Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 1120-95-2 | MDL No. : | MFCD06801356 |
Formula : | C4H3ClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IBWYHNOFSKJKKY-UHFFFAOYSA-N |
M.W : | 114.53 | Pubchem ID : | 11274989 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 27.04 |
TPSA : | 25.78 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.93 cm/s |
Log Po/w (iLOGP) : | 1.37 |
Log Po/w (XLOGP3) : | 0.1 |
Log Po/w (WLOGP) : | 1.13 |
Log Po/w (MLOGP) : | 0.57 |
Log Po/w (SILICOS-IT) : | 1.74 |
Consensus Log Po/w : | 0.98 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.25 |
Solubility : | 6.48 mg/ml ; 0.0566 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.2 |
Solubility : | 72.9 mg/ml ; 0.636 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.21 |
Solubility : | 0.705 mg/ml ; 0.00615 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.52 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
46% | Stage #1: at 85℃; for 4.5 h; Stage #2: With sodium hydroxide In water at 0℃; |
Step A 3-(2H)-pyridazinone (5.0 g, 52.0 mmole) was treated with phosphorous oxychloride (17 ml, 179 mmole) at 85° C. for 4.5 hours. The mixture was poured into 400 g ice/H2O, basified (pH>10) with 50percent NaOH, and extracted with EtOAc (4*). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The material was run through a Hak-Pak (SiO2, 1:1 hexanes/EtOAc) to give 2.8 g (46percent) of 3-chloropyridazinone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | at 60℃; for 1.5 h; | Preparation 118: 3-Chloro-pyridazine (Prepi 18); A mixture of pyridazin-3-ol (1.9 g, 19.8 mmol) in POCI3 (19 ml) was heated to 600C for 90 minutes. After cooling to room temperature, the reaction was quenched in ice/water and neutralized with solid NaHCO3. The product was extracted with ethyl acetate, the organic phase was washed with brine, dried (Na2SO4) and evaporated to give 2.1 g of the title compound as a brown solid (92percent yield). MS (ES) (m/z): 115.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With trichlorophosphate; | a 3-Chloropyridazine 3-(2H)-Pyridazinone (1 g, 10.4 mmol) was treated with phosphorous oxychloride (10 mL) at 90° C. for 4 H. The mixture was poured into ice (100 g), basified with 50percent NaOH, and extracted with CH2 Cl2 (3*150 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a yellow solid (750 mg, 63percent): MS (ES) m/e 115 [M+H]+. |
46% | Step A 3-(2H)-pyridazinone (5.0 g, 52.0 mmole) was treated with phosphorous oxychloride (17 ml, 179 mmole) at 85° C. for 4.5 hours. The mixture was poured into 400 g ice/H2O, basified (pH>10) with 50percent NaOH, and extracted with EtOAc (4*). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The material was run through a Hak-Pak (SiO2, 1:1 hexanes/EtOAc) to give 2.8 g (46percent) of 3-chloropyridazinone. | |
Example 130 2-Chloro-N-(1 -hydroxy-cyclohexylmethyl)-5-(pyridazin-3-yloxy)- benzamide130.1 3-Chloro-pyridazineA suspension of 3(2H)-pyridazinone (1 g) in phosphorus oxychloride (0.970 mL) was heated to 80°C for 18h. The reaction mixture was evaporated off and the residue was treated with ice 2M solution of NaOH and extracted with EtOAc. The organic phase was washed with brine, dried over MgS04 and concentrated in vacuo to give 857 mg of the crude titled compound as a purple solid.1H NMR ((CD3)2SO) delta: 9.27 (d, J = 4.7 Hz, 1 H), 7.95 (d, J = 8.7 Hz, 1 H), 7.82 (dd, 4 = 8.7 Hz, J2 = 4.7 Hz, 1 H) |
With trichlorophosphate; at 80℃; for 18h; | 130.1 3-Chloro-pyridazine A suspension of 3(2H)-pyridazinone (1 g) in phosphorus oxychloride (0.970 mL) was heated to 80° C. for 18 h. The reaction mixture was evaporated off and the residue was treated with ice 2M solution of NaOH and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give 857 mg of the crude titled compound as a purple solid. 1H NMR ((CD3)2SO) delta: 9.27 (d, J=4.7 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.82 (dd, J1=8.7 Hz, J2=4.7 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate; palladium diacetate; bis(pinacol)diborane; tricyclohexylphosphine; In 1,4-dioxane; at 110℃; for 0.166667h;Inert atmosphere; | General procedure: The Miyaura borylation reactions were carried out as follows: Chloropyrazines (3.0 mmol), B2pin2 (838 mg, 3.3 mmol), Pd(OAc)2 (14 mg, 2 mol percent), PCy3 (34 mg, 4 mol percent) and AcOK (750 mg, 7.5 mmol) was added in a 50 ml three necked flask fitted with a condenser, and dioxane (15 ml) was added at last. Then the reaction mixture was stirred at a preheated oil bath 110 oC under nitrogen atmosphere for 10 min. After complete completion of starting material checked by TLC, the reaction was cooled to room temperature, EtOAc (20 ml) was added. After filtration through Celite ® and concentration under vacuo, the resulting residue was precipitated from n-hexane:Et2O to afford corresponding boronic esters. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With trichlorophosphate; at 60℃; for 1.5h; | Preparation 118: 3-Chloro-pyridazine (Prepi 18); A mixture of pyridazin-3-ol (1.9 g, 19.8 mmol) in POCI3 (19 ml) was heated to 600C for 90 minutes. After cooling to room temperature, the reaction was quenched in ice/water and neutralized with solid NaHCO3. The product was extracted with ethyl acetate, the organic phase was washed with brine, dried (Na2SO4) and evaporated to give 2.1 g of the title compound as a brown solid (92percent yield). MS (ES) (m/z): 115.1 [M+H]+. |
67% | In trichlorophosphate; | 3-chloropyridazine A solution of 3-hydroxypyridazine (96 g, 1 mol) in phosphorous oxychloride (800 ml) is refluxed on an oil bath for 4 h. The excess amount of POCl3 is removed in vacuum, the residue is cooled and added to 2 kg of ice. The reaction mixture is then neutralized with aqueous ammonia and extracted with chloroform (4x500 ml). The combined organic extract is washed with brine (3x200 ml), dried over MgSO4 and the solvent is removed in vacuum, yielding the desired product (76 g, 67percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Preparation 119: 3-lodo-pyridazine (Prep119); A mixture of <strong>[1120-95-2]3-chloro-pyridazine</strong> (Prep118, 2.1 g, 18.4 mmol) and NaI, (4 g, 26.8 mmol) in57percent Hlaq (16 ml) was warmed at 50°C for 24 hours. After cooling the solution was basified with solid NaHCO3 and extracted with ethyl acetate. The organic phase was dried <n="125"/>(Na2SO4) and evaporated to give 2.1 g of the title compound as a light brown powder(55percent yield).MS (ES) (mlz): 207.