[ CAS No. 955365-80-7 ] {[proInfo.proName]}

Name: 955365-80-7|2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one|98%
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Product Details of [ 955365-80-7 ]

CAS No. :	955365-80-7	MDL No. :	MFCD17215200
Formula :	C₂₇H₃₂N₈O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BKWJAKQVGHWELA-UHFFFAOYSA-N
M.W :	500.60	Pubchem ID :	24856436
Synonyms :		Chemical Name :	2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one

Safety of [ 955365-80-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 955365-80-7 ]

* 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.

Upstream synthesis route of [ 955365-80-7 ]
Downstream synthetic route of [ 955365-80-7 ]

[ 955365-80-7 ] Synthesis Path-Upstream 1~5

1
[ 955369-56-9 ]
[ 16153-81-4 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
1.2 g	Stage #1: With 3-chloro-benzenecarboperoxoic acid In toluene for 0.333333 h; Stage #2: With N-ethyl-N,N-diisopropylamine In toluene	817 mg of m-chloroperbenzoic acid (> 65percent) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N,N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, CDCI3) δ: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3 Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501
1.2 g	Stage #1: With 3-chloro-benzenecarboperoxoic acid In toluene for 0.333333 h; Stage #2: With N-ethyl-N,N-diisopropylamine In toluene	Step 3) Production of 2-allyl-l-[6-(l -hydroxy- l-methylethyl)pyridin-2-yl]-6- [4-(4- methylpiperazin- 1 -yl)phenyl] amino} - 1 ,2-dihydro-3H-pyrazolo[3 ,4-d]pyrimidin- 3 -one: 817 mg of m-chloroperbenzoic acid (> 65percent) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred fro 20 minutes. 1.61 mL of N,N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, CDCI3) δ: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3 Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[2] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 29-30
[3] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 30-31
[4] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 32
[5] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 31
[6] Patent: WO2013/39854, 2013, A1, . Location in patent: Page/Page column 28
[7] Patent: WO2014/62454, 2014, A1, . Location in patent: Page/Page column 32
[8] Patent: US2016/8361, 2016, A1, . Location in patent: Paragraph 0164

2
[ 16153-81-4 ]
[ 955365-80-7 ]

Reference： [1] Patent: US2007/254892, 2007, A1, . Location in patent: Page/Page column 51

3
[ 26218-75-7 ]
[ 955365-80-7 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[2] Patent: US2016/8361, 2016, A1,

4
[ 638218-78-7 ]
[ 955365-80-7 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694

5
[ 955368-90-8 ]
[ 955365-80-7 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694

[ 955365-80-7 ] Synthesis Path-Downstream 1~31

1
[ 16153-81-4 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-allyl-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazine)-1-yl)phenyl)amino-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one With 3-chloro-benzenecarboperoxoic acid In water; toluene for 0.333333h; Stage #2: 4-(4-Methyl-piperazino)-anilin With N-ethyl-N,N-diisopropylamine In water; toluene	53.3 3) 3) Production of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 817 mg of m-chloroperbenzoic acid (>65%) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N,N-diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-1-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1, ethyl acetate/ethanol=98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 8.83 (1H, s), 7.86 (1H, dd, J=8.0, 7.8 Hz), 7.75 (1H, d, J=7.3 Hz), 7.49 (1H, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (1H, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (1H, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (1H, d, J=10.0 Hz), 4.94 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2007/254892, 2007, A1 Location in patent: Page/Page column 51

2
[ 955365-80-7 ]
[ 104-15-4 ]
[ 1075739-37-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; acetonitrile at 20 - 50℃; for 24.0833 - 24.1667h;	9 Example 9:Production of tosylate of Compound A103 mg of Free base of the compound A (-0.21 mmol) was dissolved in 4.0 ml of acetonitrile / THF 3:1 (v/v) at about 40 to 500C and to the clear solution was added 39.13 mg of toluenesulfonic acid (-0.21 mmol) dissolved in 1.0 ml acetonitrile. The addition of this solution was carried out drop- wise under stirring, i.e., within about 5 to 10 minutes. The yellowish solution was cooled to ambient temperature and stirred in an open reaction tube at room temperature for about one day until most of the THF and part of the acetonitrile were evaporated. Then the suspension was investigated by light microscopy which indicates that a crystalline product was obtained. After separation of the solid by filtration the product was dried under vacuum at 4O0C for about 16 hours. 109 mg of the titled tosylate was obtained as a crystal. XRPD patterns:(2 theta(degrees), Intensity(cps)): (6.6°, 1 14.8), (20.0°, 101.7), (9.8°, 91.1), (13.2°, 86.5), (14.5°, 81.4), (19.2°, 75.1).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 36

3
[ 955365-80-7 ]
[ 97-67-6 ]
[ 1075739-41-1 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 20 - 50℃; for 24.0833 - 24.1667h;	13 Example 13:Production of L-malate of Compound A82 mg of Free base of the compound A (-0.17 mmol) was dissolved in 4.0 ml of acetonitrile at about 5O0C and to the clear solution was added 0.595 ml of L-malic acid solution in acetonitrile (37.3 mg/ml = 0.17 mmol). The addition of this solution was carried out drop-wise under stirring, i.e., within about 5 to 10 minutes. Upon addition of the malic acid solution a fine suspension was formed which was stirred at ambient temperature for about one day. The reaction tube was stirred with the cap open for a few hours allowing to evaporate part of the solvent. After separation of the solid by filtration the product was dried under vacuum at 400C for about 22 hours. About 70 mg of the titled L-malate was obtained as a crystal. XRPD patterns:(2 theta(degrees), Intensity(cps)): (23.0°, 172.6), (25.1°, 139.4), (8.8°, 66.4), (17.6°, 93.6), (19.3°, 100.2), (21.7°, 91.4).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 38

4
[ 955365-80-7 ]
[ 110-16-7 ]
[ 1075739-42-2 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 20 - 60℃; for 24.0833 - 24.1667h;	14 Example 14:Production of maleate FormA (hemihvdrate) of Compound A79 mg of Free base of the compound A (-0.16 mmol) was dissolved in 4.0 ml of acetonitrile at about 6O0C and to the clear solution was added 0.463 ml of maleic acid solution in acetonitrile (39.5 mg/ml = 0.16 mmol). The addition of this solution was carried out drop-wise under stirring, i.e., within about 5 to 10 minutes. After several minutes a fine suspension is formed which was stirred at ambient temperature for about one day. The reaction tube was stirred with the cap open for a few hours allowing to evaporate part of the solvent. After separation of the solid by filtration the product was dried under vacuum at 400C for about 22 hours. About 79 mg of the titled maleate FormA was obtained as a crystal. XRPD patterns:(2 theta(degrees), Intensity(cps)): (14.5°, 28.4), (19.2°, 29.1), (8.8°, 20.5), (11.4°, 19.7), (21.1°, 26.6), (21.9°, 28.0).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 38

5
[ 955365-80-7 ]
[ 110-16-7 ]
[ 1075739-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: MK-1775; maleic acid In tetrahydrofuran; ethanol at 20 - 40℃; Stage #2: In acetonitrile at 20℃; for 22h;	15 Example 15:Production of maleate FormB of Compound A97 mg of Free base of the compound A (-0.19 mmol) was dissolved in 3.0 ml of THF/ethanol 1 :1 at about 4O0C and to the clear solution was added 22.6 mg of maleic acid dissolved in 1.0 ml THF. This solution was slowly evaporated under a weak nitrogen flow at ambient temperature. To the obtained solid residue 1.0 ml of acetonitrile was added and the resulting suspension was stirred at ambient temperature for about 22 hours.XRPD patterns:(2 theta(degrees), Intensity(cps)): (17.2°, 138.1), (23.8°, 133.9), (11.0°, 47.3), (15.5°, 47.0),(19.1°, 59.5), (23.2°, 68.5).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 38-39

6
[ 955369-56-9 ]
[ 16153-81-4 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
		3) Production of 2-allyl-l -[6-(I -hydroxy-1 -methylethyl)pyridin-2-yl]-6- [4-(4-methylpiperazin- 1 -yl)phenyl]amino}-l ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one: <n="31"/>817 mg of m-chloroperbenzoic acid (> 65 %) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N5N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. IH-NMR (400 MHz, CDCI3) delta: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.
		Reference Example 3:Production of Form A of Compound A733 mg of m-chloroperbenzoic acid (> 65 %) was added to toluene (30 mL) solution of 1.02 g of 2-allyl-l-[6-(l-hydroxy-l-methylethyl)-2-pyridinyl]-6-(methylthio)-l,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 20 minutes. 1.45 mL of N,N- diisopropylethylamine and 710 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was crystallized from ethyl acetate to obtain the entitled compound contaminated with a impurity. This impurity was removed by re-purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2) and collected the fractions not contaminated with the impurity. After concentrated, this was dissolved in ethyl acetate (10 mL) under reflux and the solution was stand over night in room temperature. The solid was collected by filtration and dried in vacuo to obtain 655 mg of the entitled compound as a yellow solid. XRPD patterns:(2 theta(degrees), Intensity(cps)): (13.8, 1039), (26.4, 544), (6.9, 162), (11.2, 484), (12.4, 135), (20.7, 137), (24.0, 151). DSC: <n="32"/>When DSC of Form A was measured using a TA Instruments DSC QlOOO instrument, the extrapolated melting temperature onset of Form A was 154C with an enthalpy of fusion of 86.4 J/g at 5 C/min under nitrogen in crimped aluminum pan. The peak melting temperature was 155C.
		Reference Example 5:Production of Form H of Compound A817 mg of m-chloroperbenzoic acid (> 65 %) was added to toluene (20 mL) solution of 1.10 g of 2-allyl-l-[6-(l-hydroxy-l-methylethyl)-2-pyridinyl]-6-(methylthio)-l,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 20 minutes. 1.61 mL of N5N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2, chloroform/methanol = 10/1). After the solvent was evaporated away, the residue was re-purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was dissolved in ethyl acetate under reflux and the solution was stand over night in room temperature. The solid was collected by filtration and dried in vacuo to obtain 1.20 g of the entitled compound as a yellow solid. XRPD patterns:(2 theta(degrees), Intensity(cps)): (5.8, 777), (11.5, 189), (11.6, 217), (5.2, 133), (16.6, 119), (23.3, 80.9), (24.0, 60.8). DSC:When DSC of Form H was measured using a TA Instruments DSC QlOOO instrument, the extrapolated melting temperature onset of Form H was 131C with an enthalpy of fusion of 43.1 J/g at 5 C/min under nitrogen in crimped aluminum pan. The peak melting temperature was 134C. Before melting, a broad endotherm peak with form conversion was detected at ~100C.

		Reference Example 4:Production of Form D of Compound A20.0 g of m-chloroperbenzoic acid (> 65 %) was added to toluene (500 mL) solution of 24.3 g of 2-allyl-l -[6-(I -hydroxy- l-methylethyl)-2-pyridinyl]-6-(methylthio)- 1,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 40 minutes. 35.5 mL of N,N- diisopropylethylamine and 14.3 g of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Tetrahydrofuran (500 mL) and aqueous saturated sodium hydrogen carbonate solution were added to the reaction liquid, extracted with ethyl acetate, washed with brine, and dried with anhydrous magnesium sulfate. After the solvent was evaporated away, the solid was collected by filtration and washed with ethyl acetate to give 11.Og of the crude entitle compound. The filtrate was concentrated and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1 and chloroform/methanol = 1/0 to 7/1). After the solvent was evaporated away, the solid was collected by filtration and washed with ethyl acetate to give 16.9g of the entitle compound. The filtrate was concentrated and the residue was purified through silica gel basic column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After the solvent was evaporated away, the solid was collected by filtration and washed with ethyl acetate to give 2.5Og of the entitle compound. The combined crude title compounds (30.4g) was recrystallized from isopropanol (300 mL) to obtain 32.2g of the entitled compound as 1 isopropanol adduct. The entitled compound 1 isopropanol adduct (32.2g) was dissolved in ethyl acetate (300 mL) under reflux and the solution was stirred over night in room temperature. The solid was collected by filtration and dried in vacuo to obtain 21.2g of the entitled compound as a yellow solid. XRPD patterns:(2 theta(degrees), Intensity(cps)): (6.5, 71.0), (10.3, 61.5), (9.3, 40.8), (14.6, 22.5), (18.7, 22.0), (19.5, 55.9), (22.2, 32.2). DSC:When DSC of Form D was measured using a TA Instruments DSC Ql 000 instrument, the extrapolated melting temperature onset of Form D was 173C with an enthalpy of fusion of 66.2 J/g at 5 C/min under nitrogen in crimped aluminum pan. The peak melting temperature was 174C. Before melting, a small endotherm peak with form conversion was detected at 135~150C.
1.2 g		817 mg of m-chloroperbenzoic acid (> 65%) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N,N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, CDCI3) delta: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3 Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501
1.2 g		Step 3) Production of 2-allyl-l-[6-(l -hydroxy- l-methylethyl)pyridin-2-yl]-6- [4-(4- methylpiperazin- 1 -yl)phenyl] amino} - 1 ,2-dihydro-3H-pyrazolo[3 ,4-d]pyrimidin- 3 -one: 817 mg of m-chloroperbenzoic acid (> 65%) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred fro 20 minutes. 1.61 mL of N,N- diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-l-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentrated, this was recrystallized from ethyl acetate to obtain 1.20 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, CDCI3) delta: 8.83 (IH, s), 7.86 (IH, dd, J=8.0, 7.8 Hz), 7.75 (IH, d, J=7.3 Hz), 7.49 (IH, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (IH, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (IH, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (IH, d, J=10.0 Hz), 4.94 (IH, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.
		817 mg of m-chloroperbenzoic acid (>65%) was added to toluene (20 mL) solution of 1.10 g of the above produce, and stirred for 20 minutes. 1.61 mL of N,N-diisopropylethylamine and 706 mg of 4-(4-methylpiperazin-1-yl)aniline were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1, ethyl acetate/ethanol=98/2). After concentrated, this was recrystallized from ethyl acetate to obtain the entitled compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta: 8.83 (1H, s), 7.86 (1H, dd, J=8.0, 7.8 Hz), 7.75 (1H, d, J=7.3 Hz), 7.49 (1H, brs), 7.48 (2H, d, J=9.0 Hz), 7.34 (1H, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (1H, ddt, J=17.2, 10.0, 6.5 Hz), 5.04 (1H, d, J=10.0 Hz), 4.94 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+ 501.

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694
[2]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 29-30
[3]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 30-31
[4]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 32
[5]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 31
[6]Patent: WO2013/39854,2013,A1 .Location in patent: Page/Page column 28
[7]Patent: WO2014/62454,2014,A1 .Location in patent: Page/Page column 32
[8]Patent: US2016/8361,2016,A1 .Location in patent: Paragraph 0164

7
[ 955365-80-7 ]
[ 64-17-5 ]
[ 77-92-9 ]
[ 1075739-34-2 ]

Yield	Reaction Conditions	Operation in experiment
	at 20 - 60℃; for 18h;	6 Example 6:Production of citrate (ethanolate) of Compound A49.5 mg of Free base of the compound A suspended in 3.0 ml ethanol and suspension heated to about 600C until clear solution was obtained. To the clear solution was added 0.39 ml of citric acid stock solution (50 mg/ml). About 60% of the solvent evaporated under nitorogen, then suspension stirred at room temperature for about 18 hours. After separation of the solid by filtration the product was dried under vacuum at room temperature for about 60 hours.XRPD patterns:(2 theta(degrees), Intensity(cps)): (6.4°, 142.3), (14.6°, 64.5), (11.6°, 36.2), (13.0°, 45.0), (24.5°, 57.6), (27.4°, 32.0).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 35

8
[ 955365-80-7 ]
[ 110-17-8 ]
[ 1075739-38-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: MK-1775; (2E)-but-2-enedioic acid In tetrahydrofuran; ethanol at 20℃; for 0.0833333 - 0.166667h; Stage #2: In acetonitrile at 20℃; for 20h;	10 Example 10: Production of fumarate (hemihydrate) of Compound A97 mg of Free base of the compound A (-0.19 mmol) was dissolved in 3.0 ml of ethanol / THF 1 :1 (v/v) at ambient temperature and to the clear solution was added 0.765 ml of a solution of fumaric acid in THF (29.5 mg/ml = 0.19 mmol). The addition of this solution was carried out drop-wise under stirring, i.e., within about 5 to 10 minutes. This solution was slowly evaporated under nitrogen, and to the obtained solid residue 3.0 ml of acetonitrile was added and to obtained suspension was stirred at ambient temperature for about 20 hours. Then the suspension was investigated by light microscopy which indicated that a crystalline product was obtained. After separation of the solid by filtration the product was dried under vacuum at 4O0C for about 4 hours. XRPD patterns:(2 theta(degrees), Intensity(cps)): (7.2°, 79.2), (14.5°, 161.2), (6.0°, 46.3), (15.9°, 56.5), (23.5°, 49.4), (26.0°, 35.4).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 36-37

9
[ 955365-80-7 ]
[ 75-75-2 ]
[ 1075739-33-1 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 20 - 60℃; for 18h;	5 Example 5:Production of Methansulfonate of Compound A209 mg of Free base of the compound A suspended in 14.0 ml acetonitrile and suspension heated to about 60°C until clear solution was obtained. Then added 0.8 mL of methanesulfonic acid stock solution (50 mg/ml in acetonitorile). About 60% of the solvent evaporated under nitrogen, then suspension stirred at room temperature for about 18 hours. Filtered and obtained yellowish solid dried under vacuum at 500C for about 60 hours. XRPD patterns:(2 theta(degrees), Intensity(cps)): (8.0°, 48.2), (18.1°, 90.7), (12.7°, 65.5), (13.2°, 65.6), (27.0°, 57.5), (29.0°, 30.0). DSC:When DSC of Methanesulfonate was measured using a Perkin-elmer DSC 7 series, the extrapolated melting temperature onset of Methanesulfonate was 230°C with an enthalpy of fusion of 106 J/g at 5 °C/min under nitrogen in crimped pan. The peak melting temperature was 231°C.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 35

10
[ 955365-80-7 ]
[ 110-15-6 ]
[ 1075739-44-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: MK-1775; succinic acid In tetrahydrofuran; ethanol at 20℃; for 0.0833333 - 0.166667h; Stage #2: In acetonitrile at 20℃; for 22h;	16 Example 16:Production of succinate of Compound A107 mg of Free base of the compound A (-0.21 mmol) was dissolved in 3.0 ml of THF/ethanol 1 :1 at ambient temperature, and to the clear solution was added 0.574 ml of succinic acid solution in THF (44 mg/ml = 0.16 mmol). The addition of this solution is carried out drop-wise under stirring, i.e., within about 5 to 10 minutes. This solution was slowly evaporated under a weak nitrogen flow at ambient temperature. To the obtained solid residue 1.0 ml of acetonitrile was added and the resulting suspension was stirred at ambient temperature for about 22 hours. XRPD patterns:(2 theta(degrees), Intensity(cps)): (5.3°, 174.1), (22.0°, 93.7), (13.0°, 61.4), (14.5°, 73.4), (17.9°, 66.0), (25.3°, 98.3).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 39

11
[ 955365-80-7 ]
[ 1075739-30-8 ]

Yield	Reaction Conditions	Operation in experiment
	With water at 20℃; for 24h;	3 Example 3:Production of Form C (sesterhvdrate) of Compound A5 mg of Form A crystalline of Compound A was added to 1 ml of water. Using TAITEC Deep-well-maximizer, the mixture was mixed at room temperature for 24 hours. The mixture was centrifuged at 14,000 rpm for 10 minutes, and then the supernatant was removed. The residual solid was dried at room temperature for 5 days. XRPD patterns:(2 theta(degrees), Intensity(cps)): (5.8°, 137), (11.2°, 58.6), (11.6°, 65.8), (18.2°, 41.1), (5.2°, 32.2), (13.8°, 36.6), (23.4°, 28.0).Thermogravimetric and Differential Thermal Analyses (TG-DTA): When TG-DTA of Form C was measured using a BRUKER axu TG-DTA 2000S A, the extrapolated melting temperature onset of Form C was 128°C at 10 °C/min heating under helium purge in open aluminum pan. The peak melting temperature was 131°C. Before melting, weight loss with dehydration was observed at -1250C.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 34

12
[ 955365-80-7 ]
[ 1075739-32-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In methanol; ethanol at 20 - 50℃;	4 Example 4:Production of Hydrochloride of Compound A200 mg of Free base of the compound A was dissolved in 10 mL of methanol at 50 °C. 0.24 mL of 2 mol/L HCl in ethanol was added to the resulting solution while keeping the temperature at 50 °C. Then the slurry was cooled to ambient temperature and aged for overnight. The solid was collected by filtration, washed with methanol and dried in vacuo at 40 °C for 3 hrs to obtain 191 mg of the title hydrochloric acid salt as a crystal. XRPD patterns:(2 theta(degrees), Intensity(cps)): (10.6°, 49.3), (16.7°, 45.7), (9.2°, 41.3), (9.9°, 40.2), (16.2°, 15.9), (18.3°, 41.6). DSC:When DSC of Hydrochloride was measured using a TA Instruments DSC QlOOO instrument, the extrapolated melting temperature onset of Hydrochloride was 293°C with an enthalpy of fusion of 219 J/g at 10 °C/min under nitrogen in crimped aluminum pan. The peak melting temperature was 295°C.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 34

13
[ 955365-80-7 ]
[ 1075739-35-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid In water; acetonitrile at 60℃; for 18h;	7 Example 7:Production of sulfate of Compound A100.4 mg of Free base of the compound A was dissolved in 8.0 ml acetonitrile at about 6O0C and to the clear solution was added 0.100 ml of IM sulfuric acid. Obtained suspension stirred (open cap) for about 18 hours (about 60% of the solvent evaporated). After separation of the solid by filtration the product was dried under vacuum at room temperature for about 60 hours. XRPD patterns:(2 theta(degrees), Intensity(cps)): (8.3°, 74.3), (16.7°, 96.6), (4.1°, 67.2), (12.5°, 64.5), (15.7°,62.9), (23.0°, 63.6).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 35-36

14
[ 955365-80-7 ]
[ 1075739-39-7 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid In tetrahydrofuran; water; acetonitrile at 20℃; for 72.0833 - 72.1667h;	11 Example 11 :Production of phosphate of Compound A104 mg of Free base of the compound A (-0.21 mmol) was dissolved in 4.0 ml of acetonitrile / THF 3:l(v/v) at about 5O0C and to the clear solution was added 0.414 ml of 0.5M aqueous phosphoric acid. The addition of this solution was carried out drop-wise under stirring, i.e., within about 5 to 10 minutes. A fine yellowish suspension was obtained, which was stirred at ambient temperature for about three days. Then the suspension was investigated by light microscopy which indicated that a crystalline product was obtained. After separation of the solid by filtration the product was dried under vacuum at 4O0C for about lhours. 105 mg of the titled phosphate was obtained as a crystal. XRPD patterns:(2 theta(degrees), Intensity(cps)): (9.9°, 81.7), (15.5°, 114.5), (7.5°, 50.6), (11.2°, 61.8), (18.6°, 80.7), (22.8°, 77.5).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 37

15
[ 955365-80-7 ]
[ 1075739-40-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide In ethanol; water; ethyl acetate at 20℃; for 24h;	12 Example 12:Production of hvdrobromide of Compound A100 mg of Free base of the compound A (-0.21 mmol) was dissolved in 4.0 ml of ethanol / ethyl acetate 1 :l(v/v) at about 4O0C and to the clear solution was added 0.400 ml of 0.5M aqueous hydrobromic acid. A fine yellowish suspension was obtained, which was stirred at ambient temperature for about one day. Then the suspension was investigated by light microscopy which indicated that a crystalline product is obtained. After separation of the solid by filtration the product was dried under vacuum at 4O0C for about 16 hours. About 98 mg of the titled hydrobromide was obtained as a crystal. XRPD patterns:(2 theta(degrees), Intensity(cps)): (10.5°, 99.2), (18.1°, 72.0), (16.0°, 48.8), (16.6°, 50.2), (23.8°,68.8), (28.2°, 61.8).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 37-38

16
[ 955365-80-7 ]
[ 98-11-3 ]
[ 1075739-36-4 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; acetonitrile at 20 - 50℃; for 24.0833 - 24.1667h;	8 Example 8:Production of benzenesulfonate (sesquihvdrate) of Compound A101 mg of Free base of the compound A (-0.2 mmol) was dissolved in 4.0 ml of acetonitrile/THF 3:1 (v/v) at about 40 to 5O0C and to the clear solution was added 31.82 mg of benzenesulfonic acid (-0.2 mmol) dissolved in 1.0 ml acetonitrile. The addition of this solution was carried out drop-wise under stirring, i.e., within about 5 to 10 minutes. The yellowish solution was cooled to ambient temperature and stirred in an open reaction tube at room temperature for about one day until most of the THF and part of the acetonitrile were evaporated. Then the suspension investigated by light microscopy which indicated that a crystalline product was obtained. After separation of the solid by filtration the product was dried under vacuum at 4O0C for about 16 hours. 88 mg of the titled benzenesulfonate (sesquihydrate) was obtained as a crystal.XRPD patterns:(2 theta(degrees), Intensity(cps)): (6.7°, 49.0), (12.8°, 64.8), (9.6°, 34.4), (15.1°, 40.4), (19.2°, 44.6), (20.7°, 35.3).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/133866, 2008, A1 Location in patent: Page/Page column 36

17
[ 638218-78-7 ]
[ 955365-80-7 ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

18
[ 26218-75-7 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: diethyl ether / 0.08 h / 20 °C / Inert atmosphere 2.1: potassium carbonate; N,N`-dimethylethylenediamine; copper(l) iodide / 1,4-dioxane / 18 h / 80 - 95 °C 3.1: 3-chloro-benzenecarboperoxoic acid / toluene / 1 h / 20 °C 3.2: 18 h / 20 °C
	Multi-step reaction with 3 steps 1: diethyl ether / Inert atmosphere 2: copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine / 1,4-dioxane / 95 °C 3: 3-chloro-benzenecarboperoxoic acid / toluene / 0.33 h

Yield	Reaction Conditions	Operation in experiment
	Stage #1: With 3-chloro-benzenecarboperoxoic acid In toluene at 20℃; for 1h; Stage #2: With N-ethyl-N,N-diisopropylamine In toluene at 20℃; for 18h;	5 General method for the preparation of aniline pyridyl pyrazolopyrimidinones (1 1a-n). General procedure: mCPBA (0.34 mmol) was added to a solution of pyrazolopyrimidinones 9a-c (0.31 mmol) in toluene (5 ml) and the resulting mixture was stirred at RT for 1 h. DIPEA (1.63 mmol) and the relevant substituted aniline 10a-e (0.40 mmol) were added, and the reaction mixture was stirred at RT for 18 h. Saturated NaHC03 solution (15 ml) was added, and the mixture was extracted with EtOAc (2 x 15 ml). The combined organic extracts were washed with brine (10 ml), dried (MgS04) and concentrated in vacuo. The resultant residue was purified via chromatography on silica (19:1 DCM:MeOH) to give the target compound as a yellow solid (55-72%). 2-Allyl-6-((4-(dimethylamino)phenyl)amino)-1 -(6-(2-hydroxypropan-2-yl)pyridin-2- yl)-1,2-dihydro-3Hpyrazolo[ 3,4-d]pyrimidin-3-one (11a). Rf 0.37 (19:1 DCM:MeOH), M.p. 173-175 °C; IR (cm-1) 3325, 3245, 3172, 3056, 2964, 2922, 2357, 1669, 161 1, 1568, 1542, 1516; 1 H NMR (400 MHz, DMSO-d6) 1.47 (6H, s, C(CH3)2), 2.88 (6H, s, N(CH3)2), 4.68 (2H, dapp, J = 6.0 Hz, N2-CH2), 4.83 (1 H, dapp, J = 17.2 Hz, allyl CHtrans), 5.00 (1 H, dapp, J = 10.1 Hz, allyl C-Hcis), 5.32 (1 H, s, OH), 5.67 (1 H, ddW = 17.2, 10.1, 6.0 Hz, allyl C- H), 6.73 (2H, d, J = 8.6 Hz, H-3"/5"), 7.49-7.57 (1 H, m, H-5'), 7.60 (2H, d, J = 8.6 Hz, H- 2"/6"), 7.76 (1 H, dapp, J = 7.3 Hz, H-5'), 8.03 (1 H, dd, J = 7.6, 7.5 Hz, H-4'), 8.81 (1 H, s, H- 4), 10.08 (1 H, br, C6-NH); 13C NMR (125 MHz, DMSO-d6) 30.9 (C(CH3)2), 41.0 (N(CH3)2), 47.1 (N2-CH2), 72.8 (C(CH3)2), 1 13.0, 1 16.0, 1 16.7, 1 18.7, 122.1, 129.0, 132.7, 139.2, 147.5, 168.0; MS [M + H] + m/z 446.3.

20
[ 955368-90-8 ]
[ 955365-80-7 ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

21
[ 955365-80-7 ]
[ 2244891-32-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With methanol; tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium 4-methylbenzenesulfinate In tetrahydrofuran at 20℃; for 2h;
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium 4-methylbenzenesulfinate In tetrahydrofuran; methanol at 20℃; for 2h;	7 (0311) Synthesis of 1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (CM-235). (0312) Sodium para-toluenesulfinate tetrahydrate (25 mg, 0.10 mmol) in MeOH (0.5 mL) was added to a solution of 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (AZD-1775, 50 mg, 0.10 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) in THF (1 mL). The reaction mixture was stirred at RT for 2 hr before EtOAc (5 mL) was added and the resultant off-white precipitate was collected by filtration (36 mg, 0.08 mmol, 80%). Rf 0.21 (1 :1 DCM:MeOH); M.p. > 350 °C; IR (cm 1) 3248, 3168, 2974, 2936, 2791, 1612, 1535; 1H NMR (400 MHz, DMSO-d6) 1.52 (6H, s, C(CH3)2), 2.23 (3H, s, N-CH3), 2.45-2.49 (4H, m, N-(CH2CH2)2-NMe), 3.05-3.09 (4H, m, N-CH2CH2-NMe), 5.83 (1H, s, OH), 6.91 (2H, d , J = 9.1Hz, H-3"/5"), 7.19 (1H, dapp, J = 7.5 Hz, H-5'), 7.69 (2H, d, J = 9.1Hz, H- 276"), 7.80 (1H, dd , J = 7.9, 7.5 Hz, H-4'), 8.13 (1H, dapp, 7 = 7.9 Hz, H-3'), 8.45 (1H, s, H-4), 9.23 (1H, s, C6-NH); 13C NMR (100 MHz, DMSO-d6) 31.2 (C(CH3)2), 46.3 (N-CH3), 49.5 (piperazine-CH2), 55.2 (piperazine-CH2), 72.3 (C(CH3)2), 1 16.4, 120.5, 133.5, 138.6, 146.4, 150.5, 152.5, 159.1, 166.4; MS [M + H]+ m/z 461.2.
1.2 %	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; ammonium formate In tetrahydrofuran Reflux; Inert atmosphere;

Reference： [1]Matheson, Christopher J.; Casalvieri, Kimberly A.; Backos, Donald S.; Reigan, Philip [ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694]
[2]Current Patent Assignee: UNIVERSITY OF COLORADO (SYSTEM) - WO2019/169065, 2019, A2 Location in patent: Page/Page column 61
[3]Guler, Satenig; DiPoto, Maria C.; Crespo, Alejandro; Caldwell, Richard; Doerfel, Benjamin; Grossmann, Nina; Ho, Kevin; Huck, Bayard; Jones, Christopher CV; Lan, Ruoxi; Musil, Djordje; Potnick, Justin; Schilke, Heike; Sherer, Brian; Simon, Stephanie; Sirrenberg, Christian; Zhang, Zhuo; Liu-Bujalski, Lesley [ACS Medicinal Chemistry Letters, 2023, vol. 14, # 5, p. 566 - 576]

22
[ 5909-24-0 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrazine / 0.08 h / 20 °C / Microwave irradiation 2.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C 4.1: 3-chloro-benzenecarboperoxoic acid / toluene / 1 h / 20 °C 4.2: 18 h / 20 °C

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN113880844, 2022, A

23
[ 100047-42-5 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C 3.1: 3-chloro-benzenecarboperoxoic acid / toluene / 1 h / 20 °C 3.2: 18 h / 20 °C

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN113880844, 2022, A

24
[ 34750-24-8 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 0.08 h / 20 °C / Microwave irradiation 2: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C 3: trimethylsilyl bromide / dichloromethane / 4 h / Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 1 h / 60 °C

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN113735863, 2021, A

25
[ 2756445-07-3 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C 2: trimethylsilyl bromide / dichloromethane / 4 h / Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 1 h / 60 °C

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN113735863, 2021, A

26
[ 2244889-51-6 ]
[ 197502-55-9 ]
[ 955365-80-7 ]

Yield	Reaction Conditions	Operation in experiment
87.9%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1h;	14-17 Example 14 Synthesis of compound Adavosertib shown in formula I At room temperature, the compound of formula 7 (32.6 g, 0.1 mol) and K2CO3 (15.9 g, 0.115 mol) were added to stirring DMF (200 mL), and then the compound of formula 8 (22.1 g, 0.105 mol) was added, The mixture was heated to 60°C and stirred for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (40 mL). The mixture was extracted with ethyl acetate (3×40 mL). The organic phases were combined and saturated brine (30 mL) was added. After washing, drying over sodium sulfate, filtering, after the filtrate was concentrated, the mixed solvent of dichloromethane/methanol with a volume ratio of 20:1 was used to carry out silica gel column chromatography purification to obtain compound Adavosertib shown in formula I, solid yield 44.0g, yield 87.9%, HPLC purity 99.5%.

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN113735863, 2021, A Location in patent: Paragraph 0081-0090

27
[ 955365-80-7 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine; dmap / tetrahydrofuran / 20 °C 2: ammonium formate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / tetrahydrofuran / Reflux; Inert atmosphere 3: tetramethylethylenediamine; copper(l) iodide; caesium carbonate / 1,4-dioxane / 6 h / 20 - 95 °C / Inert atmosphere; Sealed tube

Reference： [1]Guler, Satenig; DiPoto, Maria C.; Crespo, Alejandro; Caldwell, Richard; Doerfel, Benjamin; Grossmann, Nina; Ho, Kevin; Huck, Bayard; Jones, Christopher CV; Lan, Ruoxi; Musil, Djordje; Potnick, Justin; Schilke, Heike; Sherer, Brian; Simon, Stephanie; Sirrenberg, Christian; Zhang, Zhuo; Liu-Bujalski, Lesley [ACS Medicinal Chemistry Letters, 2023, vol. 14, # 5, p. 566 - 576]

28
[ 955365-80-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine; dmap / tetrahydrofuran / 20 °C 2.1: ammonium formate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / tetrahydrofuran / Reflux; Inert atmosphere 3.1: tetramethylethylenediamine; copper(l) iodide; caesium carbonate / 1,4-dioxane / 6 h / 20 - 95 °C / Inert atmosphere; Sealed tube 3.2: 2 h / 20 °C / Inert atmosphere

29
[ 955365-80-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
89.6 %	With Pd/C; ammonium formate In methanol Inert atmosphere; Reflux;

30
[ 955365-80-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine; dmap / tetrahydrofuran / 20 °C 2: ammonium formate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / tetrahydrofuran / Reflux; Inert atmosphere

31
[ 955365-80-7 ]
[ 24424-99-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
78.6 %	With dmap; triethylamine In tetrahydrofuran at 20℃;

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P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 955365-80-7 ] {[proInfo.proName]}

Quality Control of [ 955365-80-7 ]

Related Doc. of [ 955365-80-7 ]

Product Details of [ 955365-80-7 ]

Safety of [ 955365-80-7 ]

Application In Synthesis of [ 955365-80-7 ]

[ 955365-80-7 ] Synthesis Path-Upstream 1~5

[ 955365-80-7 ] Synthesis Path-Downstream 1~31

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry