1H-NMR (DMSO-dfi) delta: 2.18 (m, 2H); 3.15 (m, IH); 3.25-3.36 (m, 4H); 3.69 (m, 2H); <n="129"/>4.10-4.49 (m, 7H); 4.61 (dd, 2H); 6.64 (brs, IH); 6.83 (d, IH); 7.30 (s, IH); 7.72 (d, IH); 7.97 (d, IH); 8.08 (d, IH); 8.22 (m, 2H); 9.45 (brs, 2H); 10.00 (brs, IH). |
Yield | Reaction Conditions | Operation in experiment |
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A mixture of l-{2-[(35,4/?)-4-amino-3-methoxypiperidin-l-yl]ethyl}-7-methoxyquinoxalin- 2(lH)-one (Intermediate 31, 160 mg crude, 0.48 mmol) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (80 mg, 0.48 mmol) in dry methanol/chloroform (1:1, 10 mL) was heated under nitrogen over 3 A molecular sieves for one hour at 70 0C. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (310 mg, 1.44 mmol) was added. After 30 min, the reaction was filtered through celite. The filtrate was concentrated to dryness, taken up in 15% methanol in chloroform, and washed with saturated <n="134"/>sodium bicarbonate solution. The aqueous phase was re-extracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel with a gradient of 2-5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 160 mg (70%) of the free base of the title composition as an oil. This was taken up in dichloromethane/ diethyl ether (1 : 1, 5 mL) and treated with 2.0 M HCl in ether (~2 eq). The resulting precipitate was collected by filtration, reconstituted in water and lyophilized to give 148 mg of the of the title composition as a solid.1H NMR (D2O) O: 2.04-2.33 (m, 2H); 3.05-3.25 (m, 2H); 3.44 (s, 3H); 3.50-3.71 (m, 3H); 3.87 (s, 3H); 4.04 (s, IH); 4.21 (d, 3H); 4.26-4.32 (m, 3H); 4.33-4.40 (m, 2H); 4.45-4.58 (m, IH); 4.74-4.87 (m, IH); 6.82-6.92 (m, IH); 7.02-7.12 (m, 2H); 7.75 (d, IH); 8.01 (s, IH); 8.09 (s, IH). MS (ESP): 482 (MH+) for C25H3IN5O5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium tris(acetoxy)borohydride; In methanol; dichloromethane;Product distribution / selectivity; | (l) Title CompoundA mixture of 1-[(4-amino-1-piperidinyl)methyl]-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (enantiomer E2, 67 mg, 0.22 mmol) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde</strong> (for a synthesis see WO2004058144, Example 2(c)) (37 mg) in dichloromethane/methanol (3 ml/0.2 ml) was treated with sodium triacetoxyborohydride (141 mg, 0.66 mmol). After stirring overnight the mixture was partitioned between 5% methanol in dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted several times with 5% methanol in dichloromethane then the combined organic extracts were dried (magnesium sulphate) and evaporated under vacuum. The residue was chromatographed on silica gel, eluting with 0-20% methanol in DCM then a 20-50% gradient of methanol in ethyl acetate affording the free base of the title compound as a yellow oil (71 mg, 71%).deltaH (CDCl3, 250 MHz) 1.40-1.55 (2H, m), 1.80-1.95 (2H, m), 2.08 (1H, dt), 2.22 (1H, dt), 2.45-2.55 (2H, m), 2.75-2.90 (2H, m), 2.95-3.05 (1H, bd), 3.78 (2H, s), 3.95-4.05 (1H, m), 4.28-4.35 (4H, m), 4.40-4.50 (2H, m), 6.60 (1H, d), 6.80-6.90 (2H, m), 7.40 (1H, dd), 7.65 (1H, d), 8.10 (1H, s).MS (+ve ion electrospray) m/z 451 (MH+).This material was converted into the title compound by adding excess hydrogen chloride in ether (86 mg).; Example 2 1-({4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, Enantiomer E1 Dihydrochloride The E1 enantiomer free base (63 mg) was prepared from 1-[(4-amino-1-piperidinyl)methyl]-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (enantiomer EL) (64 mg) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde</strong> (35 mg) by the general method of Example 1 (I) (chromatographed on silica gel, eluting with 0-20% methanol in dichloromethane), and exhibited the same NMR and MS spectroscopic properties.The free base in methanol, was converted to the dihydrochloride salt by adding an excess of 1M hydrogen chloride in methanol, followed by evaporation to dryness and trituration with ether, to give a solid (61 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49 - 60% | With sodium tris(acetoxy)borohydride; In methanol; dichloromethane; at 20℃; for 4h;Product distribution / selectivity; | (h) Title CompoundA solution of 1-[(4-amino-1-piperidinyl)methyl]-9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one enantiomer E2 (40 mg, 0.13 mmol) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde</strong> (for a synthesis see WO2004058144, Example 2(c)) (20 mg, 0.13 mmol) in DCM (0.5 ml) and methanol (0.10 ml) was stirred at room temperature with sodium triacetoxyborohydride (85 mg, 0.40 mmol) for 4 hours at room temperature. The mixture was treated with aqueous sodium bicarbonate (2 ml) and extracted with 5% methanol in dichloromethane (2 ml) and the organic phase was chromatographed on silica gel, eluting with 0-20% methanol in dichloromethane, affording the free base as a yellow oil (30 mg, 49%).MS (+ve ion electrospray) m/z 467 (MH+).deltaH (CD3OD, 400 MHz) 1.13-1.25 (1H, m), 1.40-1.50 (1H, m), 1.70-1.78 (1H, m), 1.85-1.93 (1H, m), 2.18-2.25 (1H, t), 2.28-2.35 (1H, t), 2.50-2.58 (1H, m), 2.65-2.70 (1H, m), 3.00 (2H, s), 3.10-3.18 (1H, m), 3.80 (2H, s), 4.20 (1H, d), 4.25-4.30 (2H, m), 4.32-4.38 (2H, m), 4.65 (1H, d), 6.62 (1H, d), 6.95 (1H, s), 7.05 (1H, t), 7.68-7.72 (1H, m), 7.95 (1H, d), 8.00 (1H, s).The free base in methanol-DCM (0.5 ml/0.5 ml), was converted to the dihydrochloride salt by adding an excess of 1M hydrogen chloride in ether (2 ml), followed by more ether (3 ml), to precipitate a solid (34 mg).; Example 25A 1-({4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}methyl)-9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one Enantiomer E1 Dihydrochloride A solution of 1-[(4-amino-1-piperidinyl)methyl]-9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one enantiomer E1 (40 mg, 0.12 mmol) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde</strong> (for a synthesis see WO2004058144, Example 2(c)) (20 mg, 0.12 mmol) was reacted with sodium triacetoxyborohydride (85 mg, 0.40 mmol) by the general method described for enantiomer E2 (Example 14) affording the free base as a yellow oil (36 mg, 60%).MS (+ve