4876-59-9|4-(Dimethylamino)piperidine dihydrochloride| Ambeed

Structure of 4876-59-9

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Quality Control of [ 4876-59-9 ] Purity: 97% SDS Specification

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Product Details of [ 4876-59-9 ]

CAS No. :	4876-59-9
Formula :	C₇H₁₈Cl₂N₂
M.W :	201.14
SMILES Code :	CN(C1CCNCC1)C.[H]Cl.[H]Cl
MDL No. :	MFCD00035296
InChI Key :	XCJNSBCFLUPJAP-UHFFFAOYSA-N
Pubchem ID :	22591440

Safety of [ 4876-59-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 4876-59-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	0
Fraction Csp3	1.0
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	57.19
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	15.27 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.99
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.52
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.22
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.61
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.07

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.27
Solubility	1.07 mg/ml ; 0.00531 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.94
Solubility	2.33 mg/ml ; 0.0116 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.16
Solubility	13.9 mg/ml ; 0.069 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.11 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.3

Application In Synthesis of [ 4876-59-9 ]

* 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.

Downstream synthetic route of [ 4876-59-9 ]

[ 4876-59-9 ] Synthesis Path-Downstream 1~35

1
[ 4876-59-9 ]
C₃₇H₃₈N₂O₇S [ No CAS ]
N-[2-[4-(4-dimethylaminopiperidino)-4-oxobutoxy]-4-[(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-yl)carbonyl]phenyl]-(1,1'-biphenyl)-2-carboxamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 101 - 109.

2
[ 928038-09-9 ]
[ 4876-59-9 ]
N-(4-[2-([4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.5%	With triethylamine; In diethyl ether; hexane; water; N,N-dimethyl-formamide; at 20℃; for 10h;	(Example 18) N-(4-{(2-([4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide To a solution of phenyl N-[4-(3-fluoro-4-[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added <strong>[4876-59-9]N,N-dimethyl-N-(piperidin-4-yl)amine dihydrochloride</strong> (79.4 mg), triethylamine (0.157 ml) and water (0.10 ml), followed by stirring at room temperature for 10 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol = 20:1, then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane = 1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (30.6 mg, 70.5 %). 1H-NNM Spectrum (CDCl3) delta (ppm): 1.43-1.53 (2H, m), 1.66-1.77 (4H, m), 1.89 (2H, m), 2.30 (6H, m), 2.37 (1H, m), 2.91 (2H, m), 4.11 (2H, m), 6.56 (1H, dd, J = 2.0, 5.6 Hz), 6.91-6.95 (2H, m), 7.05 (2H, m), 7.30 (1H, s), 7.51 (2H, dd, J = 4.8, 9.2 Hz), 7.64 (1H, d, J = 2.0 Hz), 8.08 (1H, d, J = 5.6 Hz), 8.19 (1H, m), 8.89 (1H, s), 9.24 (1H, s). ESI-MS (m/z): 579 [M+H]+, 601 [M+Na]+.

References: [1]Patent: EP1889836,2008,A1 .Location in patent: Page/Page column 60; 61.

3
[ 928038-12-4 ]
[ 4876-59-9 ]
N-(4-[2-([4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In N,N-dimethyl-formamide; at 20℃;	(Example 23) N-(4-[2-([4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide To a solution of [4-(2-fluoro-4-[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-dimethylaminopiperidine dihydrochloride (80.5 mg) and triethylamine (0.112 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol = 98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane = 1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (52.1 mg, 90 %). 1H-NMR Spectrum (CDCl3) delta (ppm): 1.40-1.76 (6H, m), 1.80-1.90 (2H, m), 2.28 (6H, s), 2.35 (1H, m), 2.89 (2H, m), 4.02-4.12 (2H, m), 6.55 (1H, dd, J = 2.4, 5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H, m), 7.57 (1H, d, J = 2.4 Hz), 7.69 (1H, dd, J = 2.4, 12.0 Hz), 8.05 (1H, d, J = 5.6 Hz), 8.54 (1H, brs), 9.52 (1H, brs). ESI-MS (m/z): 579 [M+H]+.

References: [1]Patent: EP1889836,2008,A1 .Location in patent: Page/Page column 62.

4
[ 928038-49-7 ]
[ 4876-59-9 ]
N-(4-[4-([4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		(Example 102) N-(4-[4-([4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg) was dissolved in tetrahydrofuran (5 ml) under a nitrogen atmosphere, N,N-diisopropylethylamine (0.100 ml) and phenyl chloroformate (0.070 ml) were added dropwise at room temperature, followed by stirring for 15 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2.5 ml). To the solution were added 4-dimethylaminopiperidine dihydrochloride (250 mg) and triethylamine (0.400 ml) at room temperature, followed by stirring for 25 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide and brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol = 95:5), and fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane = 1:2 to precipitate a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (100.3 mg, 74 %). 1H-NMR Spectrum (CDCl3) delta (ppm): 1.46-1.56 (2H, m), 1.66-1.76 (4H, m), 1.86-1.96 (2H, m), 2.31 (6H, s), 2.38 (1H, m), 2.97 (2H, m), 4.06-4.16 (2H, m), 7.00-7.10 (3H, m), 7.39 (1H, brs), 7.44-7.54 (2H, m), 7.63 (1H, s), 8.27 (1H, dd, J = 7.2, 12.0 Hz), 8.34 (1H, s), 8.68 (1H, brs), 9.47 (1H, brs). ESI-MS (m/z): 598 [M+H]+.

References: [1]Patent: EP1889836,2008,A1 .Location in patent: Page/Page column 101.

5
[ 928038-40-8 ]
[ 4876-59-9 ]
N-(4-[2-([4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		(Example 103) N-(4-[2-([4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-25-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogen atmosphere, triethylamine (0.0631 ml) and phenyl chloroformate (0.0624 ml) were added dropwise at 0 C, followed by stirring for 20 min. The reaction mixture was stirred after addition of ethyl acetate (5 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtrated. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3.0 ml). 4-dimethylaminopiperidine dihydrochloride (227 mg) and triethylamine (0.631 ml) were added at room temperature under a nitrogen atmosphere, followed by stirring for 18 hr and 30 min. The reaction mixture was partitioned between ethyl acetate (10 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with water (10 ml, twice) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol = 10: 1), and fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white powder (107.5 mg, 78 %). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 1.20-1.30 (4H, m), 1.55-1.74 (6H, m), 2.15 (6H, s), 2.71-2.80 (1H, s), 4.06-4.12 (2H, m), 6.63 (1H, dd, J = 2.4, 5.6 Hz), 7.15-7.2 (2H, m), 7.39-7.41 (1H, m), 7.51-7.63 (3H, m), 8,05-8,1(1H, m), 8.13 (1H, d, J = 5.6 Hz), 9.23-9.26 (1H, m), 9.78-9.85 (1H, m), 10.98-11.01 (1H, m). ESI-MS (m/z): 597 [M+H]+.

References: [1]Patent: EP1889836,2008,A1 .Location in patent: Page/Page column 101; 102.

6
[ 4876-59-9 ]
[ 350-46-9 ]
[ 211247-60-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃;	To a stirred solution of 135 1-fluoro-4-nitrobenzene (1 g, 7.08 mmol, 1.0 eq) in 95 DMSO (10 mL); 758 N,N-dimethylpiperidin-4-amine (1.56 g, 7.7 mmol, 2.5 eq) and 27 DIPEA (4.93 mL, 28.3 mmol) were added under stirring and resulting mixture was heated at 100 C. The progress of the reaction was monitored by LCMS. After completion reaction was cooled and quenched with ice cold water. The resulting solid precipitate was filtered, dried to afford 759 N,N-dimethyl-1-(4-nitrophenyl)piperidin-4-amine (1.6 g, 90%) as yellow solid. (0752) LCMS: 250 [M+1]+
77%	With N-ethyl-N,N-diisopropylamine; at 95℃; for 18h;Inert atmosphere;	Step 1: A mixture of l-fluoro-4-nitrobenzene (3.00 g, 21.3 mmol), N,N-dimethylpiperidin-4- amine dihydrochloride (4.70 g, 23.4 mmol) and DIPEA (15 mL, 86.1 mmol) was stirred at 95 C for 18 h. The mixture was cooled to room temperature, diluted with 1 : 1 EtOAc/hexanes (100 mL), washed twice with aq. calcium gluconate (100 mL each, 50% saturation), and the organic layer was separated and dried over anhydrous Na2S04 and concentrated to yield the desired product as a red oil (4.1 g, 77% yield). 1H NMR (DMSO-d6, 400 MHz) delta 8.03 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 9.6 Hz, 1H), 4.04-4.01 (m, 2H), 3.02-2.95 (m, 2H), 2.39-2.32 (m, 1H), 2.17 (s, 6H), 1.85-1.81 (m, 2H), 1.44-1.34 (m, 2H); MS (ESI): calcd for C13H19N302: 249, found: 250 (MH+).
50%	With triethylamine; In methanol; at 90℃; for 3.5h;	Dimethyl-piperidin-4-yl-amine dihydrochloride (Aldrich, 2.0 g, 9.95 mmol) and 4-fluoro-nitrobenzene (Aldrich, 2.5 g, 17.7 mmol) were added to methanol (30 mL). The mixture was heated to 90 C. and stirred for 3.5 hours. The mixture was treated with 1 N HCl to pH=1 and then extracted with diethyl ether (210 mL). The aqueous layer was treated with saturated sodium carbonate to pH=10 and then extracted with methylene chloride (220 mL). The organic layer was dried with sodium sulfate and the solvent was removed to give the desired product. 1.25 g, 50%. MS (m+H)+: 250.

References: [1]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0750-0752.
[2]Patent: WO2016/138527,2016,A1 .Location in patent: Page/Page column 63; 64.
[3]Patent: US2005/239843,2005,A1 .Location in patent: Page/Page column 14.

7
[ 864245-68-1 ]
[ 4876-59-9 ]
[ 864246-06-0 ]

Yield	Reaction Conditions	Operation in experiment
68.1%		After adding triethylamine (0.0814 ml) and phenyl chloroformate (0.0641 ml) to a solution of benzyl [4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]carbamate (103 mg) in tetrahydrofuran (5.0 ml) at room temperature, the mixture was stirred for 15 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and then N,N-dimethylformamide (3.0 ml), triethylamine (1.0 ml) and 4-dimethylaminopiperidine dihydrochloride (235 mg) were added thereto and the mixture was stirred at room temperature. The reaction mixture was partitioned between 1N aqueous sodium hydroxide (50 ml) and ethyl acetate (100 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated to provide the title compound (101 mg, 68.1%) as a pale yellow oil. 1H-NMR Spectrum (CDCl3) delta (ppm): 1.27-1.55 (2H, m), 1.86 (2H, m), 2.27 (6H, s), 2.34 (1H, m), 2.87 (2H, m), 4.09-4.15 (2H, m), 5.22 (2H, s), 6.51 (1H, dd, J=2.0, 5.6 Hz), 6.85-6.93 (3H, m), 7.06 (1H, brs), 7.33-7.41 (4H, m), 7.51 (1H, brs), 7.63 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=5.6 Hz), 8.11 (1H, m). ESI-MS (m/z): 508[M+H]+, 530[M+Na]+.

References: [1]Patent: US2005/277652,2005,A1 .Location in patent: Page/Page column 121.

8
[ 4876-56-6 ]
[ 4876-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In water; isopropyl alcohol; at 20℃; for 22h;	After adding 10% palladium-carbon (2.0 g) to a solution of the crude 4-dimethylamino-1-benzylpiperidine dihydrochloride (30.0 g) in 2-propanol (300 ml)-water (300 ml), the mixture was stirred for 22 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and washed with 2-propanol. The filtrate was then concentrated. The obtained crystals were suspended in ethanol (50 ml). They were then diluted with diethyl ether (50 ml). The crystals were subsequently filtered and washed with methanol (10 ml). They were then subjected to aeration drying to provide the title compound (16.4 g) as colorless crystals. 1H-NMR Spectrum (CD3OD) delta (ppm): 1.94-2.05 (2H, m), 2.35 (2H, m), 2.89 (6H, s), 3.06-3.16 (2H, m), 3.52-3.62 (3H, m).
	With hydrogen;palladium 10% on activated carbon; In methanol; for 48h;	To l-benzyl-N,N-dimethylpiperidin-4-amine dihydrochloride (6.7 g, 23 mmol) was added Pd/C (10%, 2.4 g) under argon. Methanol (100 ml) was added via syringe, and H2 gas was introduced and the mixture stirred vigorously under an atmosphere of H2. After 48 h, the mixture was flushed with nitrogen, filtered through celite and concentrated to afford a mixture of starting material and N,N-dimethylpiperidin-4-amine dihydrochloride as a white solid. This solid was treated with l-Fluoro-2-nitro-4- trifluoromethyl-benzene (3.2 ml, 22.9 mmol), triethylamine (12.7 ml, 92 mmol), and 50 ml dry THF. The mixture was heated to 75 0C with a water-cooled reflux condenser for 12 h. The mixture was allowed to cool to ambient temperature, was filtered through a fritted funnel, and concentrated to an orange oil. The residue was purified by silica gel chromatography (MC/MeOH/cone. NH4OH) to give the desired product as an orange oil. MS (m/z) : 318.1 (M+H)+. Calc'd for C14H18F3N3O2: 317.31.

References: [1]Patent: US2005/277652,2005,A1 .Location in patent: Page/Page column 121.
[2]Patent: WO2006/44823,2006,A2 .Location in patent: Page/Page column 147-148.

10
[ 367-86-2 ]
[ 4876-59-9 ]
[ 882679-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 75℃; for 12h;	To l-benzyl-<strong>[4876-59-9]N,N-dimethylpiperidin-4-amine dihydrochloride</strong> (6.7 g, 23 mmol) was added Pd/C (10%, 2.4 g) under argon. Methanol (100 ml) was added via syringe, and H2 gas was introduced and the mixture stirred vigorously under an atmosphere of H2. After 48 h, the mixture was flushed with nitrogen, filtered through celite and concentrated to afford a mixture of starting material and <strong>[4876-59-9]N,N-dimethylpiperidin-4-amine dihydrochloride</strong> as a white solid. This solid was treated with l-Fluoro-2-nitro-4- trifluoromethyl-benzene (3.2 ml, 22.9 mmol), triethylamine (12.7 ml, 92 mmol), and 50 ml dry THF. The mixture was heated to 75 0C with a water-cooled reflux condenser for 12 h. The mixture was allowed to cool to ambient temperature, was filtered through a fritted funnel, and concentrated to an orange oil. The residue was purified by silica gel chromatography (MC/MeOH/cone. NH4OH) to give the desired product as an orange oil. MS (m/z) : 318.1 (M+H)+. Calc'd for C14H18F3N3O2: 317.31.

References: [1]Patent: WO2006/44823,2006,A2 .Location in patent: Page/Page column 147-148.

11
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride [ No CAS ]
[ 4876-59-9 ]
[ 59528-74-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In chloroform; water;	EXAMPLE 2 4-Dimethylamino-1-[4-(7-chloro-4-quinolylamino)-benzenesulphonyl]piperidine. 11.3 Grams of 4-(7-chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred mixture of 5.83 grams of 4-dimethylamino-piperidine dihydrochloride and 32 grams of sodium carbonate in 100 milliliters of water and 75 milliliters of chloroform. After stirring overnight at room temperature the mixture was filtered, the resultant solid washed with water, dried and recrystallized from ethanol/water to give 6.28 grams of the title compound. Melting point 230--231C. Analysis found: 59.1% C; 5.70% H; 12.2% N. C22 H25 ClN4 O2 S requires 59.4% C; 5.66% H; 12.6% N.

References: [1]Patent: US3933829,1976,A .

12
[ 50533-97-6 ]
(S)-3-[5-[8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl]2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl]pyrrolidine-1-pentanoic acid [ No CAS ]
[ 4876-59-9 ]
[ 530-62-1 ]
[ 740069-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; triethylamine; In N-methyl-acetamide; methanol; chloroform; water;	5.3. (S)-5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-[5-[4-(dimethyl_amino)piperidin-1-yl]-5-oxopentyl]pyrrolidin-3-yl]-1,3,4-oxadiazol-2-(3H)-one 0.24 g (0.51 mmol) of (S)-3-[5-[7-chloro-8-amino-2,3-dihydro-1,4-benzodioxin-5-yl]2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl]pyrrolidine-1-pentanoic acid dissolved in 2.5 ml of dimethylformamide, and 0.14 ml (1.01 mmol) of triethylamine are introduced into a 25 ml three-necked round-bottomed flask. A solution of 0.16 g (1.01 mmol) of 1,1'-carbonylbis-1H-imidazole in 1.1 ml of dimethylformamide is added dropwise and the mixture is stirred at room temperature for 2 h 30 min. A solution of 0.76 mmol of 4-(dimethylamino)piperidine in 1.8 ml of dimethylformamide (prepared beforehand by heating a suspension of 0.16 g (0.76 mmol) of <strong>[4876-59-9]4-(dimethylamino)piperidine dihydrochloride</strong> in 1.8 ml of dimethylformamide and 0.28 ml (2.02 mmol) of triethylamine at 60 C. for 2 h) is added and the mixture is stirred at room temperature for 18 h. The reaction medium is poured into 30 ml of water and extracted with chloroform. The product is purified by chromatography on silica gel, eluding with a 95/5/0.5 and then 80/20/2 mixture of chloroform, methanol and aqueous ammonia. 0.08 g of product is thus obtained in the form of a sticky paste. [alpha]20D =+26 (c=0.4, CHCl3).

References: [1]Patent: US6248757,2001,B1 .

13
[ 909909-26-8 ]
[ 4876-59-9 ]
1-{2-[(4aR,10bS)-3,4,4a,5,6,10b-hexahydro-1,10-phenanthrolin-1(2H)-ylmethyl]imidazo[1,2-a]pyridin-5-yl}-N,N-dimethyl-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 16h;	To a solution of (4aft,1 ObS)-I -[(5-fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-1 ,2,3,4,4a,5,6,10b-octahydro-1 ,10-phenanthroline (0.030 g, 0.089 mmol) in 2 ml_ of dimethyl sulfoxide was added potassium carbonate (0.12 g, 0.87 mmol) and N1N- dimethyl-4-piperidinamine dihydrochloride (0.066 g, 0.33 mmol). The mixture was heated at 60 9C for 16 hours and then allowed to cool to room temperature. The mixture was quenched with water and extracted 3 times with 10 ml_ of dichloromethane. The combined organic layers were concentrated and the residue purified by silica chromatography eluting with a 0% to 10% gradient of 30% aqueous ammonium hydroxide in acetonitrile to yield 39 mg (98%) of 1-{2-[(4aR,10bS)- 3,4,4a,5,6,10b-hexahydro-1 ,10-phenanthrolin-1 (2/-/)-ylmethyl]imidazo[1 ,2-a]pyridin-5- yl}-Lambda/,Lambda/-dimethyl-4-piperidinamine. 1 H NMR (400 MHz, METHANOL-D4) delta ppm 1.7(m, 7 H), 2.1 (m, 3 H), 2.4 (m, 9 H), 2.8 (m, 3 H), 3.0 (m, 1 H), 3.1 (m, 1 H), 3.5 (m, 2 H), 3.7 (m, 2 H), 4.1 (d, J=15.0 Hz, 1 H), 6.4 (d, J=7.1 Hz, 1 H), 7.2 (m, 2 H), 7.2 (m, 1 H), 7.5 (d, J=7.7 Hz, 1 H), 7.6 (s, 1 H), 8.3 (d, J=4.9 Hz, 1 H); m/z 445 (M+1).

References: [1]Patent: WO2006/96444,2006,A2 .Location in patent: Page/Page column 91.

14
[ 918938-53-1 ]
[ 4876-59-9 ]
5-chloro-6-(4-(dimethylamino)piperidin-1-yl)-N-(4-(2-fluoro-3-(trifluoromethyl)-phenyl)thiazol-2-yl)pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 50℃; for 72h;	To an 8mL reaction vessel was added 5,6-dichloro-N-(4-(2-fluoro-3- (trifluoromethyl)phenyl)thiazol-2-yl)pyridine-3-carboxamide (0.12mmol) as a 0.1 M solution in DMSO. <strong>[4876-59-9]N,N-dimethylpiperidin-4-amine dihydrochloride</strong> (0.24mmol) and DIPEA (0.6mmol) was subsequently added to the reaction vessel. The reaction vessel was sealed under nitrogen and shaken at about 500C for about 3 days. The desired product (35 mg) was isolated by Shimodzu prep. HPLC using a 25 - 100% ACN / buffer gradient; lambda = 230nm (Waters EPO <DP n="54"/>"Symmetry" 30x50mm C8 5mum column; buffer was 0.1% TFA in water). MW = 527.98, yield = 55%, HPLC (min) = 6.48, LC-MS (M+1) = 528.

References: [1]Patent: WO2007/4038,2007,A1 .Location in patent: Page/Page column 52-53.

15
[ 412293-88-0 ]
[ 4876-59-9 ]

Yield	Reaction Conditions	Operation in experiment
85.3%	With hydrogenchloride; In 1,4-dioxane; dichloromethane; water; for 8h;Cooling with ice;	10.0 g of tert-butyl 4-(dimethylamino)piperidine-1-carboxylate (0.044 mol) was dissolved in 60 mL of dichloromethane, placed in an ice bath, and 4 mol/L HCl/dioxane solution(34.5 mL, 0.138 mol) then was added dropwise mix and stir for 8 h. After the reaction is completed, a large amount of white solid precipitates, which is filtered and washed with a small amount of cold dichloromethane.The HCl was removed under the conditions.The final product was 6.4g. The yield was 85.3%.

References: [1]Patent: CN108456183,2018,A .Location in patent: Paragraph 0020; 0101-0103.
[2]Synthetic Communications,2009,vol. 39,p. 273 - 277.

16
[ 4876-59-9 ]
[ 1237519-67-3 ]

References: [1]Patent: US2011/275797,2011,A1 .
[2]Patent: EP2385036,2011,A1 .

17
[ 4876-59-9 ]
2-(5-(4-(dimethylamino)piperidin-1-yl)-2-hydroxybenzamido)-4-phenylbenzoic acid dimethanesulfonate [ No CAS ]

References: [1]Patent: US2011/275797,2011,A1 .
[2]Patent: EP2385036,2011,A1 .

18
[ 1237514-90-7 ]
[ 4876-59-9 ]
[ 1237519-66-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;bis(dibenzylideneacetone)-palladium(0); XPhos; In toluene; for 12.5h;Reflux; Inert atmosphere;	Example 94a; 4-(Dimethylamino)piperidine dihydrochloride (0.11 g), cesium carbonate (0.44 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to a toluene (2.3 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and cesium carbonate (0.13 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 7 hours. The reaction mixture was cooled to room temperature, and tripotassium phosphate (0.29 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and water and chloroform were added thereto. The insoluble substance was removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.13 g of tert-butyl 2-(2-(benzyloxy)-5-(4-(dimethylamino)piperidin-1-yl)benzamido)-4-phenylbenzoate.
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); palladium diacetate; XPhos; In toluene; for 12.5h;Reflux; Inert atmosphere;	Example 94a [Show Image] 4-(Dimethylamino)piperidine dihydrochloride (0.11 g), cesium carbonate (0.44 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to a toluene (2.3 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and cesium carbonate (0.13 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 7 hours. The reaction mixture was cooled to room temperature, and tripotassium phosphate (0.29 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and water and chloroform were added thereto. The insoluble substance was removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.13 g of tert-butyl 2-(2-(benzyloxy)-5-(4-(dimethylamino)piperidin-1-yl)benzamido)-4-phenylbenzoate.

References: [1]Patent: US2011/275797,2011,A1 .Location in patent: Page/Page column 97-98.
[2]Patent: EP2385036,2011,A1 .Location in patent: Page/Page column 118-119.

19
prop-1-en-2-yl (4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate [ No CAS ]
[ 4876-59-9 ]
4-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With 1-Methylpyrrolidine; In 1,4-dioxane; at 80℃;	Example 76 A mixture of Example C2 (0.42 g, 1.02 mmol), <strong>[4876-59-9]4-(dimethylamino)piperidine dihydrochloride</strong> (0.204 g, 1.02 mmol) and N-methylpyrrolidine (0.182 g, 2.13 mmol) in dioxane (5 mL) was heated at 80 C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The resultant material was dissolved in MeCN/H2O, frozen and lyophilized to afford 4-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-1-carboxamide as a yellowish solid (64 mg, 13%). 1H NMR (400 MHz, DMSO-d6): delta 11.17 (s, 1H), 10.40 (s, 1H), 9.23 (s, 1H), 8.18 (d, J=2.9 Hz, 1H), 8.07 (d, J=5.7 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.66 (dd, J=9.0, 2.9 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 6.56 (dd, J=5.7, 2.4 Hz, 1H), 4.13-4.01 (m, 2H), 3.37-3.11 (br s, 1H), 2.74-2.62 (m, 2 H), 2.28 (s, 6H), 1.76-1.70 (m, 2H), 1.29-1.24 (m, 2H), 1.16 (s, 9H); MS (ESI) m/z: 484.3 (M+H+).

References: [1]Patent: US2014/275016,2014,A1 .Location in patent: Paragraph 0374.

20
[ 4876-59-9 ]
[ 211247-62-0 ]

References: [1]Patent: WO2016/138527,2016,A1 .
[2]Patent: US2019/106436,2019,A1 .

21
[ 4876-59-9 ]
C₂₇H₂₈FN₇O [ No CAS ]

References: [1]Patent: WO2016/138527,2016,A1 .

22
4-bromo-6-(bromomethyl)isoquinoline [ No CAS ]
[ 4876-59-9 ]
1-[(4-bromo-6-isoquinolyl)methyl]-N,N-dimethyl-piperidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 2h;	A mixture of 200mg (0.66 mmol) of 4-bromo-6-(bromomethyl)isoquinoline (CAS 98331-27-2), 130 mg (0.66 mmol) of <strong>[4876-59-9]N,N-dimethylpiperidin-4-amine dihydrochloride</strong> (CAS 4876-59-9) and 320 mg (0.99 mmol) of K2C03 in 8 mL of DMF was stirred at 25C for 2 h. The mixture was used directly in the nextstep.MS (ESI+): 348.0/350.0 [M+H].

References: [1]Patent: WO2016/128465,2016,A1 .Location in patent: Page/Page column 56; 57.

23
[ 4876-59-9 ]
[ 122-04-3 ]
[ 1251838-36-4 ]

Yield	Reaction Conditions	Operation in experiment
36.3%	In toluene; at 20℃; for 18h;	3.5 g of 4-nitrobenzoyl chloride (0.019 mol) and 3.58 g of N,N-dimethylpiperidin-4-amine hydrochloride (17.8 mmol) were dissolved in 35 mL of toluene and stirred at room temperature for 18 h.After the reaction is complete,A total of 2.0 g of the solid product was filtered.The yield was 36.3%.

References: [1]Patent: CN108456183,2018,A .Location in patent: Paragraph 0020; 0105-0107.

24
[ 454-16-0 ]
[ 4876-59-9 ]
1-(2-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.15%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;	To a stirred solution of 538 1-fluoro-2-methoxy-4-nitrobenzene (1.0 g, 5.843 mmol, 1.0 eq) and 922 <strong>[4876-59-9]N,N-dimethylpiperidin-4-amine dihydrochloride</strong> (1.40 g, 7.012 mmol, 1.2 eq) in 47 DMF (10 mL) was added 64 potassium carbonate (2.42 g, 17.529 mmol, 2.0 eq) at rt. The resulting mixture was stirred at 90 C. for overnight. The progress of reaction was monitored by LCMS. The reaction mixture was poured into ice cold 7 water (100 mL), extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL), with brine (50 mL) dried over Na2SO4 and concentrated under reduced pressure to afford mixture of desired 923 compound 1-(2-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine (1.6 g, 98.15%) as yellow viscous. (0890) LCMS: 280.2 [M+1]+
75.9%	With potassium carbonate; In acetonitrile; at 70℃; for 3h;Inert atmosphere;	Add compound 1a to a 50 mL single-mouth flask equipped with magnetic stirring in sequence(887 mg, 4.72 mmol) and acetonitrile(20 mL), stirred and dissolved, and added the dihydrochloride salt of compound 2a (1.1 g, 5.66 mmol)And potassium carbonate (2.2 g, 15.57 mmol),The reaction mixture was heated to 70 C under a nitrogen atmosphere and stirred for 3 hours while stirring.After cooling to room temperature, the solvent was evaporated under reduced pressure, and water (60 mL)Filtered, washed with water (10 mL), dried to give the yellow solid1.0g,Yield75.9%.

References: [1]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0888-0890.
[2]Patent: CN109851638,2019,A .Location in patent: Paragraph 0293-0298.

25
[ 4876-59-9 ]
1-(4-amino-2-methoxyphenyl)-N,N-dimethylpiperidin-4-amine [ No CAS ]

References: [1]Patent: US2019/106436,2019,A1 .
[2]Patent: CN109851638,2019,A .

26
[ 881-50-5 ]
[ 4876-59-9 ]
N-(4-(4-(dimethylamino)piperidin-1-yl)-2-nitrophenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; for 4h;Inert atmosphere; Reflux;	N-(4-Bromo-2-nitrophenyl)acetamide 5a (14.17 g, 49.72 mmol), <strong>[4876-59-9]N,N-dimethylpiperidin-4-amine dihydrochloride</strong> 7a (10.00) g, 54.69 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.5 g, 19.88 mmol), tris(dibenzylideneacetone)dipalladium (9.1 g, 9.94 mmol) and cesium carbonate (48.40 g, 148.6 mmol) were dissolved in 150 mL of toluene under the protection of nitrogen, and heated to reflux for 4 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: B system) to obtain N-(4-(4-(dimethylamino)piperidin-1-yl)-2-nitrophenyl)acetamide 7b (6.40 g, brownish black solid), yield: 42%. MS m/z (ESI): 307.0 [M+1]

References: [1]Patent: EP3459952,2019,A1 .Location in patent: Paragraph 0129; 0130.

27
[ 4876-59-9 ]
3-(2,6-dichlorophenyl)-7-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimido[5,4-e][1,3]oxazin-4-one [ No CAS ]

References: [1]Patent: US2019/106436,2019,A1 .

28
[ 4876-59-9 ]
3-(2,6-dichlorophenyl)-7-(4-(4-(dimethylamino)piperidin-1-yl)phenylamino)-2H-pyrimido[5,4-e][1,3]thiazin-4(3H)-one [ No CAS ]

References: [1]Patent: US2019/106436,2019,A1 .

29
[ 4876-59-9 ]
3-(2,6-dichlorophenyl)-7-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-2H-pyrimido[5,4-e][1,3]thiazin-4(3H)-one mono-2,2,2-trifluoroacetate [ No CAS ]

References: [1]Patent: US2019/106436,2019,A1 .

30
[ 448-19-1 ]
[ 4876-59-9 ]
[ 1089279-90-2 ]

Yield	Reaction Conditions	Operation in experiment
85.3%	With potassium carbonate; In acetonitrile; at 85℃;Large scale;	At room temperature, a 100-L reaction kettle was charged with Compound 1 (13.80 kg), Compound 2 (9.78 kg), and acetonitrile (70 L), and stirred to dissolve. Potassium carbonate (27.66 kg) was added, mechanically stirred, the temperature was raised to 85 C, and the reaction was allowed to proceed overnight. The mixture was filtered under reduced pressure to room temperature, and the filtrate was distilled under reduced pressure. The obtained solid was mechanically slurried with n-heptane (40L) and isopropyl ether (20L) overnight. The compound 3 was 16.22 kg as a yellow powdery solid with a filtration rate of 85.3%. .
75.9%	With potassium carbonate; In acetonitrile; at 60℃; for 3h;Inert atmosphere;	Add compound 1 to a 50 mL single-mouth flask equipped with magnetic stirring(887 mg, 4.72 mmol) and acetonitrile(20 mL), stirred and dissolved, added the dihydrochloride salt of compound 22 (1.1 g, 5.66 mmol)And potassium carbonate (2.2 g, 15.57 mmol),The reaction mixture was heated to 60 C under a nitrogen atmosphere and stirred for 3 hours while stirring.Cool to room temperature, distill off the solvent under reduced pressure and add water (60 mL).A large amount of yellow solid was precipitated, filtered, washed with water (10 mL) and dried to give a yellow solid1.0g,The yield was 75.9%.

References: [1]Patent: CN110526915,2019,A .Location in patent: Paragraph 0078-0081.
[2]Patent: CN109851638,2019,A .Location in patent: Paragraph 0271-0277.

31
[ 4876-59-9 ]
(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)bis(methyl-d3)phosphine oxide [ No CAS ]