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CAS No. : | 571190-30-2 | MDL No. : | MFCD11840850 |
Formula : | C24H29N7O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AHJRHEGDXFFMBM-UHFFFAOYSA-N |
M.W : | 447.53 | Pubchem ID : | 5330286 |
Synonyms : |
PD 0332991
|
Num. heavy atoms : | 33 |
Num. arom. heavy atoms : | 16 |
Fraction Csp3 : | 0.46 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 136.03 |
TPSA : | 105.04 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -7.74 cm/s |
Log Po/w (iLOGP) : | 3.46 |
Log Po/w (XLOGP3) : | 1.81 |
Log Po/w (WLOGP) : | 2.2 |
Log Po/w (MLOGP) : | 1.62 |
Log Po/w (SILICOS-IT) : | 2.51 |
Consensus Log Po/w : | 2.32 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.78 |
Solubility : | 0.0736 mg/ml ; 0.000165 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.64 |
Solubility : | 0.104 mg/ml ; 0.000232 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -6.49 |
Solubility : | 0.000145 mg/ml ; 0.000000324 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.57 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P501-P273-P260-P270-P264-P280-P391-P314-P337+P313-P305+P351+P338-P301+P312+P330 | UN#: | 3077 |
Hazard Statements: | H302-H319-H372-H410 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.8% | With hydrogenchloride In ethanol; water at 20℃; for 93 h; Heating | 1.5 g (3.35 mmol) palbociclib base and 30 ml ethanol are measured into a device providing intensive stirring, then during boiling 3.18 ml (3.18 mmol) of a 1 M hydrochloric acid solution is added to it drop by drop. The solution is cooled to room temperature, mixed for 93 hours, then this crystalline product is filtered, washed with a small amount of cold ethanol and then MTBE, then dried in the air.Yield: 0.62 g (90.8percent)Mp.: 288—290°CAnalysis with respect to the chemical formula C24H30C1N702 (484.00):Calculated C: 59.56 percent H: 6.25 percent N: 20.26 percent Cl: 7.32 percent. Measured C: 59.40 percent H: 6.26 percent N: 20.00 percent Cl: 7.30 percent. 1H-NMR (DMSO-d6, 400 MHz): 10.21 (bs, 1H), 9.27 (b, 2H), 8.97 (s, 1H), 8.12 (d, 1=2.9 Hz, 1H), 7.92 (d, 1=9.0 Hz, 1H), 7.54 (dd, 11=2.9 Hz, 12=9.1 Hz, 1H), 5.83 (m, 1H), 3.40 (m, 4H),32.25 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.24 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.59 (m, 2H). 13C-NMR (DMSO-d6, 125 MHz): 202.52, 160.87, 158.62, 158.37, 154.90, 145.45, 142.48,142.16, 136.28, 129.53, 125.73, 115.11, 106.86, 53.11, 45.76, 42.61, 31.42, 27.70, 25.25,13.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | In methanol; at -8 - 20℃;Conversion of starting material; | EXAMPLE 7 Preparation of A MONO-ISETHIONATE salt of 6-ACETYL-8-CVCLOPENTYL-5-METHYL-5- IPERAZIN-1-VL-PVRIDIN-2-VLAMINO)-8H-PVRIDOF2,. 3-DLPVRIMIDIN-7-ONE (Form B) The free base (Formula 1, 0. 895 mg, 2 MMOL) was mixed with 10 mL of MeOH and seeded with 33 mg of A MONO-ISETHIONATE SALT OF THE COMPOUND OF FORMULA L (FORM B). THEN 5.6 mL of A 0. 375 M solution of isethionic acid in MeOH (2. 1 MMOL) was added in 10 even portions over 75 min time period. The mixture was stirred for an additional hour and a sample was TAKEN FOR PXRD ANALYSIS. IT CONFIRMED FORMATION OF CRYSTALLINE FORM B. THE MIXTURE WAS stirred at RT overnight and another PXRD was taken. There was no change in the crystal form. The mixture was cooled in a refrigerator AT-8C overnight, filtered, and dried at 50C in a vacuum oven to give 1.053 g (91.8 % of theory) of the above-named compound (Form B). HPLC-99.8 %, CHNS, H-NMR, IR are consistent with the structure, PXRD-Form B. |
52.5% | In methanol; at 20℃; for 3h; | 5L three bottles, put into 290.0g (0.65mol) free base, 1.2L methanol, stirred at room temperature, the moment after dropping 98.2g isethionic (0.78mol) and 500mL methanol mixture, the suspension system gradually became clear there are large amount of solid precipitated, continued stirring for 3 hours at room temperature, suction filtered, the filter cake rinsed with methanol, 45 blast drying to give a pale yellow solid, constant weight 196.0g, a yield of 52.5%. |
In methanol; water;pH 5.2; | EXAMPLE 4 Preparation of A mono-isethionate salt of 6-ACETVL-8-CVCLOPENTYL-5-METHYL-2- (5- PIPERAZIN-1-YL-PYRIDIN-2-VLAMINO)-8H-PVRIDOF2. 3-DLPVRIMIDIN-7-ONE (Form B) To A slurry of 6-ACETYL-8-CYCLOPENTYL-5-METHYL-2- (5-PIPERAZIN-1-YL-PYRIDIN-2-YLAMINO)- 8H-PYRIDO [2, 3-DIPYRIMIDIN-7-ONE (7.0 g, 15.64 MMOL, prepared as in Example 3 following contact with NaOH) dispersed in 250 mL of water was added drop-wise 30 mL OF A 0. 52 M solution of isethionic acid in MeOH (15. 64 MMOL) to A pH of 5. 2. The solution was filtered through A glass filter (fine) and the clear solution was freeze-dried to give 9. 4 G of the amorphous salt. The amorphous salt (3. 16 g) was mixed with 25 mL of MEC) H AND AFTER almost complete dissolution A new precipitate formed. Another 25 mL of MeOH was added and the mixture was stirred at 46C to 49C for four hours. The mixture was slowly cooled to 32C and put in a cold room (+4C) overnight. A sample was taken for PXRD, which indicated formation of Form B. The mixture was filtered and the precipitate was dried overnight at 50C in a vacuum oven. This furnished 2.92 G of the mono-isethionate salt of the compound of Formula 1 in 92 % yield. |
In methanol; water;pH 5.2; | Preparation 4 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Form B) To a slurry of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (7.0 g, 15.64 mmol, prepared as in Example 3 following contact with NaOH) dispersed in 250 mL of water was added drop-wise 30 mL of a 0.52 M solution of isethionic acid in MeOH (15.64 mmol) to a pH of 5.2. The solution was filtered through a glass filter (fine) and the clear solution was freeze-dried to give 9.4 g of the amorphous salt. The amorphous salt (3.16 g) was mixed with 25 mL of MeOH and after almost complete dissolution a new precipitate formed. Another 25 mL of MeOH was added and the mixture was stirred at 46 C. to 49 C. for four hours. The mixture was slowly cooled to 32 C. and put in a cold room (+4 C.) overnight. A sample was taken for PXRD, which indicated formation of Form B. The mixture was filtered and the precipitate was dried overnight at 50 C. in a vacuum oven. This furnished 2.92 g of the mono-isethionate salt of the compound of Formula 1 in 92% yield. HPLC-99.25%, PXRD-Form B, CHNS, H-NMR were consistent with the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In ethanol; water; for 1h;pH 9.0; | <strong>[827022-32-2]6-acetyl-8-cyclopentyl-5-methyl-2-[5-(piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride</strong> (6.9 g, 0.014 mol) was added to 100 ml of a mixed solvent of ethanol and water (8: 1 by volume) , 10% aqueous sodium hydroxide solution (6.8 ml, 0.017 mol) was added dropwise, Measured pH is about 9, Stirring 1h, Filtration, 60 deg C vacuum drying 5h, 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (Palbociclib) (5.9 g,Purity 99.7%Yield 95%). |
84.2% | The [...] hydrochloride 176 g, adding purified water 5 L heating to 55 C stirring 1.5 hours, cooling to 30 C to obtain solution (1);The solution (1) into the pre-cooling to the -5 C in ammonia (content is 25% -28% of 0.7 kg ammonia dissolved in 8 L purified water obtained), dropping process temperature control - 5 - 0 C, [...] - 5 - 0 C stirring 4 hours; filtering, the filter cake according to the purified water 1 L and acetone 1 L washing, vacuum drying the filter cake 24 hours to obtain the crystalline form B [...] 160 g, yield 84.2%, X - ray diffraction pattern as shown in Figure 2, the measured specific surface area is 6.8 m2/G, HPLC purity of 99.91%. | |
With sodium hydroxide; In water; | EXAMPLE 4 Preparation of A mono-isethionate salt of 6-ACETVL-8-CVCLOPENTYL-5-METHYL-2- (5- PIPERAZIN-1-YL-PYRIDIN-2-VLAMINO)-8H-PVRIDOF2. 3-DLPVRIMIDIN-7-ONE (Form B) To A slurry of 6-ACETYL-8-CYCLOPENTYL-5-METHYL-2- (5-PIPERAZIN-1-YL-PYRIDIN-2-YLAMINO)- 8H-PYRIDO [2, 3-DIPYRIMIDIN-7-ONE (7.0 g, 15.64 MMOL, prepared as in Example 3 following contact with NaOH) dispersed in 250 mL of water was added drop-wise 30 mL OF A 0. 52 M solution of isethionic acid in MeOH (15. 64 MMOL) to A pH of 5. 2. The solution was filtered through A glass filter (fine) and the clear solution was freeze-dried to give 9. 4 G of the amorphous salt. The amorphous salt (3. 16 g) was mixed with 25 mL of MEC) H AND AFTER almost complete dissolution A new precipitate formed. Another 25 mL of MeOH was added and the mixture was stirred at 46C to 49C for four hours. The mixture was slowly cooled to 32C and put in a cold room (+4C) overnight. A sample was taken for PXRD, which indicated formation of Form B. The mixture was filtered and the precipitate was dried overnight at 50C in a vacuum oven. This furnished 2.92 G of the mono-isethionate salt of the compound of Formula 1 in 92 % yield. |
1.45 g | With sodium hydroxide; In water; at 0 - 5℃; for 2h; | Process for the preparation of <strong>[827022-32-2]palbociclib</strong> free base crystalline form BPalbociclib hydrochloride (3.0 g, 5.22 mmol) was suspended in water (45 ml) and theresulting slurry was cooled to 0-5 C. Aqueous sodium hydroxide solution (0.417 gsodium hydroxide in 15 ml water) was added to the above slurry at 5 C and stirred for 2hours at the same temperature. The solid was filtered, washed with chilled water (15 ml) and dried under vacuum. Yield: 1.45 g.Specific surface area: 3.9 m2/g |
0.73 g | With potassium hydrogencarbonate; In water; at 20℃; for 4h; | The product obtained in Example 1 (1.0 g) was added slowly to a saturated solution of potassium bicarbonate (12.0 mL) andDistilled water (15.0 mL) and stirred at room temperature for 4.0 hours. Filter, solid with distilled water (3 x 5.0 mL)Washed, and dried to constant weight in an air bath at 50 C to give 0.73 g of Form C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Example 25 - Formula 2 - Compound 25a25a: 8-cyclopentyl-6-(1 -hydroxyethyl)-5-methyl-2-(5-(piperazin-1 -yl)pyridin-2- ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one To a stirred solution of compound A (100 mg, 0.22 mmol, 1 .0 eq) in MeOH (50 mL) and THF (20 mL) was added CeCI3.7H20 (164 mg, 0.44 mmol, 2.0 eq) then NaBH4 (16.3 mg, 0.44 mmol, 2.0 eq). The resulting mixture was stirred at room temperature for 48 h and then quenched with a saturated aqueous solution of NH4CI (10 mL). The aqueous layer was extracted with CH2CI2 (10 mL x 2) and the combined organic layers were washed with brine and dried over MgS04. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (CH2Cl2/MeOH, 10/1 , v/v) to give 8-cyclopentyl-6-(1 - hydroxyethyl)-5-methyl-2-(5-(piperazin-1 -yl)pyridin-2-ylamino)pyrido [2,3-d]pyrimidin-7(8H)-one (31 mg, 30percent) as a yellow solid.LC-MS (Agilent): Rt 3.02 min; m/z calculated for C24H3iN702 [M+H]+ 450.25, found 450.3.1H NMR: (400 MHz, DMSO-d6) delta (ppm): 9.86 (s, 1 H), 8.91 (s, 1 H), 8.02 (d, J = 2.8 Hz, 1 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.44 (dd, J = 8.8, 2.8 Hz, 1 H), 5.86 (m, 1 H), 5.23 (m, 1 H), 5.15 (d, J = 5.6 Hz, 1 H), 3.06 (m, 4H), 2.86 (m, 4H), 2.55 (s, 3H), 2.25 (m, 2H), 1 .91 (m, 2H), 1 .75 (m, 2H), 1 .59 (m, 2H), 1 .35 (d, J = 6.4 Hz, 3H). | |
30% | To a stirred solution of compound A (100 mg, 0.22 mmol, 1.0 eq) in MeOH (50 mL) and THF (20 mL) was added CeCl3.7H2O (164 mg, 0.44 mmol, 2.0 eq) then NaBH4 (16.3 mg, 0.44 mmol, 2.0 eq). The resulting mixture was stirred at room temperature for 48 h and then quenched with a saturated aqueous solution of NH4Cl (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL*2) and the combined organic layers were washed with brine and dried over MgSO4. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (CH2Cl2/MeOH, 10/1, v/v) to give 8-cyclopentyl-6-(1-hydroxyethyl)-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (31 mg, 30percent) as a yellow solid. LC-MS (Agilent): Rt 3.02 min; m/z calculated for C24H31N7O2 [M+H]+ 450.25. found 450.3. 1H NMR: (400 MHz, DMSO-d6) delta (ppm): 9.86 (s, 1H), 8.91 (s, 1H), 8.02 (d, J=2.8 Hz, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.44 (dd, J=8.8, 2.8 Hz, 1H), 5.86 (m, 1H), 5.23 (m, 1H), 5.15 (d, J=5.6 Hz, 1H), 3.06 (m, 4H), 2.86 (m, 4H), 2.55 (s, 3H), 2.25 (m, 2H), 1.91 (m, 2H), 1.75 (m, 2H), 1.59 (m, 2H), 1.35 (d, J=6.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: isopropylmagnesium chloride / tetrahydrofuran / 20 - 60 °C / Inert atmosphere 2: palladium diacetate; N-ethyl-N,N-diisopropylamine; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 2.5 h / 95 °C / Inert atmosphere 3: methanesulfonic acid / water; acetone / 45 - 55 °C / Large scale | ||
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 1.2: 1.91 h / 10 - 20 °C 2.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 28 h / Heating; Inert atmosphere 3.1: hydrogenchloride / ethanol / 50 °C / Inert atmosphere 3.2: 20 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran; toluene / 0.17 h / 10 °C / Inert atmosphere 1.2: 1.91 h / 10 - 20 °C 2.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; N-ethyl-N,N-diisopropylamine / butan-1-ol; dichloromethane / 24 h / Inert atmosphere; Heating 2.2: 3 h / 20 °C 3.1: hydrogenchloride / water; ethanol / 4.25 h / 70 °C / Inert atmosphere 3.2: 20.14 h / 20 - 35 °C |
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / toluene / 0.5 h / 0 - 20 °C 1.2: 0.67 h / 0 - 20 °C 2.1: palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene; N-ethyl-N,N-diisopropylamine / butan-1-ol / 20 h / 95 °C / Inert atmosphere 3.1: hydrogenchloride / dichloromethane; water / 1 h / 20 °C 4.1: trifluoroacetic acid / dichloromethane / 15 h | ||
Multi-step reaction with 3 steps 1.1: isopropyl chloride / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere; Large scale 1.2: 70 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine / butan-1-ol / 0.5 h / 20 °C / Inert atmosphere 2.2: 3 h / 80 - 100 °C / Inert atmosphere 3.1: methanesulfonic acid / water; acetone / 0.5 h / 45 - 55 °C | ||
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 30 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 12 h / 90 - 95 °C / Inert atmosphere 2.2: 70 °C 3.1: acetone / 10 h / 40 - 45 °C 4.1: sodium hydroxide / water / pH 10 - Ca. 11 | ||
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 30 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 12 h / 90 - 95 °C / Inert atmosphere 2.2: 70 °C 3.1: ethanol / 55 - 60 °C 4.1: sodium hydroxide / water / pH 10 - Ca. 11 | ||
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 30 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 12 h / 90 - 95 °C / Inert atmosphere 2.2: 70 °C 3.1: hydrogenchloride / water; methanol / 10 h / 30 - 35 °C 4.1: sodium hydroxide / water / pH 10 - Ca. 11 | ||
Multi-step reaction with 3 steps 1.1: cyclohexylmagnesiumchloride / tetrahydrofuran / 10 - 16 °C / Inert atmosphere 1.2: 10 - 16 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; bis[(2-diphenylphosphino)phenyl] ether / butan-1-ol / 25 - 100 °C / Inert atmosphere 2.2: 2 h / 55 °C 3.1: sodium hydroxide / water; methanol / 3 h / 35 - 45 °C | ||
Multi-step reaction with 4 steps 1.1: cyclohexylmagnesiumchloride / tetrahydrofuran / 10 - 16 °C / Inert atmosphere 1.2: 10 - 16 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; bis[(2-diphenylphosphino)phenyl] ether / butan-1-ol / 25 - 100 °C / Inert atmosphere 3.1: hydrogenchloride / acetone; water / 2 h / 55 °C 4.1: sodium hydroxide / water; methanol / 3 h / 35 - 45 °C | ||
Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / toluene / 1.5 h / 20 °C / Inert atmosphere 1.2: 1.5 h / 60 °C 2.1: N-ethyl-N,N-diisopropylamine; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether / butan-1-ol / 3 h / 95 - 105 °C / Inert atmosphere 3.1: methanesulfonic acid / acetone; water / 55 °C | ||
Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / -5 - 10 °C / Inert atmosphere 1.2: 12 h / 70 - 100 °C / Inert atmosphere 2.1: methanol; water / 0 - 60 °C 2.2: 14 h / 35 - 60 °C 2.3: 30 - 35 °C 3.1: sodium hydroxide / water / 31 - 40 °C / pH 6.3 - 11 | ||
Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / -5 - 10 °C / Inert atmosphere 1.2: 12 h / 70 - 100 °C / Inert atmosphere 2.1: methanol; water / 55 - 58 °C 3.1: sodium hydroxide / methanol; water / 25 - 35 °C / pH 10 | ||
Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / -5 - 10 °C / Inert atmosphere 1.2: 12 h / 70 - 100 °C / Inert atmosphere 2.1: methanol; water / 55 - 70 °C 3.1: sodium hydroxide / methanol; water / 40 °C / pH 9.5 - 10 | ||
Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / -5 - 10 °C / Inert atmosphere 1.2: 12 h / 70 - 100 °C / Inert atmosphere 2.1: water; isopropyl alcohol / 22 h / 81 °C 3.1: sodium hydroxide / methanol; water / 40 °C / pH 9.5 - 10 | ||
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 12 h / 60 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether / 24 h / 90 °C / Inert atmosphere 3.1: hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 4.1: hydrogenchloride / water; ethanol / 3 h / 70 °C / Inert atmosphere 4.2: Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: cyclohexylmagnesiumchloride / tetrahydrofuran / 3 h / 60 °C 2.1: magnesium / tetrahydrofuran / 0.5 h / Reflux 2.2: 1.5 h / -10 - 20 °C 3.1: pyridine / 4 h / 80 °C 3.2: 3 h / 5 - 45 °C | ||
Multi-step reaction with 4 steps 1: lithium hexamethyldisilazane / dichloromethane; tetrahydrofuran / 10 - 15 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / butan-1-ol / 95 - 100 °C / Inert atmosphere 3: hydrogenchloride / methanol / 60 - 65 °C 4: triethylamine / water / 0 - 40 °C | ||
Multi-step reaction with 3 steps 1.1: sodium hexamethyldisilazane / toluene; tetrahydrofuran / 0.5 h / 20 - 30 °C / Inert atmosphere 1.2: 4 h / 30 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / butan-1-ol; water / 0.17 h / Inert atmosphere 2.2: 20 h / 95 °C / Inert atmosphere 3.1: hydrogenchloride / butan-1-ol; water / 20 h / 80 °C / Industrial scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With methanesulfonic acid; In water; acetone; at 45 - 55℃;Large scale; | To a reactor was added 4-{6-[6-(1-butoxyl-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-c]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (2.70 kg, 4.47 mol, 1.0 equiv.) followed by a mixture of water (27.00 L, 10 L/kg) and acetone (13.50 L, 5 L/kg). The yellow slurry was warmed to between 50C and 55C. A solution of methanesulfonic acid (2.15 kg, 22.36 mol, 5.0 eq.) diluted with water (5.40 L, 2 L/kg of starting material) and acetone (5.40 L, 2 L/kg of starting material) was added to the reactor over approximately 10 minutes. The reaction mixture was kept between 45C and 55C for at least 12 hours. A clear yellow solution was achieved during the reaction.The reaction mixture was cooled to 35C, and a mixture of 5 wt% sodium hydroxide solution was added in portions to the reactor to raise the reaction mixture to a pH > 9. The reactor was cooled to between 20C and 25C, granulated, and filtered. The cake was washed with water followed by acetone and dried under vacuum.This method generated the small primary particle size free base of compound 1_, which was equivalent to the material prepared from treatment of the compound 1_ hydrochloride salt with aqueous NaOH in Example 4 of WO 2005/005426.In addition to the representative procedure provided above (corresponding to Experiment S in Table 10), a range of acids and aqueous solvent systems were screened to determine the impact on the reaction and subsequent quench and isolation of free base of compound Lab- scale screening experiments were run to identify reaction conditions for converting the intermediate vinyl ether to the free base compound The results of these reaction screening experiments are summarized in Table 10, indicating the generality of the method. Table 10: Summary of results from reaction screening experimentsP MSA 15% acetone/water 97 99.54Q CF3SO3H (incomplete) water N/A N/AR MSA 33% CH3CN/water 99 99.7S MSA 33% acetone/water 98 99.74T MSA 33% MeOH/water 98 99.74 u MSA 33% THF/water 96 99.76 |
98% | With methanesulfonic acid; In water; acetone; at 55℃; | 3) Add high purity intermediate II118g to 2L four-necked bottle.Add 472g (4 times) acetone,1062g (9 times) water,Warm up to 55 C,Adding methanesulfonic acid,a mixture of acetone and water (mass ratio of methanesulfonic acid, acetone and water is 0.79:1:1),Adding time 1 hour,Continue to react at 55 C for 5 to 7 hours,Until the end of the reaction,Adding sodium hydroxide solution to precipitate a solid,filter,Take the filtrate,By centrifugation,Dry to get the target product Pabusini 86g,The yield was 98%.The HPLC spectrum of the target product Pabsini is shown in Fig. 5. As can be seen from Fig. 5, the purity of the target product Pabusini is 99.80%, and the X-powder diffraction pattern of the target product Pabsini is shown in Fig. 7. Bosini. |
96.2% | With methanesulfonic acid; In water; acetone; at 45 - 55℃; for 0.5h; | 5L flask three inputs 402g (0.67mol) Compound E, 0.8L of water, 1.8L of acetone was heated to 60 deg.] C was stirred for 30 minutes, a solution of 360g (3.68mol) of methanesulfonic acid + 400mL + 400mL water-acetone mixture, the system moment after a large number of yellow solid precipitated slowly became clear to control the reaction temperature 45-55 whole system will slowly dissolve, TLC monitoring of the reaction process. After completion of the reaction system to the aqueous solution of 5% NaOH to adjust pH> 9, a large number of yellow solid precipitation, filtration, the filter cake was rinsed with water and acetone each time, 55 blast drying 8h, constant weight 298.0g, yield rate of 96.2%. |
76.3% | Ste e1 ): synthesis of palbociclib free-base (formula 10) Step e1 ): A 3 L 3-necked RBF was charged with 85.70 g of 4-{6-[6-(1 -butoxy-vinyl)-8- cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}- piperazine-1 -carboxylic acid tert-butyl ester (formula 8) (141 .9 mmol, 1 .00 eq.) and 1 .6 L absolute EtOH. The resulting slurry was heated to 50 then 288 ml of HCI 32% solution (2.98 mol, 21 .0 eq.) was added dropwise over 15 min. The mixture was stirred at 50C under argon overnight. After cooling to RT, a solution of 141 .9 g NaOH (3.55 mol, 25 eq.) in 889 ml water was slowly added. The mixture was further stirred at RT for 20 h then filtrated. The solid was successively washed with acetonitrile / water (1/1 v/v, 400 ml), acetonitrile (400 ml), TBME (400 ml) and n-hexane (600 ml) then dried at 40qC/15 mbar for 20 h to give compound palbociclib free base of formula 10 (48.50 g, 76.3% yield) as yellow solid.HPLC (Method 3): 6.15 min (96.6%) (254 nm)H NMR (400 MHz, DMSO-d6) delta ppm: 1 .5 - 1 .6 (m, 2 H), 1 .7 - 1 .8 (m, 2 H), 1 .8 - 1 .9 (m, 2 H), 2.1 - 2.3 (m, 2 H), 2.29 (s, 3 H), 2.40 (s, 3 H), 2.8 - 2.9 (m, 4 H), 3.0 - 3.1 (m, 4 H), 3.30 (s, 3 H), 5.7 - 5.9 (m, 1 H), 7.42 (dd, J=8.99, 3.13 Hz, 1 H), 7.82 (d, J=8.99 Hz, 1 H), 8.01 (d, J=3.13 Hz, 1 H), 8.93 (s, 1 H), 10.06 (s, 1 H).XRPD: An XRPD spectrum of polymorph form A is shown in Figure 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | Step e2): alternative synthesis of palbociclib free-base (formula 10) Step e2): A 10 L reactor was charged with 227.0 g of 4-[6-(6-acetyl-8-cyclopentyl-5- methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1 - carboxylic acid tert-butyl ester hydrochloride (formula 9) (0.389 mmol, 1 .00 eq.) and 2.25 L absolute EtOH. At RT, 190 ml of concentrated HCI solution (32%, 1 .94 mmol,5.0 eq.) was added dropwise over 15 min. The mixture was stirred at 70C until completion of the reaction (about 4 hours). After cooling to 50 C, the mixture was filtered and transferred back into the reactor. At 35 C, 1 .2 L of 2 N NaOH solution (2.33 mol, 6.0 eq.) was added dropwise over 25 min. Then, the mixture was cooled to RT, stirred for 20 h then filtrated. The solid was successively washed with water (2 x 1 L), acetone (2 x 0.8 L), and n-heptane (1 .5 L) then dried at 50C/15 mbar for 24 h to give 152.6 g of palbociclib free base (87.7% yield) as yellow solid.HPLC (Method 3): 6.16 min (97.4%) (254 nm).1H NMR (400 MHz, CDCI3) delta ppm: 1 .6 - 1 .8 (m, 2 H), 1 .7 - 1 .9 (m, 2 H), 1 .8 - 2.0 (m, 2 H), 2.0 - 2.2 (m, 2 H), 2.3 - 2.4 (m, 2 H), 2.38 (s, 3 H), 2.55 (s, 3 H), 3.0 - 3.1 (m, 4 H),3.1 - 3.2 (m, 4 H), 5.8 - 6.0 (m, 1 H), 7.33 (dd, J=9.19, 2.93 Hz, 1 H), 8.06 (d, J=2.74 Hz, 1 H), 8.16 (d, J=8.99 Hz, 1 H), 8.2 - 8.4 (m, 1 H), 8.83 (s, 1 H).XRPD: The XRPD spectrum corresponds to that shown in Figure 13BET (surface area): 15 m2/g.PSD: D90 = 22 muetaiota, D50 = 6.6 muetaiota, D10 = 0.7 muetaiota. 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 20℃; for 24h; | 24 Preparation of palbociclib diesylate Form A To 20.0 mL of methanol was added 95.5 mg of palbociclib. 1.0 mL of the solution was added to a glass vial, followed by the addition of 1.31 mg of 1 ,2-ethanedisulfonic acid. The mixture was stirred under ambient conditions for 24 hours. The solid was isolated and diesylate Form A was obtained, which was analyzed by XRPD. The XRPD data of palbociclib diesylate Form A obtained in this example are listed in Table 24. The XRPD pattern of diesylate Form A obtained from this example are displayed in FIG. 48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | To 15.0 mL of acetonitrile was added 1.0 g of palbociclib freebase. 300 mu, of 2- hydroethanolsulfonic acid (80wt%) was added to 3 mL of acetonitrile. Mix the two solutions by adding the acid solution dropwise. Stir the suspension at 800 rpm overnight, then centrifuge it and isethionate Forma was produced, which was analyzed by XRPD and DSC. The XRPD data of the palbociclib isethionate Form a obtained in this example are listed in Table 31. The XRPD pattern and DSC thermogram of palbociclib isethionate Form a obtained from this example are displayed in FIGs. 58 and 59, respectively. DSC thermogram exhibits two endothermic peaks with onset temperature of about 62.0 C and 264.2 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | General procedure: 4.5 Procedures for the synthesis of 3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-3-oxopropanenitrile (4c) 1-Hydroxybenzotriazole (81 mg, 0.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.6 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol) and cyanoacetic acid (43 mg, 0.5 mmol) were added in dichloromethane (10 mL) at room temperature. The mixture was stirred for 30 min. Then palbociclib (224 mg, 0.5 mmol) was added to the solution and stirred overnight. The solvent was removed under reduced pressure and purified by column chromatography to afford the desired compound 4c. Yield: 87percent; 1H NMR (DMSO-d6, 400 MHz) delta: 10.15 (s, 1H), 8.96 (s, 1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.51 (m, 1H), 5.83 (m, 1H), 4.12 (s, 2H), 3.63 (m, 2H), 3.53 (m, 2H), 3.21 (m, 4H), 2.43 (s, 3H), 2.31 (s, 3H), 2.21 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.59 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) delta: 202.9, 162.0, 161.2, 158.9, 158.7, 155.2, 145.3, 143.4, 142.5, 136.4, 129.8, 125.8, 116.5, 115.5, 107.1, 53.4, 48.9, 48.6, 45.5, 41.8, 31.7, 28.0, 25.6, 25.2, 14.1; MS m/z: 515.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dmap; In dichloromethane; at 0 - 20℃; | General procedure: To a mixture of palbociclib (220mg, 0.492mmol) and DMAP (120mg, 0.984mmol) in dry dichloromethane (10mL), chloroformate (0.6mmol) was added at 0°C. Then the reaction solution was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product. 4.2.1 Methyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (2a) Yield: 89percent; 1H NMR (CDCl3, 400 MHz) delta: 8.92 (t, 1H), 8.21 (d, 1H), 8.13 (d, 1H), 7.35 (dd, 1H), 5.89 (m, 1H), 3.76 (s, 3H), 3.68 (t, 4H), 3.16 (t, 4H), 2.56 (s, 3H), 2.38 (m, 5H), 2.08 (m, 2H), 1.82 (m, 2H), 1.69 (m, 2H); 13C NMR (CDCl3, 100 MHz) delta: 202.6, 161.4, 158.1, 157.3, 155.8, 155.6, 145.7, 143.4, 141.8, 137.3, 130.7, 126.7, 113.6, 107.6, 54.1, 52.8, 49.7, 43.6, 31.5, 28.1, 25.7, 13.9; MS m/z: 506.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; In dichloromethane; at 0 - 20℃; | General procedure: To a mixture of palbociclib (220mg, 0.492mmol) and DMAP (120mg, 0.984mmol) in dry dichloromethane (10mL), chloroformate (0.6mmol) was added at 0°C. Then the reaction solution was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product. 4.2.2 Propyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (2b) Yield: 91percent; 1H NMR (CDCl3, 400 MHz) delta: 8.95 (s, 1H), 8.20 (d, 1H), 8.13 (d, 1H), 7.35 (dd, 1H), 5.89 (m, 1H), 4.09 (t, 2H), 3.68 (t, 4H), 3.16 (t, 4H), 2.55 (s, 3H), 2.37 (m, 5H), 2.07 (m, 2H), 1.89 (m, 2H), 1.70 (m, 4H), 0.96 (t, 3H); 13C NMR (CDCl3, 100 MHz) delta: 202.7, 161.4, 158.2, 157.3, 155.6, 155.5, 145.7, 143.4, 141.9, 137.3, 130.6, 126.6, 113.6, 107.5, 67.2, 54.2, 49.7, 43.5, 31.5, 28.0, 25.7, 22.3, 13.9, 10.4; MS m/z: 534.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; In dichloromethane; at 0 - 20℃; | General procedure: To a mixture of palbociclib (220mg, 0.492mmol) and DMAP (120mg, 0.984mmol) in dry dichloromethane (10mL), chloroformate (0.6mmol) was added at 0°C. Then the reaction solution was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product. 4.2.3 Isopropyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (2c) Yield: 87percent; 1H NMR (CDCl3, 400 MHz) delta: 8.96 (s, 1H), 8.20 (d, 1H), 8.14 (d, 1H), 7.35 (dd, 1H), 5.89 (t, 1H), 4.97 (m, 1H), 3.67 (t, 4H), 3.15 (t, 4H), 2.55 (s, 3H), 2.37 (m, 5H), 2.08 (m, 2H), 1.91 (m, 2H), 1.70 (m, 2H), 1.28 (d, 6H); 13C NMR (CDCl3, 100 MHz) delta: 202.6, 161.4, 158.2, 157.3, 155.6, 155.1, 145.7, 143.4, 141.9, 137.3, 130.6, 126.5, 113.5, 107.5, 68.9, 54.2, 49.7, 43.5, 31.5, 28.0, 25.7, 22.2, 13.9; MS m/z: 534.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; In dichloromethane; at 0 - 20℃; | General procedure: To a mixture of palbociclib (220mg, 0.492mmol) and DMAP (120mg, 0.984mmol) in dry dichloromethane (10mL), chloroformate (0.6mmol) was added at 0°C. Then the reaction solution was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product. 4.2.4 Butyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (2d) Yield: 90percent; 1H NMR (CDCl3, 400 MHz) delta: 8.88 (d, 1H), 8.21 (d, 1H), 8.10 (t, 1H), 7.36 (dd, 1H), 5.90 (m, 1H), 4.15 (t, 2H), 3.69 (t, 4H), 3.16 (t, 4H), 2.57 (s, 3H), 2.40 (m, 5H), 2.08 (m, 2H), 1.90 (q, 2H), 1.74 (m, 2H), 1.66 (m, 2H), 1.42 (m, 2H), 0.97 (t, 3H); 13C NMR (CDCl3, 100 MHz) delta: 202.6, 161.4, 158.1, 157.2, 155.5, 145.6, 143.5, 141.8, 137.3, 130.8, 126.7, 113.6, 107.8, 65.6, 54.1, 49.8, 43.5, 31.5, 31.1, 28.1, 25.7, 19.2, 13.9, 13.8; MS m/z: 548.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; In dichloromethane; at 0 - 20℃; | General procedure: To a mixture of palbociclib (220mg, 0.492mmol) and DMAP (120mg, 0.984mmol) in dry dichloromethane (10mL), chloroformate (0.6mmol) was added at 0°C. Then the reaction solution was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product. 4.2.5 Isobutyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (2e) Yield: 85percent; 1H NMR (CDCl3, 400 MHz) delta: 8.86 (s, 1H), 8.22 (d, 1H), 8.09 (d, 1H), 7.36 (dd, 1H), 5.89 (m, 1H), 3.93 (d, 2H), 3.70 (t, 4H), 3.17 (t, 4H), 2.57 (s, 3H), 2.40 (m, 5H), 2.08 (m, 2H), 1.91 (q, 2H), 1.72 (m, 4H), 0.98 (d, 6H); 13C NMR (CDCl3, 100 MHz) delta: 202.6, 161.4, 158.0, 157.2, 155.5, 145.5, 143.5, 141.7, 137.3, 130.8, 126.7, 113.6, 107.8, 54.1, 49.8, 43.5, 31.5, 29.7, 28.1, 25.7, 19.1, 13.9; MS m/z: 548.