ion electrospray) m/z 467 (MH+).deltaH (CD3OD, 400 MHz): identical NMR to the E2 enantiomer (Example 14).The free base in methanol-DCM, was converted to the dihydrochloride salt by adding an excess of 1M hydrogen chloride in ether, followed by more ether to precipitate a solid (52 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 361-[((3R)-3-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-1-pyrrolidinyl)methyl]-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one Dihydrochloride This was prepared from 1-[(3R)-3-(aminomethyl)-1-pyrrolidinyl]methyl}-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (100 mg) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde</strong> (for a synthesis, see WO2003087098 Example 20(e)) (54.8 mg) by the general method of Example 32(i). The product was chromatographed on silica gel using a 0-20% methanol-DCM gradient to provide the desired compound (140 mg) as an acetate salt.MS (+ve ion electrospray) m/z 451 (MH+).The acetate salt in DCM, was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxan, followed by evaporation to dryness, and trituration with ether to give a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium tris(acetoxy)borohydride; In methanol; chloroform; at 20℃; for 1h; | (b) Title Compound1-[(4-amino-1-piperidinyl)methyl]-9-(methyloxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (0.108 g, 0.345 mmol) and <strong>[443955-90-6]2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde</strong> (see WO2004058144, Example 2(c)) (0.057 g, 0.345 mmol) was dissolved in chloroform (2.5 ml) and methanol (0.25 ml) at room temperature under argon. Sodium triacetoxyborohydride (0.219 g, 1.03 mmol) was then added and the reaction was allowed to stir at room temperature for 1 hour. After which it was purified by chromatography on silica gel (20 g) using a 0-30% methanol in dichloromethane gradient to give the acetate salt of the free base of the title compound as a clear oil (0.175 g, 100%).MS (ES+) m/z 463 (MH+).1H NMR (250 MHz) delta (MeOD) 1.55-1.97 (2H, m), 2.00 (3H, s), 2.05-2.38 (4H, m), 2.49 (1H, t), 2.90-3.30 (5H, m), 3.94 (3H, s), 4.19 (2H, s), 4.30-4.38 (6H, m), 6.43 (1H, d), 6.98 (1H, d), 7.03 (1H, s), 7.52 (1H, d), 7.81 (1H, d), 8.11 (1H, s).A portion of this material (60 mg) was purified firstly on a 5 um Chiralpak AD-H column eluting with 80:20:0.1 CH3CN:CH3OH:Isopropylamine then finally on a 5 um Chiralpak AS-H column eluting with affording 90:10:0.1CH3CN:CH3OH:Isopropylamine affording the E1 enantiomer free base (approximately 10 mg) (Rt 4.8 minutes, 100% ee, 99.5 chemical purity) then the E2 enantiomer free base (approximately 10 mg, Rt 6.9 minutes, 100% ee, 98.5% purity).Each enantiomer was separately converted to the corresponding hydrochloride salt, by dissolving the free base in methanol and the appropriate amount of 6N HCl was added. The reaction was stirred for approximately 1 hour and the methanol was removed to leave the remaining mono HCl salts. Enantiomer E1 was also converted to the dihydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | (e) Title compound; A suspension of (li?)-l-[(4-amino-l-piperidinyl)methyl]-l,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydro chloride (70mg, 0.187 mmol) in chloroform (5 ml) and methanol (0.2 ml) at room temperature under argon was treated with triethylamine (0.078 ml, 0.561 mmol) and stirred for 0.25h. Everything went into solution; 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d))) (30.9 mg, 0.187 mmol) was then added and the reaction was stirred at room temperature for 0.5h. Sodium triacetoxyborohydride (119 mg, 0.561 mmol) was then added and the reaction was stirred at room temperature. After 1.5h 1 eq more of sodium triacetoxyborohydride was added. After Ih sat NaHCO3 (50ml) was added followed by 20% MeOH/DCM (50ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20%MeOH/DCM (2x5 OmI). The combined organic extracts were dried on MgSO4, filtered and evaporated to afford 90mg of crude product which was purified by silica chromatography using a 0-20%methanol/dichloromethane gradient to afford the free base of the title compound as a pale yellow gum (60mg, 71%). deltaH CDCl3, (250MHz) 1.25-1.50 (m, 2H), 1.86 (t, 2H), 2.10-2.75 (m, 6H), 2.93 (d, IH), 3.00-3.15(m, IH), 3.79 (s, 2H), 4.20-4.45 (m, 5H), 4.50-4.65 (m, IH), 4.90-5.10 (m, IH), 6.33 (d, IH), 6.82 (s, IH), 7.76 (d, IH), 7.86 (s, IH), 8.11 (s, IH). MS (ES+) m/z 451 (MH+).The title compound was prepared by dissolving the free base in DCM/MeOH and treating it with 2 equivalents of IM HCl in diethyl ether. This was then evaporated to dryness and dried in the vacuum desiccator in the presence OfP2O5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Example 22; 2-({4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-l- piperidinyl}methyl)-l,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione hydrochloride; <n="75"/>Racemic 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)) (50mg, 0.166 mmol) was stirred in 9:1 v:v chloroform:methanol (2ml) with 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d)) (28mg, 1.0 equivalent) at room temperature for 30 minutes, then the mixture was treated with sodium triacetoxyborohydride (105mg, 3.0 equivalents) with vigorous stirring. After a further 25 minutes stirring, the reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (2ml), diluted with dichloromethane and stirred vigorously at room temperature for 20 minutes. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure to give an orange gum; this was purified by column chromatography on silica (eluting with 0-12% (2M NH3 in MeOH) in DCM). Appropriate fractions were combined and evaporated under reduced pressure to give the free base of the title compound as a cream amorphous solid (30mg, 40%). MS (ES+) m/z 451 (MH+).1H NMR (CD3OD) delta 7.98 (IH, s); 7.88 (IH, d, J= 9.7Hz); 7.77 (IH, s ); 6.94 (IH, s); 6.37 (IH, d, J= 9.7Hz); 5.12 (IH, m); 4.43 (2H, m); 4.35 (2H, m); 4.29 (2H, m); 3.73 (2H, s); 3.07 (IH, m); 3.03 (IH, m); 2.83 (IH, dd, J= 13.2Hz, 8.3Hz); 2.70 (IH, m); 2.44 (IH, m); 2.26 (IH, dt, J= 11.6Hz, 2.4Hz); 2.18 (IH, dt, J= 11.6Hz, 2.4Hz); 1.85 (2H, m); 1.33 (2H, m).The free base was dissolved in DCM (ImI) and treated with a IM solution of hydrogen chloride in diethyl ether (67 muL, 1.0 equivalent); the vessel was sealed and kept at room temperature for 5 minutes then the solvents were removed under reduced pressure to give the title compound (20mg; some product lost due to splashing on evaporation of solvents). MS (ES+) m/z 451 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | (f) Title compound; A solution of l-[(4-amino-l-piperidinyl)methyl]-l,2,5a,8b-tetrahydro-3H,8H- 2a,5,8a-triazaacenaphthylene-3,8-dione (22.8mg, 0.0757mmol) in anhydrous dichloromethane (3ml) and anhydrous methanol (0.6ml) was treated with 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (12.5mg, 0.076mmol) (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d)) and stirred, under argon, for 15 minutes and then treated with sodium triacetoxyborohydride (48mg, 0.226mmol) and stirred at room temperature for 17 hours. The reaction was then treated with a further portion of 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (2mg) and sodium triacetoxyborohydride (lOmg) and the mixture was stirred for 4 hours, treated with saturated aqueous NaHCO3 solution (ImI) and stirred for 10 minutes. The layers were separated and the aqueous layer was washed with 9:1 dichloromethane methanol <n="34"/>(2x1 OmI). The combined organic extracts were passed through a hydrophobic frit and evaporated to a brown gum which was chromatographed eluting with 0 to 30% methanol in dichloromethane to give the free base of the title compound as a yellow gum (20.6mg, 60%). C23H26N6O4 requires 450, MS (ES+) m/z 451(MH+).1H NMR (250MHz) 5(CDCl3) 1.38-1.54 (2H, m), 1.83-1.93 (2H, m), 2.19-2.36 (2H, m), 2.54-2.73 (3H, m), 2.93-2.98 (IH, m), 3.09-3.15 (IH, m), 3.85 (2H, s), 4.26-4.61 (6H, m), 4.96-5.05 (IH, m), 6.33 (IH, d), 6.82 (IH, s), 7.76 (IH, d), 7.87 (IH, s) and 8.10 (IH, s) The free base of the title compound was dissolved in anhydrous dichloromethane (2ml) and anhydrous methanol (0.5ml) and treated with IM HCl in diethyl ether (0.5ml). Diethyl ether was added (5ml) and the suspension was cooled. After centrifuging the solvent was removed and the solid was dried to give the title compound as a brown solid (23.5mg). C23H26N6O4 requires 450, MS (ES+) m/z 451(MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Example 3; l-({4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-l- piperidinyl} methyl)- 1 ,2-dihydro-4H,9H-imidazo [1 ,2,3-ij ] -1 ,8-naphthyridine-4,9- dione hydrochloride; Method A; A mixture of l-[(4-amino-l-piperidinyl)methyl]-l,2-dihydro-4H,9H- imidazo[l,2,3-zy]-l,8-naphthyridine-4,9-dione dihydro chloride (36mg, 0.0965mmol) (for a preparation see Example 2(n) in DCM (2ml) and methanol (0.1ml) under argon at rt was treated with triethylamine (43 mul, 0.309mmol) and stirred at rt for 0.25h before addition of 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d))) (16mg, 0.0965mmol). <n="39"/>The mixture was then stirred at rt for Ih before addition of NaBH(O Ac)3 (41mg, 0.193mmol). The reaction was stirred at rt for a further 0.5h before addition of saturated aqueous sodium bicarbonate (20ml). The mixture was extracted with 20% methanol/DCM (3 x 100ml). The organic extracts were dried (MgSO4), evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a clear oil (24mg, 55%). MS (ES+) m/z 450 (MH+). deltaH (CDCl3, 400MHz) 1.30-1.50 (2H, m), 1.80-1.92 (2H, m), 2.19-2.35 (2H, m) 2.49-2.72 (3H, m), 2.92-3.02 (IH, m), 3.07-3.13 (IH, m), 3.81 (2H, s), 4.22-4.51 (5H, m) 4.52-4.60 (IH, m), 4.96-5.04 (IH, m), 6.22-6.32 (2H, m), 6.81 (IH, s), 7.45-7.53 (2H, m), 8.04 (IH, s). The free base of the title compound in methanol and chloroform was converted to the hydrochloride salt by adding an equivalent of 4M hydrogen chloride in 1,4-dioxane, followed by evaporation to dryness. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Example 1; l-{(6S)-6-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]- 5,6,7,8-tetrahydro-2-naphthalenyl}-7-fluoro-2(lH)-quinolinone dihydrochloride; (a) (2S)-6-Bromo-N-(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)-l,2,3,4- tetrahydro-2-naphthalenamine; (2S)-6-Bromo-l,2,3,4-tetrahydro-2-naphthalenamine (0.5 Ig, 1.94 mmol) was treated with CHCI3 (2OmL) and MeOH (2ml) under argon at room temperature and then triethylamine (0.541ml, 3.88 mmol) was added. The reaction was stirred for lOmins at room temperature when 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.32Og, 1.94 mmol) (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) was added followed by sodium triacetoxyborohydride (1.24g, 5.83 mmol). The reaction was allowed to stir at room temperature for 16h, after which the reaction was quenched by addition of aq. sat. NaHCCh solution (20ml). The aqueous phase was then separated and then washed a further 3 times with 10% MeOH in DCM (10ml). The organic layers were then combined, dried (Na2SO4), filtered and the solvent was removed to give a yellow oil. This residue was then purified using flash column chromatography eluting with 0-100% EtOAc in hexane then 0-20% MeOH in EtOAc gradient to give a white solid (0.707g, 97%). MS (ES+) m/z 376 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Example 10; 4-(5-{ [(2,3-Dihydro [ 1 ,4] dioxino [2,3-c] pyridin-7-ylmethyl)amino] - methyl}-5,6,7,8-tetrahydro-2-naphthalenyl)-6-(methyloxy)pyrido[2,3-b]pyrazin- 3(4H)-one hydrochloride; 4-[5-(Aminomethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]-6- (methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one hydrochloride (for a preparation see Example 9(k)) (0.2g, 0.536mmol) was dissolved in CHCl3 (5ml) and MeOH (0.5ml) at room temperature under argon was treated with triethylamine (0.150ml, 1.07mmol), The reaction was stirred for 15mins then 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (for synthesis see WO2004058144 Example 2(c) or WO2003087098 Example 19(d)) (0.089g, 0.536mmol) was added. The mixture was stirred for a further 15mins before it was treated with sodium triacetoxyborohydride (0.342g, l.betalmmol) and then allowed stir