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 20h;Heating / reflux; | Step B Ethanol (10 ml) and 1.0M Na2CO3 (18 ml) were added to a suspension of the compound from step A (2.8 g, 24.0 mmole), 4-formylphenylboronic acid (4.7 g, 31.2 mmole), and tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmole0 in toluene (35 ml). The mixture was refluxed for 20 hours then cooled, diluted with EtOAc, washed with NaHCO3, washed with brine, dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 4:1 hexanes/EtOAc) yielded 4.1 g (93percent) of 4-(3-pyridazinyl)benzaldehyde. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 100℃; for 5h; | Step C: A mixture of the ester (5.2 g, crude, 5.9 mmol) obtained from Step B, <strong>[1120-95-2]3-pyridazinylchloride</strong> (1.0 g, 8.8 mmol), Na2CO3 (1.93 g, 17.9 mmol), H2O (5 mL), and DMF (25 mL) was purged with argon. PdCl2dppf (722 mg, 0.88 mmol) was added. The mixture was heated at 100° C. for 5 hours. After cooled to room temperature, the reaction was diluted with dichloromethane (100 mL), and filtered through celite. The filtrate was washed with water (200 mL) and brine (200 mL), dried (Na2SO4) and concentrated. The residue was purified by a medium pressure chromatography (eluent: MeOH/EtOAc 1:9) to give (+)-4-benzo[b]thiophen-5-yl-2-methyl-7-pyridazin-3-yl-1,2,3,4-tetrahydroisoquinoline (390 mg, 19percent for three steps) as a light-brown oil. It was dissolved in MeOH (5 mL) at room temperature, and to this solution was added fumaric acid (125 mg, 1.07 mmol). The solution was concentrated to about 2 mL. Water (20 mL) was added to the solution. The resulting suspension was lyophilized on a freeze dryer overnight to give (+)-4-benzo[b]thiophen-5-yl-2-methyl-7-pyridazin-3-yl-1,2,3,4-tetrahydroisoquinoline, fumarate salt (355 mg, 59percent, >99percent AUC HPLC) as a light-brown solid: [CC]25D+7.3° (c 0.07, methanol); mp 122-124° C.; 1H NMR (500 MHz, CD3OD) delta 9.15 (d, J=4.9 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 8.04 (s, 1H), 7.93-7.88 (m, 2H), 7.80-7.77 (m, 2H), 7.61 (d, J=5.5 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.71 (s, 4H), 4.71 (dd, J=10.5, 6.5 Hz, 1H), 4.52 (d, J=15.1 Hz, 1H), 4.44 (d, J=15.1 Hz, 1H), 3.73 (dd, J=12,0, 6.0 Hz, 1H), 3.42-3.38 (m, 1H), 2.91 (s, 3H); ESI-MS 358 [M+H]+; Anal Calcd. For C22H19N3S.1.75C4H4O4: C, 62.13; H, 4.67; N, 7.50. Found: C, 61.80; H, 4.81; N, 7.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; at 170℃; | Reference example 99:; 2-Amino-2-methyl-N-(3-pyridazinyl)propylamine[0311] To <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (770 mg, 6.70 mmol) described in WO 97/24124 were added 1,2-diamino-2-methylpropane (1.39 mL, 13.5 mmol) and [0312] N,N-diisopropylethylamine (3.48 mL, 20.0 mmol), and the mixture was stirred at 170 DEG C overnight. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography [Chromatrex (registered trademark)NH Fuji Silysia, ethyl acetate to ethyl acetate/methanol=9/1] to obtain the title compound (948 mg, 5.71 mmol).yield: 85percent<1>H NMR (CDCl3) delta (ppm): 8.50 (1H, dd, J = 4.3, 1.4 Hz), 7.13 (1H, dd, J = 8.9, 4.3 Hz), 6.71 (1H, dd, J = 8.9, 1.4 Hz), 5.43 (1H, m), 3.36 (2H, d, J = 5.9 Hz), 1.20 (6H, s).APCIMS (m/z): 167 (M + H)<+> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; In ethanol; | EXAMPLE 106 Reacting <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> with 1,3-diaminopropane in ethanol containing sodium ethoxide according to the procedure of Example 89 gives 3-(3-aminopropylamino)-pyridazine. Using this intermediate as the starting material in the procedure of Example 18 gives N-cyano-N'-[3-(3-pyridazinylamino)propyl]guanidine. The ingredients are mixed and filled into a hard gelatin capsule. Compounds of formula I where A is such that there is formed together with the carbon atom shown a five membered unsaturated heterocyclic ring having one nitrogen atom, one sulphur or oxygen atom and three carbon atoms, said unsaturated heterocyclic ring being thiazole, isothiazole, oxazole or isoxazole, and Y is oxygen or sulphur (sulphur is preferred) are exemplified by the following examples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 108 Treating 3-(3-aminopropylamino)pyridazine, prepared by reacting <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> with 1,3-diaminopropane, with benzoyl isothiocyanate by the procedure of Example 46 gives N-benzoyl-N'-[3-(3-pyridazinylamino)propyl]-thiourea. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 100℃; | Step D: To a disposable sealed tube were added the product of Step C (296 mg, 0.72 mmol) as a solution in anhydrous DMF (3 mL), sodium carbonate (228 mg, 2.2 mmol) as a solution in H2O (1.4 mL), and <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (188 mg, 1.6 mmol). The reaction mixture was degassed by a subsurface sparge with Ar for 2 minutes. PdCl2(dppf).CH2Cl2 (35 mg, 0.043 mmol) was then added under Ar. The reaction was heated to 100° C. and allowed to stir overnight. TLC analysis showed that the reaction had gone to completion. After cooling to room temperature, the reaction mixture was diluted with H2O, then extracted with ethyl acetate (3.x.). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (95:5 CH2Cl2/MeOH) yielded the desired pyridazine (128 mg, 49percent over two steps) as a light brown oil: [alpha]25D -2.9° (c 0.07, methanol); 1H NMR (500 MHz, CDCl3) delta 9.14 (dd, J=5.0, 2.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.88-7.86 (m, 2H), 7.82 (dd, J=8.5, 1.5 Hz, 1H), 7.80-7.79 (m, 1H), 7.72-7.70 (m, 1H), 7.64-7.61 (m, 1H), 7.52-7.50 (m, 1H), 7.50-7.48 (m, 2H), 7.40 (dd, J=8.5, 1.5 Hz, 1H), 6.87-6.80 (br, 1H), 4.57 (d, J=9.5 Hz, 1H), 4.11-4.05 (m, 1H), 3.92 (d, J=14.5 Hz, 1H), 3.21-3.16 (m, 1H), 3.09-3.03 (m, 1H), 2.53-2.46 (m, 1H), 2.41 (s, 3H), 2.28-2.22 (m, 1H); ESI MS m/z=366 [C25H23N3+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With triethylamine; cesium fluoride; In dimethyl sulfoxide; at 100℃; | Example 9(3R,4R,5S)-1-(r(3S.4S)-4-(5-chloropyridin-2-yl)-1-pyridazin-3-ylPyrrolidin-3-vncarbonyl)-3.5-dimethyl-4- pyridin-2-ylpiperidin-4-olTo a solution of (3R,4R,5S)-1-[(3S,4S)-4-(5-chloropyridin-2-yl)pyrrolidin-3-yl]carbonyl}-3,5-dimethyl-4- pyridin-2-ylpiperidin-4-ol (prepared by the same method as used for the amine of preparation 10, starting from (3R,4s,5S)-3,5-dimethyl-4-pyridin-2-ylpiperidin-4-ol, prepared