* 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.
In a 100 mL round-bottomed flask filled with a solution of 6.0 M NaOH (50 mL) was added 6 (9.00 g 30.2 mmol). The reaction mixture was heated under reflux for 20 h, then diluted with 300 mL water and was quenched by addition 240 mL dichloromethane. The collected organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, affording 6.42 g (94.0 percent yield) light yellow liquid. 1H NMR (300 MHz, CDCl3): δ 4.07–4.11 (m, 2H), 2.74–2.81 (m, 2H), 2.41–2.48 (m, 1H), 2.15 (s, 3H), 1.81–1.84 (m, 2H), 1.48–1.57 (m, 2H), 1.44 (s, 9H).
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 4 h; Stage #2: With dmap; triethylamine; magnesium chloride In tetrahydrofuran; acetonitrile at 0 - 20℃;
(0032) (2) Compound 4 (14.56 g, 63.5 mmol), N,N′-carbonyldiimidazole (24.00 g, 86 mmol) were dissolved in tetrahydrofuran (100 mL), stirred at room temperature for 4 hours. Compounds potassium monoethyl malonate (28.10 g, 165 mmol), anhydrous magnesium chloride (18.15 g, 191 mmol) and 4-dimethylaminopyridine (800 mg, 6.35 mmol) were dissolved in acetonitrile (100 mL) and tetrahydrofuran (200 mL), stirred at room temperature for 6 hours. The two reaction mixtures were cooled to 0° C. after they sufficiently reacted separately. Then the above-mentioned first solution and triethylamine (52 mL, 254 mmol) were simultaneously added to the second solution, and then stirred overnight at room temperature. After completion of the reaction, the solvent is removed by evaporation. The residue is diluted with water (200 mL), extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a yellow oily liquid 5 (18.06 g, 95percent).
182 g
Stage #1: With dmap; 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 15 h; Stage #2: With magnesium chloride In tetrahydrofuran at 50℃; for 35 h;
To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 mL) was added di-1H-imidazol-1-ylmethanone (159 g, 981 mmol) and N,N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The mixture was stirred at RT for 15 h (CAUTION: moderate gas evolution). In a second flask, a suspension of potassium 3-ethoxy-3-oxopropanoate (200 g, 1.18 mol) and magnesium dichloride (112 g, 1.18 mol) in tetrahydrofuran (2100 mL) was heated to 50° C. for 15 h. The resulting warm suspension was slowly added to the first flask under extensive stirring. The resulting mixture was stirred at RT for 20 h. Tetrahydrofuran was evaporated in vacuo, water (1500 mL) and ethyl acetate (1500 mL) were added. The mixture was cooled to 10° C. and 3N aqueous HCl was added until pH 1 was achieved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (1500 mL) and the combined organic phases were washed with 10percent aq. NaHCO3 (750 mL) and 10percent aq. NaCl (750 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (182 g, 505 mmol) in a purity of 83percent. LC-MS (Method 1B): Rt=1.00 min, MS (ESIPos): m/z=300 [M+H]+
Stage #1: With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 0.5 h; Stage #2: With magnesium chloride In acetonitrile for 2 h; Reflux
The intermediate 12h was obtained as describe below: piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (150 g, 0.655 mol) in anhydrous acetonitrile (800 ml), 1,1'-carbonyldiimidazole was added in small portions (132 g, 0.851 mol) under vigorous stirring. The resulting mixture was stirred for 30 min at ambient temperature. Then powder of mixture of anhydrous MgCl2 (62g, 0.655 mol) and methyl potassium malonate (102g, 0.655 mol) was added in portions. The resulted slurry was heated at reflux for 2 h. The reaction mixture was cooled down, diluted with mixture of ice-cold water and dichloromethane and neutralized by citric acid. The separated organic layer was washed with 5percent aqueous solution of potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Further flash-chromatography using ethyl acetate/ hexane (1/1) gave 151 g (81percent) of intermediate 31. 4-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (32) [0223] Acetamidine hydrochloride (29 g, 0.3 mol) was added to the solution of sodium ethylate (0.3 mol) in anhydrous ethanol (400 ml). The mixture was stirred at ambient temperature for 10 min, and compound 31 (0.3 mol) in ethanol was added. The resulting mixture was heated at reflux for 5 h (TLC control). The reaction mixture was concentrated under reduced pressure, the remains was dissolved in water and acidified with 1N HCl to pH 5.0 and extracted with ethyl acetate (2x200 ml). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography on silica gel (eluent: n-hexane/ethyl acetate - 1/1). As a result, compound 32 (50 g, 33percent) was obtained. 4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (12h) [0224] Intermediate 32 (50 g, 0.170 mol) and N,N-dimethylaniline (166 g, 1.365 mol) was dissolved in anhydrous toluene (1000 ml) and POCl3 (52 g, 0.34 mol) was added dropwise. The reaction mixture was heated at reflux for 3 h; then cooled down to ambient temperature and allowed to stay overnight. To this end, the mixture was poured into water; organic layer was separated, washed with 1N HCl and water. The crude product was concentrated under reduced pressure and purified with flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 4/1) to provide 12h (34.3 g , 65percent).
To 2, was added abs. ethanol (200 mE) and the solution was refluxed for 48 h. The solution was concentrated in vacuo and purified by flash chromatography (DCM) to give 3 as a reddish oil (14.36 g, 85percent). ‘H NMR (500 MHz, CDC13) ö 12.09 (s, 0.14H, enol OH), 4.89 (s, 0.14H enol C——H), 4.13 (q, J=7 Hz, 2H), 4.10-3.96 (m, 2H),3.42 (s, 2H), 2.81-2.67 (m, 2H), 2.62-2.52 (m, 1H), 1.85-1.71 (m, 2H), 1.55-1.43 (m, 2H), 1.39 (s, 9H), 1.21 (t, J=7 Hz, 3H); ‘3C NMR (125 MHz, CDC13) ö 204.0, 180.2 (enol), 172.7 (enol), 167.0, 154.4, 87.52, 79.51, 61.3, 48.5, 47.1, 28.2, 27.1, 13.9; Rf=0.2 (DCM). HRMS calculated for C,5H26N05 (M+H) 300.1805, found 300.1808.
0.5 g
for 20 h; Reflux
[0535] A solution of tert-butyl 4-(2,2-dimethyl-4,6-dioxo-1 ,3-dioxane-5-carbonyl) piperidine-1-carboxylate (2 g, 5.63 mmol) in ethanol (50 ml) was refluxed for 20 h, then the solvent wasremoved under vacuum, and the residue was purified by silica gel chromatography eluted withDCM to afford 0.5 g (30percent) of tert-butyl 4-(3-ethoxy-3- oxopropanoyl)piperidine-1-carboxylateas a reddish oil. MS (ESI) m/e [M+23t 322.2.
0.5 g
for 20 h; Reflux
4-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (2 g, 5.63 mmol) in ethanol (50 ml) solution, heated at reflux for 20 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica gel column eluting with DCM to give a slightly red liquid of tert-butyl 4-(3-ethoxy-3-oxopropenyl)piperidine-1-carboxylate (0.5 g). , 30percent).
To a mixture of ethyl N-Boc-piperidine-4-carboxylate (0.5 mol) and ethyl acetate (3 mol) t-BuOK(1.5 mol) was added in some portions at 0 C. The mixture was stirred at room temperature for 3h (monitored by TLC), concentrated up to a half of volume, diluted with water (200 mL) and extacted with ether. Organic layer was dried over sodium sulfate and evaporated in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane) afforded 4-(2-ethoxycarbonyl-acetyl)-piperidine-l-carboxylic acid tert- butyl ester (78 g, 52percent).
Stage #1: cyanoacetic acid amide; 4-(2-ethoxycarbonylacetyl)piperidine-1-carboxylic acid tert-butyl ester With potassium hydroxide In ethanol for 27h; Heating / reflux;
Stage #2: With P,P-dichlorophenylphosphine oxide at 140℃; for 21h;
6
(Reference Example 6) Synthesis of tert-butyl 4-(2,6-dichloro-3-cyanopyridin-4-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (104 g, 349 mmol) and 2-cyanoacetamide (29.3 g, 349 mmol) in ethanol (600 mL) was added potassium hydroxide (23 g, 349 mmol), and the mixture was heated under reflux for 27 hr. The insoluble substance was collected by filtration to give a solid (48.7 g). 6.5 g of these was added to phenylphosphonic dichloride (65 mL), and the mixture was treated at 140°C for 21 hr, and allowed to cool to room temperature. Ethyl acetate (450 ml) was added thereto. The resulting insoluble substance in this process was collected by filtration to give a solid (3.27 g) containing crude 2,6-dichloro-(4-piperidin-4-yl)nicotinonitrile. This solid was dissolved in dichloromethane (80 ml), TEA (4.8 mL) and di-tert-butyl dicarbonate (3.7 g) were added under ice-cooling, and the mixture was stirred at room temperature for 9 hr. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl 4-(2,6-dichloro-3-cyanopyridin-4-yl)piperidine-1-carboxylate (2.3 g). 1H-NMR(300MHz,CDCl3)δ(ppm): 7.25(s, 1H), 3.15-3.05(m, 1H) 2.85(t,2H), 1.91-1.86(m,2H), 1.67-1.56(m,4H), 1.47(s,9H)
Stage #1: hydrogen ethyl malonate With isopropylmagnesium chloride In tetrahydrofuran at 0 - 50℃; for 2.33333h;
Stage #2: C14H21N3O4 In tetrahydrofuran at 20℃; for 3h;
144.a
a) 4-(2-Ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester. 1-tert.Butyloxycarbonylpiperidine-4-carboxylic acid (1.20 g, 5.13 mmol) is dissolved in 25 ml of THF and cooled to 0 0C. After the addition of 0.9Og (5.55 mmol) CDI the reaction mixture is stirred for 2 h at room temperature and allowed to stand over night. Ethyl hydrogen malonate (1.0 g, 7.27 mmol) is dissolved in 10 ml of THF and treated with 5.7 ml of a 2 M solution of i-PrMgCI at 0 0C over a period of 30 min under Ar. The resulting solution is stirred for additional 20 min at 0 0C, for 45 min at room temperature and for 45 min at 50 0C and then cooled to 0 0C again. The CDI activated carboxylic acid solution is slowly added over 30 min. The mixture is allowed to react for additional 3 h at room temperature. Ice is added and the reaction mixture is neutralized with HCI (1 N) and extracted with ethyl acetate. The organic layers are washed with sat. NaHCO3 and brine and dried over Na2SO4. The crude product is purified by silica gel chromatography (hexanes-ethyl acetate gradient). 1H-NMR (400 MHz, DMSO-d6): 1.18 (t, 3H), 1.39 (s, 9H), 1.80 (d, 4H), 2.60-2.70 (m, 1 H), 3.67 (s, 2H), 3.91 (d, 4H), 7.09 (q, 2H). MS (ESI+) m/z: 322 [M+Na]+.
With sodium tetrahydroborate In ethanol at 20℃; for 0.5h;
Preparation 48: 4-(2-Ethoxycarbonyl-l-hydroxyethyl)piperidine-l-carboxylic acid tert-butyl ester: Solid sodium borohydride (374 mg, 9.88 mmol) was added to a solution of 4-(2- ethoxycarbonylacetyl)piperidine-l-carboxylic acid tert-butyl ester (2.69 g, 8.98 mmol) in EtOH (80 mL). After stirring at rt for 0.5 h, the solvent was evaporated and the residue purified by column chromatography (IH-EtOAc) to give the title ester: δH (CDCl3) 1.25 (2H, m), 1.29 (3H, t), 1.46 (9H, s), 1.52 (IH, m), 1.60 (IH, m), 1.85 (IH, dddd), 2.42 (IH, dd), 2.53 (IH, dd), 2.67 (2H, br t), 3.02 (IH, d), 3.79 (IH, m), 4.16 (2H, m), 4.19 (2H, q).
Example 1; tert-Butyl 4-(6-(4-(methylsulfonyl)benzyloxy)pyrimidin-4-yl)piperidine- 1 - carboxylate; Step 1: tert-Butyl 4-(6-hydroxypyrimidin-4-yl)piperidine-l -carboxylate; To a solution of 4-(2-ethoxycarbonyl-acetyl)-piperidine-l-carboxylic acid tert-butyl ester (9 g, 30 mmol) in anhydrous methanol (150 rnL) was added sodium methoxide (28 mL, 120 mmol) and then <strong>[6313-33-3]formamidine hydrochloride</strong> (4.8 g, 60 mmol) at room temperature. The reaction mixture was stirred at room temperature for 70 hours followed by heating at 50 0C for 2 hours. After cooling the room temperature, the mixture was concentrated under in vacuo. The residue was dissolved in water and extracted with diethyl ether. The aqueous phase was acidified with HCl and extracted with CH2Cl2. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to afford the desired product. 1H NMR (CDCl3): delta 8.12 (IH, d), 6.3 (IH, s), 4.25 (2H, br), 2.84 (2H, br), 2.6 (IH, m), 1.88 (2H, m), 1.6 (2H, m), 1.47 (9H, s).
To a solution of 4-(2-ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (9 g, 30 mmol) in anhydrous methanol (150 mL) was added sodium methoxide (28 mL, 120 mmol) and then <strong>[6313-33-3]formamidine hydrochloride</strong> (4.8 g, 60 mmol) at room temperature. The reaction mixture was stirred at room temperature for 70 hours followed by heating at 50 C. for 2 hours. After cooling the room temperature, the mixture was concentrated under in vacuo. The residue was dissolved in water and extracted with diethyl ether. The aqueous phase was acidified with HCl and extracted with CH2Cl2. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to afford the desired product. 1H NMR (CDCl3): delta 8.12 (1H, d), 6.3 (1H, s), 4.25 (2H, br), 2.84 (2H, br), 2.6 (1H, m), 1.88 (2H, m), 1.6 (2H, m), 1.47 (9H, s)
Stage #1: 4-(2-ethoxycarbonylacetyl)piperidine-1-carboxylic acid tert-butyl ester With ethanol; sodium at 0 - 20℃; for 0.166667h;
Stage #2: p-(methylthio)phenethyl bromide In ethanol for 85h; Heating / reflux;
97
Example 97: 4-[4-(4-Methylsulfanylphenyl)butyryl]piperidine-l-carboxylic acid tert-butyl esterSodium metal (127 mg, 5.52 mmol) was dissolved in dry EtOH (15 mL) and the resulting stirred solution cooled to O0C. 4-(2-Ethoxycarbonylacetyl)piperidine-l-carboxylic acid EPO tert-butyl ester (1.65 g, 5.52 mmol) was added, the mixture warmed to rt for 10 min, and a dispersion of l-(2-bromoethyl)-4-methylsulfanylbenzene (1.5 g, 5.52 mmol) in EtOH (2 mL) added. The reaction was heated under reflux for 85 h, cooled and the ethanol removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with water (25 mL) and brine (25 mL). After drying (MgSO4) the solvent was removed and the residue purified by column chromatography (IH-EtOAc 9:1 then 7:1) to afford 4-[2-ethoxycarbonyl-4-(4- methylsulfanylphenyl)butyryl]piperidine-l-carboxylic acid tert-butyl ester: RT = 4.20 min; mlz (ES+) = 450.2 [M+ H]+. A sample of this ester (897 mg, 2.0 mmol) was dissolved in MeOH (16 mL) and a solution of KOH (224 mg, 4 mmol) in water (6.5 mL) added. After heating under reflux for 2 h, the MeOH was removed and the aqueous phase extracted with EtOAc (50 mL) and dried (MgSO4). Removal of the solvent afford the title thioether: RT = 4.14 min; mlz (ES+) = 378.3 [M + H]+.