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; In dichloromethane; at 0 - 20℃; | General procedure: To a mixture of palbociclib (220mg, 0.492mmol) and DMAP (120mg, 0.984mmol) in dry dichloromethane (10mL), chloroformate (0.6mmol) was added at 0°C. Then the reaction solution was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product. 4.2.6 Pentyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (2f) Yield: 87percent; 1H NMR (CDCl3, 400 MHz) delta: 8.89 (t,1H), 8.21 (d, 1H), 8.11 (t, 1H), delta7.36 (dd, 1H), 5.89 (m, 1H), 4.13 (t, 2H), 3.69 (t,4H), 3.16 (t, 4H), 2.56 (s, 3H), 2.38 (m, 5H), 2.08 (q, 2H), 1.75 (t, 2H), 1.71 (q, 2H), 1.67 (m, 4H), 1.37 (m, 2H), 0.94 (m, 3H); 13C NMR (CDCl3, 100 MHz) delta: 202.6, 161.4, 158.1, 157.2, 155.5, 145.6, 143.5, 141.8, 137.3, 130.8, 126.6, 113.6, 107.7, 65.8, 54.1, 49.8, 43.5, 31.5, 29.7, 28.7, 28.1, 25.7, 22.4, 13.9; MS m/z: 562.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; potassium acetate; In dichloromethane; at 0 - 20℃; | 4.3 Procedures for the synthesis of acetoxymethyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (2g) Chloromethyl chloroformate (194 mg, 2.0 mmol) was added to the mixture of palbociclib (447 mg, 1.0 mmol) and DMAP (305 mg, 2.5 mmol) in dry dichloromethane (10 mL) under 0 °C. The reaction mixture was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford compound 3 in 70percent yield. Then compound 3 (162 mg, 0.3 mmol) and potassium acetate (98 mg, 1.0 mmol) was added to DMF (10 mL). The mixture was reacted at 80 °C for 4 h. The solvent was removed under reduced pressure and purified by column chromatography to afford compound 2g. Yield: 92percent; 1H NMR (CDCl3, 400 MHz) delta: 8.92 (s, 1H), 8.22 (d, 1H), 8.12 (d, 1H), 7.36 (dd, 1H), 5.89 (m, 1H), 5.84 (s, 2H), 3.72 (t, 4H), 3.18 (d, 4H), 2.56 (t, 3H), 2.38 (m, 5H), 2.15 (d, 3H), 2.09 (m, 2H), 1.90 (m, 2H), 1.73 (m, 2H); 13C NMR (CDCl3, 100 MHz) delta: 202.6, 169.9, 161.4, 158.1, 157.3, 155.6, 153.5, 145.8, 143.2, 141.8, 137.4, 130.8, 126.8, 113.6, 107.7, 54.1, 49.7, 43.9, 43.8, 43.6, 31.5, 28.0, 25.7, 20.9, 13.9; MS m/z: 564.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; In dichloromethane; at 0 - 20℃; | Chloroacetyl chloride (170mg, 1.5mmol) was added to the mixture of palbociclib (447mg, 1.0mmol) and DMAP (244mg, 2.0mmol) in dry dichloromethane (10mL) under 0°C. The reaction mixture was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford compound 5 in 86percent yield. Then ethanediamine or 3-methoxypropan-1-amine (0.5mmol) and compound 5 (162mg, 0.3mmol) was added to dichloromethane (10mL). The mixture was reacted to reflux for 4h. After completed, the solvent was removed under reduced pressure and purified by column chromatography to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In acetonitrile; for 12h;Reflux; | General procedure: Palbociclib (224mg, 0.5mmol), potassium carbonate (138mg, 1.0mmol) and haloalkane (0.7mmol) was added to acetonitrile (20mL). Then the mixture was warmed to reflux for 12h. After cooling to room temperature, the solvent was removed under reduced pressure and purified by column chromatography to afford compound the desired product. 4.7.1 6-Acetyl-8-cyclopentyl-2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (6a) Yield: 89percent; 1H NMR (DMSO-d6, 400 MHz) delta: 10.09 (s, 1H), 8.96 (s, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 7.48 (d, 1H), 5.83 (t, 1H), 3.60 (m, 4H), 3.18 (m, 4H), 2.76 (m, 2H), 2.43 (s, 3H), 2.29 (s, 3H), 2.25 (m, 2H), 1.91 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H), 1.13 (m, 3H); 13C NMR (DMSO-d6, 100 MHz) delta: 202.6, 172.8, 153.9, 140.8, 139.2, 134.7, 125.2, 124.6, 123.6, 116.1, 100.1, 64.1, 34.9, 34.2, 32.0, 29.4, 25.6, 22.5, 14.3; MS m/z: 476.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In acetonitrile; for 12h;Reflux; | General procedure: Palbociclib (224mg, 0.5mmol), potassium carbonate (138mg, 1.0mmol) and haloalkane (0.7mmol) was added to acetonitrile (20mL). Then the mixture was warmed to reflux for 12h. After cooling to room temperature, the solvent was removed under reduced pressure and purified by column chromatography to afford compound the desired product. 4.7.4 Ethyl 2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetate (6d) Yield: 81percent; 1H NMR (CDCl3, 400 MHz) delta: 8.87 (s, 1H), 8.16 (d, 1H), 8.09 (d, 1H), 7.34 (dd, 1H), 5.88 (m, 1H), 4.22 (q, 2H), 3.27 (m, 7H), 2.79 (t, 4H), 2.38 (m, 5H), 2.05 (m, 2H), 1.88 (m, 2H), 1.68 (m, 2H), 1.28 (m, 5H); 13C NMR (CDCl3, 100 MHz) delta: 202.6, 170.4, 161.2, 159.2, 154.5, 148.7, 144.7, 144.0, 142.4, 137.1, 136.1, 134.1, 129.6, 125.3, 115.6, 109.8, 107.2, 67.3, 60.3, 58.8, 52.2, 48.8, 39.4, 31.7, 28.0, 25.6, 14.1; MS m/z: 534.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In acetonitrile; for 12h;Reflux; | General procedure: Palbociclib (224mg, 0.5mmol), potassium carbonate (138mg, 1.0mmol) and haloalkane (0.7mmol) was added to acetonitrile (20mL). Then the mixture was warmed to reflux for 12h. After cooling to room temperature, the solvent was removed under reduced pressure and purified by column chromatography to afford compound the desired product. 4.7.5 Ethyl 3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propanoate (6e) Yield: 82percent; 1H NMR (CDCl3, 400 MHz) delta: 8.82 (s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.32 (dd, 1H), 5.88 (m, 1H), 4.17 (m, 2H), 3.20 (m, 4H), 2.81 (m, 2H), 2.79 (m, 4H), 2.37 (m, 5H), 2.04 (m, 5H), 1.88 (m, 2H), 1.68 (m, 2H), 1.28 (m, 5H); 13C NMR (CDCl3, 100 MHz) delta: 202.7, 170.7, 161.3, 159.0, 154.5, 148.6, 144.7, 144.1, 142.4, 137.2, 136.1, 134.0, 129.6, 125.6, 115.6, 109.9, 107.2, 67.3, 60.4, 58.8, 52.1, 48.8, 39.5, 31.7, 28.1, 25.7, 14.1; MS m/z: 548.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In acetonitrile; for 12h;Reflux; | General procedure: Palbociclib (224mg, 0.5mmol), potassium carbonate (138mg, 1.0mmol) and haloalkane (0.7mmol) was added to acetonitrile (20mL). Then the mixture was warmed to reflux for 12h. After cooling to room temperature, the solvent was removed under reduced pressure and purified by column chromatography to afford compound the desired product. 4.7.2 6-Acetyl-8-cyclopentyl-2-((5-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (6b) Yield: 83percent; 1H NMR (DMSO-d6, 400 MHz) delta: 10.08 (s, 1H), 8.96 (s, 1H), 8.05 (d, 1H), 7.85 (d, 1H), 7.46 (m, 1H), 5.83 (m, 1H), 3.48 (m, 2H), 3.26 (s, 3H), 3.16 (m, 4H), 2.59 (m, 4H), 2.57 (m, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.22 (m, 2H), 1.89 (m, 2H), 1.79 (m, 2H), 1.61 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) delta: 202.9, 161.2, 159.0, 158.7, 155.2, 144.7, 143.9, 142.5, 135.8, 129.7, 125.1, 115.7, 107.0, 70.5, 58.5, 57.5, 53.4, 48.8, 31.8, 28.0, 25.6, 14.1; MS m/z: 506.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In acetonitrile; for 12h;Reflux; | General procedure: Palbociclib (224mg, 0.5mmol), potassium carbonate (138mg, 1.0mmol) and haloalkane (0.7mmol) was added to acetonitrile (20mL). Then the mixture was warmed to reflux for 12h. After cooling to room temperature, the solvent was removed under reduced pressure and purified by column chromatography to afford compound the desired product. 4.7.7 (4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl butyrate (6g) Yield: 78percent; 1H NMR (CDCl3, 400 MHz) delta: 8.92 (s, 1H), 8.25 (d, 1H), 8.12 (d, 1H), 7.36 (dd, 1H), 5.89 (m, 1H), 3.83 (t, 2H), 3.69 (t, 2H), 3.18 (m, 4H), 2.56 (s, 3H), 2.38 (m, 7H), 2.08 (m, 2H), 1.89 (m, 4H), 1.72 (m, 4H), 1.01 (t, 3H); 13C NMR (CDCl3, 100 MHz) delta: 202.6, 171.6, 161.4, 158.1, 157.3, 155.6, 145.7, 143.2, 141.8, 137.2, 130.7, 126.6, 113.6, 107.7, 54.1, 50.1, 49.8, 45.4, 41.3, 35.2, 31.5, 28.1, 25.7, 18.7, 14.0; MS m/z: 548.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.3% | With tetrahydropyridine dichromate nickel (II); acetic acid; at 25 - 35℃; for 8h; | in the compound is added in the three-necked bottle VI 22.5g (50mmol), 21.5g TPND and of 150 ml of acetic acid, in the 25 - 35 °C stirring reaction under 8h (thin layer chromatography tracking end point of the reaction), after the reaction, the reaction mixture is poured into the 250 ml water, filtering, for solid respectively 25 ml of 5percent hydrochloric acid aqueous solution and 25 ml aqueous solution of washing, adhesive patch and ethyl ether (2:1, V/V) recrystallization, vacuum drying to obtain handkerchief abundant Sydney 21.3g, yield is: 95.3percent, purity 99.8percent (HPLC method). |
94% | With sodium selenate; In dimethyl sulfoxide; at 150 - 160℃; | Embodiment 4:To the reaction bottle 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]-5,6-dihydropyrido[2,3-d]pyrimidyl-7(8H)-one (VI) (2.25g, 5mmol), sodium selenate (1.04g, 6mmol) and dimethyl sulfoxide (DMSO) 20 ml, the temperature is increased to 150-160°C, stirring reaction 5-6 hours. Cooling to room temperature, adding water 200 ml, precipitated solid. Filtering, the filter cake washed with ethanol and ethyl ether, to obtain white solid handkerchief abundant Sydney (I) 2.1g, yield 94.0percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | With hydrogenchloride; In tetrahydrofuran; water; at 25 - 30℃; for 5h; | In a 500 ml four-necked flask,Add 200 g of 10 wt% hydrogen chloride tetrahydrofuran solution,54.5 g (0.1 mol) of Boc prepared according to the method of step (2) to protect Pabosini,The reaction was stirred at 25-30 C for 5 hours, and the liquid phase detection reaction was completed.Dropped to 5-10 C,Filtration, the filter cake was added to 300 g of ice water, and the pH was adjusted to 6-7 with a 5% aqueous sodium carbonate solution.Filtered, the filter cake was washed with 40 g of isopropyl alcohol and dried.Got 44.1 grams of Pabusini,The yield was 98.5%, and the liquid phase purity was 99.9%. |
95% | With methanesulfonic acid; In water; acetone; at 55 - 70℃; for 8h; | Add 230mL of water to a 1000mL three-neck bottle,200 mL of acetone and 21 g of compound 2.After stirring and heating the reaction liquid to 55C, 17 g of methanesulfonic acid was slowly added dropwise.After the addition, the temperature is increased to 60-70C.And stirred at this temperature for 8 hours. Cool down to 35-40 C,Add 170 mL of 5% aqueous NaOH solution to the reaction flask.A large amount of solids precipitated after the addition. Cool down to 20C,It was suction filtered and washed with 200 mL of purified water and 30 mL of acetone.The filter cake is vacuum dried at 50-60C for 12 hours.16.3 g of yellow solidPrabhexyb (Compound 3),Production rate: 95%. |
83% | With hydrogenchloride; In water; acetone; at 50℃; for 10h; | 10 g of the intermediate (2) was added to a mixed solution of 100 ml of acetone and 200 ml of water, and the mixture was stirred until the solution was uniformly dispersed, and 12 ml of 35% concentrated hydrochloric acid was added thereto, and the mixture was heated to 50 C for 10 hours.TLC (dichloromethane:methanol, 10:1) was monitored until the starting material disappeared.The temperature was lowered to 10 C, and 13 g of triethylamine was slowly added to the system to pH > 9, and the mixture was thoroughly stirred until a large amount of solid was precipitated, stirring was continued for 3 hours, suction filtration, and the filter cake was washed with water until neutral.Dry to dryness at 40 C to obtain 7.28 g of crude yellow solid I. Dissolve the crude product in 150 ml of n-butanol and 150 ml of anisole mixture, heat to 100-110 C to dissolve, add 0.5 g of activated carbon, reflux for 30 min, then heat filter. The mother liquid was naturally decrystallized at room temperature, filtered, and dried at 40 C to obtain 6.8 g of a bright yellow solid compound I in a yield: 83%. |
180 mg | With trifluoroacetic acid; In dichloromethane; for 15h; | 8)Synthesis of Palbociclib: 250mg of Compound 20 was added to 20ml ofdichloromethane. 0.5ml of trifluoroacetic acid was added dropwise, and stirredfor 15h. After completion of the reaction, saturated NaHCO3 solutionwas added, and the system was adjusted to weak alkaline. Methylene chloride wasused for extraction. The organic phase was dried, concentrated, and purified bycolumn chromatography to give 180mg yellow solid of Palbociclib. |
4.2g | With hydrogenchloride; In ethanol; water; at 80℃; for 6h; | To a dry reaction flask at room temperature, compound D2 (C33H45N7O47.2 g, 12 mmol, pure(12.0 g, 600 mmol), CH3OH (217.0 mL) was slowly mixed,The mixture was stirred at 60 C for 18 h. After the reaction was completed, the mixture was cooled and crystallized. A small amount of CHOHAnd petroleum ether to give a yellow solid E. m.p.The solid E was then suspended in C2H5OH (220.0 ml)HCl (12.0 g, 600 mmol) was added dropwise,The reaction was stirred at 80 for 6h,After completion of the reaction,Cooling crystallization, filtration,Drying that was pure Pabucclib free base 4.2g,Yield 79%. |
With trifluoroacetic acid; In dichloromethane; at 20℃; for 0.666667h; | The mixed solution of trifluoroacetic acid (10ml) and dichloromethane (15ml) was added Intermediate 4- [6- (6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8 - dihydro-pyrido [2,3-d] pyrimidin-2-ylamino) - pyridin-3-yl] - piperazine-1-carboxylic acid tert-butyl ester (X) (5.497g, 10mmol) inStir at room temperature for 40 minutes,Stop the reaction and conduct vacuum distillation.The resulting concentrate was dissolved in 5 ml of ethyl acetate.Wash the organic phase with saturated sodium bicarbonate to pH 7-8.The aqueous phase is extracted twice with ethyl acetate,Combine the organic phase,Drying with anhydrous sodium sulfate,Distilled under reduced pressure, the resulting concentrate was recrystallized from ethyl acetate and n-hexane.Vacuum drying to give a white solid product pabutinib (XI) 4.38 g;Yield 98.0%;Purity 99.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.8% | Example 11: Preparation of Pabosaibu (I) To a 250 ml four-necked flask connected to a stirrer, athermometer and a dropping funnel was added 100 g of methanol and 5.6 g (20mmole) N-cyclopentyl-3-acetyl-4-formyl-6-methyl-5-chloro-2-pyridone (IV) from Example 9 and 10.0 g N-(5-(4-N-tert-butoxycarbonyl-1-N-hexahydro-pyrazinyl)2-pyridyl)guanidine sulphate from Example 10 and 20 g of a 28percent sodium methoxide in methanolsolution and stirred at 60 to 65°C for 5 hours, cooled to 20°C, thenadded with 20 g of 10percent aqueous sodium hydroxide solution and was stirred at 20°C for 3 hours for the hydrolysis reaction, filtered, recrystallized from 100 g of isopropanol to give 7.5 g of white solid Pabosaibu (I), yield 83.8 percent, a purity of 99.7percent liquid phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 mg | With triethylamine In dichloromethane Reflux; | 19 Preparation example 19 compound 1E-3 preparation of General procedure: Apart from with bromine acetic acid ethyl ester instead of cyanopentanoyl acetyl chloride, the reaction temperature increased to the reflux temperature, with the preparation example 1 compound synthesis of 1A-1 the same method for synthesizing compound 1D-1 (70 mg).Except using butyric acid other than replaces the bromine chloro-ethyl ester of acetic acid, with the preparation example 13 synthesis of compound 1D-1 the same method for synthesizing compound 1E-3 (80 mg).1HNMR (CDCl3, 400MHz) δ: 8.92 (s, 1H), 8.25 (d, 1H), 8.12 (d, 1H), 7.36 (dd, 1H), 5.89 (m, 1H), 3.83 (t, 2H), 3.69 (t, 2H), 3.18 (m, 4H), 2.56 (s, 3H), 2.38 (m, 7H), 2.08 (m, 2H), 1.89 (m, 4H), 1.72 (m, 4H), 1.01 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.7% | With sulfuric acid; gold(I) chloride; In water; at 75℃; for 2h; | 2) The compound represented by the formula (II) obtained in the step 1), N-cyclopentyl-5-methyl-6-ethynyl-2- [[5- (1-piperazinyl) ] Amino] pyrido [2,3-d] pyrimidin-7 (8H) -one20 g was added to an acidic aqueous solution (10percent aqueous sulfuric acid solution)AuCl 0.8g catalyzed hydrolysis at 75 ° C for 2 hours,After completion of the reaction, the reaction mixture was cooled to room temperature,Ether extraction, concentration,Washed with water, recrystallized from methanol,DryingPabosini18.5 g,The yield was 88.7percentPurity 99.98percent (HPLC area normalization method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.1 g | With triethylamine; In dichloromethane; at 20℃; | A suspension of palbociclib dihydrochloride (25.0 g, 48.0 mmol, prepared according to theprocedure disclosed in example 36 of WO 2003/062236 Al) in methylene chloride (960 mL) was treated with triethylamine (44.5 mL, 321 .0 mmol) at RT. The obtained clear solution was extracted with 600 mL deionized water. Thereafter, the phases were separated and the aqueous phase was extracted with 600 mL methylene chloride and discarded. To the combined methylene chloride phases additional methylene chloride (960 mL) was added before reducing the volume to about 900 mL by distillation (Tbath = 53 °C, atmospheric pressure). The meanwhile slightly hazy solution was allowed to cool to 31 ± 1 °C before n5 heptane (960 mL) was added speedily under stirring which initiated crystallization. Theobtained suspension was further stirred at RT for 17 h. Finally, the crystals were collected by filtration and dried at RT under vacuum (20-30 mbar) for 6 h.Yield: 20.1 g (94percent of theory); SSA: 3.3 m/g, PXRD: Form A |
27.1 g | With sodium hydroxide; In water; at 20 - 30℃; for 1h; | Process for the preparation of palbociclib free base crystalline form B Palbociclib dihydrochloride trihydrate (35 g) was dissolved in water (840 ml) at room temperature. Aqueous sodium hydroxide solution (5.25 g sodium hydroxide in 53 ml of water) was added to the above slurry at 25-30 °C and stirred for 1 hr. The solid was filtered, washed with water (70 ml) and dried under vacuum. Obtained material waspassed through 40 and 20 mesh, thus obtained crystalline palbociclib free base form B.Yield: 27.1 gSpecific surface area: 10.7 m2/g;Purity: 99.8percent (by HPLC);Moisture content: 0.7percent |
74 g | With sodium hydroxide; In methanol; water; at 35 - 45℃; for 3h; | 6-Acetyl-8-cyclopentyl-5-methyl-2-(5 -piperazin- 1 -yl-pyridin-2-ylamino)-8H-pyrido[2,3 -d]pyrimidin-7-one.2HC1 (11)100 gm was added to 10 volumes of water and 10 volumes ofmethanol. The material was heated to 3 5-45°C and stirred for 20 minutes. The pH of the solution was adjusted slowly to 8 to 8.5 with 5percent aqueous NaOH solution at 35-45°C, stirred for 180 minutes at 3 5-45°C. The product obtained was filtered and washed with 3 volumes of hot water. The solid was further dried at 50-60°C under vacuum for 8 hours to get 74 gm of 6-Acetyl-8-cyclopentyl-5-methyl-2-(5 -piperazin- 1 -yl-pyridin-2-ylamino)-8H-pyrido[2,3 -d]pyrimidin-7-one (I).Specific surface area m2/g by BET: 5.575 m2/gParticle size distribution (PSD): D,o Oim): 0.81 1pm; D5o(i.m): 2.26im ; D90(lm): 7.69tm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With hydrogenchloride; In 1,4-dioxane; water; at 70℃; for 2.5h; | 4- [6-(6-Acetyl- 8-cyclopentyl-5-methyl-7-oxo-7 ,8-dihydro-pyrido [2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl] -piperazine- 1 -carboxylic acid tert-butyl ester hydrochloride (Boc-protected palbociclib hydrochloride) (1.0 g, 1.7 mmol) was suspended in a mixture of water (5 ml) and acetic acid (4 ml). 0.83 ml of HC1 32percent solution (8.6 mmol, 5.0 eq.)were added dropwise, the mixture was heated to 70°C and stuffed for 2.5 hours (until completion). After cooling to 50°C, 10 ml of water were added followed by 3.4 ml of an aqueous 2N NaOH solution. The yellow solution was cooled to 23°C (room temperature), filtered through a 1 im filter and added dropwise within 5 mm to an aqueous 2N NaOH solution (37.8 mL) at 23°C (room temperature) under magneticstuffing. A yellow solid precipitated immediately. The mixture was further stuffed for 15 mm, then it was stored for 20 mm at 23°C (room temperature) without stirring. The solid was isolated by filtration, washed with deionized water (3 x 20 mL) and dried at 50°C/b mbar for 72 h to give a yellow solid.Yield: 684 mg (89.3percent)The following data are identical in Examples 3, 3?, 3? and 3?XRPD: 1st priority reflections 6.0, 10.9, 12.8, 16.3 and 19.7°2 02nd priority reflections 6.6, 19.4, 22.0, 22.5 and 26.64°2 0?H-NMR (DMSO-D6) [oe ppm]: 1.57 (m, 2H, CH), 1.75 (m, 2H, CH), 1.86 (m, 2H,CH), 2.23 (m, 2H, CH), 2.29 (s, 3H, CH3), 2.40 (s, 3H,CH3), 2.83 (m, 4H, piperazine-CH2), 3.04 (m, 4H,piperazine-CH2), 5.80 (quintet, 1H, J = 8.9 Hz, CH),7.42 (dd, 1H, Ji = 9.0 Hz, J2 = 3.1 Hz, pyridine-CH),7.82 (d, 1H, J = 9.0 Hz, pyridine-CH), 8.02 (d, 1H, J =2.7 Hz, pyridine-CH), 8.93 (s, 1H, pyrimidine-CH),10.05 (s, 1H, NH)DSC: endotherms (onset T): 98°C, 27 1°C (Figure 9) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium hydroxide; In water; at 20℃; for 0.366667h; | Palbociclib acetic acid solvate (250 mg) was dissolved in deionized water (9 mL). The clear solution was added dropwise within 7 minutes to a mixture of aqueous iN NaOH solution (0,6 mL) and deionized water (8 mL) at room temperature under magneticstirring. A yellow solid precipitated immediately. The mixture was further stirred for15 mm, then it was stored 2 hours at room temperature without stuffing. The solid was isolated by filtration, washed with deionized water (2 x 20 mL) and dried 3 hours in open atmosphere at room temperature, then 1 hour in dynamic vacuum (2 mbar) at room temperature. A yellow powder was obtained.Yield: 156mg (71 percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | nto a 500 ml four-necked flask equipped with a stirrer, a thermometer, a water separator, a reflux condenser and a dropping funnel, 200 g of toluene, 0.2 g of 98percent concentrated sulfuric acid, 26.0 g (0.2 mol) of ethyl acetoacetate , And the reaction was carried out at 110 to 115 ° C with stirring for 5 hours. After cooling to 20 ° C, 11. 1 g (0.11 mol) of trimethyl orthoformate was added and the reaction was stirred at 30 to 35 ° C for 4 hours. Add 20 grams of 28percent sodium methoxide to methanol solution, add between 30 and 40 ° C in portions 34. 3 g (0.105 moles) of N- (5- (4-tert-butoxycarbonyl-1-hexahydro Pyrazinyl) 2-pyridyl) guanidinium sulphate, added at 60 to 65 ° C for 3 hours, at 60 to 65 ° C, 9. 4 g (0.11 moles) of cyclopentylamine, 70 to Reaction at 75 ° C for 3 hours. Cooled to 20 ° C, 50 g of water was added and stirred at 20 ° C for 3 hours. The filter cake was recrystallized from 250 g of isopropanol to give 38. 1 g of white solid papoxicin (I) in a yield of 85percent 2percent, liquid purity 99.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | the 200 g of toluene, 0.2 g of methylbenzenesulfonic acid, 26.0 g (0.2 mol) of ethyl acetoacetate added to a 500 ml four-necked flask equipped with a stirrer, a thermometer, a water separator, a reflux condenser and a dropping funnel,and reaction was carried out at 110 to 115 ° C with stirring and water reflux dehydration reaction for 5 hours. After cooling to 20 ° C, 11. 1 g (0.11 mol) of trimethyl orthoformate was added and the reaction was stirred at 30 to 35 ° C for 4 hours. Added 20 grams of 28percent sodium methoxide methanol solution, then = between 30 and 40 ° C added 34. 3 g (0.105 moles) of N N- (5- (4-tert-butoxycarbonyl-1-hexahydropiperazinyl) -2-pyridyl)guanidine hemisulfate in portions, after completion of reaction, raise the temperature in between 60 to 65 ° C and allowed to react for 3 hours. Then at 60 to 65 ° C, 9. 4 g (0.11 moles) of cyclopentylamine was added , raise the temperature in between 70 to 75 ° C and allowed to react for 3 hours. Cooled to 20 ° C, 50 g of water was added, stirred at 20 ° C for 3 hours, filtered and the filter cake was recrystallized from 250 g of isopropanol to give 40. 3 g of white solid Palbociclib(I). The yield was 90. 1percent and the liquid purity was 99.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.1% | With hydrogen bromide; In ethanol; water; at 20℃; for 48h;Heating; | 1.0 g (2.23 mmol) palbociclib base and 20 ml ethanol are measured into a device providingintensive stirring. While boiling 257.6 ml (2.23 mmol) of a 47percent aqueous HBr solution is added to it drop by drop. The solution is cooled to room temperature, stirred for 48 hours, then this crystalline product is filtered, washed with a small amount of cold ethanol, then dried in a vacuum drying cabinet (40 °C, 13 mbar, 18 h).Yield: 1.038 g (88.1percent)Mp.: no characteristic value, thermal decomposition takes place above 300 °CAnalysis with respect to the chemical formula C24H30BrN7O2 (528.46):Calculated C: 54.55 percent H: 5.72 percent N: 18.55 percent Br: 15.12 percent. Measured C: 54.46 percent H: 5.80 percent N: 18.05 percent Br: 14.77 percent. 1H-NMR (DMSO-d6, 400 MHz): 10.26 (bs, 1H), 8.98 (s, 1H), 8.81 (b, 2H), 8.12 (d, 1=2.8 Hz,1H), 7.91 (d, 1=9.0 Hz, 1H), 7.57 (dd, 11=2.8 Hz, 12=9.1 Hz, 1H), 5.84 (m, 1H), 3.44 (m, 8H),2.43 (s, 3H), 2.32 (s, 3H), 2.24 (m, 2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.59 (m, 2H).?3C-NMR (DMSO-d6, 125 MHz): 202.62, 160.90, 158.61, 158.40, 154.94, 145.44, 142.47,142.21, 135.99, 129.63, 126.05, 115.23, 106.97, 53.12, 45.83, 42.81, 31.49, 27.75, 25.32,13.84. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.8% | With hydrogenchloride; In ethanol; water; at 20℃; for 93h;Heating; | 1.5 g (3.35 mmol) palbociclib base and 30 ml ethanol are measured into a device providing intensive stirring, then during boiling 3.18 ml (3.18 mmol) of a 1 M hydrochloric acid solution is added to it drop by drop. The solution is cooled to room temperature, mixed for 93 hours, then this crystalline product is filtered, washed with a small amount of cold ethanol and then MTBE, then dried in the air.Yield: 0.62 g (90.8%)Mp.: 288-290CAnalysis with respect to the chemical formula C24H30C1N702 (484.00):Calculated C: 59.56 % H: 6.25 % N: 20.26 % Cl: 7.32 %. Measured C: 59.40 % H: 6.26 % N: 20.00 % Cl: 7.30 %. 1H-NMR (DMSO-d6, 400 MHz): 10.21 (bs, 1H), 9.27 (b, 2H), 8.97 (s, 1H), 8.12 (d, 1=2.9 Hz, 1H), 7.92 (d, 1=9.0 Hz, 1H), 7.54 (dd, 11=2.9 Hz, 12=9.1 Hz, 1H), 5.83 (m, 1H), 3.40 (m, 4H),32.25 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.24 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.59 (m, 2H). 13C-NMR (DMSO-d6, 125 MHz): 202.52, 160.87, 158.62, 158.37, 154.90, 145.45, 142.48,142.16, 136.28, 129.53, 125.73, 115.11, 106.86, 53.11, 45.76, 42.61, 31.42, 27.70, 25.25,13.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With sulfuric acid; In acetonitrile; at 20℃; for 48h;Cooling with ice; | 1.0 g (2.23 mmol) palbociclib base and 20 ml acetonitrile are measured into a deviceproviding intensive stirring, then during ice-water cooling 59.7 ml (1.12 mmol) of a solutionof cc. H2S04 prepared with 5 ml of acetonitrile is added to it drop by drop. The solution iscooled to room temperature, stirred for 48 hours, then the crystalline product is filtered, washed with a small amount of cold acetonitrile and then dried in a vacuum drying cabinet (50 °C, 15 mbar, 17 h). Yield: 1.061 g (89.3percent). Mp.: no characteristic value, thermal decomposition takes place above 240 °CAnalysis with respect to the chemical formula C48H68N14O10S (1065.24): Calculated C: 54.12 percent H: 6.43 percent N: 18.41 percent S: 3.01 percent. Measured C: 54.66 percent H: 6.44 percent N: 18.43 percent S: 3.17 percent. 1H-NMR (DMSO-d6, 400 MHz): 10.015 (bs, 1H), 8.96 (s, 1H), 8.08 (s, 1H), 7.88 (d, 1=9.0 Hz, 1H), 7.49 (d, 1=7.3 hz, 1H), 5.82 (m, 1H), 3.23 (m, 4H), 3.08 (m, 4H), 2.42 (s, 3H), 2.31 (s, 3H), 2.24 (m, 2H), 1.89 (m, 2H), 1.77 (m, 2H), 1.59 (m, 2H). 13C-NMR (DMSO-d6, 125 MHz): 202.59, 160.92, 158.71, 158.40, 155.03, 143.24, 142.21,139.83, 136.00, 129.49, 125.35, 115.30, 106.84, 53.11, 47.47, 44.02, 31.46, 27.72, 25.26,13.78. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.0% | In acetone; at 20℃; for 24h;Reflux; | 1.0 g (2.23 mmol) palbociclib base and 20 ml acetone are measured into a device providing intensive stirring, then during heating at reflux 558.2 mg (2.23 mmol) 1S-(+)-camphor-10- sulfonic acid is added. The solution is cooled to room temperature, stirred for 24 hours, then the crystalline product is filtered, washed with a small amount of cold acetone and then dried in the air. Yield: 1.38 g (91.0percent). Mp.: no characteristic value, thermal decomposition takes place above 290 °C. Analysis with respect to the chemical formula C34H45N7011S (679.84): Calculated C: 60.07 percent H: 6.67 percent N: 14.42 percent S: 4.72 percentMeasured C: 59.66 percent H: 6.66 percent N: 14.35 percent S: 4.76 percent. 1H-NMR (DMSO-d6, 400 MHz): 10.21 (bs, 1H), 8.97 (s, 1H), 8.75 (b, 2H), 8.12 (d, 1=2.8 Hz, 1H), 7.92 (d, 1=9.0 Hz, 1H), 7.54 (dd, 11=2.9 Hz, 12=9.0 Hz, 1H), 5.83 (m, 1H), 3.39 (m, 4H),3.27 (m, 4H), 2.88 (d, 1=14.7 Hz, 1H), 2.67 (m, 1H), 2.43 (s, 3H), 2.39 (d, 1=14.7 Hz, 1H),2.32 (s, 3H), 2.24 (m, 3H), 1.93 (m, 1H), 1.86 (m, 1H), 1.80 (m, 1H), 1.79 (m, 2H), 1.77 (m,2H), 1.59 (m, 2H), 1.28 (m, 2H), 1.05 (s, 3H), 0.74 (s, 3H). 13C-NMR (DMSO-d6, 125 MHz): 216.51, 202.60, 160.90, 158.67, 158.43, 154.92, 145.50, 142.52, 142.21, 136.33, 129.55, 125.76, 115.17, 106.88, 58.41, 53.11, 47.23, 46.89, 45.92,42.91, 42.43, 42.31, 31.47, 27.73, 26.57, 25.29, 24.32, 20.30, 19.73, 13.80. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.3% | In acetone; at 20℃; for 48h;Reflux; | 1.0 g (2.23 mmol) palbociclib base and 25 ml acetone are measured into a device providingintensive stirring, then during heating at reflux 505.44 mg (2.23 mmol) naphthalene-2-sulfonic acid monohydrate is added. The solution is cooled to room temperature, stirred for 48hours, then the crystalline product is filtered, washed with a small amount of cold acetone and then dried in a vacuum drying cabinet (55 °C, 6 mbar, 18 h). Yield: 1.32 g (90.3percent). Mp.: no characteristic value, thermal decomposition takes place above 280 °C. Analysis with respect to the chemical formula C34H37N705S (655.77):Calculated C: 62.27 percent H: 5.69 percent N: 14.95 percent S: 4.89 percent Measured C: 61.83 percent H: 5.67 percent N: 14.90 percent S: 4.85 percent. 1H-NMR (DMSO-d6, 500 MHz): 10.17 (bs, 1H), 8.96 (s, 1H), 8.62 (b, 2H), 8.14 (s, 1H), 8.12(d, 1=2.8 Hz, 1H), 7.96 (m, 1H), 7.90 (m, 2H), 7.85 (d, 1=8.6 Hz, 1H), 7.72 (dd, 11=1.5 Hz,12=8.6 Hz, 1H), 7.54 (dd, 11=2.8 Hz, 12=9.0 Hz, 1H), 7.52 (m, 2H), 5.83 (m, 1H), 3.38 (m,4H), 3.27 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.25 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.59(m, 2H). 13C-NMR (DMSO-d6, 125 MHz): 202.50, 160.86, 158.62, 158.34, 154.90, 154.86, 145.83,145.47, 142.42, 142.14, 132.84, 132.29, 129.57, 128.56, 127.56, 127.38, 126.50, 126.38,125.85, 124.14, 115.18, 106.90, 53.10, 45.86, 42.85, 31.42, 27.69, 25.24, 13.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.7% | In acetonitrile; at 20℃; for 48h;Reflux; | 500 mg (1.12 mmol) palbociclib base and 10 ml acetonitrile are measured then during heating at reflux 130 mg (2.23 mmol) maleic acid is added. The solution is cooled to room temperature, stirred for 48 hours, then this crystalline product is filtered, washed with a small amount of cold acetonitrile and then dried in the air. Yield: 0.585 g (92.7percent). Mp.: 198-200°C. Analysis with respect to the chemical formula C28H33N706 (563.61):Calculated C: 59.67 percent H: 5.90 percent N: 17.40 percentMeasured C: 59.20 percent H: 5.87 percent N: 17.17 percent. 1H-NMR (DMSO-d6, 500 MHz): 10.15 (b, 1H), 8.96 (s, 1H), 8.12 (d, 1=2.9 Hz, 1H), 7.92 (d,1=9.1 Hz, 1H), 7.54 (dd, 11=3.0 Hz, 12=9.1 Hz, 1H), 6.03 (s, 2H), 5.83 (m, 1H), 3.37 (m, 4H),3.28 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.26 (m, 2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.59 (m, 2H). 13C-NMR (DMSO-d6, 500 MHz): 202.52, 167.31, 160.88, 158.64, 158.37, 154.90, 145.52,142.44, 142.16, 136.33, 136.13, 129.54, 125.75, 115.15, 106.88, 53.11, 45.90, 42.85, 31.43,27.70, 25.24, 13.77. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.6% | 2.8 g (0.01 mol) of Intermediate 6 was dissolved in 80 mL of methyl tert-butyl ether while adding 1 M THFOf lithium bis (trimethylsilyl) amide, 9.0 g (0.01 mol)After stirring for 30 min, 3.1 g (0.01 mol) of a mixture of intermediate 4 and 50 mL of methyl tert-butyl ether was added and stirred at room temperature for 1 h. The reaction was complete.To the system by adding 20mL saturated ammonium chloride solution quenching system. Filter, cake with 50mL washed with 20mL methyl tert-butyl ether washing, and finally with 50mL acetone beating and filtration, drying to obtain yellow solid 3.87g. Yield: 86.6percent, HPLC ? 99.0percent | |
82.6% | In the nitrogen atmosphere, the 6-acetyl-8-cyclopentyl-5-methyl-2-chlorine-pyrido[2,3-d]pyrimidin-7(8H)-one (VI) (1.53 g, 5 mmol), 4-(6-amino-3-pyridinyl)-1- piperazinecarboxylic acid 1,1-dimethylethyl ester (VII) (2.78 g, 10 mmol), Lithium bis(trimethylsilyl)amide (2.0 g, 10 mmol) and methylbenzene of 50 mL were added into the reaction bulb. They were heated up to 50-55° C. and react for 2-3 hours, and then cooled down to the room temperature after the completion of TLC detection reaction. The organic layer was separated out by pouring the reaction mixture into icy water, extraction was conducted for the water layer with methylbenzene for two times, and organic phases were combined. The organic layer was washed with water and saline solution respectively, and dried and concentrated to dry with anhydrous sodium sulfate. The residues obtained were dissolved into the dichloromethane of 50 mL, which was added with the concentrated hydrochloric acid of 5 mL and stirred in the room temperature for 12 hours. The organic phase was separated out and washed with water and solution of 10percent sodium bicarbonate. The solvent was recycled under normal pressure and added with diethyl ether to separate solids. The crude products obtained were recrystallized with normal hexane and ethyl acetate, and off-white solid Palbociclib (I) of 1.85 g was obtained; yield: 82.6percent; mass spectrometry (EI): m/z 448(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In the nitrogen atmosphere, the 6-acetyl-8-cyclopentyl-5-methyl-2-methylsulfinyl-pyrido[2,3-d]pyrimidin-7(8H)-one (VI) (1.67 g, 5 mmol), 4-(6-amino-3-pyridinyl)-1- piperazinecarboxylic acid 1,1-dimethylethyl ester (VII) (2.78 g, 10 mmol) and methylbenzene of 50 mL were added into the reaction bulb. They were heated up to 70-75° C. and react for 2-3 hours, and then cooled down to the room temperature after the completion of TLC detection reaction. The organic layer was separated out by pouring the reaction mixture into the icy water, extraction was conducted for the water layer with methylbenzene for two times, and organic phases were combined. The organic layer was washed with water and saline solution respectively, and dried and concentrated to dry with anhydrous sodium sulfate. The residues obtained were dissolved into the dichloromethane of 50 mL, which was added with the concentrated hydrochloric acid of 10 mL and stirred in the room temperature for 12 hours. The organic phase was separated out and washed with ammonium hydroxide of 5percent and pure water. The solvent was recycled under normal pressure and added with diethyl ether to separate solids. The crude products obtained were recrystallized with normal hexane and ethyl acetate, and off-white solid Palbociclib (I) of 3.8 g was obtained; yield: 85.0percent; mass spectrometry (EI): m/z 448(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In water;pH 10 - Ca. 11; | Patchine Lib Acetate Free:175 g (0.29 mol) of the pamilyclidine acetate was added to 8 L of purified water, stirred and dissolved,With 5percent aqueous sodium hydroxide to adjust the pH to 10 ~ 11, a yellow solid precipitation,Add 9L of DCM solution extraction, standing stratification,The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and weighed 115 g in 88percent yield.Pamilabelib recrystallization:115 g (0.25 mol) of free PABALIBE material was added to 2000 mL of n-butanol:Anisole is a 3: 1 mixed solvent, stirring was heated to 120 ~ 125 ,Clear, slowly cooled to room temperature, stirred overnight,Filter, filter cake washed with 300mL of methanol once,Pumping filter dry,Weigh 110g of highly purified pachinebubble compound.purity:99.3percent single-mixed 0.1percent or less,Yield 95percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With water; sodium hydroxide; at 100℃; | 1.6 g palbociclib hydrochloride (prepared in example 2) was dissolved into 40 ml water to form palbociclib hydrochloride solution. 0.38 g sodium hydroxide was dissolved in 30 ml water and stirred at 100° C., and the palbociclib hydrochloride solution was added dropwise into the solution of sodium hydroxide with stirring, then a yellow solid was precipitated. After that, suction filtration and drying was introduced to obtain 1.32 g (yield: 96percent) yellow solid, with HPLC purity of 99.9percent. The product was analyzed by XRPD as the crystal form A. |
90% | With sodium hydroxide; In water;pH 10 - Ca. 11; | 410 g (0.70 mol) of the aforementioned pectoralib hydrochloride was added to 30 L of purified water,Stirring and dissolving, adjusting the pH to 10-11 with 5percent sodium hydroxide aqueous solution, precipitating with yellow solid,Add 10L of DCM solution extraction, standing stratification,The organic phase was dried over anhydrous sodium sulfate, concentrated and weighed 270g. Yield 87percent.Pamilabelib recrystallization:170 g (0.37 mol) of free PABALIBE material was added to 3000 mL of n-butanol:Anisole 2: 3 mixed solvent, stirring heated to 120 ~ 125 , clear,Slowly cooled to room temperature, stirred overnight, filtered, the filter cake washed once with 300mL of methanol,Pumping dry, weighing and weighed 155g of high purity pachycipalub compounds.purity:99.5percent single miscellaneous 0.1percent or less, yield 90percent. |
With sodium hydroxide; In water;pH 11 - 12.5;Large scale; | A NaOH aqueous solution was prepared with 0.37 kg of NaOH dissolved in 5kg of water. (0120) This solution was added to the solution of Palbociclib.HCl, during 60-80 min until final pH (0121) 11-12.5. Yellow solid of Palbociclib free base precipitated from the mixture. (0122) Isolated solid was isolated by filtration and washed with 9,1 kg of water and 2.5 kg of acetone. The obtained solid was dried on the filter for at least 12 hours. The solid was then dried at room temperature for at least 10 hours. The solid was milled over a sieve with 0.8 mm mesh. The milled product was dried at 28-30°C for at least 4 hours. (0123) Palbociclib with surface area 6.9 m /g , a needle morphology and D90 11.5muiotaeta was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydroxide; In water;pH 10 - Ca. 11; | 160mg (0.27mol) of pramipexole trifluoroacetate was added to 80L of purified water, stirred and dissolved,With 5% aqueous sodium hydroxide to adjust the pH to 10 ~ 11, a yellow solid precipitation,Add 5L of DCM solution extraction, standing stratification, the organic phase was dried over anhydrous sodium sulfate,Concentrated dry, weighed 110g, yield 91%.Pamilabelib recrystallization:110 g (0.24 mol) of the free pamiracemic material was added to 3000 mL of n-butanol:Anisole is a 1: 1 mixed solvent, stirring was heated to 120 ~ 125 ,Clear, slowly cooled to room temperature,Stirred overnight, filtered, the filter cake washed once with 100mL of methanol, filtered and dried,Dried and weighed 98g of high purity of pachycil, compound Purity:99.5% single miscellaneous 0.1% or less, yield 89%. |
2.6 g | With sodium hydroxide; In methanol; water; at 40℃;pH 9.5 - 10; | A mixture of trifluoroacetic acid salt of palbociclib (4 g), water (24 mL) and methanol (16 mL) was heated to 40 °C and the pH of the heterogeneous reaction mass was adjusted to 9.5- 10.0 using aqueous solution of sodium hydroxide (IN). The reaction mass was cooled to 20- 25 °C and the precipitated solid was filtered. The solid was washed with water (20 mL) and methanol (20 mL). The solid was dried at 50 °C under vacuum to provide the title compound. Yield: 2 6 g Purity (By HPLC): 99.1percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; potassium iodide; In acetonitrile; at 80℃; for 16h;Inert atmosphere; | To a solution of <strong>[571190-30-2]6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one</strong> (550 mg, 1.229 mmol) in MeCN (15 mL) was added tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (384 mg, 1.229 mmol), potassium iodide (204 mg, 1.229 mmol) and potassium carbonate (340 mg, 2.458 mmol). The reaction mixture was stirred at 80 C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to 25 C, poured into ice-water (50 mL), the resulting precipitate was isolated by filtration, washed with water (3 x 10 mL), cooled MeOH (5 mL) and EtOAc (10 mL). Further drying in vacuo afforded the title compound (750 mg, 1.106 mmol, 90%) as a yellow solid. LC-MS: [M+H]+ = 679.40 1H NMR (400 MHz, CDCl3) delta = 8.83 (s, 1H), 8.27 (br s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.36 - 7.29 (m, 1H), 5.88 (t, J = 8.9 Hz, 1H), 5.12 (br s, 1H), 3.67 (t, J = 5.6 Hz, 2H), 3.65 - 3.62 (m, 4H), 3.58 - 3.53 (m, 2H), 3.33 (br d, J = 4.9 Hz, 2H), 3.25 - 3.20 (m, 4H), 2.75 - 2.67 (m, 5H), 2.55 (s, 3H), 2.41 - 2.32 (m, 5H), 2.12 - 2.01 (m, 2H), 1.93 - 1.84 (m, 2H), 1.77 - 1.60 (m, 3H), 1.45 (s, 9H). |
85% | With potassium carbonate; potassium iodide; In acetone;Reflux; | To a solution of 6-ace -8-cyc]opentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2- yl)arnino)pyrido[2,3-i/]pyrirnidin-7(8H)-one (Paibociclib, 2-1) (20 mg, 0.045 mmol) in acetone (0.5 mL) was added tert-butyl 2-(2-(2-bromoethoxy)ethoxy)ethylcarbamate (2-6, 21 .2 mg, 0.068 mmol), followed by K2CO3 (12.3 mg, 0.09 mmol) and KI (1 1.3mg, 0,068 mmol) and the resulting mixture was then heated to reflux and stirred overnight. The reaction mixture was diluted with EtOAc and Eta2Omicron, extracted, and washed with brine. The organic layer was dried over anhydrous Na?,S04, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give Boc protected amine 2-7 as a yellow solid (26.0 mg, 85%). LCMS: m/z 679.4 [M+1] |
85% | With potassium carbonate; potassium iodide; In acetone;Reflux; | To a solution of <strong>[571190-30-2]6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one</strong> (Palbociclib, 2-1) (20 mg, 0.045 mmol) in acetone (0.5 mL) was added tert- butyl 2-(2-(2-bromoethoxy)ethoxy)ethylcarbamate (2-6, 21.2 mg, 0.068 mmol), followed by K2CO3; (12,3 mg, 0.09 mmol) and KI (11 3 mg, 0.068 mmol) and the resulting mixture was then heated to reflux and stirred overnight. The reaction mixture was diluted with EtOAc and H2O, extracted, and washed with brine. The organic layer was dried over anhydrous NaiSCri, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give Boc protected amine 2-7 as a yellow solid (26.0 mg, 85%). LCMS: m/z 679.4 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In a round-bottom flask, <strong>[571190-30-2]6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one</strong> (50 mg, 0.11 mmol) was dissolved in NMP (3 mL) followed by addition of anhydrous K2CO3 (31 mg, 0.22 mmol). Reaction mixture was stirred for 10 minutes followed by addition of tert-Butyl bromoacetate (20 L, 0.13 mmol) and stirred at 50 C for 12 h. Progress of the reaction was monitored by TLC. Crude mixture was diluted in ethyl acetate, washed with brine, and dried over anhydrous MgSO4. After filtration and evaporation, the crude residue was purified by flash column chromatography to give tert-butyl 2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetate as a yellow solid (60 mg, 96%). 1H NMR (400 MHz, CDCl3) delta (ppm): 8.71 (s, 1H), 8.12 (d, 1H, J = 2.8 Hz), 7.56 (d, 1H, J = 8.8 Hz), 7.29 - 7.26 (m, 1H), 5.73 (br, 1H), 4.82 (s, 1H), 3.39 - 3.34 (m, ), 3.39 - 3.34 (m, 6H), 2.52 (s. 3H), 2.32 (s, 3H), 1.87 - 1.56 (8H), 1.49 (s, 9H), 1.44 (m, 7H). ESI-MS calcd for C30H39N7O4 m/z 561.31, found: 562.26. | |
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | To a solution of 6-acetyl-8-cyclopent}4-5-methyl-2-((5-(piperazin-l-yl)pyridin-2- y])amino)pyrido[2,3-i/]pyrimidin-7(8H)-one (Palbociclib, 2-1) (20 mg, 0.045 mmol) in DMF (0.5 mL) was added tert-butyl bromoacetate (2-9, 13.2 mg, 0.068 mmol), followed by K2CO3 (12.3 mg, 0.09 mmol) and the resulting mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and Eta2Omicron, extracted, and washed with brine. The organic layer was dried with Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give t-butyl ester 2-10 as a yellow solid (22 mg, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; potassium iodide; In acetone;Reflux; | To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-[((5-piperazin-1-yl)pyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one (Palbociclib, 2-1) (20 mg, 0.045 mmol) in acetone (0.5 mL) was added tert-butyl 4-bromobutyicarbamate (2-2, 17.2 mg, 0.068 mmol), followed by 2CO3 (12,3 mg, 0.09 mmol) and KI (1 .3mg, 0.068 mmol). The resulting mixture was then heated to reflux and stirred overnight. The reaction mixture was diluted with EtOAc and Eta2Omicron, extracted, and washed with brine. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give Boc protected amine 2-3 as a yellow solid (22.3 mg, 80%). LCMS: m/z 620.3 [M+l]. |
80% | With potassium carbonate; potassium iodide; In acetone;Reflux; | To a solution of 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-l-yl)pyridin-2- yi)amino)pyrido[2,3-i/]pyrimidin-7(8 /)-one (Palbociclib, 2-1) (20 mg, 0.045 mmol) in acetone (0.5 mL) was added <strong>[164365-88-2]tert-butyl 4-bromobutylcarbamate</strong> (2-2, 17.2 mg, 0.068 mmol), followed by K2CO3 (12.3 mg, 0.09 mmol) and KT (1 1 3 mg, 0.068 mmol). Tire resulting mixture was then heated to reflux and stirred overnight. The reaction mixture was diluted with EtOAc and H?0, extracted, and washed with brine. The organic layer was dried over anhydrous NazSOr, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give Boc protected amine 2-3 as a yellow solid (22.3 mg, 80%). LCMS: m/z 620.3 [M+l] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.68 g | With sodium hydrogencarbonate In water at 20℃; for 4h; | 6 Preparation of palbociclib Form A and Form C mixed crystals The product from Example 3 (0.72 g) was added slowly to a saturated solution of sodium bicarbonate (13.0 mL) andDistilled water (15.0 mL) and stirred at room temperature for 4.0 hours. Filter, solid with distilled water (3 x 5.0 mL)Washed and dried to constant weight in an air bath at 50 ° C to give 0.68 g of a pure yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.89% | 17.12 g of compound 3 was mixed with 200 ml of isopropanol and 4.05 g of cyclopentylamine was added. Control temperature 20 ~ 60 °C, heating reflux 4h, Add 5.10g of sodium ethoxide, stir for 30min, 6.46g of compound 2 was added for reflux reaction for 3h, It was cooled to room temperature, filtered, washed with deionized water, and vacuum dried to give 19.55 g of compound 1, The yield was 91.89percent and the purity was 99.91percent. | |
91.85% | (2) 17.12 g of compound 3 is mixed with 200 ml of isopropanol, 4.26 g of cyclopentylamine is added, the temperature is controlled at 20-60° C., and the mixture is heated under reflux for 4 h, 3.40 g of sodium ethoxide is added, and after stirring for 30 min, 6.46 g of compound 2 is added for refluxing reaction. After 3 h, it was cooled to room temperature, filtered, washed with deionized water and vacuum dried to give 20.59 g of compound 1 in a yield of 91.85percent and a purity of 99.81percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide; In ethanol; water; at 19 - 25℃; for 21h; | Palbociclib dihydrochloride dihydrate (45 g) was dissolved in water (427.5 ml) and ethanol (127.5 ml) while stifling the solution at 20-25°C. Aqueous sodium hydroxide solution (7.4 g in 90 ml) was added dropwise at 19-25°C. The resulting mixture was stirred at 20-25°C for 21 hours thenfiltered. The solid collected was washed with water (450 ml) followed by acetone (450 ml) and n-heptane (675 ml). The solid was then suck dried at 20-30°C for 2 hours and dried under vacuum at 50-55°C for 6 hours to get substantially pure palbociclib as a yellow solid (34 g, 94percent, Purity by HPLC > 99.8percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.6% | With hydrogen; sodium hydroxide; In ethanol; at 40 - 50℃; for 4h; | The reaction flask was evacuated and replaced with hydrogen three times. Under anhydrous hydrogen, 6.5 ml of anhydrous ethanol was added.Ethanol solution 13.5 ml (3.2 x 10-3 M), sodium hydroxide 2.90 g and compound VII 34.90 g. The reaction takes place in atmospheric hydrogen,The reaction temperature is 40-50 °C, after 4h reaction, filtration, the product 32.08g, the yield of 98.6percent, purity 99.59percent. |
97.1% | With hydrogen; sodium hydroxide; palladium dichloride; In ethanol; at 40 - 50℃; for 4h; | d, the reaction flask was evacuated and replaced with hydrogen three times, and 6.5 mL of absolute ethanol was added under hydrogen conditions.A solution of palladium chloride in ethanol (13.5 mL, 3.2 x 10-3 M), 2.90 g of sodium hydroxide, and 34.90 g of compound VII was used.The reaction is carried out in atmospheric hydrogen at a reaction temperature of 40-50°C, reacted for 4 h, filtered,Paparkley crude 36.02g.(2) Refinement of PabokliTake 30g of the above raw Berkeley crude, add 1.8L of deionized water, and heat to 70°C to dissolve completely.Cool to 0-5 °C to precipitate solids, filter, add ethanol 1440mL and 2-butanone 600mL,Heat to reflux to complete dissolution, add active carbon to decolorize for 30 minutes, filter, and the filtrate is cooled to 5°C to 10°C,The crystals were statically decrystallized for 1 h, filtered, rinsed with ethanol, and dried in vacuo to obtain 29.13 g of Pabokli's fine product. The yield was 97.1percent and the purity was 99.98percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; | To a solution of palbociclib (50 mg. 0.112 mmol) in DMF (5 ml) and DCM (20 ml) were added NMM (34 mg. 0.335 mmol). 8-methoxv-8-oxooctanoic acid (25 mg. 0.134 mmol). HOAt (20 mg, 0.146 mmol), and EDCI (28 mg, 0.146 mmol). The mixture was allowed to stir at RT overnight. After palbociclib was consumed, the reaction was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to yield the product (69 mg, 98percent) as yellow solid. HRMS (ESI-TOF) m/z: [M+Hj calculated for C33H44N705, 618.3398; found:618.3401. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | A solution of intermediate 6 (20 mg, 0.03 08 mmol) in HCO2H (5 mL) was stirred overnight atRT. The reaction was concentrated under reduced pressure and the resulting residue was dissolved in DCM/DMSO (10 ml/2 ml). To the resulting solution were added palbociclib (13.7mg, 0.0308 mmol), NMM (16 mg, 0.154 mmol), HOAt (5.4 mg, 0.0399 mmol), and EDCI (7.6 mg, 0.0399 mmol). The reaction mixture was allowed to stir at RT overnight. After palbociclib was consumed, the reaction was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to yield the product (25 mg, 90percent) as yellow solid. ?H NMR (600MI-Tz, CD3OD) oe 8.98 (s, 1H), 8.13 (d, J 9.7 Hz, 1H), 7.72 (d, J= 2.9 Hz, 1H), 7.44? 7.35(m, 2H), 6.94 (d, J= 8.6 Hz, 1H), 6.77 (d, J= 7.1 Hz, 1H), 6.03 ? 5.93 (m, 1H), 5.09 (dd, J5.5, 12.7 Hz, 1H), 3.87 ? 3.75 (m, 8H), 3.67 (t, J= 5.2 Hz, 2H), 3.65 ? 3.58 (m, 9H), 3.41 ?3.37 (m, 2H), 2.92 ? 2.84 (m, 1H), 2.79 ? 2.63 (m, 4H), 2.52 (s, 3H), 2.42 (s, 3H), 2.36 ? 2.28(m, 2H), 2.13 ? 2.07 (m, 4H), 1.97 ? 1.88 (m, 2H), 1.75 ? 1.67 (m, 2H). HRMS (ESI-TOF)m/z: [M+Hj calculated for C46H55N10010, 907.4097; found: 907.4095. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1h;Microwave irradiation; | A solution of palbociclib (50 mg, 0.112 mmol), methyl 7-bromoheptanoate (75 mg, 0.335 mmol)and K2C03 (46 mg, 0.335 mmol) in DMF (5 ml) was heated at 60 °C in a microwave reactorfor 1 h. After being cooled to RT, the reaction mixture was filtered and concentrated, and the resulting residue was purified by prep-HPLC to yield the title compound (40 mg, 60percent) as yellow solid. ?H NMR (600 MHz, CD3OD) oe 9.10 (s, 1H), 8.21 (dd, J= 9.6, 2.7 Hz, 1H), 7.98 (d, J 2.5 Hz, 1H), 7.59 (d, J 9.6 Hz, 1H), 5.99 (p, J= 8.8 Hz, 1H), 3.93 (s, 2H), 3.75 (s,2H), 3.65 (s, 3H), 3.38 ? 3.16 (m, 6H), 2.49 (s, 3H), 2.42 (s, 3H), 2.37 ?2.25 (m, 4H), 2.13 ?2.03 (m, 2H), 1.94 ? 1.86 (m, 2H), 1.85 ? 1.78 (m, 2H), 1.72 ? 1.59 (m, 4H), 1.47 ? 1.36 (m, 4H). HRMS (ESI-TOF) m/z: [M+Hj calculated for C32H44N704, 590.3449; found: 590.3446. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In isopropyl alcohol; at 130℃; for 0.25h;Microwave irradiation; | A solution of palbociclib (40 mg, 0.09 mmol), 6-bromohexanoicacid (55 mg, 0.28 mmol) and TEA (0.05 mL, 0.36 mmol) in i-PrOH (1 ml) was heated at 130°C in a microwave reactor for 15 mm. After being cooled to RT, the reaction mixture wasconcentrated, and the resulting residue was purified by prep-HPLC to yield the intermediate 11(44 mg, 88percent) as yellow solid. To a stirring solution of intermediate 11 (44 mg, 0.065 mmol)in DCM/DMSO (5 ml/1 ml) were added TEA (0.05 mL, 0.36 mmol), VHL-1 (34 mg, 0.073mmol), and TBTU (22 mg, 0.070 mmol). After the mixture was stirred at RT overnight, thereaction was concentrated. The resulting residue was purified by prep-HPLC to yield the title compound (37 mg, 59percent) as yellow solid. ?H NMR (600 MHz, CD3OD) oe 9.12 (s, 1H), 9.12 (s, 1H), 8.23 (dd, J= 9.8, 2.4 Hz, 1H), 8.00 (d, J= 2.7 Hz, 1H), 7.60 (d, J 9.6 Hz, 1H), 7.49 (d, J= 7.8 Hz, 2H), 7.44 (d, J= 8.1 Hz, 2H), 6.02 (p, J= 8.8 Hz, 1H), 4.67 (s, 1H), 4.62?4.49(m, 3H), 4.40 (d, J= 15.5 Hz, 1H), 3. 96? 3.71 (m, 6H), 3.30? 3.20 (m, 6H), 2.52 (s, 3H),2.51 (s, 3H), 2.45 (s, 3H), 2.40? 2.21 (m, 5H), 2.16? 2.05 (m, 3H), 1.97 ? 1.88 (m, 2H), 1.88? 1.78 (m, 2H), 1.72? 1.67 (m4H), 1.49? 1.40 (m, 2H), 1.07 (s, 9H). HRMS (ESI-TOF)m/z:[M+Hj calculated for C52H68N1106S, 974.5069; found: 974.5069. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | A solution of pomalidomide (278 mg, 1 mmol), 4-nitrophenyl carbonochloridate (307 mg, 1.52 mmol) in THF (5 ml) was heated at reflux overnight. After being cooled to RT, the reaction mixture was concentrated. The resultingresidue was washed with ethyl acetate, dried over NaSO4, and concentrated to yield the intermediate 13 (240 mg, 55percent) as yellow solid. To a stirring solution of intermediate 13 (19 mg, 0.043 mmol) in DMF (1 mL) were added DIEA (0.014 mL, 0.1 mmol) and palbociclib (18 mg, 0.041 mmol). The mixture was stirred at RT overnight, before being concentrated. The resulting residue was purified by prep-HPLC to yield the title compound (14 mg, 46percent) asyellow solid. ?H NMR (600 MHz, CD3OD) 39.07 (s, 1H), 8.56 (d, J= 8.5 Hz, 1H), 8.10 (dd,J 9.6, 2.6 Hz, 1H), 7.78 ? 7.70 (m, 1H), 7.64 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 7.3 Hz, 1H),5.97 (p, J 8.9 Hz, 1H), 5.07 (dd, J 12.5, 5.5 Hz, 1H), 3.86 ? 3.79 (m, 4H), 3.45 ? 3.40 (m,4H), 2.89?2.72 (m, 3H), 2.54 (s, 3H), 2.44 (s, 3H), 2.33 ?2.27 (m, 2H), 2.22?2.15 (m, 1H),2.11 ?2.06 (m, 2H), 1.96? 1.86 (m, 2H), 1.73 ? 1.59 (m, 2H). HRMS (ESI-TOF) m/z: [M+Hjcalculated for C38H39N1007, 747.2998; found: 747.2970. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a stirring solution of intermediate 14 (22 mg, 0.03 1 mmol) in DMF (1 ml) were added TEA (0.015 mL, 0.11 mmol), palbociclib (13.1 mg, 0.029 mmol), and TBTU (11.3 mg, 0.035 mmol). The mixture was stirred at RT overnight before being concentrated. The resulting residue was purified by prep-HPLC to yield the title compound (22mg, 75percent) as yellow solid. ?H NMR (600 MHz,CDOD) oe 9.11 (s, 1H), 8.92 (s, 1H), 8.19 (d, J 7.9 Hz, 1H), 7.93 (d, J= 2.7 Hz, 1H), 7.59(d, J 9.6 Hz, 1H), 7.47 (d, J 7.8 Hz, 2H), 7.42 (d, J= 8.1 Hz, 2H), 6.03 (p, J= 8.8 Hz, 1H),4.65 ? 4.49 (m, 4H), 4.38 (d, J 15.5 Hz, 1H), 3.97 (d, J= 10.8 Hz, 1H), 3.90? 3.64 (m, 5H),3.64 ? 3.51 (m, 2H), 3.43 ? 3.36 (m, 4H), 3.10 ? 3.02 (m, 2H), 2.93 (s, 3H), 2.93 ? 2.85 (m,4H), 2.52 (s, 3H), 2.49 (s, 3H), 2.45 (s, 3H), 2.37?2.29 (m, 2H), 2.29?2.20 (m, 1H), 2.16?2.07 (m, 3H), 1.97?1.88 (m, 2H), 1.76?1.66 (m, 2H), 1.07 (d,J= 10.7 Hz, 9H). HRMS (ESITOF) m/z: [M+Hj calculated for C53H69N1207S, 1017.5127; found: 1017.5013. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of spiro[3.3jheptane-2,6- dicarboxylic acid (250 mg, 1.36 mmol) in DCM/THF (1:1, 5 ml) were added VHL-1 (218 mg, 0.47 mmol), triethylamine (0.21 ml, 1.4 mmol), and EDCI (112 mg, 0.59 mmol) sequentiallyat 0 °C. The resulting solution was stirred for 2 h at 0 °C, before being warmed to roomtemperature (RT). After stirring overnight at RT, the reaction was quenched with water, andconcentrated under reduced pressure. The resulting residue was purified by reverse-phasechromatography to yield the intermediate 15 (210 mg, 75percent) as white solid. To a stirringsolution of intermediate 15 (19 mg, 0.03 1 mmol) in DMF (1 ml) were added TEA (0.01 mL,0.07 mmol), palbociclib (12.7 mg, 0.028 mmol), and TBTU (14.2 mg, 0.044 mmol). Themixture was stirred at RT overnight before being concentrated. The resulting residue waspurified by prep-HPLC to yield the title compound (26 mg, 90percent) as yellow solid. ?H NMR(600 MI-Tz, CD3OD) oe 9.11 (s, 1H), 8.97 (s, 1H), 8.21 (dd, J= 9.6, 3.0 Hz, 1H), 7.88 (d, J 2.4Hz, 1H), 7.57 (d, J= 9.6 Hz, 1H), 7.48 (dd, J= 8.0, 1.6 Hz, 2H), 7.45 ? 7.42 (m, 2H), 6.02 (p,J= 8.8 Hz, 1H), 4.69 ? 4.62 (m, 1H), 4.62 ? 4.47 (m, 3H), 4.41 ? 4.27 (m, 1H), 3.92 (dd, J11.0, 4.4 Hz, 1H), 3.86? 3.70 (m, 3H), 3.71 ? 3.56 (m, 2H), 3.37 ? 3.22 (m, 6H), 3.17 ? 3.03(m, 1H), 2.52 (s, 3H), 2.50 (s, 3H), 2.45 (s, 3H), 2.40 ? 2.04 (m, 13H), 1.96 ? 1.88 (m, 2H),1.76 ? 1.68 (m, 2H), 1.04 (d, J= 3.4 Hz, 9H). HRMS (ESI-TOF) m/z: [M+Hj calculated forC55H68N1107S, 1026.5018; found: 1026.4985. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of (E)-oct-4-enedioic acid (250 mg, 1.45 mmol) in THF (5 ml) were added VHL-1 (239 mg, 0.51 mmol), triethylamine(0.21 ml, 1.4 mmol), and EDCI (104 mg, 0.S4mmol) sequentially at 0°C. The resulting solution was stirred for 2 h at 0 °C, before being warmed to room temperature (RT). After stirring overnight at RT, the reaction was quenched with water and concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to yield theintermediate 16 (208 mg, 70percent) as white solid. To a stirring solution of intermediate 16 (19 mg,0.032 mmol) in DMF (1 ml) were added TEA (0.01 mL, 0.07 mmol), palbociclib (11.1 mg,0.025 mmol), and TBTU (10.4 mg, 0.032 mmol). The mixture was stirred at RT overnightbefore being concentrated. The resulting residue was purified by prep-HPLC to yield the titlecompound (24 mg, 95percent) as yellow solid. ?H NMR (600 MHz, CD3OD) oe 9.12 (s, 1H), 9.00 (s,1H), 8.21 (dd, J= 9.6, 2.9 Hz, 1H), 7.88 (d, J= 2.8 Hz, 1H), 7.56 (d, J 9.6 Hz, 1H), 7.49 (d,J= 8.1 Hz, 2H), 7.43 (d, J= 8.1 Hz, 2H), 6.03 (p, J= 8.8 Hz, 1H), 5.61 ? 5.50 (m, 2H), 4.66(s, 1H), 4.60?4.48 (m, 3H), 4.37 (dd,J= 15.3, 8.6 Hz, 1H), 3.92(d,J= 11.0 Hz, 1H), 3.83?3.77 (m, 5H), 3.31 ? 3.25 (m, 3H), 2.54 (t, J 7.8 Hz, 2H), 2.51 (s, 3H), 2.49 (s, 3H), 2.45 (s,3H), 2.40?2.28 (m, 9H), 2.26?2.23 (m, 1H), 2.16?2.07 (m, 3H), 1.96? 1.87 (m, 2H), 1.76? 1.66 (m, 2H), 1.04 (s, 9H). HRMS (ESI-TOF) m/z: [M+Hj calculated for C54H68N1107S,1014.5018; found: 1014.5011. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; | A solution of pomalidomide (90 mg, 0.33 mmol) and 2-chloroacetyl chloride (0.026 mL, 0.33 mmol) in THF (2 ml) was heated at reflux overnight. After being cooled to RT, the reaction mixture was concentrated, and the resulting residue was washed with ethyl acetate to yield the intermediate 21 (75 mg, 65percent) as yellowsolid. To a stirring solution of intermediate 13 (36 mg, 0.082 mmol) in DMSO (lmL) were added DIEA (0.043 mL, 0.24 mmol) and palbociclib (39 mg, 0.087 mmol). The mixture was heated at 80°C. After the starting materials were consumed, the reaction was concentratedunder reduced pressure. The resulting residue was purified by prep-HPLC to yield the title compound (36 mg, 54percent) as yellow solid. ?H NMR (600 MI-Tz, CDC13) oe 11.19 (s, 1H), 8.89 (d, J= 8.5 Hz, 1H), 8.81 (s, 1H), 8.20 (d, J= 9.1 Hz, 1H), 8.14 (d, J 2.8 Hz, 1H), 7.71 (t, J 4.2 Hz, 1H), 7.55 (d, J= 7.3 Hz, 1H), 7.38 (dd, J= 9.1, 2.9 Hz, 1H), 5.87 (p, J 9.0 Hz, 1H), 4.94(dd, J= 12.7, 5.3 Hz, 1H), 3.39 (br, 4H), 3.34 (AB, Jab = 17.4 Hz, 1H), 3.27 (AB, Jab = 17.4 Hz, 1H), 2.92 ? 2.73 (m, 8H), 2.54 (s, 3H), 2.40 ? 2.29 (m, 4H), 2.14 ? 2.09 (m, 1H), 2.08 ?2.00 (m, 2H), 1.90 ? 1.81 (m, 2H), 1.70 ? 1.59 (m, 2H). HRMS (ESI-TOF) m/z: [M+Hj calculated for C39H41N1007, 761.3154; found: 761.3157. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-d6-formamide; at 20℃; | A solution of palbociclib (43 mg, 0.096 mmol) inDMF were added 2-(4-(methoxycarbonyl)piperidin-1-yl)acetic acid (20 mg, 0.1 mmol), TEA(0.035 mL, 0.25 mmol), and TBTU (42 mg, 0.13 mmol) sequentially at RT. After being stirredovernight at RT, the reaction was quenched with water. After concentration under reducedpressure, the resulting residue was purified by reverse-phase chromatography to yield theintermediate 20 (50 mg, 82percent) as white solid. To a stirring solution of intermediate 20 (50 mg,0.079 mmol) in THF/H20 (5:1, 3 mL) was added anhydrous LiOH (6 mg, 0.025 mmol). Themixture was stirred at RT and the reaction progress was monitored by LC/MS. After totalconsumption of intermediate 20, the reaction was concentrated. The resulting residue wasdissolved in DMF (1 ml). To the solution were added TEA (0.02 mL, 0.14 mmol), VHL-1 (26 mg, 0.055 mmol), and TBTU (16 mg, 0.05 mmol). The reaction mixture was stirred at RT overnight before being concentrated. The resulting residue was purified by prep-HPLC to yield the title compound (30 mg, 37percent) as yellow solid. ?H NMR (600 MHz, CD3OD) oe 9.15 (s, 1H),9.13 (s, 1H), 8.24 (dd, J 9.6, 2.7 Hz, 1H), 7.93 (d, J= 2.2 Hz, 1H), 7.58 (d, J= 9.6 Hz, 1H),7.51 (d, J 8.1 Hz, 2H), 7.46 (d, J 8.2 Hz, 2H), 6.03 (p, J= 8.8 Hz, 1H), 4.65 (d, J= 8.3 Hz,1H), 4.62 ? 4.51 (m, 3H), 4.42 ? 4.32 (m, 3H), 3.91 (d, J= 9.6 Hz, 1H), 3.87 ? 3.82 (m, 3H),3.79 ? 3.70 (m, 1H), 3.65 (br, 2H), 3.50 (br, 1H), 3.40 (br, 2H), 3.37 ? 3.34 (m, 3H), 3.20 ?3.07 (m, 1H), 2.74 (br, 1H), 2.52 (s, 3H), 2.52 (s, 3H), 2.45 (s, 3H), 2.36 ? 2.24 (m, 3H), 2.21?2.03 (m, 7H), 1.97 ? 1.88 (m, 2H), 1.77? 1.64 (m, 2H), 1.07 (s, 9H). HRMS (ESI-TOF) m/z:[M+Hj calculated for C54H69N1207S, 1029.5127; found: 1029.5106. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃; | To a solution of intermediate 27 (10 mg, 0.01mmol), HOAt (1-hydroxy-7-azabenzo-triazole) (4.3 mg, 0.03 mmol), and intermediate 2 (5 mg,0.01 mmol) in DMSO (1 mL) were added NMM (14 tL, 0.13 mmol) and EDCI (6.05 mg, 0.03mmol) at room temperature. After being stirred overnight at room temperature, the mixture waspurified by preparative HPLC (10percent-100percent methanol/ 0.1percent TFA in H20) to afford example 67as white solid (6 mg, 54percent). ?H NMR (600 MHz, CD3OD) oe 9.07 (s, 1H), 8.15 (dd, J= 10.0,2.7 Hz, 1H), 7.83 (s, 1H), 7.51 (d, J= 9.6 Hz, 1H), 7.29 (s, 1H), 7.18 (dd, J= 8.5, 2.2 Hz, 1H),7.13 (d, J 2.1 Hz, 1H), 6.77 (d, J 8.5 Hz, 1H), 6.59 (s, 1H), 6.14 (s, 1H), 6.04 ? 5.97 (m,1H), 5.72 (t, J= 2.1 Hz, 1H), 5.61 (t, J= 2.1 Hz, 1H), 4.52?4.25 (m, 2H), 3.97?3.83 (m,4H), 3.82 ? 3.78 (m, 3H), 3.75 (t, J= 6.5 Hz, 2H), 3.60 (s, 6H), 3.39 (s, 5H), 3.24 (s, 6H), 2.99(s, 3H), 2.50 (s, 3H), 2.43 (s, 3H), 2.31 (dt, J= 15.7, 8.4 Hz, 2H), 2.09 (dq, J 12.3, 7.0 Hz,2H), 2.02 ? 1.87 (m, 4H), 1.83 (p, J= 6.8 Hz, 2H), 1.76 ? 1.65 (m, 4H), 1.00 (t, J= 7.4 Hz,3H). HRMS (ESI-TOF) m/z: [M+Hj calcd for C57H70N1 ,O, ,S, 1116.4971; found, 1116.4961. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | To a solution of palbociclib (12 mg, 0.0268 mmol) in DMSO (1 mL) and DCM (5 mL) were added NMM (13.6 mg, 0.134 mmol), linker 4 (15 mg, 0.0268 mmol), HOAt (5.5 mg, 0.042 mmol) and EDCI (7.7 mg, 0.042 mmol). The mixturewas allowed to stir at rt overnight. After the starting materials were consumed, the reaction was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to yield the product (24 mg, 81percent) as yellow solid. ?H NMR (600 MI-Tz, CD3OD) oe 9.09 (s, 1H), 8.95 (s, 1H), 8.19 (dd, J= 9.6, 2.9 Hz, 1H), 7.86 (d, J 2.8 Hz, 1H), 7.54 (d, J 9.6 Hz, 1H), 7.46 (d, J 8.2 Hz, 2H), 7.40 (d, J 8.2 Hz, 2H), 6.00 (p, J= 8.9 Hz, 1H), 4.63 (s, 1H), 4.60 ?4.48(m, 3H), 4.36 (d, J= 15.6 Hz, 1H), 3.90 (d, J= 11.1 Hz, 1H), 3.83?3.73 (m, 5H), 3.35?3.31 (m, 2H), 3.29 ? 3.25 (m, 2H), 2.50 (s, 3H), 2.47 (s, 3H), 2.43 (s, 3H), 2.36 ? 2.27 (m, 4H), 2.24?2.19 (m, 1H), 2.13 ?2.05 (m, 3H), 1.94?1.86 (m, 2H), 1.73?1.61 (m, 6H), 1.41?1.24 (m, 2H), 1.04 (s, 9H). HRMS (ESI-TOF) m/z: [M+Hj calculated for C52H66N1107S, 988.4862; found: 988.4871. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | To asolution of palbociclib (25 mg, 0.0559 mmol) in DMSO (1 ml) and DCM (10 ml) were addedNMM (34 mg, 0.335 mmol), 2,2?-oxydiacetic acid (18 mg, 0.135 mmol), HOAt (20 mg, 0.134mmol), and EDCI (28 mg, 0.134 mmol). The mixture was allowed to stir at room temperatureovernight. After palbociclib was consumed, the reaction was concentrated under reducedpressure. The resulting residue was purified by prep-HPLC to yield the product (30 mg, 96percent).?H NMR (600 MHz, CD3OD) oe 9.10 (s, 1H), 8.20 (d, J= 9.5 Hz, 1H), 7.88 (s, 1H), 7.55 (d, J= 9.5 Hz, 1H), 6.00 (p, J= 8.9 Hz, 1H), 4.41 (s, 2H), 4.21 (s, 2H), 3.85 ? 3.70 (m, 4H), 3.39 ?3.26 (m, 4H), 2.49 (s, 3H), 2.43 (s, 3H), 2.35 ?2.25 (m, 2H), 2.13 ?2.04 (m, 2H), 1.95 ? 1.85(m, 2H), 1.74 ? 1.64 (m, 2H). HRMS (ESI-TOF) m/z: [M+Hj calculated for C28H34N706,564.2565; found: 564.2560. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With water; sodium carbonate; at 30℃; for 1h; | 40.0 g palbociclib isethionate (prepared in example 1) was dissolved into 700 ml water to form palbociclib isethionate solution. 20.0 g sodium carbonate was dissolved into 320 ml water and stirred at 30 C., and then palbociclib isethionate solution was added dropwise into the solution of sodium carbonate with stirring, and a yellow solid was precipitated. After that, the mixture was stirred at a constant temperature of 30 C. for 1 hour. Suction filtration and drying was introduced to obtain 0.97 g (yield: 97.0%) yellow solid, with HPLC purity of 99.8%. |
32.2 g | With sodium hydroxide; In methanol; water; at 25 - 35℃;pH 10; | A mixture of isethionic acid salt of palbociclib (54 g) and water (270 mL) was stirred at 25 °C for about 10 minutes. To the above reaction mass was added methanol (172 mL) at 25 °C and stirred for about 5 minutes. The above reaction mass was then filtered through hyflow and washed with a mixture of 50percent water in methanol (108 mL). The above filtrate was heated to 35 °C and pH was adjusted to 10.0 using aqueous solution of sodium hydroxide (IN, 155 mL). The reaction mass was cooled to 20-25 °C and the precipitated solid was filtered. The solid was washed with water (108 mL) and methanol (108 mL), dried at 25 °C for 15 hours. The resulting wet solid was further dried at 50 °C for about 10 hours to provide the title compound.Yield: 32 2 g Purity (by HPLC): 99 90 percent Surface Area (BET method): 9 38 m2/g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 80℃; for 16h; | In a round-bottom flask, 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino) pyrido[2,3-d]pyrimidin-7(8H)-one (10 mg, 0.022 mmol) was dissolved in NMP (2 mL) followed by addition of N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-6-iodohexanamide (11 mg, 0.022 mmol) and anhydrous DIEA (20 L mg, 0.11 mmol). Reaction mixture was heated at 80 C for 16h under argon atmosphere. The residue was diluted in acetonitrile and was purified by reverse phaseHPLC (20-100% CH3CN in H2O) to give 6-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide (9 mg, 50%). 1H NMR (500 MHz, CD3OD) delta 9.09 (s, 1H), 8.62 (d, 1H, J = 8.5 Hz), 8.19 - 8.16 (m, 1H), 7.98 (d, 1H, 2.5 Hz), 7.79 (t, 1H, J = 8.5 Hz), 7.62 - 7.59 (m, 2H), 6.02 - 5.99 (m, 1H), 5.16 - 5.13 (m, 1H), 3.73 (t, 1H, J = 5 Hz), 3.57 (t, 1H, j = 4.5 Hz), 3.35 (t, 1H, J = 7.0 Hz), 3.25 - 3.15 (m, 3H), 2.82 - 2.59 (m, 4H), 2.58 (t, 2H, J = 7.0 Hz), 2.50 (s, 3H), 2.43 (s, 3H), 2.37 - 2.28 (m, 3H), 2.18 - 2.00 (m, 4H), 1.94 - 1.81 (m, 6H), 1.72 - 1.69 (m, 2H) and 1.57 - 1.51 (m, 2H). ESI-MS calcd for C43H48N10O7 m/z 816.37, found: 817.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide; In water; acetone; at 28℃; for 1.75h;pH 12;Large scale; | Palbociclib dimesylate (3.51 kg,) was suspended in water (40 L) and acetone (23 L). The suspension was stirred at 28 °C until dissolution. Aqueous sodium hydroxide (10percent w/w) was added in 85 minutes, until pH = 12, causing the precipitation of Palbociclib. The suspension was stirred for 20 minutes, then filtered and washed with water and acetone. Upon drying in oven at 45 °C under vacuum, the title compound was obtained (2.13 kg, yield 92percent, purity 100.0percent, SSA 4.9 m2/g). The product was analyzed by PXRD, indicating that Form A was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | 50 mmol of the compound of the formula (V), 30 mL of pyridine and 25 mL of acetic anhydride were placed in a reaction flask, and the mixture was stirred and mixed. The temperature of the system was raised to 80 C, and the reaction was stirred at this temperature for 4 h, the heating was stopped, most of the solvent was distilled off under reduced pressure, 60 mL of xylene was added in three portions, and the residual solvent was evaporated under reduced pressure. The mixture was neutralized with sodium bicarbonate solution and extracted with EtOAc (EtOAc) EtOAc. To the solid obtained in Example 4, 150 mL of methanol and 30 mL of water were added, and the mixture was stirred uniformly, the reaction temperature was lowered to 5 to 10 C, and 25 mL of concentrated hydrochloric acid was added dropwise. After the completion of the dropwise addition, the reaction temperature was raised to 40 to 45 C, and The reaction was kept for 3 hours, cooled to room temperature, and then placed in a refrigerator for 1 hour to precipitate a yellow solid. After suction filtration, 100 mL of methanol and 20 mL of water were added to the obtained crude solid, and then a 2.5 mol 1 /L sodium hydroxide solution was added dropwise at room temperature to pH -9 to 10. The solid which precipitated was filtered off with suction, and the cake was washed with water and methanol, and dried to give the compound of the formula (1) in a yield of 83% [based on the compound of the formula (V)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With trimethylamine In dichloromethane at 20℃; for 6h; | 5.2. Chemical synthesis Compounds 1-2 were synthesized according to the reportedliterature [27], and the details are shown in the Supplementarydata. The synthesis of compound 3 was as follows: Palbociclib(447 mg, 1 mmol) and compound 2 (440 mg, 1 mmol) were addedto 30 mL of dichloromethane in a 100 mL round-bottom flask,followed by the addition of 200 μL of trimethylamine. The mixturewas allowed to stir at room temperature for 6 h. The solvent wasthen removed under reduced pressure, and the residue was purifiedvia silica gel column chromatography (dichloromethane/methanol =10/1) to obtain compound 3 as yellow powder (178 mg,yield 23%). 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.12 (s,1H), 8.98 (s, 1H), 8.91 (s, 1H), 8.22 (dd, J= 2.3, 0.8 Hz, 1H), 8.05 (d,J= 2.9 Hz, 1H), 7.99 (dd, J= 7.8, 1.4 Hz, 1H), 7.86 (d, J= 9.0 Hz, 1H),7.75 (dd, J= 7.7, 1.5 Hz, 1H), 7.70 (dd, J= 8.6, 2.3 Hz, 1H), 7.47 (dd,J= 9.1, 3.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.28-7.21 (m, 2H), 5.78 (p,J =8.9 Hz, 1H), 3.66 (m, 4H), 3.19 (m, 4H), 2.38 (s, 3H), 2.26 (s, 3H),2.24-2.15 (m, 2H), 1.90-1.79 (m, 2H), 1.74 (m, 2H), 1.61-1.49 (m,2H). 13C NMR (100 MHz, DMSO-d6) δ 203.04, 168.25, 161.28, 159.00,158.78, 158.39, 155.28, 148.19, 146.36, 145.34, 143.69, 142.62, 141.36,138.12, 136.53, 132.56, 129.83, 129.27, 128.13, 127.31, 125.96, 125.66,122.17, 115.51, 107.16, 106.17, 53.49, 49.25, 49.13, 31.83, 28.10, 25.67,14.16. HRMS (m/z): 749.2618 (calc. 749.2618 for C37H37N10O6S[M-Na]-). |
With triethylamine In dichloromethane at 20℃; for 6h; | a a. Synthesis of ligand HYNICPBB: Weigh 447 mg of Pabotini and 440 mg of Compound C in a 100 mL round bottom flask.200 μL of triethylamine and 30 mL of dichloromethane were added and reacted at room temperature for 6 h.After the reaction is completed, the solvent is removed by rotary evaporation.The crude product was separated and purified using silica gel column chromatography (dichloromethane:methanol = 10:1).After drying, the compound HYNICPBB was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; | Add 2-1 (448mg, 1mmol), IV (320mg, 1mmol), potassium carbonate (150mg, 1.2mmol) and DMF to 10mL in a 25mL three-neck, and react at 100 C for 1 hour under nitrogen protection.The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine,It was dried over anhydrous sodium sulfate and separated by medium chromatography to obtain 304 mg of a light yellow solid represented by the following formula (1-1). The yield was 61%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | To a suspension of Palbociclib (3-13, 100 mg, 0.22 mmol) in DMSO (5 mL) was added tert-butyl (2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethyl)carbamate (3-14, 156 mg, 0.44 mmol) and DIPEA (0.115 mL, 0.66 mmol). The mixture was heated to 80 C and kept stirring for 48 hours. The mixture was then cooled down to room temperature, extracted, dried, filtered and concentrated. The residue was purified by reverse phase HPLC (5-95% Me OH in H2O) to give tert-butyl (2-(2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)carbamate (3-15, TFA salt) as a yellow solid (103 mg, 65%). LC-MS: miz 723 [M+l] T I NMR (500 MHz, DMSO-cfe) d 10.34 (s, 1IT), 8.97 (s, HI), 8.12 (d,,/= 3.0 Hz, 1 1 1). 7.90 (d, J= 9.1Hz, 1H), 7.64-7.58 (m, 1H), 6.81-6.74 (m, 1H), 5.89-5.78 (m, 1H), 3.93-3.75 (m, 4H), 3 67-3.60 (m, 4H), 3.59-3.55 (m, 2H), 3.55-3.46 (m, 4H), 3.44-3.35 (m, 4IT), 3.27 (br, 2H), 3.15-3.01 (m, 4H), 2.42 (s, 3H), 2.32 (s, 3H), 2.28-2.19 (m, 21 1). 1.95-1.84 (m, 21 1). 1.83-1.71 (m, 21 1). 1.64-1.52 (m, 2F1), 1.36 (s,91 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h; | A mixture of palbociclib (224 mg, 0.5 mmol) and but-3-ynoic acid (50 mg, 0.5 mmol) in DMF (10 ml) was treated with DIPEA (166 pL, 1.0 mmol) and then HATU (190 mg, 0.5 mmol) and stirred at ambient temperature for 1 hour. After which time the reaction mixture was diluted with H20 and extracted with EtOAc. The organic layer was dried by Na2S04and concentrated in vacuum. The resulting material was purified by chromatography on silica to afford palbociclib-alkyne YX-2-76 (185 mg, 70% yield). LC-MS RT = 1.43, ES+ve 528. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6 g | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; | 1 Preparation of 2-((5-(4-(3-(1,3-dioxolan-2-yl)propyl)piperazin-1-yl)pyridin-2-yl)amino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one Palbociclib (1.36 g, 3 mmol) was dissolved in dimethylformamide (50 mL). Diisopropylethylamine (775 mg, 6 mmol) and 2-(3-bromopropyl)-1,3-dioxolane (700 mg, 3.6 mmol) were added to the solution. After being stirred overnight at 60° C., the reaction solution was diluted with ethyl acetate, washed with saline, dried and then purified by column chromatography to yield a product of 1.6 g. [M+H]+=562.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 5h; | 4.1.1. tert-butyl3-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo7,8-dihydropyrido [2,3 -d]pyr-imidin-2-ylamino)pyridin-3-yl) piperazin-1-yl)propanoate (PD-2) Tert-Butyl acrylate (0.045 mL, 0.312 mmol) and DBU (0.044 mL, 0.296 mmol) were added to a solution of Palbociclib (44.75 mg, 0.1 mmol) in DCM (15 mL), and the mixture was stirred at room temperature for 5 h. When TLC indicated full consumption of the starting material, the reaction was evaporated under reduced pressure. Then the reaction was diluted with EtOAc and washed twice with brine. The green layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give PD-2 as a green solid (54 mg, 94%).1 H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.16 (d, J =9.1 Hz, 1H), 8.08 (d, J= 2.7 Hz, 1H), 7.32 (dd, J =9.1, 2.9 Hz, 1H), 3.27-3.17 (m, 4H), 2.74 (t, J =7.3 Hz, 2H), 2.70-2.61 (m, 4H), 2.55 (s, 3H), 2.46 (t, J= 7.3 Hz, 2H), 2.42-2.31 (m, 5H), 2.10-2.02 (m, 2H), 1.92-1.87 (m, 2H), 1.45 (s, 9H), 1.26 (s, 3H) |
94% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 5h; | 1 Synthesis of the intermediate PD-2 Pabociclib (44.75mg, 0.1mmol) was dissolved in 15mL DCM, DBU (0.044mL, 0.296mmol), tert-butyl acrylate (0.045mL, 0.312mmol) was stirred at room temperature for 5h. TLC monitors the reaction until the reaction is complete. Post-treatment: first reduce pressure concentration to remove the solvent DCM, then add 30mL of water, extract (3×25mL) aqueous layer with EtOAc, merge the organic phase, wash three times with saturated table salt water and then dry with anhydrous sodium sulfate, after distillation under reduced pressure, column chromatography separation with DCM/MeOH system as mobile phase to obtain green solids 54mg, yield 94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; | 4.1.18. N-(2-(2-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d] pyrimidin-2-ylamino)pyridin-3-yl)piperazin1-yl)acetamido)ethyl)acrylamide (A-1) General procedure: To a solution of compound 3a (50 mg, 0.233 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting solution was stirred for 3 h at room temperature. The mixture was evaporated under reduced pressure, which directly dissolved into DMF (10 mL). To the DMF solution was added PD-5 (98 mg, 0.194 mmol), HATU (89 mg, 0.233 mmol), DIPEA (261 mg, 1.94 mmol). The reaction was stirred at room temperature overnight. Then water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL 3), washed with brine (30 mL 3). The green organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to crude product. The crude material was purified by flash column chromatography to give A-1 as a green solid (16 mg, 14%). |
With triethylamine In dichloromethane at 0℃; | General procedure for synthesis of compounds A1-A2 Palbociclib (0.5 mmol) and triethylamine (0.75 mmol) were added to15 ml of dichloromethane (DCM), and the resulting solution was cooledto 0 by an ice bath. Then corresponding acyl chloride (0.6 mmol) wasadded drop by drop. After stirring for 1.5 h at 0 , the formed depositwas filtrated off, and the solvent was removed under reduced pressure.The obtained crude product was further purified by column chromatography(DCM:methanol = 60:1, V/V). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; dimethyl sulfoxide at 20℃; for 16h; | 4-(( 2-( 4-( 6-( ( 6-Acetyl-8-cvclopentyl-5-methyl- 7-oxo- 7, 8-dihydropwido[ 2, 3-d]pyrimidin- 2-yl)amino)pyridin-3-yl)piperazin-l-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione (MS 140) To a solution of (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)glycine (0.017 g, 0.051 mmol) in DCM (10 mL) and DMSO (2 mL) were added palbociclib (0.023 g, 0.051 mmol), 4-methylmorpholine (0.020 g, 0.20 mmol), l-hydroxy-7-azabenzotriazole (0.0090 g, 0.066 mmol) and /V-(3-dimethylaminopropyl)-/V’-ethylcarbodiimide hydrochloride (0.013 g, 0.066 mmol). The reaction mixture was stirred at room temperature for 16 h, before being concentrated under reduce pressure. The resulting residue was purified by reverse-phase prep-HPLC to yield the product (0.028 g, 72%) as yellow solid. 1H NMR (600 MHz, CD30D) d 9.08 (s, 1H), 8.21 (dd, J= 9.6, 2.8 Hz, 1H), 7.86 (d, J= 2.8 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.03 (d, J= 7.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.04 - 5.97 (m, 1H), 5.08 (dd, J= 12.7, 5.5 Hz, 1H), 4.24 (s, 2H), 3.88 - 3.73 (m, 4H), 3.42 - 3.31 (m, 4H), 2.92 - 2.82 (m, 1H), 2.80 - 2.67 (m, 2H), 2.50 (s, 3H), 2.43 (s, 3H), 2.35 - 2.27 (m, 2H), 2.15 - 2.06 (m, 3H), 1.94 - 1.87 (m, 2H), 1.73 - 1.66 (m, 2H). HRMS (ESI-TOF) m/z: [M+H]+ calcd for C39H41N10O7, 761.3160; found: 761.3150 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 1h; | 5.1 The first step: tert-butyl 3-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-pyridyl]piperazin-1-yl]azetidine-1-carboxylate (5b) Add 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridyl)amino]pyrido[2,3-d]pyrimidine-7- Ketone (5a)(0.100g, 0.223mmol) was dissolved in 2mL 1,2-dichloroethane, followed by addition of tert-butyl 3-oxoazetidine-1-carboxylate (0.0765g, 0.447mmol) and glacial acetic acid (0.0335g ,0.558mmol),Then add sodium triacetoxyborohydride (0.0947g, 0.447mmol), and react at room temperature for 1 hour after the addition is complete.Add 1mol/L sodium hydroxide solution dropwise to the reaction solution to adjust the pH to 10, separate the layers, extract the aqueous layer with 20 mL of dichloromethane, combine the organic phases, wash the organic phase with 30 mL of saturated sodium chloride solution, and dry with anhydrous sodium sulfate After concentration under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100:0-9:1), tert-butyl 3-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-pyridyl]piperazin-1-yl]azetidine-1-carboxylate (5b) (0.120 g, yield: 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 1h; | 10.1 The first step: 2-[4-[6-[(6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl) Amino]-3-pyridyl]piperazin-1-yl]-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (10a) Add 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-yl-2-pyridyl)amino]pyrido[2,3-d]pyrimidine-7- Ketone (5a) (0.500g, 1.12mmol) was dissolved in 5mL 1,2-dichloroethane, and 2-oxo-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (0.535g, 2.24mmol) and glacial acetic acid (0.168g, 2.80mmol), then sodium triacetoxyborohydride (0.474g, 2.24mmol) was added, and after the addition, react at room temperature for 1 hour. Add 1mol/L sodium hydroxide solution dropwise to the reaction solution to adjust the pH to 10, separate the layers, extract the aqueous phase with 20mL dichloromethane, combine the organic phases, wash with 30mL saturated sodium chloride solution, dry with anhydrous sodium sulfate, and depressurize The crude product obtained after concentration was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100:0-97:3) to obtain 2-[4-[6-[(6-acetyl-8-cyclopenta) 5-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-pyridinyl]piperazin-1-yl]-7-azaspiro[3.5 ] Tert-Butyl Non-7-carboxylate (10a) (0.620 g, Yield: 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.7% | With hydrogenchloride In water; butan-1-ol at 80℃; for 20h; Industrial scale; | 7; 8 Example 8: Industrial preparation of Palbociclib In a 5000L glass-lined reaction kettle, add 100kg of the compound of formula 5, 900kg of n-butanol, 1500kg of anisole and 1000kg of water, raise the temperature to 80°C, dropwise add 25kg (0.25mol, 37.3%) hydrochloric acid solution, the dripping is completed, and the reaction is incubated for 20h. , HPLC detection control reaction end point.After the reaction is completed, the temperature is lowered to 60°C, the pH is adjusted to 10 with 30% sodium hydroxide solution, the liquid is separated, the water layer is discarded, and the water layer is washed twice with 1000kg*2 water. PP material) was press-filtered to the D-level zone, the filtrate was distilled under reduced pressure to obtain about 550kg of solvent, the remaining material was slowly cooled to 0-5°C, crystallized for 3h, filtered, and dried to obtain 70.1kg of high-purity bright yellow Palbociclib. The yield was 94.7%, and the HPLC purity was 99.95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: PD 0332991; Boc-GFLG-OH With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at -5℃; for 0.5h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -5 - 20℃; | 6; 7; 10; 14; 16 Palbociclib (10.0000 g, 22.3448 mmol, referred to as PCB), HBTU (12.7111 g, 33.5172 mmol), and HOBT (7.8809 g, 33.5172 mmol) were added to the DMF (200 mL) solution of Product 13-195 (13.2076 g, 26.8138 mmol); the obtained solution was stirred at -5° C. for about 20 min to react, and then DIEA (16.6200 mL, 100.5516 mmol) was slowly added dropwise over 20 min; the obtained solution was further stirred at -5° C. for 2 h, and then stirred overnight at room temperature to react. At the end of the reaction, the reaction solution was transferred to a 2 L beaker, a saturated sodium bicarbonate solution (150 mL) was added to separate out a solid, the suction filtering was carried out, and the filter cake was washed with deionized water (100 mL×4) and then dried in a vacuum oven, thus obtaining 20.6 g of Product 13-196 with a yield of 100%. H-NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.96 (s, 1H), 8.10 (dd, J=12.0, 4.2 Hz, 2H), 7.88 (t, J=7.8 Hz, 2H), 7.52 (m, 7H), 6.97 (s, 1H), 5.94-5.61 (m, 1H), 4.39 (s, 1H), 4.00 (d, J=5.4 Hz, 2H), 3.58 (dd, J=16.1, 5.4 Hz, 4H), 3.16 (d, J=19.0 Hz, 4H), 2.43 (s, 3H), 2.31 (s, 3H), 2.25 (s, 2H), 1.89 (s, 2H), 1.82-1.70 (m, 5H), 1.66-1.56 (m, 3H), 1.52-1.43 (m, 2H), 1.38 (s, 9H), 1.24 (d, J=6.4 Hz, 2H), 0.86 (dd, J=15.4, 6.5 Hz, 6H). MALDI-TOF MS: [M+H+] 922.50 |
100% | Stage #1: PD 0332991; Boc-GFLG-OH With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at -5℃; for 0.5h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -5 - 20℃; | 6; 7; 10; 14; 16 Palbociclib (10.0000 g, 22.3448 mmol, referred to as PCB), HBTU (12.7111 g, 33.5172 mmol), and HOBT (7.8809 g, 33.5172 mmol) were added to the DMF (200 mL) solution of Product 13-195 (13.2076 g, 26.8138 mmol); the obtained solution was stirred at -5° C. for about 20 min to react, and then DIEA (16.6200 mL, 100.5516 mmol) was slowly added dropwise over 20 min; the obtained solution was further stirred at -5° C. for 2 h, and then stirred overnight at room temperature to react. At the end of the reaction, the reaction solution was transferred to a 2 L beaker, a saturated sodium bicarbonate solution (150 mL) was added to separate out a solid, the suction filtering was carried out, and the filter cake was washed with deionized water (100 mL×4) and then dried in a vacuum oven, thus obtaining 20.6 g of Product 13-196 with a yield of 100%. H-NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.96 (s, 1H), 8.10 (dd, J=12.0, 4.2 Hz, 2H), 7.88 (t, J=7.8 Hz, 2H), 7.52 (m, 7H), 6.97 (s, 1H), 5.94-5.61 (m, 1H), 4.39 (s, 1H), 4.00 (d, J=5.4 Hz, 2H), 3.58 (dd, J=16.1, 5.4 Hz, 4H), 3.16 (d, J=19.0 Hz, 4H), 2.43 (s, 3H), 2.31 (s, 3H), 2.25 (s, 2H), 1.89 (s, 2H), 1.82-1.70 (m, 5H), 1.66-1.56 (m, 3H), 1.52-1.43 (m, 2H), 1.38 (s, 9H), 1.24 (d, J=6.4 Hz, 2H), 0.86 (dd, J=15.4, 6.5 Hz, 6H). MALDI-TOF MS: [M+H+] 922.50 |
10.3 g | Stage #1: PD 0332991; Boc-GFLG-OH With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at -5℃; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | 5 30-30 Compound 30-28 (13.97 mmoL), PCB (5 g, 11.17 mmoL), HBTU (6.35 g, 16.76 mmoL) and HOBT (2.26 g, 16.76 mmoL) were added in a 500 mL round-bottomed flask and then dissolved with DMF (100 mL), and the mixed solution was stirred at -5° C. for 30 min. Then DIEA (8.31 mL, 50.28 mmoL) was slowly added dropwise, and then the mixed solution reacted at a low temperature for 2 h; after that, the reaction device was placed at room temperature and the reaction solution was stirred overnight to react. At the end of the reaction, deionized water (1000 mL) was added to rinse DMF, and a pale yellow solid was precipitated and then dried to obtain 10.3 g of the product. |
10.3 g | Stage #1: PD 0332991; Boc-GFLG-OH With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at -5℃; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | 5 30-30 Compound 30-28 (13.97 mmoL), PCB (5 g, 11.17 mmoL), HBTU (6.35 g, 16.76 mmoL) and HOBT (2.26 g, 16.76 mmoL) were added in a 500 mL round-bottomed flask and then dissolved with DMF (100 mL), and the mixed solution was stirred at -5° C. for 30 min. Then DIEA (8.31 mL, 50.28 mmoL) was slowly added dropwise, and then the mixed solution reacted at a low temperature for 2 h; after that, the reaction device was placed at room temperature and the reaction solution was stirred overnight to react. At the end of the reaction, deionized water (1000 mL) was added to rinse DMF, and a pale yellow solid was precipitated and then dried to obtain 10.3 g of the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: PD 0332991; Boc-Gly-Leu-Gly-OH With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at -5℃; for 0.5h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -5 - 20℃; | 12 PCB (PaLbocicLib (PD-0332991)) (5.1380 g, 11.4808 mmol), HOBT (2.3271 g, 17.2212 mmol), and HBTU (6.5310 g, 17.2212 mmol) were added to the DMF solution of Product 16-40 (14.9250 mmol), the obtained solution was placed in a -5° C. low-temperature constant temperature bath and stirred to react for 30 min, and then DIEA (8.5390 mL, 51.6636 mmol) was added dropwise. Two hours later, the obtained solution reacted overnight at room temperature. At the end of the reaction, deionized water (1 L) was added to the reaction solution, suction filtering was carried out, and the filter cake was washed three times (200 mL×3) with methyl tert-butyl ether. The filter cake was collected and dried in a vacuum oven, thus obtaining 10 g of the product with a yield of 100%. |
100% | Stage #1: PD 0332991; Boc-Gly-Leu-Gly-OH With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at -5℃; for 0.5h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -5 - 20℃; | 12 PCB (PaLbocicLib (PD-0332991)) (5.1380 g, 11.4808 mmol), HOBT (2.3271 g, 17.2212 mmol), and HBTU (6.5310 g, 17.2212 mmol) were added to the DMF solution of Product 16-40 (14.9250 mmol), the obtained solution was placed in a -5° C. low-temperature constant temperature bath and stirred to react for 30 min, and then DIEA (8.5390 mL, 51.6636 mmol) was added dropwise. Two hours later, the obtained solution reacted overnight at room temperature. At the end of the reaction, deionized water (1 L) was added to the reaction solution, suction filtering was carried out, and the filter cake was washed three times (200 mL×3) with methyl tert-butyl ether. The filter cake was collected and dried in a vacuum oven, thus obtaining 10 g of the product with a yield of 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 55℃; for 6h; | 2 Preparation of (E)-6-Acetyl-2-((5-(4-(but-2-enoyl)piperazin-1-yl)pyridin-2-yl)amino)-8-Cyclopentyl-5-methylpyridone[2,3-d]pyrimidin-7(8H)-one (Compound 1-1) General procedure: Dissolve 2-butenoic acid in N,N-dimethylformamide, add HATU to it with stirring,Continue to stir for 5 minutes, add DIPEA to the reaction system, stir for 3 minutes,Palbociclib (2-butenoic acid: HATU: DIPEA: Palbociclib in a molar ratio of 1.3:1.5:1.5:1) was then added to the solution, and the reaction was heated at 55° C. for 6 hours.The progress of the reaction was monitored by TCL, and the reaction was stopped when the point of the reactant completely disappeared. The solvent was removed with a rotary evaporator, and then dichloromethane and water were added for liquid separation and extraction, and the organic phase was taken. After drying the organic phase with anhydrous sodium sulfate, the solvent was removed. A small amount of dichloromethane was added to it just enough to dissolve the product. Then, petroleum ether was added to it, and the precipitation of yellow solid could be observed, and the crude product was obtained after filtration. Finally, the crude product is purified by sand making, and the product is obtained after purification by column chromatography (eluent is dichloromethane/methanol=100:1), and the yield is 82.3%. |
Stage #1: (E)-4,4,4-trifluorobut-2-enoate With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Stage #2: PD 0332991 at 55℃; | General procedure for synthesis of compounds A4-A5 The corresponding acid (1.3 mmol) was dissolved in 15 ml of DMF,and the resulting solution was stirred at room temperature. Then, HATU(1.5 mmol) and DIPE (1.5 mmol) were added successively. After stirringfor 10 min palbociclib (1.0 mmol) was added. The reaction solution washeated to 55 and stirred for 2 h. Thereafter, the solvent was removedunder reduced pressure, and the residue was dissolved in 30 ml of amixture of DMC/water (1:1, V/V). The organic phase was collected,dried over anhydrous Na2SO4, and concentrated under reduced pressure,giving the crude product which was further purified by columnchromatography (DCM:methanol = 60:1, V/V). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 55℃; for 6h; | 3 Preparation of (E)-6-Acetyl-2-((5-(4-(but-2-enoyl)piperazin-1-yl)pyridin-2-yl)amino)-8-Cyclopentyl-5-methylpyridone[2,3-d]pyrimidin-7(8H)-one (Compound 1-1) General procedure: Dissolve 2-butenoic acid in N,N-dimethylformamide, add HATU to it with stirring,Continue to stir for 5 minutes, add DIPEA to the reaction system, stir for 3 minutes,Palbociclib (2-butenoic acid: HATU: DIPEA: Palbociclib in a molar ratio of 1.3:1.5:1.5:1) was then added to the solution, and the reaction was heated at 55° C. for 6 hours.The progress of the reaction was monitored by TCL, and the reaction was stopped when the point of the reactant completely disappeared. The solvent was removed with a rotary evaporator, and then dichloromethane and water were added for liquid separation and extraction, and the organic phase was taken. After drying the organic phase with anhydrous sodium sulfate, the solvent was removed. A small amount of dichloromethane was added to it just enough to dissolve the product. Then, petroleum ether was added to it, and the precipitation of yellow solid could be observed, and the crude product was obtained after filtration. Finally, the crude product is purified by sand making, and the product is obtained after purification by column chromatography (eluent is dichloromethane/methanol=100:1), and the yield is 82.3%. |
Stage #1: (E)-3-cyclopropylprop-2-enoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Stage #2: PD 0332991 at 55℃; | General procedure for synthesis of compounds A4-A5 General procedure: The corresponding acid (1.3 mmol) was dissolved in 15 ml of DMF,and the resulting solution was stirred at room temperature. Then, HATU(1.5 mmol) and DIPE (1.5 mmol) were added successively. After stirringfor 10 min palbociclib (1.0 mmol) was added. The reaction solution washeated to 55 and stirred for 2 h. Thereafter, the solvent was removedunder reduced pressure, and the residue was dissolved in 30 ml of amixture of DMC/water (1:1, V/V). The organic phase was collected,dried over anhydrous Na2SO4, and concentrated under reduced pressure,giving the crude product which was further purified by columnchromatography (DCM:methanol = 60:1, V/V). |
Tags: 571190-30-2 synthesis path| 571190-30-2 SDS| 571190-30-2 COA| 571190-30-2 purity| 571190-30-2 application| 571190-30-2 NMR| 571190-30-2 COA| 571190-30-2 structure
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H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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