at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3 solution (10ml). The aqueous layer was separated and washed a further 3 times with 10% MeOH in DCM (10ml). The organic layers were then combined, dried (Na2SO4), filtered and the solvent removed to give a dark brown oil. This residue was then purified twice using flash column chromatography eluting 0-100% EtOAc in hexane then 0-30% MeOH in EtOAc gradient to give the free base of the title compound as a clear oil (0.104g, 40%). MS (ES+) m/z 486 (MH+).1H NMR (250MHz) delta(MeOD) 1.72 - 2.02 (4H, m), 2.78 - 2.95 (4H, m), 3.06 - 3.13 (IH, m), 3.58 (3H, s), 3.80 (IH, d), 3.85 (IH, d), 4.26 - 4.36 (4H, m), 6.74 (IH, d), 6.96 - 7.08 (3H, m), 7.37 (IH, d), 8.00 (IH, s), 8.75 (IH, d) and 8.13 (IH, s).The free base of the title compound was converted to the HCl salt by dissolving the obtained free base in MeOH (2ml), adding IM HCl in MeOH and removing the solvent to give a solid (0.075g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Example 14; Cis-4-{7- [(2,3-Dihydro [ 1 ,4] dioxino [2,3-c] pyridin-7-ylmethyl)amino] -6- hydroxy-5,6,7,8-tetrahydro-3-quinolinyl}-6-(methyloxy)pyrido[2,3-6]pyrazin-3(4H)- one; To a solution of cis-4-(7-amino-6-hydroxy-5,6,7,8-tetrahydro-3-quinolinyl)-6- (methyloxy)pyrido[2,3-delta]pyrazin-3(4H)-one (for a preparation see Example 12(i)) (131 mg, 0.39 mmol) in DCM (5 rnL) and MeOH (0.5 rnL) at room temperature was added 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) (71 mg, 0.43 mmol) then sodium triacetoxyborohydride (165 mg, 0.78 mmol). The resulting suspension was stirred at room temperature overnight then the reaction mixture was diluted with DCM (10 mL) and washed with sat. aq. NaHCO3 (10 mL). The aqueous was then separated and washed a further three times with DCM (10 mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated to deliver a yellow foam. This residue was then purified twice by flash column chromatography, eluting with 0-10% MeOH:DCM to afford a yellow solid (112 mg, 59%). MS (ES+) m/z 489 (MH+).1H NMR (400MHz) 5(CDCl3) 3.07-3.13 (4H, m), 3.16-3.19 (IH, m), 3.67 (3H, s), 3.96 (2H, dd), 4.20-4.22 (IH, m), 4.28-4.31 (2H, m), 4.34-4.36 (2H, m), 6.74 (IH, d), 6.79 (IH, s), 7.45 (IH, d), 8.07 (IH, d), 8.13 (IH, s), 8.26 (IH, s), 8.39 (IH, d).The free base of the title compound was converted to the HCl salt by dissolving in MeOH, adding a large excess of 1 M HCl in MeOH (~2 mL) and then removing the solvent to give the hydrochloride salt of the title compound (106 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | (1) Title compound; A solution of trans-4-[(6R/S,7R/S)-7-amino-6-hydroxy-5,6,7,8-tetrahydro-3- quinolinyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (41.1 mg, 0.121 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for synthesis see WO2004058144 Example 2(c) or WO2003087098 Example 19(d)) (16 mg, 0.097 mmol) in dichloromethane (5 ml) and methanol (0.5 ml) and N,N-Dimethylformamide (0.1 ml) at rt was stirred at rt for 30 min then sodium triacetoxyborohydride (51.3 mg, 0.242 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (10 mL), washed with saturated aq. NaHCO3 (10 mL) and back-extracted with DCM (20 mL). Combined organics were washed with half-saturated brine/water (5 mL), dried over MgSOphi filtered and evaporated to deliver an orange oil. The crude residue was purified on silica, eluting with 5-10% MeOH/DCM. Relevant fractions were combined and evaporated to deliver the free base of the title compound as a clear yellow/orange oil (33 mg, 0.07 mmol, 70%). MS (ES+) m/z 489 (MH+).1H NMR (400MHz) 5(CDCl3) 2.83-3.13 (6H, m), 3.25 (IH, dd), 3.46 (IH, dd), 3.67 (3H, s), 3.85-3.95 (2H, m), 4.27-4.62 (4H, m), 6.72-6.85 (2H, m), 7.45 (IH, d), 8.02-8.13 (2H, m), 8.27 (IH, s), 8.38 (IH, d). <n="84"/>This compound was converted to the di-HCl salt by dissolving the free base in MeOH, adding a large excess of 1 M HCl in MeOH (~2 rnL) and then removing the solvent to give the title compound (30 mg). MS (ES+) m/z 489 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Example 27; 4-{6-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-5,6,7,8-tetrahydro-2-quinazolinyl}-6-(methyloxy)pyrido[2,3-6]pyrazin-3(4H)-one hydrochloride; A mixture of 4-(6-amino-5,6,7,8-tetrahydro-2-quinazolinyl)-6- (methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one hydrochloride (for a preparation see Example 26(k)) (46 mg, 0.142 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (for synthesis see WO2004058144 Example 2(c) or WO2003087098 Example 19(d)) (23.4 mg, 0.142 mmol), and sodium bicarbonate (119 mg, 1.42 mmol) in DCM (4 ml) and methanol (0.8 ml) was treated with sodium sulfate (200 mg, 1.408 mmol) and stirred overnight. Sodium triacetoxyborohydride (90 mg, 0.425 mmol) was added and the reaction was stirred under nitrogen for 4 hours. The mixture was then absorbed onto silica and chromatographed using 0 - 20% MeOH/DCM (containing 1% NH4OH) giving the free base of the title compound a solid (18 mg, 25%). 1H NMR deltaH CDCl3, (250MHz) 1.8-2.25 (m, 4H), 2.8(m, IH), 3.0-3.3 (m, 4H), 3.6 (s, 3H), 3.95 (s, 2H), 4.3(dd, 2H), 4.35(dd, 2H), 6.7 (d, IH), 6.8 (bs, IH), 8.1 (d, IH), 8.15 (d, IH), 8.25 (s, IH), 8.7 (s,lH). MS (ES+) m/z 510.4 (MH+).This material was converted into the title compound by addition of 1 equivalents of IM HCl in ether to the solution of the compound in DCM followed by evaporation to dryness. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Example 16; 4-(8-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino] methyl}-7,8-dihydro-5H-pyrano [4,3-b] pyridin-3-yl)-6- (methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one dihydrochloride; <n="76"/>4-[8-(Aminomethyl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl]-6- (methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (for a preparation see Example 30(h)) (0.05 g, 0.147 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde(for synthesis see WO2004058144 Example 2(c) or WO2003087098 Example 19(d)) (0.024 g, 0.147 mmol) was dissolved in chloroform (2 ml) and methanol (0.2 ml) at room temperature under argon, whereupon sodium triacetoxyborohydride (0.094 g, 0.442 mmol) was added portionwise. After 2 hours, the reaction was quenched with saturated NaHCO3 (5ml) and diluted with 10% MeOH in DCM (5ml). The aqueous phase was separated and washed a further 3 times with 10% MeOH in DCM (5ml). The organics were combined, dried (Na2SO4), filtered and the solvent removed to give a yellow oil (0.053g). This residue was then chromatographed eluting with 0-30% MeOH in DCM, to give the free base of the title compound as a clear oil (0.035 g, 49%). MS (ES+) m/z 489 (MH+).1H NMR (400MHz) delta(MeOD) 2.96-3.08 (2H, m), 3.11-3.17 (IH, m), 3.62 (3H, s), 3.63 (3H, s), 3.85 (2H, d), 4.07 (IH, dd), 4.18 (IH, dd), 4.27-4.30 (2H, m), 4.33-4.37 (2H, m), 4.83 (2H, d), 6.81 (IH, d), 6.89 (IH, s), 7.62 (IH, d), 7.99 (IH, s), 8.13 (IH, d), 8.19 (IH, s), and 8.46 (IH, d).This compound was converted to the title compound by dissolving the obtained free base in MeOH (2ml) whereupon (0.145 ml, 2 eq.) of IM HCl in MeOH was added. This solution was then evaporated to dryness to give the title compound (0.0342g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Example 34; l-{7-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]- 5,6,7,8-tetrahydro-3-quinolinyl}-7-(methyloxy)pyrido[2,3-b]pyrazin-2(lH)-one; <n="101"/>A solution of l-(7-amino-5,6,7,8-tetrahydro-3-quinolinyl)-7-(methyloxy)pyrido[2,3-b]pyrazin-2(lH)-one (obtainable from the hydrochloride salt (for a preparation see Example 32(h)) by dissolving in methanol and purification on a SCX cartridge eluting with methanol, 0.2M ammonia in methanol, then IM ammonia in methanol) (60 mg, 0.186 mmol) in anhydrous dichloromethane (DCM) (4 ml) and anhydrous methanol (0.4 ml) was treated with 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (for synthesis see WO2004058144 Example 2(c) or WO2003087098 Example 19(d)) (30.6 mg, 0.186 mmol) and the solution was stirred at 20 0C, under argon for 15 minutes. The orange solution was cooled in an ice-bath and sodium triacetoxyborohydride (118 mg, 0.557 mmol) was added in one go and the yellow solution was stirred at room temperature for 1.5 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (1 ml) and stirred for 10 minutes. The layers were separated and the aqueous was washed with 10: 1 DCM: methanol (2 x 20 ml). The organic extracts were combined and dried by passing through a hydrophobic frit and evaporated to a yellow gum which was chromatographed eluting with a 0 to 100% ethyl acetate in iso-hexane gradient followed by a 0 to 30% methanol in ethyl acetate gradient. The product fractions were combined and evaporated to a yellow gum which was mixed with dichloromethane (2 ml) and diluted with anhydrous diethyl ether (50 ml) and allowed to stand. The pale yellow solid was collected by filtration, washed well with ether and dried at 4O0C to give the title compound as a yellow solid (39.1 mg, 44%).MS (ES+) m/z 473(MH+).NMR(CDCl3) 1.80 (IH, m), 2.16 (IH, m), 2.82-3.06 (3H, m), 3.20-3.38 (2H, m), 3.83 (3H, m), 3.93 (2H, m), 4.30 (4H, m), 6.48-6.55 (IH, m), 6.82-6.87(1H, m), 7.38 (IH, m), 8.14 (IH, m), 8.32-8.36 (2H, m), 8.44 (IH, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Example 8; 4-{7-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]- 5,6,7,8-tetrahydro-3-quinolinyl}-6-(methyloxy)pyrido[2,3-6]pyrazin-3(4H)-one hydrochloride; To a solution of 4-(7-amino-5,6,7,8-tetrahydro-3-quinolinyl)-6- (methyloxy)pyrido[2,3-delta]pyrazin-3(4H)-one (for a preparation see Example 6(f)) (145 mg, 0.45 mmol) in DCM (5 mL) and MeOH (0.5 mL) at room temperature was added 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (97 mg, 0.59 mmol) (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) then sodium triacetoxyborohydride (286 mg, 1.35 mmol). The resulting suspension was stirred at room temperature for 1 h then the reaction mixture was diluted with DCM (10 mL) and washed with sat. aq. NaHCO3 (10 mL). The aqueous was then separated and washed a further three times with DCM (10 mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated to deliver an orange oil. This residue was then purified by flash column chromatography (three sequential columns required), eluting with 0-10% MeOH:DCM to afford the free base of the title compound as a clear orange oil (25 mg, 11%). MS (ES+) m/z 473 (MH+)1H NMR (400MHz) 5(CDCl3) 1.72-1.81 (IH, m), 2.12-2.17 (IH, m), 2.83-3.01 (3H, m), 3.12-3.19 (IH, m), 3.32 (IH, dd,), 3.67 (3H, s), 3.92 (2H, s), 4.27-4.29 (2H, m), 4.32-4.35 (2H, m), 6.74 (IH, d), 6.85 (IH, s), 7.41 (IH, d), 8.07 (IH, d), 8.13 (IH, s), 8.27 (IH, s), 8.37 (IH, d).The free base of the title compound was converted to the HCl salt by dissolving the free base in MeOH, adding 1 M HCl in MeOH (0.08 ml) and then removing the solvent to give the hydrochloride salt of the title compound (25 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 81; (6R)-6-[4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]-4-(hydroxymethyl)-l-piperidinyl]methyl}-3-fluoro-5,6-dihydro- 8H- [1 ,4] oxazino [2,3,4-de] - 1 ,5-naphthyridin-8-one dihydrochloride; (a) 1-(1,1-Dimethylethyl) 4-methyl 4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]-l,4-piperidinedicarboxylate; To a solution of 1 -( 1 , 1 -dimethylethyl) 4-methyl 4-amino- 1 ,4- piperidinedicarboxylate (methyl 4-amino l-tert-butoxycarbonylpiperidine-4- carboxylate) (5.76g, 22.3 mmol) and (2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) (3.6 Ig, 21.8 mmol) in DMF (60 mL) at 600C was <n="81"/>added sodium triacetoxy borohydride (14.2g, 66.9 mmol) portionwise with cooling as necessary to control effervescence. The mixture was then stirred at RT for 2h then heated to 670C overnight. The mixture was cooled then partitioned between 1 : 1 water / saturated brine (100 mL) and ethyl acetate (100 mL). The aqueous layer was made basic by addition of saturated sodium bicarbonate solution then extracted with ethyl acetate (3 x 100 mL). The combined organics were separated and washed with water (100 mL), then brine (100 mL), dried over magnesium sulphate, filtered and evaporated to dryness. Chromatography on silica gel eluting with a gradient of 80 - 100% ethyl acetate / hexane gave the title compound as a yellow oil (6.82g). MS(ES+), m/z408 (MH+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | (i) Title compound; (6i?)-6-[(4-Amino-l-piperidinyl)methyl]-3-fluoro-5,6-dihydro-8H- [l,4]oxazino[2,3,4-fe]-l,5-naphthyridin-8-one dihydrochloride ( 2.98g , containing 5.56 mmol of assumed di-hydrochloride) was dissolved in methanol ( 20ml) containing acetic acid (0.2 ml) and treated with sodium acetate ( 1.36g , 3.0 equiv) followed by 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde ( 918mg, 5.56 mmol) (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)). After stirring at room temperature for 40 min, (polystyrylmethyl)trimethylammonium cyanoborohydride 4.0 mmoles / gm (5.56g, 4.0 equiv ) was added and the mixture stirred at RT overnight. The mixture was then filtered and the filtrate evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 15% 2M ammonia / methanol in DCM gave the title compound as a free base as a white foam (1.69g, 65%). 1H NMR (400 MHz, CDCl3) delta 1.47-1.56 (2H, m), 1.88 - 1.95 (2H, m), 2.02 - 2.10 ( IH, m) , 2.13 - 2.20 ( IH, m) , 2.29 (IH, dt, J 2.4, 11.6 Hz), 2.42 - 2.62 (2H, m), 2.85 (IH, d, J 11.2 Hz), 3.15 (IH, d, J 11.6 Hz) , 3.84 (2H, s), 4.13 ( IH, dd, J 0.8, 11.2 Hz) , 4.27 - 4.29 ( 2H, m) 4.33 - 4.35 (2H, m), 4.92 - 4.96 ( IH, m) , 5.07 (IH, d, J 10.4 Hz), 6.82 (IH, s), 6.83 (IH, d , J 10.0 Hz), 7.86(1H, d, J 10.0 Hz), 8.10 (IH, s,), 8.37 (IH, d, J 2.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In methanol; at 20℃; | (f) Title compound; (3i?)-3-[(4-Amino-l-piperidinyl)methyl]-10-fluoro-2,3-dihydro- 5H[l,4]oxazino[2,3,4-z/]quinolin-5-one ( 0.29 g, 0.92 mmole ) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde ((0.152g, 0.92mmol) (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) were dissolved in methanol ( 25 ml ) and treated with acetic acid ( 0.25 ml ). This was treated with. (Polystyrylmethyl) trimethylammonium cyanoborohydride 4.0 mmoles / gm (0.92g, 3.7 mmol) was added and the mixture stirred at RT overnight. The mixture was then filtered and the filtrate evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 10% 2M ammonia / methanol in DCM gave the free base of the title compound as a pale yellow foam. (0.21, g). 1H NMR (400 MHz, CDCl3) delta 1.72 -1.85 (3H,m), 1.87 - 1.93 ( 2H,m), 2.16 - 2.19 (lH,m), 2.25 -2.31 (lH,m), 2.37 - 2.41 (lH,m), 2.48 - 2.55 (lH,m), 2.59 - 2.63 (lH,m), 2.84 - 2.87 (lH,m), 3.18 - 3.21 (lH,m), 3.78 (2H,s), 4.00 - 4.4.03 (lH,m), 4.28 - 4.34 ( 4 H,m), 4.95 - 4.99 ( 2H,m), 6.61 (lH,d, J = 8 Hz), 6.82 (lH,s), 6.99 - 7.09 (lH,m), 7.10 - 7.13 (lH,m), 7.64 (1 H,d, J= 8 Hz), 8.10 (1 H,s). MS (ES+) m/z 467 (MH+, 100 %). <n="47"/>The free base was dissolved in methanol (5 ml), IM HCl in diethyl ether (1.34 ml, 3 equiv) was added dropwise and the solution concentrated in vacuo to give the title compound as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium tris(acetoxy)borohydride; triethylamine; In dichloromethane; for 76h; | (g) Title compound; Ethyl (2E)-3-{(3i?)-3-[(4-amino-l-piperidinyl)methyl]-10-fluoro-5-oxo-2,3- dihydro-5H-[l,4]oxazino[2,3,4-zy]quinolin-8-yl}-2-propenoate dihydrochloride salt (0.15g, 0.3mmol) was suspended in dichloromethane (2ml) and triethylamine (0.13ml, 0.9mmol) added. 2,3-Dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.05 Ig, 0.3mmol) (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 <n="49"/>Example 19(d) was added to the resulting solution followed by sodium triacetoxyborohydride (0.32g, 1.5mmol) and stirred for 4h, after which time further sodium triacetoxyborohydride (0.28g, 1.3mmol) was added and the solution stirred for 72h. The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate then brine. The organics were isolated, dried and concentrated to yield an oil. Chromatography over silica (5g SPE, gradient elution with dichloromethane to dichloromethane/methanol 95:5) provided the title compound as an oil which on trituration under ether provided the product as a white solid (0.14g, 81%). MS (ES+) m/z 565 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | (i) Title compound; 6-[(4-Amino-l-piperidinyl)methyl]-3-fluoro-5,6-dihydro-4H,8H-pyrido[3,2,l- fe]-l,5-naphthyridin-8-one (0.14g, 0.44 mmole) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) (0.072g, 0.44 mmole) were dissolved in methanol (20 mL) and acetic acid (0.02 ml) The reaction was stirred for 5 min and treated with (polystyrylmethyl)trimethylammonium cyanoborohydride 4.0 mmoles / gm (0.44g, 1.76 mmoles) The reaction was stirred at RT overnight. The mixture was then filtered and the filtrate was evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 10% 2M ammonia/ methanol in DCM gave the free base of the title compound as a white foam (150 mg 73 %. ).1H NMR (250 MHz, CDCl3): delta 1.35 - 2.88 (14H, m), 3.13 - 3.21 (2H, m), 3.81 (2H, s), 4.25 - 4.38 (4H, m), 5.22 - 5.33 (IH, m), 6.80 - 6.85 (2H, m), 7.85 (IH, d, J 9.7 Hz), 8.10 (IH, s ), 8.35 (IH, s).MS (ES+), m/z 466 (MH+, 40%). 488 ( MNa+, 10 % ).The free base of the title compound ( 22 mg, 0.047 mmol) was dissolved in dichloromethane and treated with a solution of HCl in diethyl ether (0.2 ml, 0.2 mmol) . A white precipitate formed which was collected by filtration and dried in vacuo, to give the title compound as a white solid (18 mg). MS as for the free base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(d) Title compound; l,l-Dimethylethyl (l-[(6i?)-3-cyano-8-oxo-5,6-dihydro-8H- [l,4]oxazino[2,3,4-(ie]-l,5-naphthyridin-6-yl]methyl}-4-piperidinyl)carbamate (86mg, 0.2 mmol) was dissolved in dry dichloromethane (2 ml) , treated with TFA (2ml) and stirred at room temperature for 20 min. The solvent was evaporated, the residue taken up in dichloromethane and re-evaporated. The process was repeated three times to afford a white foam. This was dissolved in in methanol (2 mL), and acetic acid (0.02 ml) and treated with sodium acetate (anhydrous, 49mg, 3.0 equiv) followed by 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) (0.046g, 0.28 mmole) . After stirring at room temperature for 40 min,(polystyrylmethyl)trimethylammonium cyanoborohydride 4.0 mmoles / gm (0.3g, 1.2 mmol) was added and the mixture stirred at RT overnight. The mixture was then filtered and the filtrate evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 20% 2M ammonia / methanol in DCM gave the free base of the title compound as a colourless oil (40mg). The presence of 20% of the corresponding 3-Bromo compound was noted as an impurity. The product was purified to >90% purity and converted to the di-formate salt by mass- directed preparative etaPLC using 0.1% formic acid in acetonitrile/water as eluant to afford the title compound (15mg). <n="55"/>1H NMR (400 MHz, MeOD) delta 1.67 - 1.70 (2H, m), 2.06 - 2.30 (4H, m), 2.50 - 2.65(2H, m) , 3.01 - 3.20 (3H, m ), 4.20 (2H, s), 4.31 - 4.33 ( 2H, m) 4.36 - 4.39 (2H, m), 4.44 ( lH,dd, J 2.4, 11.6 Hz) , 5.06 - 5.09 (2H, m,), 7.00 (IH, s), 7.04 (IH, d, J 10.0 Hz), 8.01(1H, d, J 10.0 Hz), 8.13 (IH, s,), 8.25 (2H, br. s), 8.63 (IH, s). MS (ES+), m/z 475 (MH+ 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (polystyrylmethyl)trimethylammonium cyanoborohydride; acetic acid; In methanol; at 20℃; | (c) Title compound; (3R)-3-[(3R,4S)-4-Amino-3-hydroxy-l-piperidinyl]methyl}-10-fiuoro-2,3- dihydro-5H-[l,4]oxazino[2,3,4-ij]quinolin-5-one ( 0.05g, 0.15 mmol ) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) (0.025g, 0.15 <n="56"/>mmol ) was dissolved in methanol ( 10 ml ) and treated with acetic acid ( 0.1 ml ). This was treated with, (polystyrylmethyl) trimethyl ammonium cyanoborohydride 4.0 mmoles / gm (0.2g, 0.6 mmol) was added and the mixture stirred at RT overnight. The mixture was then filtered and the filtrate evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 10% 2M ammonia / methanol in DCM gave the title compound as a free base as a pale yellow oil. (Yield 0.05 g). 1H NMR (400 MHz, CDC13) d 2.04-2.13 (3H, m), 2.30 - 2.35 (2H,m), 2.45-2.49 (lH,m), 2.65-2.71 (IH, m), 2.83- 2.85 (lH,m), 3.22-3.25 (IH, m ), 3.78 (3H, s), 4.03- 4.05 (2H, m), 4.25-4.35 (5H, m), 4.91-5.02 (2H,m), 6.62 (IH, d, J=12Hz ), 6.83 (lH,s), 6.95-7.00 (lH,m), 7.02-7.11 (lH,m), 7.64 (IH, d, J=12 Hz), 8.10 (IH, s). MS (ES+), m/z 483 (MH+, 10% ).The free base of the title compound was dissolved in methanol (2 ml) IM HCl in diethyl ether 3 equivalents. (0.35 ml) was added dropwise and the solution concentrated in vacuo to give the title compound as a solid. (Yield 0.06 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (polystyrylmethyl)trimethylammonium cyanoborohydride; acetic acid; In methanol; at 20℃; for 18h; | (d) Title compound; A mixture of (3i?)-3-[(36f,45)-3-(aminomethyl)-4-hydroxy-l- pyrrolidinyl]methyl}-10-fluoro-2,3-dihydro-5H-[l,4]oxazino[2,3,4-z/]quinolin-5-one(35mg, 0.1 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (0.94g, 5.7 mmole) (for a synthesis see WO2004058144, Example 2(c) orWO2003087098 Example 19(d)) (0.017g, 0.1 mmole) in methanol (2 mL) and acetic acid (20 microlitres) was treated with (polystyrylmethyl)trimethylammonium cyanoborohydride 4.0 mmoles / gm (O.lg, 0.4 mmoles) and stirred at RT for 18h. The mixture was then filtered and evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 20% 2M ammonia / methanol in DCM gave the free base of the title compound as a colourless oil (0.018g).1H NMR (400MHz, CDCl3): delta 2.35 - 2.41 (IH, m), 2.43 - 2.47 (IH, m,), 2.54 - 2.62(IH, m), 2.78 - 2.93 (6H, m), 3.78 (2H, s), 3.97 - 4.03 (IH, m), 4.28 - 4.29 (2H, m),4.32 - 4.34 (2H, m) , 4.45 - 4.48 (IH, m), 4.96 (2H, d, J 11.2 Hz), 4.98 - 5.02 ( IH, m), 6.59 (IH, d, J 9.6 Hz), 6.76 (IH, s), 6.95 - 7.00 (IH, m), 7.12 - 7.15 (IH, m),7.64 (IH, d, J 9.6 Hz), 8.13 (IH, s).MS (ES+), m/z 483 (MH+, 40%).The free base of the title compound ( 18 mg, 0.037 mmol) was dissolved in methanol (2ml) and treated with a solution of HCl in diethyl ether (0.13 ml, 3 equiv) . The solvent was evaporated to afford the title product as a pale yellow solid.MS as for the free base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | (g) Title compound; (6i?)-6-[(4-Amino-l-piperidinyl)methyl]-3-fluoro-5,6-dihydro-8H- [l,4]thiazmo[2,3,4-de]-l,5-naphthyridin-8-one dihydrochloride. ( 37 mg, containing 0.08 mmol ) was dissolved in methanol ( 4 ml ) and acetic acid ( 0.04 ml ) and treated with sodium acetate anhydrous ( 21 mg, 2.5 mmol ) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) ( 20 mg, 0.12 mmol ). The reaction mixture was left stirring at room temperature for 20 min. Sodium cyanoborohydride ( 6.22 mg, 0.1 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was applied to a SCX cartridge (2 g ) and eluted with methanol ( 10 ml ). and 0.2 M ammonia in methanol ( 10 ml ). Fractions containing the compound were combined and evaporated. The residue was chromatographed on silica gel eluting <n="71"/>with a gradient of 0-20% 2M methanolic ammonia in dichloromethane to give the free base of the title compound as a pale yellow solid. ( 18.5 mg, 39 % ) H NMR ( 400 MHz, CDCl3 ) delta 1.71- 1.95 (2H,m ), 2.03 -2.15 (2H,m), 2.24 - 2.33 (2H,m ), 2.49 - 2.56 (lH,m), 2.72 -2.78 (lH,m ), 2.84 (2H,m ), 3.07 - 3.16 (lH,m), 3.19- 3.23 (lH,m), 3.43 - 3.53 (4H,m), 4.26 - 4.34 (4H, m), 5.57 - 5.60 (IH, m ), 6.79 -6.84 (2H,m), 7.86 ( lH,d,J=8 Hz), 8.10 (lH,s) , 8.29 ( IH, s ). MS (ES+), m/z 484 (MH+, 100%)., m/z 633 (MH+, 50%).,The free base of the title compound ( 18.5mg, 0.038 mmol) was dissolved in methanol ( 2 ml ) and treated with IM HCl in diethyl ether ( 0.11 ml, 3 eqs.) . The resulting mixture was evaporated to dryness to afford the di-HCl salt as a yellow solid. MS (ES+), m/z 484, 532 (MH+, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | (e) 10-Chloro-3-({4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridm-7-ylmethyl)ammo]-l- piperidinyl}methyl)-2,3,6,7-tetrahydro-5H-[l,4]oxazino[4,3,2-(ie]quinoxalin-5-one (Enantiomer 2); 3-[(4-Amino-l-piperidinyl)methyl]-10-chloro-2,3-dihydro-5H-[l,4]oxazino[4,3,2-fe]quinoxalin-5-one Enantiomer 2 ( 150 mgs, 0.50 mmol) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) (0.83mg, 0.50 mmol) in methanol (20 ml) and acetic acid (0.2 ml) was treated with(polystyrylmethyl)trimethylammonium cyanoborohydride 4.0 mmol / gm (0.5g, 2 mmol) and stirred at room temperature overnight The mixture was then filtered and the filtrate was evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 10% 2M ammonia / methanol in DCM gave the title compound as a yellow oil, a free base ( 80 mg, 33 % ). MS (ES+), m/z 486 (MH+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (polystyrylmethyl)trimethylammonium cyanoborohydride; acetic acid; In methanol; chloroform; at 20℃; for 60h; | (m) Title compound; A mixture of 3-[(4-amino- 1 -piperidinyl)methyl]- 10-fluoro-2,3-dihydro- lH,5H-pyrido[3,2,l-z/]quinolin-5-one (0.04g, 0.13 mmole) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d) (0.021g, 0.13 mmole) in chloroform (5 mL), methanol (5 mL) and acetic acid (5 drops) was treated with (polystyrylmethyl)trimethylammonium cyanoborohydride 4.0 mmoles / gm (0.27g, 1.1 mmoles) and stirred at RT for 2.5 days. The mixture was then filtered and the resin washed with 1 : 1 DCM / methanol (2 x 20 mL) and the combined filtrate and washings evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 12% 2M ammonia / methanol in DCM gave the title compound as a free base (0.052g). <n="32"/>1H NMR ^SO MHZ5 CDCI3)I O 1.35 - 2.88 (14H, m), 2.93 - 3.21 (2H, m), 3.81 (2H, s), 4.22 - 4.38 (4H, m), 5.22 - 5.33 (IH, m), 6.61 (IH, d, J 9.5 Hz), 6.79 (IH, s), 6.89 (IH, t, J 8 Hz), 7.29 - 7.39 (IH, m), 7.59 (IH, d, J 9.5 Hz), 8.12 (IH, s). MS (ES+), m/z 465 (MH+, 100%).The free base in methanol was converted to the dihydrochloride salt by addition of 4.0M hydrogen chloride in 1,4-dioxane then evaporating to dryness to give a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | (f) Title compound; l,l-dimethylethyl (l-[(6i?)-3-bromo-8-oxo-5,6-dihydro-8H-[l,4]oxazino[2, 3,4-de]-l, 5-naphthyridm-6-yl]methyl}-4-piperidmyl)carbamate ( 134 mg, 0.28 mmol) was dissolved in dichloromethane (5 ml) and treated with a solution of 4M HCl in 1,4-dioxane ( 1.0 ml, 4.0 mmol) . The reaction mixture was stirred at room temperature for 30 mins then evaporated under reduced pressure to give a white solid. (147 mg, assumed to be the hydrated di-hydrochloride). This was dissolved in methanol (5 mL), and acetic acid (0.05 ml) and treated with 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO2003087098 Example 19(d)) (0.046g, 0.28 mmole) . After stirring at room temperature for 40 min,(polystyrylmethyl)trimethylammonium cyanoborohydride 4.0 mmoles / gm (0.3g, 1.2 mmol) was added and the mixture stirred at RT overnight. The mixture was then filtered and the filtrate evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0 - 15% 2M ammonia / methanol in DCM gave the title compound as a free base as a colourless oil (lOOmg, 67%).1H NMR (400 MHz, CDCl3) delta 1.35 - 1.49 (2H, m), 1.79 - 1.95 (2H, m), 2.13 - 2.20 ( IH, m) , 2.28 (IH, dt, J 2.4, 11.2 Hz), 2.40 (IH, dd, J 2.8, 12.4 Hz), 2.45 - 2.53 (2H, m), 2.85 (IH, d, J 11.2 Hz), 3.15 (IH, d, J 11.6 Hz) , 3.79 (2H, s), 4.16 ( IH, d, J 10.8 Hz) , 4.26 - 4.28 ( 2H, m) 4.31 - 4.34 (2H, m), 4.90 - 4.96 ( IH, m) , 5.10 (IH, dd, J 10.8 Hz), 6.81 (IH, s), 6.91 (IH, d , J 10.0 Hz), 7.86(1H, d, J 10.0 Hz), 8.10 (IH, s,), 8.50 (IH, s). MS (ES+), m/z 530, 532 (MH+, 60%).The free base of the title compound (lOOmg, 0.19 mmol) was dissolved in methanol and treayed with IM HCl in diethyl ether ( 0.8 ml, 0.8 mmol) . After 10 min that resulting mixture was evaporated to dryness to afford the di-HCl salt as a yellow solid. MS (ES+), m/z 530, 532 (MH+, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 0.65 g of tert-butyl 3-(aminomethyl)piperidine-1-carboxylate in 5 mL of dichloromethane, 0.50 g of (<strong>[443955-90-6]2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde</strong> and 0.17 mL of acetic acid were added. Subsequently, 0.96 g of sodium triacetoxyborohydride was added thereto and the mixture was stirred at room temperature for 1 hour 15 minutes. The reaction mixture was charged with chloroform and adjusted to pH 8.6 with a saturated aqueous sodium hydrogen carbonate solution and a 20percent aqueous sodium hydroxide solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidine-1-carboxylate as a yellow oily substance. 1H-NMR (CDCl3) delta: 1.12-1.92 (5H, m), 1.45 (9H, s), 2.20-2.72 (3H, m), 2.80-2.90 (1H, m), 3.78 (2H, s), 3.78-3.98 (2H, m), 4.22-4.35 (4H, m), 6.84 (1H, s), 8.10 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 0.28 g of tert-butyl 3-(aminomethyl) pyrrolidine-1-carboxylate in a mixture of 7 mL of methanol and 20 mL of dichloromethane, 0.23 g of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 0.50 g of molecular sieves 3A were added, the mixture was stirred at room temperature for 3 hours, and then, the reaction mixture was charged with 79 mg of sodium borohydride and stirred at room temperature for 5 hours 30 minutes. Thereto was added water under cooling with ice, the organic layer was separated, and the aqueous layer was extracted with chloroform. 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 to obtain 0.48 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)pyrrolidine-1-carboxylate as a colorless oily substance. 1H-NMR (CDCl3) delta: 1.45 (9H, s), 1.50-3.60 (9H, m), 3.77 (2H, s), 4.26-4.36 (4H, m), 6.81 (1H, s), 8.11 (1H, s) |
Tags: 443955-90-6 synthesis path| 443955-90-6 SDS| 443955-90-6 COA| 443955-90-6 purity| 443955-90-6 application| 443955-90-6 NMR| 443955-90-6 COA| 443955-90-6 structure
[ 478148-61-7 ]
Furo[2,3-c]pyridine-5-carboxaldehyde
Similarity: 0.69
[ 527681-61-4 ]
3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde
Similarity: 0.69
[ 4363-94-4 ]
6-Methoxyquinoline-4-carbaldehyde
Similarity: 0.63
[ 864274-04-4 ]
2-Methylbenzo[d]oxazole-6-carbaldehyde
Similarity: 0.60
[ 478148-61-7 ]
Furo[2,3-c]pyridine-5-carboxaldehyde
Similarity: 0.69
[ 527681-61-4 ]
3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde
Similarity: 0.69
[ 478148-62-8 ]
Furo[2,3-c]pyridine-5-carboxylic acid
Similarity: 0.66
[ 129421-32-5 ]
2,3-Dihydro-1,4-dioxino[2,3-b]pyridine
Similarity: 0.65
[ 478148-60-6 ]
Furo[2,3-c]pyridin-5-ylmethanol
Similarity: 0.63
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H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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