according to international patent application publication number WO 2005/077935) (50 mg, 0.12 mmol) in DMSO (2 ml_) was added 3- <strong>[1120-95-2]chloropyridazine</strong> (28 mg, 0.24 mmol), caesium fluoride (18 mg, 0.12 mmol) and triethylamine (0.05 ml_, 0.36 mmol). The mixture was stirred at 100°C under nitrogen overnight. The reaction mixture was diluted with 10 mL ethyl acetate and washed with 3 x 20 m L of water. The combined aqueous extracts were extracted with 10 mL ethyl acetate and the combined organic extracts were washed with 10 mL brine, dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica) eluting with dichloromethane/methanol/aq. ammonia 99/1/0.1, increasing polarity to 95/5/0.5. This gave the title compound (16 mg, 27percent) as a yellow gum. 1H NMR (CD3OD, 400 MHz) delta 0.20-0.37 (6H, 4 x d), 0.91-1.13, 1.67-1.76 and 1.94-2.09 (2H, 3 x m), 2.54-2.62 (1 H, m), 2.87-2.93 and2.99-3.05 (1 H, 2 x m), 3.61-3.74 (3H, m), 3.86-4.08 (4H, m), 4.20-4.26 (1H, m), 6.83-6.88 (1H, m), 7.11-7.44 (4H, m), 7.63-7.78 (2H, m), 8.30-8.46 (3H, m); LRMS (El+) 493 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; trans-1,2-cyclohexanediamine; at 120℃; for 8h; | Intermediate 23; Ethyl (trans^-oxo-S-O-pyridazinvD-i-oxa-S-azaspiroK.deltaidecane-delta-carboxylatet; Ethyl (trans)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (prepared in an analogous fashion to Intermediate 15, 250 mg, 1.100 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (for a preparation see WO2001007416, 126 mg, 1.100 mmol), trans-1 ,2-diaminocyclohexane (0.066 ml, 0.550 mmol), copper(l) iodide (105 mg, 0.550 mmol), K3PO4 (1168 mg, 5.50 mmol) were collected and shaken at 120 0C for 8 h. Solvent was removed under vacuum, rinsed with DCM (10 ml) and filtered over a separation tube. The resulting solution was then purified with Biotage SP1 , over a Silica 25M column, eluting with a gradient of DCM and Et2O. The title compound was eluted with ca 15percent Et2O and recovered as a colourless solid (1 10 mg). <n="38"/>1H NMR (400 MHz, CDCI3): delta 8.97 (dd, 1 H), 8.56 (dd, 1 H), 7.50 (dd, 1 H), 4.20 (s, 2H), 2.55-2.46 (m, 1 H), 2.10-1.74 (m, 8h); UPLC-MS: 0.62 m, 306 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 100℃; for 2h;Product distribution / selectivity; | The boronate ester (19 g, crude) from Step F above, 3-chloro- pyridazine (4.8 g, 42 mmol), and cesium carbonate (21 g, 63 mmol) were suspended in DMF (120 mL) and water (30 mL). The mixture was purged with argon. 1,1'- Bis(diphenylphosphino)ferrocenedichloropalladium (240 mg, 0.33 mmol) was added to the mixture. The mixture was heated at 1000C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane, and filtered through a pad of Celite. The filtrate was washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (98:1.8:0.2 to 95:4.5:0.5 dichloromethane/methanol/concentrated ammonium hydroxide) to give 5-(tert-butyldimethylsilyloxy)-2-methyl-8-(pyridazin-3-yl)-2, 3,4,5- tetrahydro-lH-benzo[c]azepine (4.7 g, 40percent for 2 steps) as an oil. This oil was resolved using Chiralcel OD column (eluente :80 etaep:20 IPA:0.1 DEA) to give (+)- enantiomer (2.3 g, 98percent, ([alpha]25D, +26.9° (C, 0.29 Methanol) and (-)-enantiomer (2.3 g, 98percent, [alpha]25D, -23.2° (C, 0.28 Methanol)): 1H NMR (CDCl3, 300 MHz) delta 9.15 (d, J= 4.8 Hz, IH), 7.91-7.84 (m, 3H), 7.54-7.50 (m, 2H), 4.96 (t, J= 5.2 Hz, IH), 4.26-4.05 (m, IH), 3.85-3.73 (m, IH), 3.30-3.21 (m, IH), 2.97-2.91 (m, IH), 2.32 (s, 3H) 1.95- 1.85 (m, 2H), 0.91 (s, 9H), 0.097-0.085 (m, 6H); ESI MS m/z 370 [M+H]+.The boronate ester (5.5 g, crude) from Step F above, 3-chloro- pyridazine (2.0 g, ~16 mmol), and cesium carbonate (4.2 g, 13 mmol) were suspended in DMF (30 mL) and water (8 mL). The mixture was purged with argon. 1,1'- Bis(diphenylphosphino)ferrocenedichloropalladium (400 mg, 0.52 mmol) was added to the mixture. The mixture was heated at 1000C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane, and filtered through a pad of celite. The filtrate was washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography <n="83"/>(98:1.8:0.2 to 95:4.5:0.5 dichloromethane/methanol/concentrated ammonium hydroxide) to give 5-(tert-butyldimethylsilyloxy)-2-methyl-8-(pyridazin-3-yl)-2, 3,4,5- tetrahydro-lH-benzo[c]azepine (1.3 g, 55percent for 2 steps) as an brown oil: 1H NMR (CDCl3, 300 MHz) delta 9.15 (d, J= 4.8 Hz, IH), 7.91-7.84 (m, 3H), 7.54-7.50 (m, 2H), 4.96 (t, J= 5.2 Hz, IH), 4.20-4.10 (m, IH), 3.85-3.73 (m, IH), 2.97-2.91 (m, IH), 2.32 (s, 3H) d, J= 7.9 Hz, IH), 7.24 (d, J= 7.9 Hz, IH ), 4.82 (t, J= 4.9 Hz, IH), 3.64-3.61 (m, IH), 3.27-3.18 (m IH), 2.36 (s, 3H), 1.95-1.85 (m, 2H), 1.80-1.63 (m, 2H), 0.91 (s, 9H), 0.097-0.085 (m, 6H); ESI MS m/z 370 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; ethanol; at 130 - 155℃; for 15h; | [Example 3] Synthesis of (+-)-3',5',8',11'-tetraaza-11'-(6-chloronaphthalen-2-ylsulfonyl)-1-(3-pyridazinyl) spiro[piperidine-4,6'-tricyclo[6.4.0.01,5]dodecane]-4',9'-dione The compound obtained in Example 2, <step 4> (20 mg) was suspended in dioxane (1.5 ml) and ethanol (1.5 ml). After adding triethylamine (17 mul) and <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (19 mg), the mixture was stirred in a sealed tube at 130 to 140°C for 2 hours, and at 140 to 155°C for 5.5 hours. Another portion of <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (9 mg) was added, and the mixture was stirred at 140 to 155°C for 7.5 hours. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin-layer chromatography [Chromatorex NH.(TM).)](developing solvent: methylene chloride / methanol = 19/1) to produce the title compound (8 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 12h; | INTERMEDIATE 306,6-Dimethyl-2-[6-(pyrida2in-3-yloxy)-2,3-dihvdro-4H-l,4-benzoxazin-4-yl]-6,7- dihvdro[ 1 ,3]thiazolor5,4-clpyridin-4(5H)-oneA mixture of Intermediate 17 (53 mg, 0.16 mmol), cesium carbonate (105 mg,0.32 mmol) and 3,6-di<strong>[1120-95-2]chloropyridazine</strong> (24 mg, 0.16 mmol) in NMP (2 mL) was heated to 1100C for 12 h. After cooling to r.t. it was concentrated in vacuo. Purification by preparative etaPLC (Method 5) gave the title compound (15 mg, 23percent) as an off-white solid. deltaeta (CDCl3) 8.94 (IH, dd, J4.5, 1.3 Hz), 8.02 (IH, d, J2.4 Hz), 7.49 (IH, dd, J8.9,4.5 Hz), 7.19 (IH, dd, J 8.9, 1.3 Hz), 6.89-7.03 (2H, m), 5.21 (IH, s), 4.31-4.39 (2H, m),4.09-4.18 (2H, m), 2.86 (2H, s), 1.37 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 85℃; for 15h; | (i?)