Morpholine-4-carboxamidine; hydrobromide[ No CAS ]
[ 479630-08-5 ]
[ 1373492-40-0 ]
Yield
Reaction Conditions
Operation in experiment
40.5%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol at 20℃; for 18h;
13.2
Morpholine-4-carboxamidine hydrobromide (0.267 g) and 4-(2- ethoxycarbonylacetyl)-piperidine-l-carboxylic acid tert-butyl ester (0.38 g, 1.27 mmol) were stirred in ethanol (10 mL) and diazobicycloundecane (285 μ) was added. The reaction stirred for 18 hours at room temperature. The ethanol was removed under reduced pressure and water (25 mL) was added. The solution was acidified (to pH = 4) with acetic acid. The product was extracted with dichloromethane (4x30 mL). The dichloromethane was removed and crude product was purified twice on silica gel (Combiflash), eluting with 10% methanol in dichloromethane to provide 4-(6-hydroxy-2- morpholin-4-ylpyrimidin-4-yl)-piperidine-l-carboxylic acid tert-butyl ester (0.15 g, 40.5% yield) as a white solid. 1H NMR (300 MHz, CDCI3/TMS): δ = 5.63 (s, 1H), 4.25- 4.05 (m, 2H), 3.75 (m, 8H), 2.75-2.65 (m, 2H), 2.47-2.35 (m, 1H), 1.00-1.75 (m, 2H), 1.70-1.50 (m, 2H), 1.46 (s, 9H). 13C NMR (75 MHz, CDCI3/TMS): δ= 173.35, 166.87, 154.96, 154.06, 98.88, 79.70, 66.72, 45.13, 44.24, 30.64, 28.82, 27.58.
10 tert-butyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3)
To 2, was added abs. ethanol (200 mE) and the solution was refluxed for 48 h. The solution was concentrated in vacuo and purified by flash chromatography (DCM) to give 3 as a reddish oil (14.36 g, 85%). ‘H NMR (500 MHz, CDC13) ö 12.09 (s, 0.14H, enol OH), 4.89 (s, 0.14H enol C--H), 4.13 (q, J=7 Hz, 2H), 4.10-3.96 (m, 2H),3.42 (s, 2H), 2.81-2.67 (m, 2H), 2.62-2.52 (m, 1H), 1.85-1.71 (m, 2H), 1.55-1.43 (m, 2H), 1.39 (s, 9H), 1.21 (t, J=7 Hz, 3H); ‘3C NMR (125 MHz, CDC13) ö 204.0, 180.2 (enol), 172.7 (enol), 167.0, 154.4, 87.52, 79.51, 61.3, 48.5, 47.1, 28.2, 27.1, 13.9; Rf=0.2 (DCM). HRMS calculated for C,5H26N05 (M+H) 300.1805, found 300.1808.
0.5 g
In ethanol for 20h; Reflux;
28.2 [0534] Step 2: tert-Butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate
[0535] A solution of tert-butyl 4-(2,2-dimethyl-4,6-dioxo-1 ,3-dioxane-5-carbonyl) piperidine-1-carboxylate (2 g, 5.63 mmol) in ethanol (50 ml) was refluxed for 20 h, then the solvent wasremoved under vacuum, and the residue was purified by silica gel chromatography eluted withDCM to afford 0.5 g (30%) of tert-butyl 4-(3-ethoxy-3- oxopropanoyl)piperidine-1-carboxylateas a reddish oil. MS (ESI) m/e [M+23t 322.2.
0.5 g
In ethanol for 20h; Reflux;
28.2 Step 2: Tert-butyl 4-(3-ethoxy-3-oxopropenyl)piperidine-1-carboxylate
4-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (2 g, 5.63 mmol) in ethanol (50 ml) solution, heated at reflux for 20 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica gel column eluting with DCM to give a slightly red liquid of tert-butyl 4-(3-ethoxy-3-oxopropenyl)piperidine-1-carboxylate (0.5 g). , 30%).
With potassium carbonate In methanol; water at 70℃; for 12h;
33%
Stage #1: acetamidine hydrochloride With sodium ethanolate In ethanol at 20℃; for 0.166667h;
Stage #2: 4-(2-ethoxycarbonylacetyl)piperidine-1-carboxylic acid tert-butyl ester In ethanol for 5h; Reflux;
32 4-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (32)
The intermediate 12h was obtained as describe below: piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (150 g, 0.655 mol) in anhydrous acetonitrile (800 ml), 1,1'-carbonyldiimidazole was added in small portions (132 g, 0.851 mol) under vigorous stirring. The resulting mixture was stirred for 30 min at ambient temperature. Then powder of mixture of anhydrous MgCl2 (62g, 0.655 mol) and methyl potassium malonate (102g, 0.655 mol) was added in portions. The resulted slurry was heated at reflux for 2 h. The reaction mixture was cooled down, diluted with mixture of ice-cold water and dichloromethane and neutralized by citric acid. The separated organic layer was washed with 5% aqueous solution of potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Further flash-chromatography using ethyl acetate/ hexane (1/1) gave 151 g (81%) of intermediate 31. 4-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (32) [0223] Acetamidine hydrochloride (29 g, 0.3 mol) was added to the solution of sodium ethylate (0.3 mol) in anhydrous ethanol (400 ml). The mixture was stirred at ambient temperature for 10 min, and compound 31 (0.3 mol) in ethanol was added. The resulting mixture was heated at reflux for 5 h (TLC control). The reaction mixture was concentrated under reduced pressure, the remains was dissolved in water and acidified with 1N HCl to pH 5.0 and extracted with ethyl acetate (2x200 ml). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography on silica gel (eluent: n-hexane/ethyl acetate - 1/1). As a result, compound 32 (50 g, 33%) was obtained. 4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (12h) [0224] Intermediate 32 (50 g, 0.170 mol) and N,N-dimethylaniline (166 g, 1.365 mol) was dissolved in anhydrous toluene (1000 ml) and POCl3 (52 g, 0.34 mol) was added dropwise. The reaction mixture was heated at reflux for 3 h; then cooled down to ambient temperature and allowed to stay overnight. To this end, the mixture was poured into water; organic layer was separated, washed with 1N HCl and water. The crude product was concentrated under reduced pressure and purified with flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 4/1) to provide 12h (34.3 g , 65%).
The intermediate 12h was obtained as describe below: piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (150 g, 0.655 mol) in anhydrous acetonitrile (800 ml), 1,1'-carbonyldiimidazole was added in small portions (132 g, 0.851 mol) under vigorous stirring. The resulting mixture was stirred for 30 min at ambient temperature. Then powder of mixture of anhydrous MgCl2 (62g, 0.655 mol) and <strong>[38330-80-2]methyl potassium malonate</strong> (102g, 0.655 mol) was added in portions. The resulted slurry was heated at reflux for 2 h. The reaction mixture was cooled down, diluted with mixture of ice-cold water and dichloromethane and neutralized by citric acid. The separated organic layer was washed with 5percent aqueous solution of potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Further flash-chromatography using ethyl acetate/ hexane (1/1) gave 151 g (81percent) of intermediate 31. 4-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (32) [0223] Acetamidine hydrochloride (29 g, 0.3 mol) was added to the solution of sodium ethylate (0.3 mol) in anhydrous ethanol (400 ml). The mixture was stirred at ambient temperature for 10 min, and compound 31 (0.3 mol) in ethanol was added. The resulting mixture was heated at reflux for 5 h (TLC control). The reaction mixture was concentrated under reduced pressure, the remains was dissolved in water and acidified with 1N HCl to pH 5.0 and extracted with ethyl acetate (2x200 ml). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography on silica gel (eluent: n-hexane/ethyl acetate - 1/1). As a result, compound 32 (50 g, 33percent) was obtained. 4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (12h) [0224] Intermediate 32 (50 g, 0.170 mol) and N,N-dimethylaniline (166 g, 1.365 mol) was dissolved in anhydrous toluene (1000 ml) and POCl3 (52 g, 0.34 mol) was added dropwise. The reaction mixture was heated at reflux for 3 h; then cooled down to ambient temperature and allowed to stay overnight. To this end, the mixture was poured into water; organic layer was separated, washed with 1N HCl and water. The crude product was concentrated under reduced pressure and purified with flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 4/1) to provide 12h (34.3 g , 65percent).
5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide[ No CAS ]
[ 479630-08-5 ]
5-oxo-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With acetic acid at 90℃; for 16h;
28.3 [0536] Step 3: 5-0xo-2-( 4-phenoxyphenyl)-7 -(piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide
[0537] A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (412 mg, 1.4mmol) and tert-butyl4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (420 mg, 1.4 mmol)in HOAc (20 mL) was stirred at 90 °C for 16 hr. The solvent was removed under vacuum, andthe residue was partitioned between aq. NaHC03 and ethyl acetate. The organic layer waswashed with brine, dried over Na2S04 and concentrated under vacuum. The residue was purifiedby Pre-HPLC eluting from 25% to 90% CH3CN in 0.1% TFA in H20. Fractions containing thedesired product were combined and lyophilized overnight to afford 5-oxo-2-(4-phenoxyphenyl)-7- (piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide (0.3 g, 50%) as a whitesolid. 1H NMR (400 MHz, DMSO-d6) 8 11.71 (br s, 1H), 8.68-8.65 (m, 1H), 8.42-8.39 (m, 1H),7.74 (d, J = 8.4 Hz, 2H), 7.47-7.41 (m, 2H), 7.22-7.18 (m, 1H), 7.14-7.09 (m, 4H), 5.72 (s, 1H), 3.50-3.35 (m, 2H), 3.17-3.06 (m, 1H), 3.01-2.87 (m, 2H), 2.15-2.05 (m, 2H), 1.83-1.72 (m, 2H).MS (ESI) m/e [M+1t 430.1.
50%
With acetic acid at 90℃; for 16h;
28.3 Step 3: 5-oxo-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide
5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (412 mg, 1.4 mmol)And a mixture of tert-butyl 4-(3-ethoxy-3-oxopropenyl)piperidine-1-carboxylate (420 mg, 1.4 mmol) in HOAc (20 mL),Stir at 90°C for 16 hours.The solvent was removed under reduced pressure and the residue was partitioned between aq. NaHCO3 and ethyl acetate.The organic phase was washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.The residue was purified by HPLC. The aqueous phase was eluted with a gradient of 0.1% TFA and 25% to 90% CH3CN. The combined product was collected and lyophilized overnight.Obtained white solid 5-oxo-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3 - Formamide (0.3g, 50%).
tert-butyl 4-(7-fluoro-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
44A Tert-butyl 4-(7-fluoro-2-oxo-l ,2-dih dropyrimido[l ,2-b]indazol-4-yl)piperidine-l-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 7-fluoro- lH-indazol-3-amine (336 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6) by the addition of IN HCl. The mixture was extracted with ethyl acetate (2x 30 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was triturated with MTBE (5 mL), fitered and washed with MTBE (2 mL). The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 2 h at 50°C in vacuo to the title compound (92 mg, 11 % of theory) as off-white solid. LC-MS (Method IB): Rt = 1.03 min, MS (ESIPos): m/z = 387 [M+H]+
92 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
44.A Tert-butyl 4-(7-fluoro-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 7-fluoro-1H-indazol-3-amine (336 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6) by the addition of 1N HCl. The mixture was extracted with ethyl acetate (2*30 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was triturated with MTBE (5 mL), filtered and washed with MTBE (2 mL). The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 2 h at 50° C. in vacuo to the title compound (92 mg, 11% of theory) as off-white solid. LC-MS (Method 1B): Rt=1.03 min, MS (ESIPos): m/z=387 [M+H]+
tert-butyl 4-(2-oxo-1,2-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
169 mg
With potassium phosphate; at 180.0℃; for 0.25h;Microwave irradiation;
Example 45A Tert-butyl 4-(2-oxo-1,2-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), <strong>[76006-17-2]1H-pyrazolo[3,4-c]pyridin-3-amine</strong> (299 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180 C. for 15 min After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 7) by the addition of 1N HCl. The precipitate was filtered, washed with water (10 mL) and dried for 16 h at 50 C. in vacuo to yield the title compound (169 mg, 75% purity, 16% of theory). LC-MS (Method 1B): Rt=0.73 min, MS (ESIPos): m/z=370 [M+H]+
With potassium phosphate; at 180.0℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 1H- pyrazolo[3,4-c]pyridin-3-amine (299 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 7) by the addition of IN HCl. The precipitate was filterered, washed with water (10 mL) and dried for 16 h at 50C in vacuo to yield the title compound (169 mg, 75% purity, 16% of theory). LC-MS (Method IB): Rt = 0.73 min, MS (ESIPos): m/z = 370 [M+H]+
tert-butyl 4-[2-oxo-7-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
46A Tert-butyl 4-[2-oxo-7-(trifluoromethyl)-l,2-dihydropyriniido[l,2-b]indazol-4-yl]piperidine-l- carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 7- (trifluoromethyl)-lH-indazol-3-amine (299 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 6) by the addition of IN HCl and extracted with ethyl acetate (2x 50 mL). The combined organic phases were washed with water (30 mL), brine (30 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with MTBE (5 mL), filtered, washed with MTBE (2 mL) ) and dried for 16 h at 50°C in vacuo to yield the title compound (122 mg, 12% of theory). LC-MS (Method IB): Rt = 1.16 min, MS (ESIPos): m/z = 437 [M+H]
122 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
46.A Tert-butyl 4-[2-oxo-7-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate
Example 46A Tert-butyl 4-[2-oxo-7-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 7-(trifluoromethyl)-1H-indazol-3-amine (299 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 6) by the addition of 1N HCl and extracted with ethyl acetate (2*50 mL). The combined organic phases were washed with water (30 mL), brine (30 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with MTBE (5 mL), filtered, washed with MTBE (2 mL)) and dried for 16 h at 50° C. in vacuo to yield the title compound (122 mg, 12% of theory). LC-MS (Method 1B): Rt=1.16 min, MS (ESIPos): m/z=437 [M+H]+
tert-butyl 4-(4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
239 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
17.A Tert-butyl 4-(4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.50 g, 5.01 mmol, 1 eq), 1H-indazol-3-amine (1.00 g, 7.52 mmol, 1.5 eq) and potassium phosphate (2.13 g, 10.0 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (15 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was neutralized (pH 6-7) by the addition of 1N HCl, diluted with water (60 mL), and extracted with ethyl acetate (2*, 100 mL and 50 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was triturated with acetonitrile (5 mL). The precipitate was filtered, washed with acetonitrile (8 mL) and dried for 2 h at 50° C. in vacuo to give the title compound (239 mg, 13% of theory). LC-MS (Method 1B): Rt=0.98 min, MS (ESIPos): m/z=369 [M+H]+
tert-butyl 4-[2-oxo-9-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47 mg
With potassium phosphate In 1,4-dioxane at 150℃; for 3h; Microwave irradiation;
18.A Tert-butyl 4-[2-oxo-9-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate
Example 18A Tert-butyl 4-[2-oxo-9-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (450 mg, 81% purity, 1.22 mmol, 1 eq), 5-(trifluoromethyl)-1H-indazol-3-amine (245 mg, 1.22 mmol, 1.0 eq) and potassium phosphate (517 mg, 2.43 mmol, 2 eq) were suspended in dioxane (4.3 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 150° C. for 1 h. Another 1 eq of tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate was added and the mixture was heated in a microwave to 150° C. for 1 h. Again, 1 eq of tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate was added and the mixture was heated in a microwave to 150° C. for 1 h. The solvent was evaporated in vacuo and the residue was diluted with water (20 mL), and extracted with ethyl acetate (2*, 50 mL and 25 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound (47 mg, 9% of theory) as solid. LC-MS (Method 1B): Rt=1.17 min, MS (ESIPos): m/z=437 [M+H]+
47 mg
With potassium phosphate In 1,4-dioxane at 150℃; for 3h; Microwave irradiation;
18A Tert-butyl 4-[2-oxo-9-(trifluoromethyl)-l,2-dihydropyrimido[l,2-b]indazol-4-yl]piperidm^ carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (450 mg, 81% purity, 1.22 mmol, 1 eq), 5-(trifluoromethyl)-lH-indazol-3-amine (245 mg, 1.22 mmol, 1.0 eq) and potassium phosphate (517 mg, 2.43 mmol, 2 eq) were suspended in dioxane (4.3 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 150°C for 1 h. Another leq of tert-butyl 4-(3- ethoxy-3-oxopropanoyl)piperidine-l -carboxylate was added and the mixture was heated in a microwave to 150°C for 1 h. Again, leq of teri-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate was added and the mixture was heated in a microwave to 150°C for 1 h. The solvent was evaporated in vacuo and the residue was diluted with water (20 mL), and extracted with ethyl acetate (2x, 50 mL and 25 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound (47 mg, 9% of theory) as solid. LC-MS (Method IB): Rt = 1.17 min, MS (ESIPos): m/z = 437 [M+H]+
tert-butyl 4-(10-chloro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.63 g
With potassium phosphate; at 180℃; for 0.5h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (9.11 g, 30.4 mmol, 1.5 eq), <strong>[20925-60-4]4-chloro-1H-indazol-3-amine</strong> (3.4 g, 20.3 mmol, 1 eq) and potassium phosphate (8.61 g, 40.6 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (70 mL) and split to seven 20 mL microwave vials. The vials were capped and the mixture was heated in a microwave to 180 C. for 15 min Another 1.5 eq of tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate was added in 1-methoxy-2-propanol (2 mL for each vial), and the mixture was heated in a microwave to 180 C. for 15 min again. After cooling to RT, the combined suspensions were evaporated in vacuo, diluted with water (150 mL), neutralized (pH 6) by the addition of 1N HCl, and extracted with ethyl acetate (2*, 200 mL). The combined organic phases were washed with water (2*100 mL) and brine (50 mL) and evaporated in vacuo. The partially crystalline residue was triturated with ethyl acetate (50 mL). The precipitate was filtered, washed with ethyl acetate (20 mL) and acetonitrile (10 mL) and dried for 16 h at 50 C. in vacuo to yield the title compound (2.63 g, 96% purity, 31% of theory). LC-MS (Method 1B): Rt=1.12 min, MS (ESIPos): m/z=403 [M+H]+
tert-butyl 4-(10-fluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62 mg
With tert-butyl 4-(10-bromo-9-fluoro-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate at 180℃; for 0.25h; Microwave irradiation;
20.A Tert-butyl 4-(10-fluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.66 g, 2.2 mmol, 1 eq), 4-fluoro-1H-indazol-3-amine (0.50 g, 3.31 mmol, 1.5 eq) and potassium phosphate (0.936 g, 4.41 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (9 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (15 mL), neutralized (pH 5-6) by the addition of 1N HCl, and extracted with ethyl acetate (2*, 15 mL). The combined organic phases were evaporated in vacuo. The residue was triturated with water (30 mL), filtered, and the residue was resuspended in acetonitrile (30 mL). The precipitate was filtered, washed with acetonitrile (2 mL) and dried for 16 h at 50° C. in vacuo to yield the title compound (62 mg, 7% of theory). LC-MS (Method 1B): Rt=1.02 min, MS (ESIPos): m/z=387 [M+H]+
tert-butyl 4-(9-chloro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30 mg
With potassium phosphate; In 1,4-dioxane; at 150℃; for 2.0h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (450 mg, 81% purity, 1.22 mmol, 1 eq), <strong>[5685-72-3]5-chloro-1H-indazol-3-amine</strong> (204 mg, 1.22 mmol, 1.0 eq) and potassium phosphate (517 mg, 2.43 mmol, 2 eq) were suspended in dioxane (4.3 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 150 C. for 1 h. Another 1 eq of tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate was added and the mixture was heated in a microwave to 150 C. for 1 h. The solvent was evaporated in vacuo, the residue was diluted with water (20 mL) and extracted with ethyl acetate (2*, 50 mL and 25 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound (30 mg, 6% of theory) as solid. LC-MS (Method 2B): Rt=1.97 min, MS (ESIPos): m/z=403 [M+H]+
tert-butyl 4-(9-fluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.3 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
23.A Tert-butyl 4-(9-fluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Example 23A Tert-butyl 4-(9-fluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (264 mg, 0.882 mmol, 1 eq), 5-fluoro-1H-indazol-3-amine (200 mg, 1.32 mmol, 1.5 eq) and potassium phosphate (374 mg, 1.76 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (2.6 mL) in a microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 5-6) by the addition of 1N HCl, and extracted with ethyl acetate (2*15 mL). The combined organic phases were evaporated in vacuo. The residue was triturated with acetonitrile (10 mL). The precipitate was filtered, washed with acetonitrile (2 mL) and dried for 2 h at 50° C. in vacuo to yield the title compound (61.3 mg, 18% of theory). LC-MS (Method 1B): Rt=1.02 min, MS (ESIPos): m/z=387 [M+H]+
tert-butyl 4-(10-methoxy-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
128 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
24.A Tert-butyl 4-(10-methoxy-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-methoxy-1H-indazol-3-amine (363 mg, 2.23 mmol, 1.5 eq) and potassium phosphate (945 mg, 10.2 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 5-6) by the addition of 1N HCl, and extracted with ethyl acetate (2*50 mL). The combined organic phases were washed with brine (20 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The resulting suspension was filtered, the residue was washed with water (10 ml) and dried for 16 h at 50° C. in vacuo to give the title compound (128 mg, 14% of theory) as light yellow solid. LC-MS (Method 1B): Rt=1.04 min, MS (ESIPos): m/z=399 [M+H]+
tert-butyl 4-(9-oxo-9,10-dihydropyrido[3',2':3,4]pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
25A Tert-butyl 4-(9 -oxo-9 , 10-dihydropyrido [3 ' ,2' : 3 ,4] pyr azolo [ 1 ,5 -a] pyrimidin-7 -yl)piperidine- 1 - carboxylate
7eri-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (49 mg, 0.497 mmol, 1 eq), 1H- pyrazolo[4,3-b]pyridin-3-amine (100 mg, 0.745 mmol, 1.5 eq) and potassium phosphate (210 mg, 0.993 mmol, 2 eq) were suspended in l-methoxy-2-propanol (1.5 mL) in a microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 5-6) by the addition of IN HCl, and extracted with ethyl acetate (2x 15 mL). The combined organic phases were evaporated in vacuo. The residue was triturated with water (40 mL). The precipitate was filterered, triturated with acetonitrile (6 mL), filterered, washed with acetonitrile (2 mL) and dried for 16 h at 50°C. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (2x15 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (15 mg, 8% of theory). LC-MS (Method IB): Rt = 0.91 min, MS (ESIPos): m/z = 370 [M+H]+
15 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
25.A Tert-butyl 4-(9-oxo-9,10-dihydropyrido[3',2':3,4]pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate
Example 25A Tert-butyl 4-(9-oxo-9,10-dihydropyrido[3',2':3,4]pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (49 mg, 0.497 mmol, 1 eq), 1H-pyrazolo[4,3-b]pyridin-3-amine (100 mg, 0.745 mmol, 1.5 eq) and potassium phosphate (210 mg, 0.993 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (1.5 mL) in a microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 5-6) by the addition of 1N HCl, and extracted with ethyl acetate (2*15 mL). The combined organic phases were evaporated in vacuo. The residue was triturated with water (40 mL). The precipitate was filtered, triturated with acetonitrile (6 mL), filtered, washed with acetonitrile (2 mL) and dried for 16 h at 50° C. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (2*15 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (15 mg, 8% of theory). LC-MS (Method 1B): Rt=0.91 min, MS (ESIPos): m/z=370 [M+H]+
tert-butyl 4-(10-bromo-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
222 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
26.A Tert-butyl 4-(10-bromo-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-bromo-1H-indazol-3-amine (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6) by the addition of 1N HCl. The precipitate was filtered, washed with water (10 mL), MTBE (4 mL) and dried for 16 h at 50° C. in vacuo to yield the title compound (222 mg, 22% of theory). LC-MS (Method 1B): Rt=1.13 min, MS (ESIPos): m/z=447 [M+H]+
tert-butyl 4-[2-oxo-8-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
27A Tert-butyl 4-[2-oxo-8-(trifluoromethyl)-l,2-dihydropyrimido[l,2-b]indazol-4-yl]piperidm^ carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6- (trifluoromethyl)-lH-indazol-3-amine (448 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (50 mL) and neutralized (pH 5-6) by the addition of IN HCl and extracted with ethyl acetate (2x 100 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The brown residue was triturated with MTBE (4 mL) under ultrasound irradiation. The precipitate was filterered, washed with water (20 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (381 mg, 95% purity, 37% of theory) as off-white solid. LC-MS (Method 1 B) : Rt = 1.15 min, MS (ESIPos) : m/z = 437 [M+H] +
381 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
27.A Tert-butyl 4-[2-oxo-8-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-(trifluoromethyl)-1H-indazol-3-amine (448 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (50 mL) and neutralized (pH 5-6) by the addition of 1N HCl and extracted with ethyl acetate (2*100 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The brown residue was triturated with MTBE (4 mL) under ultrasound irradiation. The precipitate was filtered, washed with water (20 mL) and dried for 16 h at 50° C. in vacuo to yield the title compound (381 mg, 95% purity, 37% of theory) as off-white solid. LC-MS (Method 1B): Rt=1.15 min, MS (ESIPos): m/z=437 [M+H]+
tert-butyl 4-(10-(trifluoromethyl)-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
28A Tert-butyl 4-(10-(trifluoromethyl)-4-oxo-l ,4-dihydropyrimido[l ,2-b]indazol-2-yl)piperidine-l - carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4- (trifluoromethyl)-lH-indazol-3-amine (448 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 5) by the addition of IN HCl and extracted with ethyl acetate (2x 30 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The brown residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to yield the title compound (116 mg, 12% of theory) as colorless solid. LC-MS (Method IB): Rt = 1.19 min, MS (ESIPos): m/z = 437 [M+H]+
116 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
28.A Tert-butyl 4-(10-(trifluoromethyl)-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-(trifluoromethyl)-1H-indazol-3-amine (448 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 5) by the addition of 1N HCl and extracted with ethyl acetate (2*30 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The brown residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50° C. in vacuo to yield the title compound (116 mg, 12% of theory) as colorless solid. LC-MS (Method 1B): Rt=1.19 min, MS (ESIPos): m/z=437 [M+H]+
6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-(8-(tert-butyl)-2-oxo-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56.6 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
29.A Tert-butyl 4-(8-tert-butyl-4-oxo-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-3-amine (448 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6) by the addition of 1N HCl and extracted with ethyl acetate (2*50 mL). The combined organic phases were washed with water (2*20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The brown residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50° C. in vacuo to yield the title compound (56.6 mg, 90% purity, 5% of theory). LC-MS (Method 2B): Rt=2.07 min, MS (ESIPos): m/z=426 [M+H]+
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
29A Tert-butyl 4-(8-te^butyl-4-oxo-l,4-dihydropyrido[23':3,4]pyrazolo[l,5-a]pyrimidin-2-yl)piperidine-l- carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-tert- butyl-lH-pyrazolo[3,4-b]pyridin-3-amine (448 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6) by the addition of IN HCl and extracted with ethyl acetate (2x 50 mL). The combined organic phases were washed with water (2x 20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The brown residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to yield the title compound (56.6 mg, 90% purity, 5% of theory). LC-MS (Method 2B): Rt = 2.07 min, MS (ESIPos): m/z = 426 [M+H]+
4-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-(10-methyl-2-oxo-8-(trifluoromethyl)-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
30A Tert-butyl 4-(8-(trifluoromethyl)-4-oxo-l,4-dihydropyrido[23':3,4]pyrazolo[l,5-a]pyrimidin-2- yl)piperidine- 1 -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-methyl- 6-(trifluoromethyl)-lH-pyrazolo[3,4-b]pyridin-3-amine (448 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 5-6) by the addition of IN HC1. The precipitate was filtered and washed with water (10 mL). The combined filtrates were extracted with ethyl acetate (2x 30 mL), adjusted to pH 8-9 by the addition of IN NaOH, and extracted with ethyl acetate (20 mL). The combined organic phases were washed with water (2x 10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The yellow residue was triturated with MTBE (5 mL) under ultrasound irradiation, fitered and washed with MTBE (4 mL) and ethyl acetate (1 mL). The filtrate was evaporated in vacuo and purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to yield the title compound (123 mg, 12% of theory) as off-white solid. LC-MS (Method IB): Rt = 1.08 min, MS (ESIPos): m/z = 452 [M+H]+
123 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
30.A Tert-butyl 4-(8-(trifluoromethyl)-4-oxo-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (448 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 5-6) by the addition of 1N HCl. The precipitate was filtered and washed with water (10 mL). The combined filtrates were extracted with ethyl acetate (2*30 mL), adjusted to pH 8-9 by the addition of 1N NaOH, and extracted with ethyl acetate (20 mL). The combined organic phases were washed with water (2*10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The yellow residue was triturated with MTBE (5 mL) under ultrasound irradiation, filtered and washed with MTBE (4 mL) and ethyl acetate (1 mL). The filtrate was evaporated in vacuo and purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50° C. in vacuo to yield the title compound (123 mg, 12% of theory) as off-white solid. LC-MS (Method 1B): Rt=1.08 min, MS (ESIPos): m/z=452 [M+H]+
tert-butyl 4-(9-methyl-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
31A Tert-butyl 4-(9-methyl-4-oxo- 1 ,4-dihydropyrimido[ 1 ,2-b]indazol-2-yl)piperidine-l -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 5-methyl- lH-indazol-3-ylamine (328 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The yellow residue was triturated with MTBE (5 mL), filterered, washed with ethyl acetate (1 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (148 mg, 95% purity, 17% of theory) as yellow solid. LC-MS (Method IB): Rt = 1.04 min, MS (ESIPos): m z = 383 [M+H]+
148 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
31.A Tert-butyl 4-(9-methyl-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 5-methyl-1H-indazol-3-ylamine (328 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The yellow residue was triturated with MTBE (5 mL), filtered, washed with ethyl acetate (1 mL) and dried for 16 h at 50° C. in vacuo to yield the title compound (148 mg, 95% purity, 17% of theory) as yellow solid. LC-MS (Method 1B): Rt=1.04 min, MS (ESIPos): m/z=383 [M+H]+
tert-butyl 4-(8-amino-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
32A Tert-butyl 4-(8-amino-4-oxo-l,4- dine-l-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-amino- lH-indazol-3-ylamine (330 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The yellow residue was triturated with acetonitrile (4 mL), filterered, washed with acetonitrile (2 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (31 mg, 4% of theory) as yellow solid. LC-MS (Method IB): Rt = 0.81 min, MS (ESIPos): m/z = 384 [M+H]+
31 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
32.A Tert-butyl 4-(8-amino-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-amino-1H-indazol-3-ylamine (330 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The yellow residue was triturated with acetonitrile (4 mL), filtered, washed with acetonitrile (2 mL) and dried for 16 h at 50° C. in vacuo to yield the title compound (31 mg, 4% of theory) as yellow solid. LC-MS (Method 1B): Rt=0.81 min, MS (ESIPos): m/z=384 [M+H]+
4,5-dimethyl-1H-pyrazolo[3,4-c]pyridazin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-(3,4-dimethyl-8-oxo-5,8-dihydropyrimido[1',2':1,5]pyrazolo[3,4-c]pyridazin-6-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
33A Tert-butyl 4-(3,4-dimethyl-8-oxo-5,8-dihydropyrimido[ ,2': l ,5]pyrazolo[3,4-c]pyridazin-6- yl)piperidine- 1 -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 0.334 mmol, 1.5 eq), 4,5- dimethyl-lH-pyrazolo[3,4-C]pyridazin-3-amine (363 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was triturated with MTBE (4 mL), filterered, washed with ethyl acetate (1 mL). The filtrate was evaporated in vacuo and purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile and lyophilized to give the title compound (62.3 mg, 7% of theory). LC-MS (Method IB): Rt = 0.75 min, MS (ESIPos): m z = 399 [M+H]+
62.3 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
33.A Tert-butyl 4-(3,4-dimethyl-8-oxo-5,8-dihydropyrimido[1',2':1,5]pyrazolo[3,4-c]pyridazin-6-yl)piperidine-1-carboxylate
Example 33A Tert-butyl 4-(3,4-dimethyl-8-oxo-5,8-dihydropyrimido[1',2':1,5]pyrazolo[3,4-c]pyridazin-6-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 0.334 mmol, 1.5 eq), 4,5-dimethyl-1H-pyrazolo[3,4-C]pyridazin-3-amine (363 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was triturated with MTBE (4 mL), filtered, washed with ethyl acetate (1 mL). The filtrate was evaporated in vacuo and purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile and lyophilized to give the title compound (62.3 mg, 7% of theory). LC-MS (Method 1B): Rt=0.75 min, MS (ESIPos): m/z=399 [M+H]+
tert-butyl 4-(8-fluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-fluoro- lH-indazol-3-ylamine (337 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was triturated with 4 mL MTBE/ethyl acetate (1 : 1), filterered, washed with ethyl acetate (2 mL) and dried for 16 h at 50C in vacuo to yield the title compound (66 mg, 7% of theory) as colorless solid. LC-MS (Method IB): Rt = 1.01 min, MS (ESIPos): m z = 387 [M+H]+
66 mg
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Example 34A Tert-butyl 4-(8-fluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), <strong>[404827-75-4]6-fluoro-1H-indazol-3-ylamine</strong> (337 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180 C. for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was triturated with 4 mL MTBE/ethyl acetate (1:1), filtered, washed with ethyl acetate (2 mL) and dried for 16 h at 50 C. in vacuo to yield the title compound (66 mg, 7% of theory) as colorless solid. LC-MS (Method 1B): Rt=1.01 min, MS (ESIPos): m/z=387 [M+H]+
tert-butyl 4-(9-bromo-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3%
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 5-bromo- lH-indazol-3-ylamine (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was triturated with 4 mL MTBE/ethyl acetate (1 : 1), filterered, washed with ethyl acetate (2 mL) and dried for 16 h at 50C in vacuo to yield the title compound (37 mg, 3% of theory). LC-MS (Method IB): Rt = 1.11 min, MS (ESIPos): m/z = 447 [M+H]+
37 mg
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), <strong>[61272-71-7]5-bromo-1H-indazol-3-ylamine</strong> (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180 C. for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was triturated with 4 mL MTBE/ethyl acetate (1:1), filtered, washed with ethyl acetate (2 mL) and dried for 16 h at 50 C. in vacuo to yield the title compound (37 mg, 3% of theory). LC-MS (Method 1B): Rt=1.11 min, MS (ESIPos): m/z=447 [M+H]+
tert-butyl 4-(10-iodo-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (0.750 g, 2.50 mmol, 1.5 eq), 4-iodo- lH-indazol-3-ylamine (472 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 mg, 3.34 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50C in vacuo to yield the title compound (56 mg, 7% of theory). LC-MS (Method 1 B) : Rt = 1.19 min, MS (ESIPos) : m z = 495 [M+H] +
56 mg
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.750 g, 2.50 mmol, 1.5 eq), <strong>[599191-73-8]4-iodo-1H-indazol-3-ylamine</strong> (472 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 mg, 3.34 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180 C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50 C. in vacuo to yield the title compound (56 mg, 7% of theory). LC-MS (Method 1B): Rt=1.19 min, MS (ESIPos): m/z=495 [M+H]+
tert-butyl 4-(8-bromo-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-bromo- lH-indazol-3-ylamine (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50C in vacuo to yield the title compound (94 mg, 9% of theory) as yellowish solid. LC-MS (Method IB): Rt = 1.12 min, MS (ESIPos): m z = 447 [M+H]+
94 mg
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Example 37A Tert-butyl 4-(8-bromo-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), <strong>[404827-77-6]6-bromo-1H-indazol-3-ylamine</strong> (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (11 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180 C. for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50 C. in vacuo to yield the title compound (94 mg, 9% of theory) as yellowish solid. LC-MS (Method 1B): Rt=1.12 min, MS (ESIPos): m/z=447 [M+H]+
tert-butyl 4-(7-chloro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
38A Tert-butyl 4-(7-chloro-4-oxo-l ,4-dih dropyrimido[l ,2-b]indazol-2-yl)piperidine-l-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 7-chloro- lH-indazol-3-ylamine (373 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and concentrated in vacuo to 5 mL. The resulting suspension was filterered, washed with ethyl acetate (5 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (83 mg, 9% of theory). LC-MS (Method IB): Rt = 1.09 min, MS (ESIPos): m z = 403 [M+H]+
83 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
38.A Tert-butyl 4-(7-chloro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Example 38A Tert-butyl 4-(7-chloro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 7-chloro-1H-indazol-3-ylamine (373 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and concentrated in vacuo to 5 mL The resulting suspension was filtered, washed with ethyl acetate (5 mL) and dried for 16 h at 50° C. in vacuo to yield the title compound (83 mg, 9% of theory). LC-MS (Method 1B): Rt=1.09 min, MS (ESIPos): m/z=403 [M+H]+
tert-butyl 4-(8,10-difluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
39.A Tert-butyl 4-(8,10-difluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate
Example 39A Tert-butyl 4-(8,10-difluoro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4,6-difluoro-1H-indazol-3-ylamine (377 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50° C. in vacuo to yield the title compound (27 mg, 90% purity, 3% of theory). LC-MS (Method 2B): Rt=1.92 min, MS (ESIPos): m/z=405 [M+H]+
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
39A Tert-butyl 4-(8 , 10-difluoro-4-oxo-l ,4-dihydropyrimido[l ,2-b]indazol-2-yl)piperidine-l -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4,6- difluoro-lH-indazol-3-ylamine (377 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to yield the title compound (27 mg, 90% purity, 3% of theory). LC-MS (Method 2B): Rt = 1.92 min, MS (ESIPos): m z = 405 [M+H]+
tert-butyl 4-(8-methyl-4-oxo-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
40A Tert-butyl 4-(8-methyl-4-oxo-l,4-dihydropyrido[23':3,4]pyrazolo[l,5-a]pyrirnidin-2-yl)piperidine-l- carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-methyl- lH-pyrazolo[3,4-b]pyridin-3-amine (330 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 2A). The combined product fractions were lyophilized to give the title compound (64 mg, 7% of theory). LC-MS (Method 2B): Rt = 1.64 min, MS (ESIPos): m z = 384 [M+H]+
64 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
40.A Tert-butyl 4-(8-methyl-4-oxo-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate
Example 40A Tert-butyl 4-(8-methyl-4-oxo-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 6-methyl-1H-pyrazolo[3,4-b]pyridin-3-amine (330 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 2A). The combined product fractions were lyophilized to give the title compound (64 mg, 7% of theory). LC-MS (Method 2B): Rt=1.64 min, MS (ESIPos): m/z=384 [M+H]+
4-nitro-6-(trifluoromethyl)-1H-indazol-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-[10-nitro-2-oxo-8-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
47A Tert-butyl 4-[10-nitro-2-oxo-8-(trifluoromethyl)-l ,2-dm^ carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-nitro-6- (trifluoromethyl)-lH-indazol-3-amine (548 mg, 2.23 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1 A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to give the title compound (90.8 mg, 8% of theory). LC-MS (Method 1 B) : Rt = 1.16 min, MS (ESIPos) : m z = 482 [M+H] +
90.8 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
47.A Tert-butyl 4-[10-nitro-2-oxo-8-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate
Example 47A Tert-butyl 4-[10-nitro-2-oxo-8-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-nitro-6-(trifluoromethyl)-1H-indazol-3-amine (548 mg, 2.23 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50° C. in vacuo to give the title compound (90.8 mg, 8% of theory). LC-MS (Method 1B): Rt=1.16 min, MS (ESIPos): m/z=482 [M+H]+
Tert-butyl 4-(8,10-dimethyl-4-oxo-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
48.A Tert-butyl 4-(8,10-dimethyl-4-oxo-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate
Example 48A Tert-butyl 4-(8,10-dimethyl-4-oxo-1,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-3-amine (361 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (9 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (50 mL), neutralized (pH 5-6) by the addition of 1N HCl and extracted with ethyl acetate (2*100 mL). The combined organic phases were washed with water, (2*25 mL), brine (25 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was triturated with acetonitrile (4 mL) and DMSO (4 mL). The precipitate was filtered, washed with acetonitrile (2*2 mL) and dried for 2 h at 50° C. in vacuo to yield the title compound (50 mg, 5% of theory) as yellow solid. LC-MS (Method 1B): Rt=0.92 min, MS (ESIPos): m/z=398 [M+H]+
tert-butyl 4-(7-bromo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
50A Tert-butyl 4-(7-bromo-2-oxo-l ,2-dih dropyrirnido[l ,2-b]indazol-4-yl)piperidine-l-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)-2-methylpiperidine-l -carboxylate (750 mg, 2.50 mmol, 1.5 eq), 7-bromo-lH-indazol-3-amine (354 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 mg, 3.34 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6-7) by the addition of IN HC1. The resulting aqueous suspension filtered, the residue was washed with ethyl acetate (10 mL) and acetonitrile (5 mL) and dried for 16 h at 50°C in vacuo to give the title compound (42.3 mg, 7% of theory). LC-MS (Method IB): Rt = 1.12 min, MS (ESIPos): m/z = 447 [M+H]+
42.3 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
50.A Tert-butyl 4-(7-bromo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)-2-methylpiperidine-1-carboxylate (750 mg, 2.50 mmol, 1.5 eq), 7-bromo-1H-indazol-3-amine (354 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 mg, 3.34 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6-7) by the addition of 1N HCl. The resulting aqueous suspension filtered, the residue was washed with ethyl acetate (10 mL) and acetonitrile (5 mL) and dried for 16 h at 50° C. in vacuo to give the title compound (42.3 mg, 7% of theory). LC-MS (Method 1B): Rt=1.12 min, MS (ESIPos): m/z=447 [M+H]+
tert-butyl 4-(2-oxo-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4%
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 1H- Pyrazolo[3,4-b]pyridin-3-amine (299 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the mixture was diluted with water (20 mL) and acidified (pH 5) by the addition of IN HCl. The resulting suspension was filtered, washed with water (20 mL) and the residue was purified by preparative HPLC (Method 2A). The combined product fractions were lyophilized to give the title compound (36.3 mg, 4% of theory). LC-MS (Method IB): Rt = 0.78 min, MS (ESIPos): m/z = 370 [M+H]+
36.3 mg
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 1H-Pyrazolo[3,4-b]pyridin-3-amine (299 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180 C. for 15 min After cooling to RT, the mixture was diluted with water (20 mL) and acidified (pH 5) by the addition of 1N HCl. The resulting suspension was filtered, washed with water (20 mL) and the residue was purified by preparative HPLC (Method 2A). The combined product fractions were lyophilized to give the title compound (36.3 mg, 4% of theory). LC-MS (Method 1B): Rt=0.78 min, MS (ESIPos): m/z=370 [M+H]+
tert-butyl 4-(10-methyl-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
52A Tert-butyl 4-( 10-methyl-2-oxo- 1 ,2-dih dropyrimido[ 1 ,2-b] indazol-4-yl)piperidine- 1 -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (750 mg, 2.50 mmol, 1.5 eq), 4- methyl-lH-indazol-3-amine (246 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 mg, 3.34 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 6) by the addition of IN HCl and extracted with ethyl acetate (2x 30 mL). The combined organic phases were washed with water, (50 mL), brine (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to give the title compound (63.8 mg, 10% of theory). LC-MS (Method IB): Rt = 1.07 min, MS (ESIPos): m/z = 383 [M+H]+
63.8 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
52.A Tert-butyl 4-(10-methyl-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (750 mg, 2.50 mmol, 1.5 eq), 4-methyl-1H-indazol-3-amine (246 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 mg, 3.34 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 6) by the addition of 1N HCl and extracted with ethyl acetate (2*30 mL). The combined organic phases were washed with water, (50 mL), brine (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50° C. in vacuo to give the title compound (63.8 mg, 10% of theory). LC-MS (Method 1B): Rt=1.07 min, MS (ESIPos): m/z=383 [M+H]+
tert-butyl 4-[2-oxo-10-(trifluoromethoxy)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
53A Tert-butyl 4-[2-oxo-10-(trifluoromethoxy)-l,2-dihydropyrimido[l,2-b]indazol-4-yl]piperid^ carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (750 mg, 2.50 mmol, 1.5 eq), 4- (trifluoromethoxy)-lH-indazol-3-amine (363 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 mg, 3.34 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 6) by the addition of IN HCl and extracted with ethyl acetate (2x 30 mL). The combined organic phases were washed with water, (50 mL), brine (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to give the title compound (64 mg, 8% of theory) as off-white solid. LC-MS (Method 2B): Rt = 2.51 min, MS (ESIPos): m/z = 453 [M+H]+
64 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
53.A Tert-butyl 4-[2-oxo-10-(trifluoromethoxy)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate
Example 53A Tert-butyl 4-[2-oxo-10-(trifluoromethoxy)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (750 mg, 2.50 mmol, 1.5 eq), 4-(trifluoromethoxy)-1H-indazol-3-amine (363 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 mg, 3.34 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 6) by the addition of 1N HCl and extracted with ethyl acetate (2*30 mL). The combined organic phases were washed with water, (50 mL), brine (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50° C. in vacuo to give the title compound (64 mg, 8% of theory) as off-white solid. LC-MS (Method 2B): Rt=2.51 min, MS (ESIPos): m/z=453 [M+H]+
tert-butyl 4-(9-oxo-9,10-dihydropyrazino[2',3':3,4]pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (750 mg, 2.50 mmol, 1.5 eq), 1H- pyrazolo[3,4-b]pyrazin-3-amine (226 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 g, 3.34 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (3: 1), filtered through a short pad of silica gel with 150 mL dichloromethane/methanol (3: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were lyophilized to give the title compound (31.1 mg, 5% of theory) as yellow solid. LC-MS (Method IB): Rt = 0.85 min, MS (ESIPos): m z = 371 [M+H]+
31.1 mg
With potassium phosphate; at 180℃; for 0.25h;
Example 54A Tert-butyl 4-(9-oxo-9,10-dihydropyrazino[2',3':3,4]pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (750 mg, 2.50 mmol, 1.5 eq), <strong>[81411-64-5]1H-pyrazolo[3,4-b]pyrazin-3-amine</strong> (226 mg, 1.67 mmol, 1 eq) and potassium phosphate (709 g, 3.34 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180 C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (3:1), filtered through a short pad of silica gel with 150 mL dichloromethane/methanol (3:1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were lyophilized to give the title compound (31.1 mg, 5% of theory) as yellow solid. LC-MS (Method 1B): Rt=0.85 min, MS (ESIPos): m/z=371 [M+H]+
tert-butyl 4-(8-chloro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.2 mg
With potassium phosphate; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;
Example 55A Tert-butyl 4-(8-chloro-4-oxo-1,4-dihydropyrimido[1,2-b]indazol-2-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (450 mg, 81% purity, 1.22 mmol, 1 eq), <strong>[16889-21-7]6-chloro-1H-indazol-3-amine</strong> (204 mg, 1.22 mmol, 1.0 eq) and potassium phosphate (517 mg, 2.43 mmol, 2 eq) were suspended in dioxane (4.3 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 150 C. for 1 h. The solvent was evaporated in vacuo, the residue was diluted with water (20 mL) and extracted with ethyl acetate (2*, 50 mL and 25 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 2A). The combined product fractions were evaporated in vacuo. The residue was purified again by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound (5.2 mg, 1% of theory). LC-MS (Method 1B): Rt=1.13 min, MS (ESIPos): m/z=403 [M+H]+
5.2 mg
With potassium phosphate; at 150℃; for 1h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (450 mg, 81% purity, 1.22 mmol, 1 eq), 6-chloro-lH-indazol-3-amine (204 mg, 1.22 mmol, 1.0 eq) and potassium phosphate (517 mg, 2.43 mmol, 2 eq) were suspended in dioxane (4.3 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 150C for 1 h. The solvent was evaporated in vacuo, the residue was diluted with water (20 mL) and extracted with ethyl acetate (2x, 50 mL and 25 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 2A). The combined product fractions were evaporated in vacuo. The residue was purified again by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound (5.2 mg, 1% of theory). LC-MS (Method 1 B) : Rt = 1.13 min, MS (ESIPos) : m z = 403 [M+H] +
N4,N4-dimethyl-1H-pyrazolo[3,4-b]pyridine-3,4-diamine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-[10-(dimethylamino)-2-oxo-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
64A Tert-butyl 4-[10-(dimethylamino)-2-oxo-l,2-dihydropyrido[23':3,4]pyrazolo[l,5-a]pyrimidm yl]piperidine-l -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (842 mg, 2.33 mmol), N4,N4-dimethyl- lH-pyrazolo[3,4-b]pyridine-3,4-diamine (303 mg, 1.56 mmol) and potassium phosphate (661 mg, 3.11 mmol) were suspended in l-methoxy-2-propanol (7 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the solvent was evaporated and the residue was diluted in water and extracted with ethyl acetate. After separation of the two layers, the aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified with HCl IN until pH 7 was achieved and then evaporated under vacuo. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with a 33% ammonia solution and then acetonitrile was evaporated. The resulting aqueous phase was extracted with ethyl acetate and the collected organic phases were dried over sodium sulfate, filtrated and evaporated. The resulting solid was dried under vacuo to yield the title compound (11 mg, 2% of theory). LC-MS (Method IB): Rt = 0.77 min, MS (ESIPos): m/z = 413 [M+H]+
11 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
64.A Tert-butyl 4-[10-(dimethylamino)-2-oxo-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl]piperidine-1-carboxylate
Example 64A Tert-butyl 4-[10-(dimethylamino)-2-oxo-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl]piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (842 mg, 2.33 mmol), N4,N4-dimethyl-1H-pyrazolo[3,4-b]pyridine-3,4-diamine (303 mg, 1.56 mmol) and potassium phosphate (661 mg, 3.11 mmol) were suspended in 1-methoxy-2-propanol (7 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the solvent was evaporated and the residue was diluted in water and extracted with ethyl acetate. After separation of the two layers, the aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified with HCl 1N until pH 7 was achieved and then evaporated under vacuo. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with a 33% ammonia solution and then acetonitrile was evaporated. The resulting aqueous phase was extracted with ethyl acetate and the collected organic phases were dried over sodium sulfate, filtrated and evaporated. The resulting solid was dried under vacuo to yield the title compound (11 mg, 2% of theory). LC-MS (Method 1B): Rt=0.77 min, MS (ESIPos): m/z=413 [M+H]+
4-chloro-6-(trifluoromethyl)-1H-indazol-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-[10-chloro-2-oxo-8-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
65A Tert-butyl 4-[10-chloro-2-oxo-8-(trifluoromethyl)-l ,2-dihydropyrimido[l ,2-b]indazol-4-yl]piperidine-l - carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.03 g, 2.87 mmol), 4-chloro-6- (trifluoromethyl)-lH-indazol-3-amine (500 mg, 1.91 mmol) and potassium phosphate (811 mg, 3.82 mmol) were suspended in l-methoxy-2-propanol (9 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. After separation of the layers the aqueous layer was extracted with ethyl acetate. The collected organic layers were dried over magnesium sulfate, filtrated and evaporated. The crude product was purified by preparative (Method 1A). The combined product fractions were neutralized with a 33% ammonia solution and then acetonitrile was evaporated. The resulting solid in the aqueous phase was filtered and dried under vacuo to yield the title compound (287 mg, 32% of theory). LC-MS (Method IB): Rt = 1.27 min, MS (ESIPos): m/z = 471 [M+H]+
287 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
65.A Tert-butyl 4-[10-chloro-2-oxo-8-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate
Example 65A Tert-butyl 4-[10-chloro-2-oxo-8-(trifluoromethyl)-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.03 g, 2.87 mmol), 4-chloro-6-(trifluoromethyl)-1H-indazol-3-amine (500 mg, 1.91 mmol) and potassium phosphate (811 mg, 3.82 mmol) were suspended in 1-methoxy-2-propanol (9 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. After separation of the layers the aqueous layer was extracted with ethyl acetate. The collected organic layers were dried over magnesium sulfate, filtrated and evaporated. The crude product was purified by preparative (Method 1A). The combined product fractions were neutralized with a 33% ammonia solution and then acetonitrile was evaporated. The resulting solid in the aqueous phase was filtered and dried under vacuo to yield the title compound (287 mg, 32% of theory). LC-MS (Method 1B): Rt=1.27 min, MS (ESIPos): m/z=471 [M+H]+
6-(4-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-[8-(4-fluorophenyl)-2-oxo-10-(trifluoromethyl)-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With potassium phosphate at 180℃; for 0.75h; Microwave irradiation;
66A Tert-butyl 4-[8-(4-fluorophenyl)-2-oxo-10-(trifluoromethyl)-l,2-dihydropyrido[2',3':3,4]pyrazolo[l,5- a]pyrimidin-4-yl]piperidine- 1 -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (630 mg, 1.75 mmol), 6-(4- fluorophenyl)-4-(trifluoromethyl)-lH-pyrazolo[3,4-b]pyridin-3-amine (352 mg, 1.17 mmol) and potassium phosphate (494 mg, 2.33 mmol) were suspended in l-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After this period the mixture was additionally heated in the MW at 180°C for 30 min. After cooling to RT, the solvent was evaporated and the residue was diluted in water and extracted with ethyl acetate. After separation of the layers the aqueous layer was extracted with ethyl acetate. The collected organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with a 33% ammonia solution and then acetonitrile was evaporated. The resulting solid in the aqueous phase was filtered and dried under vacuo to yield the title compound (62 mg, 10% of theory). LC-MS (Method IB): Rt = 1.29 min, MS (ESIPos): m/z = 532 [M+H]+
62 mg
With potassium phosphate at 180℃; for 0.75h; Microwave irradiation;
66.A Tert-butyl 4-[8-(4-fluorophenyl)-2-oxo-10-(trifluoromethyl)-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl]piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (630 mg, 1.75 mmol), 6-(4-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (352 mg, 1.17 mmol) and potassium phosphate (494 mg, 2.33 mmol) were suspended in 1-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After this period the mixture was additionally heated in the MW at 180° C. for 30 min After cooling to RT, the solvent was evaporated and the residue was diluted in water and extracted with ethyl acetate. After separation of the layers the aqueous layer was extracted with ethyl acetate. The collected organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with a 33% ammonia solution and then acetonitrile was evaporated. The resulting solid in the aqueous phase was filtered and dried under vacuo to yield the title compound (62 mg, 10% of theory). LC-MS (Method 1B): Rt=1.29 min, MS (ESIPos): m/z=532 [M+H]+
4-methyl-1H-pyrazolo[3,4-b]pyridin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-(10-methyl-2-oxo-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
72A Tert-butyl 4-(10-methyl-2-oxo-l,2-dihydropyri^ carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (818 mg, 2.27 mmol), 4-methyl-lH- pyrazolo[3,4-b]pyridin-3-amine (224 mg, 1.51 mmol) and potassium phosphate (642 mg, 3.02 mmol) were suspended in l-methoxy-2-propanol (8 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. The reaction mixture was diluted with water and neutralized (pH 6) by the addition of IN HC1. The resulting solid was filtrated, washed with ethyl acetate and water and dried under vacuo. The solid was stirred in a mixture of water, ammonia and acetonitrile. The solid was filtered off and the filtrate was purified by preparative HPLC (Method 2A) to yield the title compound (40 mg, 7% of theory). LC-MS (Method 3B): Rt = 1.75 min, MS (ESIPos): m/z = 384 [M+H]+
40 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
72.A Tert-butyl 4-(10-methyl-2-oxo-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (818 mg, 2.27 mmol), 4-methyl-1H-pyrazolo[3,4-b]pyridin-3-amine (224 mg, 1.51 mmol) and potassium phosphate (642 mg, 3.02 mmol) were suspended in 1-methoxy-2-propanol (8 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. The reaction mixture was diluted with water and neutralized (pH 6) by the addition of 1N HCl. The resulting solid was filtrated, washed with ethyl acetate and water and dried under vacuo. The solid was stirred in a mixture of water, ammonia and acetonitrile. The solid was filtered off and the filtrate was purified by preparative HPLC (Method 2A) to yield the title compound (40 mg, 7% of theory). LC-MS (Method 3B): Rt=1.75 min, MS (ESIPos): m/z=384 [M+H]+
6-phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-(2-oxo-8-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
68A Tert-butyl 4-(2-oxo-8-phenyl-l,2-dihydropyrido[23':3,4]pyrazolo[l,5-a]pyrimidin-4-yl)piperidine-l- carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 2.77 mmol), 6-phenyl-lH- pyrazolo[3,4-b]pyridin-3-amine (393 mg, 1.85 mmol) and potassium phosphate (785 mg, 3.70 mmol) were suspended in l-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the reaction mixture was diluted with water and neutralized (pH 6) by the addition of IN HC1. The resulting solid was filtrated, washed with ethyl acetate and dried under vacuo. The solid was stirred in a mixture of DMSO/water, filtered and dried under vacuo to yield a first fraction of title compound. The filtrate was purified by preparative HPLC (Method 2A) to yield a second fraction of the title compound. Overall yield: 112 mg, 14%. LC-MS (Method IB): Rt = 1.07 min, MS (ESIPos): m/z = 446 [M+H]+
112 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
68.A Tert-butyl 4-(2-oxo-8-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate
Example 68A Tert-butyl 4-(2-oxo-8-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 2.77 mmol), 6-phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine (393 mg, 1.85 mmol) and potassium phosphate (785 mg, 3.70 mmol) were suspended in 1-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the reaction mixture was diluted with water and neutralized (pH 6) by the addition of 1N HCl. The resulting solid was filtrated, washed with ethyl acetate and dried under vacuo. The solid was stirred in a mixture of DMSO/water, filtered and dried under vacuo to yield a first fraction of title compound. The filtrate was purified by preparative HPLC (Method 2A) to yield a second fraction of the title compound. Overall yield: 112 mg, 14%. LC-MS (Method 1B): Rt=1.07 min, MS (ESIPos): m/z=446 [M+H]+
4-phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine[ No CAS ]
tert-butyl 4-(2-oxo-10-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
70A Tert-butyl 4-(2-oxo-10-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1 g, 2.77 mmol), 4-phenyl-lH- pyrazolo[3,4-b]pyridin-3-amine (389 mg, 1.85 mmol) and potassium phosphate (785 mg, 3.70 mmol) were suspended in l-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the reaction mixture was diluted with water and neutralized (pH 6) by the addition of IN HCl. The resulting solid was filtrated, washed with ethyl acetate and water and dried under vacuo. The solid was stirred in a mixture of water, ammonia and acetonitrile. The solid was filtered off and the filtrate was purified by preparative HPLC (Method 2A) to yield the title compound (49 mg , 6% of theory). LC-MS (Method IB): Rt = 0.98 min, MS (ESIPos): m/z = 446 [M+H]+
49 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
70.A Tert-butyl 4-(2-oxo-10-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate
Example 70A Tert-butyl 4-(2-oxo-10-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1 g, 2.77 mmol), 4-phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine (389 mg, 1.85 mmol) and potassium phosphate (785 mg, 3.70 mmol) were suspended in 1-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the reaction mixture was diluted with water and neutralized (pH 6) by the addition of 1N HCl. The resulting solid was filtrated, washed with ethyl acetate and water and dried under vacuo. The solid was stirred in a mixture of water, ammonia and acetonitrile. The solid was filtered off and the filtrate was purified by preparative HPLC (Method 2A) to yield the title compound (49 mg, 6% of theory). LC-MS (Method 1B): Rt=0.98 min, MS (ESIPos): m/z=446 [M+H]+
tert-butyl 4-(2-oxo-9-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
69A Tert-butyl 4-(2-oxo-9^henyl-l ,2-dihydropyrido[23':3,4]pyrazolo[l ,5-a]pyrimidin-4-yl)piperidine-l - carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1 g, 2.77 mmol), 5-phenyl-lH- pyrazolo[3,4-b]pyridin-3-amine (389 mg, 1.85 mmol) and potassium phosphate (785 mg, 3.70 mmol) were suspended in l-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the reaction mixture was diluted with water and neutralized (pH 6) by the addition of IN HC1. The resulting solid was filtrated, washed with ethyl acetate and water and dried under vacuo. The solid was stirred in a mixture of water and DMSO, filtered und dried under vacuo. The solid was stirred again in a mixture of water, ammonia and acetonitrile. The resulting solid was filtered and the filtrate was purified by preparative HPLC Method 2A) to yield the title compound (70 mg, 8% of theory). LC-MS (Method IB): Rt = 1.02 min, MS (ESIPos): m/z = 446 [M+H]+
70 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
69.A Tert-butyl 4-(2-oxo-9-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate
Example 69A Tert-butyl 4-(2-oxo-9-phenyl-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1 g, 2.77 mmol), 5-phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine (389 mg, 1.85 mmol) and potassium phosphate (785 mg, 3.70 mmol) were suspended in 1-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the reaction mixture was diluted with water and neutralized (pH 6) by the addition of 1N HCl. The resulting solid was filtrated, washed with ethyl acetate and water and dried under vacuo. The solid was stirred in a mixture of water and DMSO, filtered and dried under vacuo. The solid was stirred again in a mixture of water, ammonia and acetonitrile. The resulting solid was filtered and the filtrate was purified by preparative HPLC Method 2A) to yield the title compound (70 mg, 8% of theory). LC-MS (Method 1B): Rt=1.02 min, MS (ESIPos): m/z=446 [M+H]+
4-bromo-1H-pyrazolo[3,4-c]pyridin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-(10-bromo-2-oxo-1,2-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
67A Tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrido[34':3,4]pyrazolo[l,5-a]pyrimidin-4-yl)piperidm^ carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol), 4-bromo-lH- pyrazolo[3,4-c]pyridin-3-amine (474 mg, 2.23 mmol) and potassium phosphate (945mg, 4.45 mmol) were suspended in l-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the mixture was diluted with water and neutralized until pH 6 was achieved by the addition of IN HCl. The resulting solid was filtrated, washed with ethyl acetate and dried under vacuo at 60 °C overnight to yield the first fraction of title compound. After separation of filtrate layers the aqueous layer was extracted with ethyl acetate. The collected organic layers were washed with water und brine solution. The resulting precipitate formed in the organic phase was filtered and dried under vacuo at 60 °C for 2 h to give a second fraction of the title compound. Overall yield (176 mg, 18% of theory). LC-MS (Method IB): Rt = 0.98 min, MS (ESIPos): m/z = 450 [M+H]+
176 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
67.A Tert-butyl 4-(10-bromo-2-oxo-1,2-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate
Example 67A Tert-butyl 4-(10-bromo-2-oxo-1,2-dihydropyrido[3',4':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol), 4-bromo-1H-pyrazolo[3,4-c]pyridin-3-amine (474 mg, 2.23 mmol) and potassium phosphate (945 mg, 4.45 mmol) were suspended in 1-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the mixture was diluted with water and neutralized until pH 6 was achieved by the addition of 1N HCl. The resulting solid was filtrated, washed with ethyl acetate and dried under vacuo at 60° C. overnight to yield the first fraction of title compound. After separation of filtrate layers the aqueous layer was extracted with ethyl acetate. The collected organic layers were washed with water and brine solution. The resulting precipitate formed in the organic phase was filtered and dried under vacuo at 60° C. for 2 h to give a second fraction of the title compound. Overall yield (176 mg, 18% of theory). LC-MS (Method 1B): Rt=0.98 min, MS (ESIPos): m/z=450 [M+H]+
tert-butyl 4-(9-iodo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
73A Tert-butyl 4-(9 odo-2-oxo-l,2- e-l-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1 g, 2.27 mmol), 5-iodo-lH-indazol- 3-amine (504 mg, 1.85 mmol) and potassium phosphate (785 mg, 3.70 mmol) were suspended in 1- methoxy-2-propanol (10ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT the residue was diluted with water and extracted with ethyl. The layers were separated and the aqueous layer was extracted with ethyl acetate. The collected organic phases were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide. After the evaporation of acetonitrile a white solid was formed in the aqueous phase, which was filtered and dried under vacuo to yield the title compound (108 mg ,12% of theory). LC-MS (Method 3B): Rt = 2.46 min, MS (ESIPos): m/z = 495 [M+H]+
180 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
73.A Tert-butyl 4-(9-iodo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate
Example 73A Tert-butyl 4-(9-iodo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1 g, 2.27 mmol), 5-iodo-1H-indazol-3-amine (504 mg, 1.85 mmol) and potassium phosphate (785 mg, 3.70 mmol) were suspended in 1-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT the residue was diluted with water and extracted with ethyl. The layers were separated and the aqueous layer was extracted with ethyl acetate. The collected organic phases were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide. After the evaporation of acetonitrile a white solid was formed in the aqueous phase, which was filtered and dried under vacuo to yield the title compound (108 mg, 12% of theory). LC-MS (Method 3B): Rt=2.46 min, MS (ESIPos): m/z=495 [M+H]+
(0032) (2) Compound 4 (14.56 g, 63.5 mmol), N,N?-carbonyldiimidazole (24.00 g, 86 mmol) were dissolved in tetrahydrofuran (100 mL), stirred at room temperature for 4 hours. Compounds potassium monoethyl malonate (28.10 g, 165 mmol), anhydrous magnesium chloride (18.15 g, 191 mmol) and 4-dimethylaminopyridine (800 mg, 6.35 mmol) were dissolved in acetonitrile (100 mL) and tetrahydrofuran (200 mL), stirred at room temperature for 6 hours. The two reaction mixtures were cooled to 0 C. after they sufficiently reacted separately. Then the above-mentioned first solution and triethylamine (52 mL, 254 mmol) were simultaneously added to the second solution, and then stirred overnight at room temperature. After completion of the reaction, the solvent is removed by evaporation. The residue is diluted with water (200 mL), extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a yellow oily liquid 5 (18.06 g, 95%).
182 g
To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 mL) was added di-1H-imidazol-1-ylmethanone (159 g, 981 mmol) and N,N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The mixture was stirred at RT for 15 h (CAUTION: moderate gas evolution). In a second flask, a suspension of potassium 3-ethoxy-3-oxopropanoate (200 g, 1.18 mol) and magnesium dichloride (112 g, 1.18 mol) in tetrahydrofuran (2100 mL) was heated to 50 C. for 15 h. The resulting warm suspension was slowly added to the first flask under extensive stirring. The resulting mixture was stirred at RT for 20 h. Tetrahydrofuran was evaporated in vacuo, water (1500 mL) and ethyl acetate (1500 mL) were added. The mixture was cooled to 10 C. and 3N aqueous HCl was added until pH 1 was achieved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (1500 mL) and the combined organic phases were washed with 10% aq. NaHCO3 (750 mL) and 10% aq. NaCl (750 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (182 g, 505 mmol) in a purity of 83%. LC-MS (Method 1B): Rt=1.00 min, MS (ESIPos): m/z=300 [M+H]+
To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 mL) was added di- lH-imidazol-l-ylmethanone (159 g, 981 mmol) and N,N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The mixture was stirred at RT for 15h (CAUTION: moderate gas evolution). In a second flask, a suspension of potassium 3-ethoxy-3-oxopropanoate (200 g, 1.18 mol) and magnesium dichloride (112 g, 1.18 mol) in tetrahydrofuran (2100 mL) was heated to 50C for 15 h. The resulting warm suspension was slowly added to the first flask under extensive stirring. The resulting mixture was stirred at RT for 20 h. Tetrahydrofuran was evaporated in vacuo, water (1500 mL) and ethyl acetate (1500 mL) were added. The mixture was cooled to 10 C and 3N aqueous HQ was added until pH 1 was achieved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (1500 mL) and the combined organic phases were washed with 10% aq. NaHCCh (750 mL) and 10% aq. NaCl (750 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (182 g, 505 mmol) in a purity of 83%. LC-MS (Method IB): Rt = 1.00 min, MS (ESIPos): m/z = 300 [M+H]+
To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 niL) was added di- lH-iniidazol-l-ylmethanone (159 g, 981 mmol) and N,N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The mixture was stirred at RT for 15h (CAUTION: moderate gas evolution). In a second flask, a suspension of potassium 3-ethoxy-3-oxopropanoate (200 g, 1.18 mol) and magnesium dichloride (112 g, 1.18 mol) in tetrahydrofuran (2100 mL) was heated to 50C for 15 h. The resulting warm suspension was slowly added to the first flask und extensive stirring. The resulting mixture was stirred at RT for 20 h. Tetrahydrofuran was evaporated in vacuo, water (1500 mL) and ethyl acetate (1500 mL) were added. The mixture was cooled to 10 C and 3N aqueous HQ was added until pH 1 was achieved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (1500 mL) and the combined organic phases were washed with 10% aq. NaHC03 (750 mL) and 10% aq. NaCl (750 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (182 g, 505 mmol) in a purity of 83% of theory. LC-MS (Method IB): Rt = 1.00 min, MS (ESIPos): m/z = 300 [M+H]+
6-fluoro-1H-pyrazolo[4,3-b]pyridin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-(3-fluoro-9-oxo-9,10-dihydropyrido[3',2':3,4]pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
41A Tert-butyl 4-(3-fluoro-9-oxo-9J0-dihydropyrido[32':3,4]pyrazolo[l ,5-a]pyrirnidin-7-yl)piperidine-l - carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (932 mg, 3.11 mmol, 1.5 eq), 6-fluoro- lH-pyrazolo[4,3-b]pyridin-3-amine (395 mg, 80% purity, 2.07 mmol, 1 eq) and potassium phosphate (881 mg, 4.15 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1 A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to give the title compound (59.2 mg, 95% purity, 7% of theory) as yellowish solid. LC-MS (Method IB): Rt = 0.96 min, MS (ESIPos): m/z = 388 [M+H]+
59.2 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
41.A Tert-butyl 4-(3-fluoro-9-oxo-9,10-dihydropyrido[3',2':3,4]pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (932 mg, 3.11 mmol, 1.5 eq), 6-fluoro-1H-pyrazolo[4,3-b]pyridin-3-amine (395 mg, 80% purity, 2.07 mmol, 1 eq) and potassium phosphate (881 mg, 4.15 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50° C. in vacuo to give the title compound (59.2 mg, 95% purity, 7% of theory) as yellowish solid. LC-MS (Method 1B): Rt=0.96 min, MS (ESIPos): m/z=388 [M+H]+
tert-butyl 4-(10-ethoxy-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
42A Tert-butyl 4-(10-ethoxy-2-oxo-l 2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.07 g, 3.58 mmol, 1.5 eq), 4-ethoxy- lH-indazol-3-amine (423 mg, 2.39 mmol, 1 eq) and potassium phosphate (1.01 g, 4.78 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was triturated with MTBE (15 mL), filterered, washed with MTBE (2 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (161 mg, 15% of theory). LC-MS (Method IB): Rt = 1.11 min, MS (ESIPos): m z = 413 [M+H]+
161 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
42.A Tert-butyl 4-(10-ethoxy-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.07 g, 3.58 mmol, 1.5 eq), 4-ethoxy-1H-indazol-3-amine (423 mg, 2.39 mmol, 1 eq) and potassium phosphate (1.01 g, 4.78 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was triturated with MTBE (15 mL), filtered, washed with MTBE (2 mL) and dried for 16 h at 50° C. in vacuo to yield the title compound (161 mg, 15% of theory). LC-MS (Method 1B): Rt=1.11 min, MS (ESIPos): m/z=413 [M+H]+
7-bromo-1H-pyrazolo[4,3-c]pyridin-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-(7-bromo-2-oxo-1,2-dihydropyrido[4',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
43A Tert-butyl 4-(7-bromo-2-oxo-l,2-dihydropyrido[43':3,4]pyrazolo[l,5-a]pyrimidin-4-yl)piperidine-l- carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 7-bromo- lH-pyrazolo[4,3-c]pyridin-3-amine (474 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was triturated with acetonitrile (10 mL) and filterered. The residue was triturated with DMSO (6 mL), washed with acetonitrile (8 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (116 mg, 12% of theory). LC-MS (Method IB): Rt = 0.98 min, MS (ESIPos): m/z = 448 [M+H]+
116 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
43.A Tert-butyl 4-(7-bromo-2-oxo-1,2-dihydropyrido[4',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate
Example 43A Tert-butyl 4-(7-bromo-2-oxo-1,2-dihydropyrido[4',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 7-bromo-1H-pyrazolo[4,3-c]pyridin-3-amine (474 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in 1-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180° C. for 15 min After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4:1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4:1) and evaporated in vacuo. The residue was triturated with acetonitrile (10 mL) and filtered. The residue was triturated with DMSO (6 mL), washed with acetonitrile (8 mL) and dried for 16 h at 50° C. in vacuo to yield the title compound (116 mg, 12% of theory). LC-MS (Method 1B): Rt=0.98 min, MS (ESIPos): m/z=448 [M+H]+
tert-butyl 4-(8,10-dimethyl-2-oxo-1,2-dihydropyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
48A Tert-butyl 4-(8, 10-dimethyl-4-oxo-l ,4-dihydropyrido[2',3':3,4]pyrazolo[l ,5-a]pyrimidin-2- yl)piperidine- 1 -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4,6- Dimethyl-lH-pyrazolo[3,4-b]pyridin-3-amine (361 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (9 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (50 mL), neutralized (pH 5-6) by the addition of IN HC1 and extracted with ethyl acetate (2x 100 mL). The combined organic phases were washed with water, (2x 25 mL), brine (25 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was triturated with acetonitrile (4 mL) and DMSO (4 mL). The precipitate was filterered, washed with acetonitrile (2x 2 mL) and dried for 2 h at 50°C in vacuo to yield the title compound (50 mg, 5% of theory) as yellow solid. LC-MS (Method IB): Rt = 0.92 min, MS (ESIPos): m/z = 398 [M+H]+
tert-butyl 4-(2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
17A Tert-butyl 4-(4-oxo-l ,4-dihydropyrimido l ,2-b]indazol-2-yl)piperidine-l -carboxylate
7eri-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.50 g, 5.01 mmol, 1 eq), lH-indazol- 3-amine (1.00 g, 7.52 mmol, 1.5 eq) and potassium phosphate (2.13 g, 10.0 mmol, 2 eq) were suspended in l-methoxy-2-propanol (15 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was neutralized (pH 6- 7) by the addition of IN HC1, diluted with water (60 mL), and extracted with ethyl acetate (2x, 100 mL and 50 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was triturated with acetonitrile (5 mL). The precipitate was filterered, washed with acetonitrile (8 mL) and dried for 2 h at 50°C in vacuo to give the title compound (239 mg, 13% of theory). LC-MS (Method IB): Rt = 0.98 min, MS (ESIPos): m/z = 369 [M+H]+
tert-butyl 4-(10-chloro-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With potassium phosphate; at 180℃; for 0.5h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (9.11 g, 30.4 mmol, 1.5 eq), 4-chloro- lH-indazol-3-amine (3.4 g, 20.3 mmol, 1 eq) and potassium phosphate (8.61 g, 40.6 mmol, 2 eq) were suspended in l-methoxy-2-propanol (70 mL) and split to seven 20 mL microwave vials. The vials were capped and the mixture was heated in a microwave to 180C for 15 min. Another 1.5 eq of tert-butyl 4- (3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate was added in l-methoxy-2-propanol (2 mL for each vial), and the mixture was heated in a microwave to 180C for 15 min again. After cooling to RT, the combined suspensions were evaporated in vacuo, diluted with water (150 mL), neutralized (pH 6) by the addition of IN HC1, and extracted with ethyl acetate (2x, 200 mL). The combined organic phases were washed with water (2x 100 mL) and brine (50 mL) and evaporated in vacuo. The partially crystalline residue was triturated with ethyl acetate (50 mL). The precipitate was filterered, washed with ethyl acetate (20 mL) and acetonitrile (10 mL) and dried for 16 h at 50C in vacuo to yield the title compound (2.63 g, 96% purity, 31% of theory). LC-MS (Method IB): Rt = 1.12 min, MS (ESIPos): m/z = 403 [M+H]+
tert-butyl 4-(10-fluoro-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
20A Tert-b tyl 4-(10-fluoro-4-oxo-l,4-dih dropyrimido[l,2-b]indazol-2-yl)piperidine-l -carboxylate
7ri-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (0.66 g, 2.2 mmol, 1 eq), 4-fluoro-lH- indazol-3-amine (0.50 g, 3.31 mmol, 1.5 eq) and potassium phosphate (0.936 g, 4.41 mmol, 2 eq) were suspended in l-methoxy-2-propanol (9 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (15 mL), neutralized (pH 5-6) by the addition of IN HC1, and extracted with ethyl acetate (2x, 15 mL). The combined organic phases were evaporated in vacuo. The residue was triturated with water (30 mL), filtrered, and the residue was resuspended in acetonitrile (30 mL). The precipitate was filterered, washed with acetonitrile (2 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (62 mg, 7% of theory). LC-MS (Method IB): Rt = 1.02 min, MS (ESIPos): m/z = 387 [M+H]+
tert-butyl 4-(9-chloro-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30 mg
With potassium phosphate; In 1,4-dioxane; at 150℃; for 2.0h;Microwave irradiation;
7ri-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (450 mg, 81 % purity, 1.22 mmol, 1 eq), 5-chloro-lH-indazol-3-amine (204 mg, 1.22 mmol, 1.0 eq) and potassium phosphate (517 mg, 2.43 mmol, 2 eq) were suspended in dioxane (4.3 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 150C for 1 h. Another leq of teri-butyl 4-(3-ethoxy-3- oxopropanoyl)piperidine-l -carboxylate was added and the mixture was heated in a microwave to 150C for 1 h. The solvent was evaporated in vacuo, the residue was diluted with water (20 mL) and extracted with ethyl acetate (2x, 50 mL and 25 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound (30 mg, 6% of theory) as solid. LC-MS (Method 2B): Rt = 1.97 min, MS (ESIPos): m/z = 403 [M+H]+
tert-butyl 4-(9-fluoro-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
23A Tert-butyl 4-(9-fluoro-4-oxo-l,4-dihydropyrimido[l,2-b]indazol-2-yl)piperidine-l-carboxylate
7eri-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (264 mg, 0.882 mmol, 1 eq), 5-fluoro- lH-indazol-3-amine (200 mg, 1.32 mmol, 1.5 eq) and potassium phosphate (374 mg, 1.76 mmol, 2 eq) were suspended in l-methoxy-2-propanol (2.6 mL) in a microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 5-6) by the addition of IN HC1, and extracted with ethyl acetate (2x 15 mL). The combined organic phases were evaporated in vacuo. The residue was triturated with acetonitrile (10 mL). The precipitate was filterered, washed with acetonitrile (2 mL) and dried for 2 h at 50°C in vacuo to yield the title compound (61.3 mg, 18% of theory). LC-MS (Method IB): Rt = 1.02 min, MS (ESIPos): m/z = 387 [M+H]+
tert-butyl 4-(10-methoxy-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
24A Tert-butyl 4-( 10-methoxy-4-oxo- 1 4-dihydropyrimido[ 1 ,2-b] indazol-2-yl)piperidine- 1 -carboxylate
7ri-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4- methoxy-lH-indazol-3-amine (363 mg, 2.23 mmol, 1.5 eq) and potassium phosphate (945 mg, 10.2 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 5-6) by the addition of IN HCl, and extracted with ethyl acetate (2x 50 mL). The combined organic phases were washed with brine (20 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide and acetonitrile was evaporated in vacuo. The resulting suspension was filtered, the residue was washed with water (10 ml) and dried for 16 h at 50°C in vacuo to give the title compound (128 mg, 14% of theory) as light yellow solid. LC-MS (Method IB): Rt = 1.04 min, MS (ESIPos): m/z = 399 [M+H]+
tert-butyl 4-(10-bromo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
26A Tert-butyl 4-( 10-bromo-4-oxo- 1 ,4-dih dropyrimido[ 1 ,2-b] indazol-2-yl)piperidine- 1 -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-bromo- lH-indazol-3-amine (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6) by the addition of IN HC1. The precipitate was filterered, washed with water (10 mL), MTBE (4 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (222 mg, 22% of theory). LC-MS (Method IB): Rt = 1.13 min, MS (ESIPos): m/z = 447 [M+H]+
22%
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
174A tert-butyl 4-(10-bromo-2-oxo-l, -dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l-carboxylate
Teri-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-bromo- lii-indazol-3-amine (472 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (11.8 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL) and neutralized (pH 6) by the addition of IN HCl. The precipitate was filterered, washed with water (10 mL), MTBE (4 mL) and dried for 16 h at 50°C in vacuo to yield the title compound (222 mg, 22% of theory). LC-MS (Method IB): Rt = 1.13 min, MS (ESIPos): m/z = 447 [M+H]+
4.4 Synthesis of 7
In a 100 mL round-bottomed flask filled with a solution of 6.0 M NaOH (50 mL) was added 6 (9.00 g 30.2 mmol). The reaction mixture was heated under reflux for 20 h, then diluted with 300 mL water and was quenched by addition 240 mL dichloromethane. The collected organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, affording 6.42 g (94.0 % yield) light yellow liquid. 1H NMR (300 MHz, CDCl3): δ 4.07-4.11 (m, 2H), 2.74-2.81 (m, 2H), 2.41-2.48 (m, 1H), 2.15 (s, 3H), 1.81-1.84 (m, 2H), 1.48-1.57 (m, 2H), 1.44 (s, 9H).
With trifluoroacetic acid In ethanol at 80℃; for 12h;
1.4
(4) Compound 5 (15 g, 45 mmol) and compound 6 (9.45 g, 49.5 mmol) were dissolved in anhydrous ethanol (400 mL). Trifluoroacetic acid (20 mL) was added. The mixture was heated at 80° C. for 12 hours, then the heat is stopped. After cooling to room temperature, the solvent was evaporated to dryness. The residue was diluted with water (100 mL), adjusted to pH 8 with 1M NaOH. extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by silica gel column (methanol:dichloromethane=1:20) to give compound 7 (13.82 g, 72%).
72%
With trifluoroacetic acid In ethanol at 80℃; for 12h;
1.4
Compound 5 (15 g, 45 mmol) was dissolved in anhydrous ethanol (400 mL) with compound 6 (9.45 g, 49.5 mmol), followed by addition of trifluoroacetic acid (20 mL) and heating at 80 ° C for 12 hours. Cool to room temperature and spin the solvent. The reaction mixture was diluted with water (100 mL), extracted with 1 M NaOH, and extracted with ethyl acetate (3x200 mL). The extract was dried over anhydrous sodium sulfate, filtered and dried with methanol: dichloromethane = 1:20 Compound 7 (13. 82 g, 72%) was isolated.
tert-butyl 4-(5-oxo-3-phenyl-4,5-dihydropyrazolo[1,5a]pyrimidin-7-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13.5 mg
With potassium phosphate; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (450 mg, 81% purity, 1.22 mmol), phenyl- lH-pyrazol-3 -amine (194 mg, 1.22 mmol, 1 eq) and potassium phosphate (517 mg, 2.43 mmol, 2 eq) were suspended in dioxane (4.3 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 150C for 1 h. After cooling to RT, the mixture was evaporated in vacuo, diluted with water (20 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were adjusted to pH 7 by addition of - - aqueous ammonium hydroxide. Acetonitrile was evaporated in vacuo, the remaining water was extracted with ethyl acetate, the organic layer was dried with sodium sulfate, filtered and evaporated in vacuo to give the title compound (13.5 mg, 3% of theory). LC-MS (Method IB): Rt = 1.10 min, MS (ESINeg): m/z = 393 [M-H]"
tert-butyl 4-[7-oxo-3-(pyridin-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
240 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
12A Example 12A 7rt-butyl 4-[7-oxo-3-(pyridin-2-yl)- -dihydropyrazolo[l,5-a]pyrimidin-5-yl]piperidine-l -carboxylate
rt-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (2.00 g, 6.68 mmol, 1.5 eq), 4- (pyridin-2-yl)-lH-pyrazol-3-amine (713 mg, 4.45 mmol, 1 eq) and potassium phosphate (1.89 g, 8.91 mmol, 2 eq) were suspended in l-methoxy-2-propanol (20 mL) in two 20 mL microwave vials. The vials were capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (20 mL), neutralized (pH 6) by the addition of IN HCl and extracted with ethyl acetate (2x 50 mL). The combined organic phases were dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were concentrated in vacuo to remove acetonitrile. The resulting suspension was filtered, the residue was washed with water (2 ml) and dried for 16 h at 50°C in vacuo to give the title compound (240 mg, 14% of theory). LC-MS (Method IB): Rt = 1.08 min, MS (ESIPos): m/z = 396 [M+H]+
5-(methoxymethyl)-4-(4-methoxyphenyl)-1H-pyrazol-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-[2-(methoxymethyl)-3-(4-methoxyphenyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.6 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
13A Example 13A 7rt-butyl 4-[2-(methoxymethyl)-3-(4-methoxyphenyl)-5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidin-7- yl]piperidine-l -carboxylate
7rt-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (350 mg, 1.00 mmol), 5- (methoxymethyl)-4-(4-methoxyphenyl)-lH-pyrazol-3-amine (351 mg, 1.50 mmol, 1.5 eq) and - - potassium phosphate (425 mg, 2.00 mmol, 2 eq) were suspended in l-methoxy-2-propanol (3 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with water (5 mL), neutralized (pH 6) by the addition of IN HC1 and extracted with ethyl acetate (2x 20 mL). The combined organic phases were dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were adjusted to pH 7 by addition of aqueous ammonium hydroxide. Acetonitrile was evaporated in vacuo, the resulting suspension was filtered, the residue was washed with water (2 mL) and dried for 16 h at 50°C in vacuo to give the title compound (86.6 mg, 18% of theory). LC-MS (Method IB): Rt = 1.09 min, MS (ESIPos): m/z = 469 [M+H]+
tert-butyl 4-[3-(4-fluorophenyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-5-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
14A Example 14A 7rt-butyl 4-[3-(4-fluorophenyl)-7-oxo-4,7-dihydropyrazolo[l ,5-a]pyrimidin-5-yl]piperidine-l -carboxy- late
rt-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-(4- fluorophenyl)-lH-pyrazol-3-amine (395 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile, the remaining water was extracted with ethyl acetate, the organic layer was dried with magnesium sulfate, filtered and evaporated in vacuo to give the title compound (64 mg, 90% purity, 6% of theory). LC-MS (Method 1 B) : Rt = 1.11 min, MS (ESIPos) : m z = 413 [M+H] +
tert-butyl 4-[5-oxo-3-(pyridin-3-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-5-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11.3 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
15A Example 15A 7rt-butyl 4-[7-oxo-3-(pyridin-3-yl)-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl]piperidine-l -carboxylate
rt-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (561 mg, 1.87 mmol, 1.5 eq), 4- (pyridin-3-yl)-lH-pyrazol-3-amine (200 mg, 1.25 mmol, 1 eq) and potassium phosphate (530 mg, 2.50 mmol, 2 eq) were suspended in l-methoxy-2-propanol (4 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the suspension was diluted with 20 mL dichloromethane/methanol (4: 1), filtered through a short pad of silica gel with 100 mL dichloromethane/methanol (4: 1) and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were evaporated in vacuo to remove acetonitrile and lyophilized to give the title compound (11.3 mg, 2% of theory). LC-MS (Method IB): Rt = 0.79 min, MS (ESIPos): m z = 396 [M+H]+
tert-butyl 4-[3-(2-methoxyphenyl)-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.8 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
16A Example 16A Tert-butyl 4-[3-(2-methoxyphenyl)-2-methyl-7-oxo-4,7-dihydropyrazolo[l ,5-a]pyrimidin-5-yl]piperi- dine- 1 -carboxylate
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (221 mg, 0.74 mmol, 1.5 eq), 4-(2- methoxyphenyl)-5-methyl-lH-pyrazol-3-amine (100 mg, 0.49 mmol, 1 eq) and potassium phosphate (209 mg, 0.98 mmol, 2 eq) were suspended in l-methoxy-2-propanol (2 mL) in a 5 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the mixture was evaporated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were adjusted to pH 7 by addition of aqueous ammonium hydroxide. Acetonitrile was evaporated in vacuo, the resulting suspension was filtered, the residue was washed with water (0.5 mL) and dried for 16 h at 50°C in vacuo to give the title compound (4.8 mg, 2% of theory). LC-MS (Method 1 B) : Rt = 1.12 min, MS (ESIPos) : m z = 439 [M+H] + - -
3-methyl-4-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-{2-methyl-5-oxo-3-[3-(trifluoromethyl)phenyl]-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl}piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
212 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
23A Example 23A 7rt-butyl 4-{2-methyl-5-oxo-3-[3-(trifluoromethyl)phenyl]-4,5-dihydropyrazolo[l ,5-a]pyrimidin-7- yl}piperidine-l -carboxylate
7rt-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (2.41 g, 6.68 mmol), 3-methyl-4-[3- (trifluoromethyl)phenyl]-lH-pyrazol-5 -amine (1.07 g, 4.45 mmol) and potassium phosphate (1.89 g, - - 8.91 mmol) were suspended in l-methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the mixture was evaporated and the residue was diluted in water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The collected organic phases were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with aqueous ammonium hydroxide. After the evaporation of acetonitrile a white solid was formed in the aqueous phase, which was filtered and dried under vacuo to yield the title compound (212 mg, 10% of theory). LC-MS (Method IB): Rt = 1.26 min, MS (ESIPos): m/z = 477 [M+H]+
tert-butyl 4-(3-cyano-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.2 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
18A Example 18A Tert-butyl 4-(3-cyano-2-methyl-5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidin-7-yl)piperidine-l-carboxy- late
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l -carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 3-amino- 5-methyl-lH-pyrazole-4-carbonitrile (272 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (6.5 mL) in a 20 mL microwave vial. The vial - - was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the mixture was evaporated in vacuo, diluted with water (5 mL), adjusted to pH 7 with IN HC1 and extracted with ethyl acetate (3x10 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were adjusted to pH 7 by addition of aqueous ammonium hydroxide. Acetonitrile was evaporated in vacuo, the resulting suspension was filtered, the residue was washed with water (0.5 mL) and dried for 16 h at 50°C in vacuo to give the title compound (62.2 mg, 8% of theory). LC-MS (Method IB): Rt = 0.96 min, MS (ESINeg): m/z = 356 [M-H]"
ethyl 7-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31.1 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
19A Example 19A Ethyl 7-[l -(^er butoxycarbonyl)piperidin-4-yl]-2-methyl-5-oxo-4,5-dihydropyrazolo[l ,5-a]pyrimidine- 3-carboxylate
7rt-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), ethyl 5- amino-3-methyl-lH-pyrazole-4-carboxylate (377 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the mixture was evaporated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were adjusted to pH 7 by addition of aqueous ammonium hydroxide. Acetonitrile was evaporated in vacuo, the resulting aqueous solution was extracted with ethyl acetate (2x20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound (31.1 mg, 3% of theory). LC-MS (Method IB): Rt = 1.11 min, MS (ESINeg): m/z = 403 [M-H]"
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 4-(4- bromophenyl)-3-methyl-lH-pyrazol-5-amine (585 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the mixture was evaporated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were adjusted to pH 7 by addition of aqueous ammonium hydroxide. Acetonitrile was evaporated in vacuo, the resulting suspension was filtered, the residue was washed with water (0.5 mL) and dried for 16 h at 50C in vacuo to give the title compound (180 mg, 16% of theory). LC-MS (Method IB): Rt = 1.23 min, MS (ESIPos): m/z = 487 [M+H]+
5-(methoxymethyl)-4-phenyl-1H-pyrazol-3-amine[ No CAS ]
[ 479630-08-5 ]
tert-butyl 4-[2-(methoxymethyl)-5-oxo-3-phenyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
303 mg
With potassium phosphate at 180℃; for 0.25h; Microwave irradiation;
21A Example 21A 7rt-butyl 4-[2-(methoxymethyl)-5-oxo-3^henyl-4,5-dihydropyrazolo[l,5-a]pyrimidin-7-yl]piperidine- 1-carboxylate
7rt-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.00 g, 3.34 mmol, 1.5 eq), 5- (methoxymethyl)-4-phenyl-lH-pyrazol-3-amine (476 mg, 2.27 mmol, 1 eq) and potassium phosphate (945 mg, 4.45 mmol, 2 eq) were suspended in l-methoxy-2-propanol (10 mL) in a 20 mL microwave vial. The vial was capped and the mixture was heated in a microwave to 180°C for 15 min. After cooling to RT, the mixture was evaporated in vacuo, diluted with water (5 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (Method 1A). The combined product fractions were adjusted to pH 7 by addition of aqueous ammonium hydroxide. Acetonitrile was evaporated in - - vacuo, the resulting suspension was filtered, the residue was washed with water (0.5 mL) and dried for 16 h at 50°C in vacuo to give the title compound (303 mg, 30% of theory). LC-MS (Method IB): Rt = 1.09 min, MS (ESIPos): m/z = 439 [M+H]+
tert-butyl 4-[5-oxo-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
132 mg
With potassium phosphate; at 180℃; for 0.25h;Microwave irradiation;
Tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-l-carboxylate (1.0 g, ca. 2.77 mmol), 3- (trifluoromethyl)-lH-pyrazol-5 -amine (0.28 g, 1.85 mmol) and potassium phosphate (0.79 g, 3.70 mmol) were suspended in 1 -methoxy-2-propanol (10 ml) in a 20 ml microwave vial. The vial was capped and the mixture was heated in a microwave to 180C for 15 min. After cooling to RT, the solvent was evaporated and the residue was treated with water and ethyl acetate. After separation of the layers the aqueous phase was neutralized by addition of HQ 4N and extracted with ethyl acetate. The collected organic layers were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (Method 1A). The combined product fractions were neutralized with a 33% ammonia solution and then acetonitrile was evaporated. The aqueous phase was extracted with ethyl acetate and the collected organic fractions were dried over sodium sulfate, filtered and evaporated under vacuo to yield the title compound (132 mg, 19% of theory). LC-MS (Method IB): Rt = 1.06 min, MS (ESIPos): m/z = 387 [M+H]+
tert-butyl 4-[6-oxo-2-(4-pyridyl)-1H-pyrimidin-4-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
Stage #1: 4-amidinopyridine hydrochloride With sodium methylate In methanol at 20℃; for 0.166667h;
Stage #2: 4-(2-ethoxycarbonylacetyl)piperidine-1-carboxylic acid tert-butyl ester In methanol at 60℃; for 4h;
tert-Butyl 4-[6-oxo-2-(4-pyridyl)- lH-pyrimidin-4-yl]piperi dine- 1 -carboxy late (1-001)
Pyridine-4-carboximidamide hydrochloride (0.30 g, 2 mmol) was added to a round bottom flask and methanol (5 mL) and sodium methoxide (0.152 g, 4 mmol) were added. The mixture was allowed to stir at room temperature for 10 minutes then 4-(2-ethoxycarbonyl-acetyl)-piperidine-l - carboxylic acid tert-butyl ester (0.59 g, 2 mmol) was added and the reaction mixture was heated at 60 °C for 4 hours. The solvent was removed under reduced pressure and the residue was triturated with diisopropylether to provide a grey solid. This was dissolved in ethyl acetate (10 niL) and washed with water (10 mL) and brine (10 mL), dried (MgS04), filtered and evaporated under reduced pressure to give the title compound as an off-white solid (0.12 g, 17% yield). LCMS : RT: 3 08 mm, MI 357, Method (4LCMS1).
4-methylthiazole-5-carboxamidine hydrochloride[ No CAS ]
[ 479630-08-5 ]
C18H24N4O3S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In methanol for 24h; Reflux;
Synthesis of tert-butyl 4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1 H-pyrimidin-4- yl]piperidine-1-carboxylate (1-002)
[00195] 4-Methylthiazole-5-carboxamidine hydrochloride (1-001) (2.00 g, 14.2 mmol) was dissolved in MeOH (50 mL) and tert-butyl-4-(3-ethoxy-3-oxopropanoyl)tetrahydro-1 (2H)- pyridinecarboxylate (4.24 g, 14.2 mmol) was added, followed by DBU (8.47 mL, 56.7 mmol). The reaction mixture was heated to reflux for 24 h. The reaction mixture was then concentrated under vacuum and the residue suspended in EtOAc (20 mL) then sonicated. The precipitate obtained was collected by vacuum filtration. The solid collected was partitioned between DCM and 1 N HCI solution (aq). The organic phase was separated, dried (MgS04), filtered and concentrated under vacuum to give the title compound (2.59 g, 49%). 1 H NMR (300 MHz, CDCI3) δ 1 1 .93 (br s, 1 H), 8.83 (s, 1 H), 6.21 (s, 1 H), 4.23 (br s, 2H), 2.89 - 2.72 (m, 5H), 2.68 - 2.55 (m, 1 H), 1 .90 (d, J= 12.9 Hz, 2H), 1 .65 (qd, J= 12.4, 4.3 Hz, 2H), 1 .47 (s, 9H).
Stage #1: ethyl potassium malonate With dmap; magnesium chloride In tetrahydrofuran; acetonitrile at 20℃; for 5h; Cooling with ice;
Stage #2: tert-butyl 4-(1H-imindazole-1-carbonyl)piperidine-1-carboxylate In tetrahydrofuran; acetonitrile at 0℃; for 18h;
Stage #1: ethyl potassium malonate With dmap; magnesium chloride In tetrahydrofuran; acetonitrile at 0 - 20℃; for 6h;
Stage #2: tert-butyl 4-(1H-imindazole-1-carbonyl)piperidine-1-carboxylate With triethylamine In tetrahydrofuran; acetonitrile at 0 - 20℃;
Stage #3: With hydrogenchloride In tetrahydrofuran; water; acetonitrile at 0℃;
1.c Step c: Synthesis of intermediate 3:
6.8 g (40 mmol) of monoethyl malonate potassium salt was added to a 500 mL round bottom flask, 100 mL of freshly distilled THF and 50 mL of re-steamed CH3CN were added, the temperature was lowered to 0 ° C, anhydrous MgCl 2 was added, 3.8 g (40 mmol), DMAP 244 mg (2mmol). Raise to room temperature and fall for 6h. The temperature was lowered to 0 °C, and the intermediate 25.58 g (20 mmol) was dissolved in 10 mL of freshly-purified THF, and Et3N 3.03 g (40 mmol) was added dropwise to the round bottom flask, and the mixture was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the temperature was lowered to 0 ° C, and 1 mL of HCl 150 mL, Et 2 O (100 mL×3) was added, and the Et 2 O phase was washed with saturated brine. Drying with anhydrous MgSO4, filtering and sifting, and then separating with 200-300 mesh silica gel to obtain intermediate 3 as a pale yellow oily liquid. The yield in two steps was 88.65%.
1.e Step e: Synthesis of Compound M106:
Intermediate 5 3.78 g (19.8 mmol), intermediate 36 g (18 mmol),A 500 mL round bottom flask was added, and 200 mL of re-evaporated EtOH was added, 15 mL of TFA was added dropwise, and refluxed at 80 ° C overnight.After the completion of the reaction, EtOH and TFA were evaporated to dryness, and 1 NaOH was added dropwise, and a large white solid was precipitated, and the solid was washed with a small amount of methanol to obtain Compound M106 as a white powdery solid, yield 78.6%.
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