-2-Methyl-l-{3-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenoxy]propyl} -pyrrolidine (1.1 g, 3.2 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (0.485 g, 4.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.258 g, 0.223 mmol), K2CO3 (1.19 g, 8.6 mmol) in 1,2-dimethoxyethane (25 mL) and water (11.5 mL) were combined and degassed with argon. The reaction was heated at 85 0C for 15 h, cooled to rt, filtered through celite, taken up in CH2Cl2 (30 mL) and washed with water and saturated NaHCO3 solution. The CH2Cl2 layer was dried (Na2SO4) and evaporated. The product was purified by ISCO chromatography on silica gel, eluting with 5-15percent MeOH/ DCM / 0.5percent NH4OH. The HCl salt was prepared MeOH - ether-HCl to give a white solid, m.p. 198-201 0C; LCMS m/z = 298 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 105℃; for 24h;Product distribution / selectivity; | Ethyl (cis)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate and ethyl (trans)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate mixture (85/15 mixture) (obtained from combination of four different batches prepared in a similar fashion to preparation of Intermediates 2 and 3, procedures a and b, 10 g, 44.0 mmol), K3PO4 (28.0 g, 132 mmol), copper(I) iodide (0.838 g, 4.40 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (prepared according to WO/0107416, 6.05 g, 52.8 mmol) were collected into a 250 ml reaction flask, deareated, and then suspended in 1,4-dioxane (150 ml) under nitrogen. Trans-1,2-diaminocyclohexane (1.058 ml, 8.80 mmol) was added to the resulting mixture. The reaction was then warmed up to reflux (ext temp. 130° C., int temp 105° C.). The reaction mixture was stirred at that temperature for overall 24 hours. The reaction mixture was taken up with DCM (1000 ml) and poured into water (300 ml) containing 10 ml of ammonium hydroxide, and left under stirring for 10 min. Then, the resulting organic phase was washed with water (2.x.100 ml) and brine (2.x.100 ml), dried over Na2SO4, filtered and then concentrated. The resulting crude was purified with Biotage SP1, over 65i silica column, using cyclohexane and EtOAc as eluent to afford two different batches of the title compound.Batch 1: Ethyl (trans)-2-oxo-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (3.4 g) was isolated as a single isomer, colourless solid, contaminated by ca 30percent of starting <strong>[1120-95-2]chloropyridazine</strong>. This batch left at room temperature, in the light, after some days, resulted in a strongly dark coloured and degradated residue.Batch 2: A 80/20 mixture of trans/cis isomers was isolated as a colourless solid (2.2 g) and repurified on Biotage SP1, with a Biotage 65i silica column, using cyclohexane and ethyl acetate as eluent to give isomerically pure ethyl (trans)-2-oxo-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (1.6 g)1H NMR (400 MHz, CDCl3): delta 8.96 (dd, 1H), 8.56 (dd, 1H), 7.50 (dd, 1H), 4.20 (s, 2H), 4.18 (q, 2H), 2.51 (quint, 1H), 2.17-1.75 (m, 8H), 1.29 (t, 3H); UPLC-MS: 0.60 min, 306 [M+H]+.From these two purifications two batches of cis isomer were also isolated:Batch 1: ethyl (cis)-2-oxo-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decane-8-carboxylate as single isomer and colourless solid (4.7 g)Batch 2: ethyl (cis)-2-oxo-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (0.5 g).1H NMR (400 MHz, CDCl3): delta 8.96 (dd, 1H), 8.57 (dd, 1H), 7.50 (dd, 1H), 4.18 (q, 3H), 4.14 (s, 2H), 2.51 (quint, 1H), 2.46-2.37 (m, 1H), 2.21-1.66 (m, 8H), 1.29 (t, 3H); UPLC-MS: 1.04 min, 306 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 120℃; for 8h; | To a solution of (trans)-8-[(5-phenyl-2-pyridinyl)amino]methyl}-1-oxa-3-azaspiro[4.5]decan-2-one (Intermediate 17, 35 mg, 0.104 mmol) and <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (14.26 mg, 0.124 mmol) in 1,4-dioxane (3 ml) were added copper(I) iodide (19.76 mg, 0.104 mmol), (+/-)-trans-1,2-diaminocyclohexane (0.025 ml, 0.207 mmol) and potassium phosphate (110 mg, 0.519 mmol). The mixture was stirred at 120° C. for 8 hours. 1,4-Dioxane was evaporated and the crude was dissolved in ethyl acetate (50 ml) and washed with a pH 3 citrate buffer solution (10 ml), the organic phase was dried on Na2SO4 and concentrated under vacuo. The crude was purified on a NH cartridge eluting with a gradient of cyclohexane/ethyl acetate (from 10percent to 100percent) to give trans-8-[(5-phenyl-2-pyridinyl)amino]methyl}-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one (23.9 mg).1H NMR (400 MHz, CDCl3): delta 1.60-1.96 (m, 6H), 2.01-2.11 (m, 4H), 3.27-3.33 (m, 2H), 4.22-4.25 (m, 2H), 6.50 (dd, 1H), 7.29-7.36 (m, 1H), 7.40-7.47 (m, 2H), 7.47-7.56 (m, 3H), 7.70 (dd, 1H), 8.36 (dd, 1H), 8.58 (dd, 1H), 8.97 (dd, 1H); UPLC-MS: 0.59 min, 416 [M+H]+The above compound was dissolved in DCM (2 ml) a 1M solution of hydrochloric acid in diethyl ether (0.127 ml, 0.127 mmol) was added dropwise under stirring. The solution was left at r.t. under stirring for 30 min and then the precipitate was separated, triturated with diethyl ether (2 ml), concentrated under a flow of nitrogen and dried for 6 hours under high vacuum at 40° C. to give the title compound (9 mg, 32percent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 130℃; for 4h; | Example 4-4 (Trans)-8-([6-(2-methylphenyl)-3-pyridazinyl]amino}methyl)-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one dihydrochloride (Trans)-8-([6-(2-methylphenyl)-3-pyridazinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one (Intermediate 45, 40.0 mg, 0.114 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (prepared according to WO/0107416, 13 mg, 0.114 mmol), copper(I) iodide (21.62 mg, 0.114 mmol), trans-1,2-diaminocyclohexane (0.027 ml, 0.227 mmol), K3PO4 (72.3 mg, 0.341 mmol) were collected in a closed vial and suspended in 1,4-dioxane (4 ml). The resulting mixture was stirred at 130° C. for 4 hours. Solvent was removed under vacuum. The crude was taken up with DCM (8 ml) and filtered over a separating tube. The resulting solution was purified with Biotage SP1, over a 12M NH2 Varian cartridge, eluding with a gradient of cyclohexane and ethyl acetate. The title compound was eluted with EtOAc and recovered as colourless oil. Then it was further purified with Biotage SP1, over a 12M NH2 Varian cartridge, eluding with a gradient of cyclohexane and ethyl acetate to recover the title compound as nearly chemically pure colourless oil (30 mg). 1H NMR (400 MHz, CDCl3): delta 8.97 (dd, 1H), 8.58 (dd, 1H), 7.52 (dd, 1H), 7.45-7.41 (m, 1H), 7.36-7.29 (m, 4H), 6.75 (m, 1H), 4.92 (brs, 2H), 3.45 (t, 2H), 2.43 (s, 3H), 2.15-1.11 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 120℃; | Example 4-5 (Trans)-8-([6-(3,5-dimethylphenyl)-3-pyridazinyl]amino}methyl)-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one dihydrochloride (Trans)-8-([6-(3,5-dimethylphenyl)-3-pyridazinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one (Intermediate 46, 20 mg, 0.055 mmol), trans-1,2-diaminocyclohexane (0.013 ml, 0.109 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (prepared according to WO/0107416, 12.50 mg, 0.109 mmol), K3PO4 (34.8 mg, 0.164 mmol), copper(I) iodide (10.39 mg, 0.055 mmol) were suspended in 1,4-dioxane (4 ml) and shaken at 120° C. in a closed vial overnight. The resulting dark mixture was concentrated under vacuum, taken up with DCM (20 ml) and filtered over a separation tube. The organic solution was concentrated and purified with Biotage SP1 over a 12S NH2 Varian cartridge, eluding with a gradient of cyclohexane and EtOAc. (Trans)-8-([6-(3,5-dimethylphenyl)-3-pyridazinyl]amino}methyl)-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one was eluted with ca 70percent EtOAc and recovered as a colourless oil (12 mg, 0.027 mmol, 49percent). 1H NMR (400 MHz, CDCl3): delta 8.97 (dd, 1H), 8.58 (dd, 1H), 7.63-7.61 (m, 3H), 7.50 (dd, 1H), 7.07 (br s, 1H), 6.73 (d, 1H), 4.86 (br t, 1H), 4.23 (s, 2H), 3.46 (t, 2H), 2.41 (s, 6H), 2.12-1.07 (m, 9H); HPLC-MS: 1.69 min, 445 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 130℃; for 4h; | Example 4-42 (Trans)-8-[({6-[3,5-bis(trifluoromethyl)phenyl]-3-pyridazinyl}amino)methyl]-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one Dihydrochloride (Trans)-8-[({6-[3,5-bis(trifluoromethyl)phenyl]-3-pyridazinyl}amino)methyl]-1-oxa-3-azaspiro[4.5]decan-2-one (Intermediate 72, 49.7 mg, 0.105 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (prepared according to WO/0107416, 12 mg, 0.105 mmol), copper(I) iodide (19.95 mg, 0.105 mmol), trans-1,2-diaminocyclohexane (0.025 ml, 0.210 mmol), K3PO4 (66.7 mg, 0.314 mmol) were collected in a closed vial and suspended in 1,4-dioxane (4 ml). The resulting mixture was stirred at 130° C. for 4 hours. Solvent was removed under vacuum and the crude was taken up with DCM (8 ml) and filtered. The resulting solution was purified by flash chromatography over a 12M NH2 Varian cartridge (Biotage SP1), eluding with a gradient of cyclohexane and ethyl acetate. The required product was eluted with EtOAc and recovered as a colourless oil (38 mg). It was further purified by an ion exchange SCX cartridge (0.5 g Varian) washing with MeOH and eluding with 2M ammonia in MeOH and then by KP-NH flash chromatography (Biotage SP1, 12M Biotage cartridge) eluding with cyclohexane and EtOAc to give (trans)-8-[({6-[3,5-bis(trifluoromethyl)phenyl]-3-pyridazinyl}amino)methyl]-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one as a colourless film (33 mg). 1H NMR (400 MHz, CDCl3): delta 8.97 (dd, 1H), 8.58 (dd, 1H), 8.49 (s, 2H), 7.91 (s, 1H), 7.71 (dd, 1H), 7.51 (dd, 1H), 6.81 (d, 1H), 5.07 (br s, 1H), 4.24 (s, 2H), 3.51 (t, 2H), 2.17-1.15 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 100℃; | Example 1-59 (Trans)-8-([6-(2-fluorophenyl)-3-pyridinyl]amino}methyl)-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5-]decan-2-one.hydrochloride In a sealed tube to a solution of (trans)-8-([6-(2-fluorophenyl)-3-pyridinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one (Intermediate 96, 0.026 ml, 0.141 mmol) and <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (16.11 mg, 0.141 mmol) in 1,4-dioxane (2 ml), copper(I) iodide (26.8 mg, 0.141 mmol), (+/-)-trans-1,2-diaminocyclohexane (0.034 ml, 0.281 mmol) and potassium phosphate (149 mg, 0.703 mmol) were added. The mixture was stirred at 100° C. overnight. The solvent was evaporated. Dichloromethane (5 ml) was added to the residue which was then filtered washing with more dichloromethane (2*1 ml). The organic solution was concentrated in vacuo and the residue was purified by KP-NH chromatography (Biotage SP1, 25M NH column) eluding in gradient with 30percent-100percent EtOAc/cyclohexane to give (trans)-8-([6-(2-fluorophenyl)-3-pyridinyl]amino}methyl)-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one (43 mg, 0.099 mmol, 70percent). 1H NMR (400 MHz, CDCl3): delta 1.64-1.74 (m, 1H), 1.77-1.84 (m, 1H), 1.85-1.96 (m, 2H), 2.02-2.10 (m, 5H), 3.10-3.16 (m, 2H), 4.00 (t, 1H), 4.23 (s, 2H), 6.95 (dd, 1H), 7.09-7.16 (m, 1H), 7.20-7.33 (m, 2H), 7.47-7.55 (m, 1H), 7.62-7.71 (m, 1H). 7.90-7.96 (m, 1H), 8.12-8.20 (m, 1H), 8.53-8.61 (m, 1H), 8.93-9.00 (m, 1H); UPLC-MS: 0.63 min, 433 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 80℃; | Example 1-53 (Trans)-3-(3-pyridazinyl)-8-([5-(3-pyridazinyl)-2-pyridinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one hydrochloride In a 8 ml vial, PdCl2(dppf)-CH2Cl2 adduct (64.4 mg, 0.079 mmol) and 2.0M aq sodium carbonate (0.394 ml, 0.788 mmol) were added to a mixture of <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (54.2 mg, 0.473 mmol) and [6-([(trans)-2-oxo-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]dec-8-yl]methyl}amino)-3-pyridinyl]boronic acid (Intermediate 111, 151 mg, 0.394 mmol) in dry DMF (3 ml) and the resulting mixture was shaken at 80° C. overnight. Additional 2.0M aq sodium carbonate (0.394 ml, 0.788 mmol), PdCl2(dppf)-CH2Cl2 adduct (64.4 mg, 0.079 mmol) and <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (54.2 mg, 0.473 mmol) were added and the mixture was shaken at 80° C. for further 6 hours. The mixture was cooled down, filtered through a filter tube and concentrated in vacuo (Biotage V10-evaporator system) to give a brown residue. The residue was dissolved into MeOH and DCM and loaded onto SCX cartridge (5 g), washed with MeOH and eluted with 2.0M NH3 in MeOH. After concentration in vacuo of ammonia\\methanolic solution a brown residue was obtained. The crude was partially purified by RP-flash chromatography (Biotage SP1, SNAP C18 60 g column) eluding in gradient with 0percent-40percent phase B (acetonitrile)\\phase A (H2O+5percent acetonitrile+0.1percent HCO2H) (in 15 cv) then 40percent-95percent phase B\\phase A (in 6 cv), 95percent phase B (2 cv) and 95percent-0percent phase B (in 2 cv) to recover a yellow solid. The residue was purified by flash chromatography on KP-NH column (12+M Biotage) eluding in gradient with 70percent-100percent EtOAc\\cyclohexane (in 12 cv) then 100percent EtOAc (5 cv) to recover (trans)-3-(3-pyridazinyl)-8-([5-(3-pyridazinyl)-2-pyridinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one as a white solid (31.4 mg, 0.075 mmol, 19percent). 1H NMR (400 MHz, CDCl3): delta 1.20-1.37 (m, 2H), 1.85-1.99 (m, 2H), 2.00-2.13 (m, 4H), 3.36 (t, 2H), 4.24 (s, 2H), 4.93-5.03 (m, 1H), 6.57 (d, 1H), 7.48-7.56 (m, 2H), 7.80 (dd, 1H), 8.34 (dd, 1H), 8.59 (dd, 1H), 8.74 (d, 1H), 8.96-8.99 (m, 1H), 9.11 (dd, 1H); UPLC\\MS: 0.59 min, 418 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 65℃; for 1.5h; | 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methyl-2-pyridinecarbonitrile D67 (150 mg) <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (74.7 mg, 0.652 mmol), cesium fluoride (198 mg, 1.304 mmol), copper(I) iodide (20.98 mg, 0.110 mmol), Pd(Ph3P)4 (37.7 mg, 0.033 mmol) were suspended in 1,4-Dioxane (2.6 ml) and stirred at 65° C. for 1.5 hours. After this time the reaction mixture was filtered through a celite pad, rinsed with EtOAc (20 ml) and the organic solution was evaporated under reduced pressure to give a black oil which was purified by silica gel chromatography (SNAP KP-Sil 25 g cartridge; eluted with Cy/EtOAc: 100percent Cy to 80/20 Cy/EtOAc). Collected and evaporated fractions gave title compound D90 (61 mg) as yellow solid. UPLC (Basic GEN_QC): rt=0.47 minutes, peak observed 197 (M+1), C11H8N4 requires 196. 1H NMR (400 MHz, DMSO-d6) delta ppm 2.64 (s, 3H) 7.80 (d, 1H) 7.94 (dd, 1H) 8.22 (dd, 1H) 8.32 (d, 1H) 9.38 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 10h;Inert atmosphere; Sealed flask; | To a sealed flask were added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-amine 145-1 (1.54 g, 7 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> 145-2 (0.8 g, 7 mmol), Pd(PPh3)4 (500 mg, 0.7 mmol), toluene (50 mL), ethanol (12 mL) and 2M Na2CO3 (11 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90 °C for 10 hours. After cooled to room temperature, the solvents were evaporated and the residue was redissolved in dichloromethane (200 ml) and treated with IM HCl aqueous solution (50 mL). The two layers were separated and the aqueous layer was treated with 10percent NaOH aqueous solution to adjust the pH to around 13. The resulting solution was evaporated and the remaining solid was exacted with ethyl acetate (100 mL x 3). The combined organic phases were concentrated to give 5- (pyridazin-3-yl)pyridin-2-amine 145-3 as dark brown solid. MS m/z 173.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere; | <strong>[1120-95-2]3-Chloropyridazine</strong> (51 mg, 0.44 mmol) was added to a mixture of the boronate ester from Step E (0.293 mmol, crude) and cesium carbonate (287 mg, 0.88 mmol) in DMF (3 mL) and water (0.4 mL). The reaction mixture was degassed with argon. Dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.029 mmol) was added and the reaction mixture was stirred at 900C for 2 hours, cooled, diluted with water and extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (2 to 5percent methanol/ dichloromethane) followed by preparative HPLC gave 4-(3,4-dichlorophenyl)-l,l- dimeihyl-7-(pyridazin-3-yl)-l,2,3,4-tetraliydroisoquinoline (37 mg, 33percent over 2 steps): 1H NMR (CDCl3, 500 MHz) delta 9.16 (dd, J= 4.9, 1.5 Hz, IH), 8.16 (d, J = 1.7 Hz, IH), 7.85 (dd, /= 8.6, 1.5 Hz, IH), 7.70 (dd, / = 8.0, 1.8 Hz, IH), 7.54 (dd, /= 8.6, 4.9 Hz, IH), 7.38 (d, /= 8.2 Hz, IH), 7.20 (d, /= 2.0 Hz, IH), 7.01 (d, /= 8.1 Hz, IH), 6.95 (dd, / = 8.2, 2.0 Hz, IH), 4.10 (t, / = 5.2 Hz, IH), 3.46 (dd, /= 13.4, 5.0 Hz, IH), 3.10 (dd, /= 13.4, 5.6 Hz, IH), 1.63 (s, 3H), 1.58 (s, 3H); ESI MS m/z 384 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In propyl cyanide; at 140℃;Inert atmosphere; sealable flask; | In a sealable flask, a suspension of the phenol, 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenol, prepared as described in Example 1 (47 mg, 0.17 mmol), heteroaryl chloride (39 mg, 0.34 mmol), Cs2CO3 (111 mg, 0.34 mmol), and butyronitrile (1 mL) is heated to 140° C. overnight. The reaction is concentrated and purified by RP-HPLC to afford the desired product, 6-(4-(pyridazin-3-yloxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.MS m/z 358.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;Inert atmosphere; | General procedure (0.5-3.0 mmol scale) for the preparation of compounds 2a-t: A thick-glass, screw-capped pressure tube (50 mL) was charged with a suspension of the starting imidazoline (1.0 equiv), heteroaryl halide (1.1 equiv) and Cs2CO3 (1.0-3.0 equiv, an additional equivalent per salt component of the reactants) in toluene (3 mL/mmol). Pd(OAc)2 (0.02 equiv) and BINAP (0.4 equiv) were weighed out into a vial, suspended in toluene (2 mL/mmol) and shaken in a 100 °C oil bath for 2 min. The resulting clear, purple catalyst solution was added in one portion to the vigorously stirred reaction mixture. The tube was filled with argon, capped, and stirred at 100 °C for 16-20 h. The mixture was cooled, and partitioned between EtOAc and H2O. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel using an appropriate gradient of acetone in hexane (or MeOH in CH2Cl2) as eluent to provide the target product 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Scheme 6 A suspension of 0.508 g (4.44 mmol) of compound 17 and 0.338 g (4.44 mmol) of thiourea in 18 mL of ethanol was heated at 90°C for 2 h. After this time, the reaction mixture was cooled to room temperature and concentrated. To the residue was added 30 mL of water, followed by 0.235 g (2.22 mmol) of sodium carbonate and the resulting solution was extracted with four 25 mL portions of methylene chloride. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 0.34 g (68percent) of compound 18 as a dark-yellow solid: MS: Calcd. for C4H5N2S (MH+), m/z = 113.0; found 113.0. Retention time: 1.56 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 5-chloro-1,3-benzenediamine; In 1-methyl-pyrrolidin-2-one; at 120℃; | A mixture of 2-cloropyridazine (3 eq.) and 1,4 cyclohexane methyl amine (1 eq.) and DABC (5-Chloro-l ,3-benzenediamine) were dissolved in N-methylpyrollidone and heated over night at 120°C to obtain compound 3 in 85percent yield. HI NMR (400, MEOD), d =4.52(8) 5.090V) 7.38 (S) 7.82 (m)), 7.88(m), 7.91 (m), 8.12 9m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 1.5h;Microwave irradiation; | A solution of the compound (556 mg, 1.0 mmol) obtained in Example 16-5), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (172 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130°C for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate = 0:100 to 20:80, gradient) to obtain the title compound (292 mg, 58percent) as a light yellow oily substance. 1H-NMR (400 MHz, CDCl3) delta: 0.05 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.47-1.71 (4H, m), 2.51-2.58 (1H, m), 2.65-2.73 (1H, m), 3.40 (2H, s), 3.49-3.57 (2H, m), 4.04-4.11 (1H, m), 4.28-4.35 (1H, m), 7.20-7.25 (2H, m), 7.51-7.56 (1H, m), 7.81-7.85 (1H, m), 8.00-8.04 (2H, m), 9.14-9.17 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h; | General procedure: A flask was charged with 2-formylpyrrole 1 (5.00 g, 52.6 mmol), K2CO3 (8.72 g, 63.1 mmol), 2-fluoropyridine 2 (9.0 mL, 105.2 mmol) and DMF (26 mL).The mixture was heated at 100 °C for 20 h and then cooled to rt. The reaction mixturewas diluted with water, extracted with MTBE, and the organic phase was dried (MgSO4), filtered, and concentrated. The crude product was purified by chromatography on SiO2(hexanes/EtOAc, 95:5 to 85:15 v/v) to give the product 3 (5.71 g, 63percent) as a tan solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; | General procedure: To a suspension of NaH (1.1 mmol) in anhydrous DMF, cooled at 0 °C, a solution of the appropriate aryl chloride (1.0 mmol) and of the appropriate glycidol (1.0 mmol) in the same solvent was added dropwise. The reaction mixture was stirred at room temperature overnight, quenched with H2O and extracted with AcOEt (3 × 20 mL). The organic layers were collected, dried over Na2SO4 and concentrated under reduced pressure. The crude was purified on a silica gel column (CHCl3/AcOEt, 9:1 as eluent) to give pure compound as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 115℃; for 5h;Inert atmosphere; | In a 250 mL round-bottomed flask, 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (950 mg, 3.75 mmol, Eq: 1.00), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (437 mg, 3.82 mmol, Eq: 1.02) and tetrakis(triphenylphosphine)palladium(O) (437 mg, 378 flmol, Eq: 0.101) were combined with toluene (38.0 mL) to give a brown solution. A 2.0 M aqueous solution of sodium carbonate (7.6 ml, 15.2 mmol, Eq: 4.06) and ethanol (7.6 mL) were added. The reaction mixture was stirred at115 oc for 5 hours.The reaction mixture was cooled to room temperature, and it was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic phase was dried (Na2S04), filtered, then concentrated over silica gel. The silica-supported crude product was loaded onto a 115 gram silica gel column (Analogix). Flash chromatography (70percent ethyl acetate in hexanes) gave 3-chloro-4-pyridazin-3-yl-phenylamine (700 mg, 90percent) containing triphenylphosphine oxide as a minor impurity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 1h;Microwave irradiation; | A mixture of 1-(4-hydroxyphenyl)ethanone (283 mg, 2.08 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (238 mg, 2.08 mmol) and potassium carbonate (574 mg, 4.16 mmol) in DMF (5 mL) is irradiated in a microwave reactor (Biotage Initiator) for 60 mm. at 140 oC. After cooling, the reaction mixture is filtered through Celite pad and the filter cake is washed with EtOAc. The filtrate and washings are washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 10-80percent ethyl acetate in DCM to give the the titled compound (58 mg, 13percent yield) as a white solid.1HNMR (270 MHz, DMSO-d6): delta 9.07 (dd, J = 4.6, 1.3 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.84 (dd, J = 9.2, 4.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 2.60 (s, 3H).MS (ESI) mlz: 215.1 (M+H)÷. |
13% | With potassium carbonate; In d7-N,N-dimethylformamide; at 140℃; for 1h;Microwave irradiation; | A mixture of i-(4-hydroxyphenyl)ethanone (283 mg, 2.08 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (238 mg, 2.08 mmol) and potassium carbonate (574 mg, 4.16 mmol) in DMF (5 mL) was iffadiated in a microwave reactor (Biotage Initiator) for 60 mm. at 140°C. After cooling, the reaction mixture was filtered through Celite pad and the filtrate was washed with EtOAc. The filtrate was diluted with water and the organic layer was separated. After the extraction of the aqueous layer with EtOAc, the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Biotage) on silica gel (25 g) eluting with 10-80percent EtOAc in DCM to give the titled compound (58 mg, 13percent yield) as a white solid.1HNMR (270 MHz, DMSO-d6): delta 9.07 (dd, J = 4.6, 1.3 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.84 (dd, J = 9.2, 4.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 2.60 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 16h;Inert atmosphere; | 5-Boronothiophene-2-carboxylic acid (1.51 g, 8.79 mmol), <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (0.915 g, 7.99 mmol) andK2C03 (1.10 g, 7.99 mmol) were mixed in DME (40 mL) and water (10 mL) and degassed with Ar.Tetrakis(triphenylphosphine)palladium(0) (0.462 g, 0.399 mmol) was added and the RM was stirred at100 °C for 16 h. The reaction RM was poured into water (300 mL) and washed with EtOAc (300 mL). Theaqueous phase was acidified with aqueous 1 M HCI to pH 3-4. The aquous layer was concentrated in vacuo and redissolved in 2 mL H20. The solid was filtered off and washed with Et20 yielding INT-6A (0.390 g, 1.80 mmol, 22percent). LCMS: calc. for [M+H)=207.01, found 207.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 10519] To intermediate 8-10 (266 g, 1.2 mmol) in THF (4 mE) at 00 C. was added NaH (60 wt percent in mineral oil, 70 g, 1.8 mmol). After 15 mi 3-chioropyridazine (160 g, 1.4 mmol) was added. The reaction allowed to warm to rt. Afier 18 h, H20 was added and the mixture extracted with EtOAc. The organic layer was dried. Purification via silica gel chromatography (0-30percent EtOAc in heptane) gave the title compound (300 g, 90percent). MS (ESI) mass calcd. for C,6H23N303, 305.2; mlz found 306.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2?,4?, 6?-triisopropyl- 1,1?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); potassium carbonate; In tert-butyl alcohol; at 100℃;Inert atmosphere; | To a solution of (3S)-1-(2-aminopyridin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile obtained in Example 2 (100 mg) in 2-methyl-2-propanol (2.0 mL) were added <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (52 mg), potassium carbonate (110 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (11 mg) and chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (16 mg) under argon atmosphere, and the mixture was stirred overnight at 100 C. The reaction mixture was cooled to 0 C., saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). To the obtained fraction was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (20 mg). MS(ESI+): [M+H]+ 320.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
600 mg | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 3h; | To a solution of 3-chioropyridazine (0.5 g, 4.38 mmoi) in NMP (2.5 mL) was added potassium carbonate (1.8 g, 13.15 mmoi). Then lerl-Butyi 2?cyanoacetate (0.88 mL, 6.14 mmol) was added. The yellow suspension was warmed up to 80 °C and stirred 3 hours at 80 °C. The brown suspension was cooled down to room temperature. Then it was added to water (10 mL). The brown solution was acidified with HCI (gas evolution, strong foaming), There was a precipitation. The suspension was filtrated and the filter cake was washed with water. The filter cake was dissolved in ethyl acetate, dried with Na2SO4. filtrated and the organic phase evaporated to yield 600 mg of desired product as a yellow oil. ?H-NMR (400 MHz, CDC13) (ppm): 14.3 (bs, I H), 7.68 (dd, 1 H), 7.35 (d, I H), 1.55 (s, 9H). MS [MI{] calcd for C,0H,,N302 206.1, found 206.1; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; | To the solution of ethyl 8-(hydroxymethyl)- 1 ,4-dioxaspiro[4 .5jdecane-8-carboxylate (300 mg, 1.23 mmol) in DMF (6 mL) at 0 °C was added potassium tert-butoxide (1.84 mL, 1.84 mmol) followed by <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (211 mg, 1.84 mmol). The resulting suspension was stirred at 0 °C then warmed to RT overnight. The reaction mixture was diluted withethyl acetate (10 mL), washed with water, dried over sodium sulfate, and concentrated in vacuo to give cmde product. LC/MS: m/e 323.20 (M+H), 2.09 mm (LCMS Method 7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation of tert-butyl 4-(pyridazin-3-yloxy)piperidine-l-carboxylate. To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (140 mg, 0.696 mmol) in DMF (2.3 mL) was added sodium hydride (60percent w/w, 56 mg, 1.39 mmol). The reaction was stirred for 10 min at ambient temperature. Then <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (159 mg, 1.39 mmol) was added and reaction stirred 3 h at 95°C. The reaction was cooled to ambient temperature and diluted with water and extracted with EtOAc. Combined organics were washed with saturated NaHC03(aq), water, and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo to afford the title compound (assumed quantative yield, 194 mg) in sufficient purity for step 2. MS (apci) m/z = 280.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 16h; | A mixture of <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (1 g, 8.73 mmol), tert-butyl piperazine-1-carboxylate(1.626 g, 8.73 mmol), and K2C03 (2.413 g, 17.46 mmol) in NMP (10 mL) was stirred at 120 °C for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/20) to afford tertbutyl 4-(pyridazin-3-yl)piperazine-1-carboxylate (709 mg, 2.68 mmol, 31percent) as a yellow oil. ESIMS (EI+, m/z): 265.4 [M+H]t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium tert-butylate; In tetrahydrofuran; for 16h;Reflux; | General procedure: . Following GP2, t-BuOK (0.1 g, 1 eq., 0.88 mmol) was added to a solution of tert-butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (0.2 g, 1 eq., 0.88 mmol), and <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (0.1 g, 1 eq., 0.88 mmol) in dry THF (7 mL). The reaction mixture was refluxed for 16 h. Then, the mixture was quenched with water (15 mL) and extracted with DCM (210 mL). The organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 70percent) to give the pure title compound as colourless oil (0.06 g, 21percent). UPLC-MS (method A): Rt. 2.26 min (TIC); ionization ES+306 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta 8.87 (dd, J=4.4, 1.3 Hz, 1H), 7.62 (dd, J=8.9, 4.4 Hz, 1H), 7.20 (dd, J=9.0, 1.3 Hz, 1H), 5.52 (t, J=5.0 Hz, 1H), 4.18-3.99 (m, 2H), 2.19-2.00 (m, 4H), 1.99-1.84 (m, 4H), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.5% | [00578] To a solution of tert-butyl (1-((1r,4r)-4-hydroxycyclohexyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)(methyl)carbamate (0.0207 g, 0.0485 mmol) in N,N-dimethylformamide (0.48 mL) was added sodium hydride (0.00140 g, 0.0582 mmol). After 5 mins, <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (0.0111 g, 0.0971 mmol) was added and heated to 95 °C overnight. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL), extracted with ethyl acetate (2x5mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated. The crude oil was resuspended in dichloromethane (5 mL) and TFA (5 mL) was added. After 1 hour, the reaction mixture was concentrated in vacuo and the resultant oil was resuspended in 1 mL of a solution of 60:40 ACN:water with 2percent TFA modifier. The product was purified by HPLC (5-95percent ACN in water with 0.2percent TFA modifier). The product containing fractions were partitioned between DCM and aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated to obtain N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-((1r,4r)-4-(pyridazin-3-yloxy)cyclohexyl)-1H-pyrazolo[4,3-c]pyridin-6-amine (0.0105 g, 0.0260 mmol, 53.5 percent yield) as a white solid. Mass spectrum (apci) m/z = 405.2 (M+H). 1H NMR (CDCl3) delta 8.83 (m, 1H), 8.699(s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.37 (dd, J = 9.0, 4.5 Hz, 1H), 6.95 (dd, J = 9.0, 1.2 Hz, 1H), 6.04 (s, 1H), 5.49 (tt, J = 11.0, 4.3 Hz, 1H), 4.87 (br s, 1H), 4.35 (tt, J = 11.7, 4.1 Hz, 1H), 4.00 (s, 3H), 2.98 (d, J = 5.1 Hz, 3H), 2.51 (m, 2H), 2.35 (m, 2H), 2.15 (m, 2H), 1.75 (m, 2H). |
Tags: 1120-95-2 synthesis path| 1120-95-2 SDS| 1120-95-2 COA| 1120-95-2 purity| 1120-95-2 application| 1120-95-2 NMR| 1120-95-2 COA| 1120-95-2 structure
A135523[ 856847-77-3 ]
3-Chloropyridazine hydrochloride
Reason: Free-Salt
[ 300843-36-1 ]
1-Chlorophthalazine hydrochloride
Similarity: 0.81
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :