[ CAS No. 938443-19-7 ]

Name: 938443-19-7|7-Chloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione|98%
Brand: Ambeed
SKU: A728117
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Quality Control of [ 938443-19-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 938443-19-7 ]

SDS Specification

Alternatived Products of [ 938443-19-7 ]

Product Details of [ 938443-19-7 ]

CAS No. :	938443-19-7	MDL No. :	MFCD12755863
Formula :	C₇H₄ClN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DJHNDPHQSQMESD-UHFFFAOYSA-N
M.W :	197.58	Pubchem ID :	40152233
Synonyms :

Calculated chemistry of [ 938443-19-7 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	47.99
TPSA :	78.61 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.03 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.94
Log Po/w (XLOGP3) :	0.67
Log Po/w (WLOGP) :	0.26
Log Po/w (MLOGP) :	0.85
Log Po/w (SILICOS-IT) :	2.36
Consensus Log Po/w :	1.02

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.06
Solubility :	1.74 mg/ml ; 0.00878 mol/l
Class :	Soluble
Log S (Ali) :	-1.9
Solubility :	2.5 mg/ml ; 0.0127 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.39
Solubility :	0.0803 mg/ml ; 0.000406 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.77

Safety of [ 938443-19-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 938443-19-7 ]

* 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 [ 938443-19-7 ]
Downstream synthetic route of [ 938443-19-7 ]

[ 938443-19-7 ] Synthesis Path-Upstream 1~1

1
[ 938443-19-7 ]
[ 938443-20-0 ]

Yield	Reaction Conditions	Operation in experiment
48%	Stage #1: With N-ethyl-N,N-diisopropylamine In toluene at 70℃; for 0.5 h; Stage #2: With trichlorophosphate In toluene at 20 - 100℃; for 2.5 h;	d) 2,4, 7-Trichloro-pyrido[2,3-d]pyrimidine (Inter.5); To a stirred 0.5 M suspension of the dione (Inter. 4)(1 equiv.) in anhydrous toluene under an inert atmosphere was slowly added diisopropylethylamine (3 equiv.). The reaction mixture was then heated to 70⁰C for 30 minutes and then cooled to room temperature prior to the addition of POCl₃ (3 equivalents). The reaction was then heated to 100°C for 2.5 hours before being cooled and concentrated in vacuo to give a crude slurry which was then suspended in EtOAc and filtered through a thin pad of Celite.(TM).. The filtrate was concentrated in vacuo to give a brown, oil which was dissolved in CH₂Cl₂ and stirred over silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate concentrated and the crude residue purified by flash chromatography (SiO₂) to give the title compound in analytically pure form (48percent yield, 96percent purity), m/z (LC-MS, ESP): 234 [M+H]⁺ R/T = 4.21 mins
48%	Stage #1: With N-ethyl-N,N-diisopropylamine In toluene at 70℃; for 0.5 h; Stage #2: With trichlorophosphate In toluene at 100℃; for 2.5 h;	To a stirred 0.5 M suspension of the appropriate dione (1 equiv) in anhydrous toluene under an inert atmosphere was slowly added diisopropylethylamine (3 equiv). The reaction mixture was then heated to 70 ⁰C for 30 minutes and then cooled to room temperature prior to the addition of POCl₃ (3 equiv). The reaction was then heated to 100 ⁰C for 2.5 hours before being cooled and concentrated in vacuo to give a crude slurry which was then suspended in EtOAc and filtered through a thin pad of Celite.(TM).. The filtrate was concentrated in vacuo to give a brown, oil which was dissolved in CH₂Cl₂ and stirred over silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate concentrated and the crude residue purified by flash chromatography (SiO₂) to give the title compound in analytically pure form.2,4,7-Trichloro-ρyrido[2,3-d]pyrimidine- X=N, Y=C, Z=C: (48 percent yield, 96 percent purity) m/z (LC-MS, ESP): 234 [M+H]⁺ R/T = 4.21 min
0.5 g	Stage #1: With N-ethyl-N,N-diisopropylamine In toluene at 70℃; for 0.5 h; Stage #2: at 0 - 110℃; for 4 h;	To the reaction bottle 7-chloro-pyrido [2,3-d] pyrimidine -2,4 (1H, 3H)-dione (1.98g, 10mmol), diisopropyl ethylamine (3.87g, 30mmol) and toluene, for 70 °C reaction 30 minutes, cooling dropping POCl ₃ (4.59g, 30mmol), 110 °C reaction under 4h to the column product splines, 0.5g, the yield is 21.4percent.

Reference： [1] Patent: WO2007/60404, 2007, A1, . Location in patent: Page/Page column 57; 59
[2] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 101
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1212 - 1216
[4] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 102-103
[5] Patent: CN102887895, 2016, B, . Location in patent: Paragraph 0310; 0313; 0314

[ 938443-19-7 ] Synthesis Path-Downstream 1~69

1
[ 79-37-8 ]
[ 64321-24-0 ]
[ 938443-19-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	In toluene;	7-Chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Inter. 4) To a stirred solution (0.06 M) of <strong>[64321-24-0]2-amino-6-chloronicotinamide</strong> (Inter. 3) (1 equiv) in anhydrous toluene under an inert atmosphere was added oxalyl chloride (1.2 equiv) in a dropwise manner. The resulting mixture was then heated to reflux (115 C.) for 4 hours whereupon it was cooled and stirred for a further 16 hours. The crude reaction mixture was then concentrated to half its volume in vacuo and filtered to give the desired product in suitably pure form (95% yield, 96% purity) to be used without any further purification. m/z (LC-MS, ESP): 196 [M-H]-R/T=3.22 mins
95%	In toluene; at 115℃; for 20h;	To a stirred solution (0.06 M) of substrate (1 equiv) in anhydrous toluene under an inert atmosphere was added oxalyl chloride (1.2 equiv) in a dropwise manner. The resulting mixture was then heated to reflux (115 0C) for 4 hours whereupon it was cooled and stirred for a further 16 hours. The crude reaction mixture was then concentrated to half its volume in vacuo and filtered to give the desired product in suitably pure form to be used without any further purification. <n="102"/>7-Chloro-lH-pyrido[2,3-d]pyrimidine-2,4-dione- X=N, Y=C, Z=C: (95 % yield, 96 % purity) m/z (LC-MS, ESP): 196 [M-H]" R/T = 3.22 min
	In toluene; at 20 - 110℃; for 20h;	The reaction flask was added <strong>[64321-24-0]2-amino-6-chloro-nicotinamide</strong> (1.72g, 10mmol), oxalyl chloride (2.6g, 20mmol), and toluene (20 mL), then for 4h at 110 the reaction at room temperature 16h, concentrated precipitated solid was suction filtered crude product 1.5g, was used directly in the next step without purification

Reference： [1]Patent: US2009/99174,2009,A1
[2]Patent: WO2008/23161,2008,A1 .Location in patent: Page/Page column 100-101
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1212 - 1216
[4]Patent: CN102887895,2016,B .Location in patent: Paragraph 0310-0312

2
[ 64321-24-0 ]
[ 938443-19-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With oxalyl dichloride; In toluene; at 115℃; for 20h;	c) 7-Chloro-lH-pydo[2,3~d]pyrimidine-2,4-dione (Inter. 4); To a stirred solution (0.06 M) of <strong>[64321-24-0]2-amino-6-chloronicotinamide</strong> (Inter. 3)(1 equiv) in anhydrous toluene under an inert atmosphere was added oxalyl chloride (1.2 equiv) in a <n="60"/>dropwise manner. The resulting mixture was then heated to reflux (115C) for 4 hours whereupon it was cooled and stirred for a further 16 hours. The crude reaction mixture was then concentrated to half its volume in vacuo and filtered to give the desired product in suitably pure form (95% yield, 96% purity) to be used without any further purification, m/z (LC-MS, ESP): 196 [M-H]' R/T = 3.22 mins

Reference： [1]Patent: WO2007/60404,2007,A1 .Location in patent: Page/Page column 57-59

3
[ 938443-19-7 ]
[ 938443-20-0 ]

Yield	Reaction Conditions	Operation in experiment
48%		d) 2,4, 7-Trichloro-pyrido[2,3-d]pyrimidine (Inter.5); To a stirred 0.5 M suspension of the dione (Inter. 4)(1 equiv.) in anhydrous toluene under an inert atmosphere was slowly added diisopropylethylamine (3 equiv.). The reaction mixture was then heated to 700C for 30 minutes and then cooled to room temperature prior to the addition of POCl3 (3 equivalents). The reaction was then heated to 100C for 2.5 hours before being cooled and concentrated in vacuo to give a crude slurry which was then suspended in EtOAc and filtered through a thin pad of Celite. The filtrate was concentrated in vacuo to give a brown, oil which was dissolved in CH2Cl2 and stirred over silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate concentrated and the crude residue purified by flash chromatography (SiO2) to give the title compound in analytically pure form (48% yield, 96% purity), m/z (LC-MS, ESP): 234 [M+H]+ R/T = 4.21 mins
48%		To a stirred 0.5 M suspension of the appropriate dione (1 equiv) in anhydrous toluene under an inert atmosphere was slowly added diisopropylethylamine (3 equiv). The reaction mixture was then heated to 70 0C for 30 minutes and then cooled to room temperature prior to the addition of POCl3 (3 equiv). The reaction was then heated to 100 0C for 2.5 hours before being cooled and concentrated in vacuo to give a crude slurry which was then suspended in EtOAc and filtered through a thin pad of Celite. The filtrate was concentrated in vacuo to give a brown, oil which was dissolved in CH2Cl2 and stirred over silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate concentrated and the crude residue purified by flash chromatography (SiO2) to give the title compound in analytically pure form.2,4,7-Trichloro-rhoyrido[2,3-d]pyrimidine- X=N, Y=C, Z=C: (48 % yield, 96 % purity) m/z (LC-MS, ESP): 234 [M+H]+ R/T = 4.21 min
		Alternatively, to a stirred 0.47 M suspension of the appropriate dione (1 equiv) in anhydrous anisole under an inert atmosphere was added POCl3 (2.6 equiv). The mixture was heated to 55 0C and then diisopropylethylamine (2.6 equiv) was slowly added. The reaction mixture was then heated to 85-90 0C for 30 minutes. Water was added in portions (0.15 equiv), and the reaction mixture was held at 85-90 0C for a further 30 minutes. The reaction was cooled to 50 0C, and then 15% of the anisole solvent was removed by vacuum distillation. The mixtutre was then cooled to -5 0C and diisopropylethylamine (1.1 equiv) was added. A 4.9M solution of the appropriate amine (1.05 equiv) in anisole was then added to the reaction mixture continuously over a period of 1 hour. The solution was then warmed to 30 0C and the reaction monitored by HPLC until reation completion.One third of the resulting mixture from the above reaction was then added over lOmin to a stirred mixture of 1.95M aqueous potassium hydroxide (3.9 equiv) and z-butanol (6.9 equiv) at 60 0C. The stirring was stoped, the phases were allowed to separate, and the aqueous phase was removed. Stirring was resumed, and 1.95M aqueous potassium hydroxide (3.9 equiv) was added to the retained organic phase. The second third of the resulting reaction mixture from the reaction above was then added over lOmin at 60 0C. Again, stirring <n="104"/>was stoped, the phases were allowed to separate, and the aqueous phase was removed. Stirring was resumed, and 1.95M aqueous potassium hydroxide (3.9 equiv) was added to the retained organic phase. The remaining third of the resulting reaction mixture from the reaction above was then added over lOmin at 60 0C. Again, stirring was stoped, the phases were allowed to separate, and the aqueous phase was removed. Water was then added to the organic phase with stirring, and the stirred mixture heated to 75 0C. Stirring was stoped, the phases were allowed to separate, and the aqueous phase was removed. The resulting organic phase was stirred and allowed to cool to 30 0C, and then as the mixture was heated to 60 0C heptane (11.5 equiv) was added over 20min when the mixture was around 40 0C. After being heated to 60 0C, the mixture was cooled over 2.5h to 10 0C. After 30min, the resulting slurry was filtered off, washed with a 10:1 heptane-.anisole mixture (2 x 1.4equiv) and then washed with heptane (2 x 1.4equiv). The solid was then dried in a vacuum oven at 50 0C to leave the title compound in suitable clean form to be used without any further purification.

0.5 g

To the reaction bottle 7-chloro-pyrido [2,3-d] pyrimidine -2,4 (1H, 3H)-dione (1.98g, 10mmol), diisopropyl ethylamine (3.87g, 30mmol) and toluene, for 70 C reaction 30 minutes, cooling dropping POCl 3 (4.59g, 30mmol), 110 C reaction under 4h to the column product splines, 0.5g, the yield is 21.4%.

Reference： [1]Patent: WO2007/60404,2007,A1 .Location in patent: Page/Page column 57; 59
[2]Patent: WO2008/23161,2008,A1 .Location in patent: Page/Page column 101
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1212 - 1216
[4]Patent: WO2008/23161,2008,A1 .Location in patent: Page/Page column 102-103
[5]Patent: CN102887895,2016,B .Location in patent: Paragraph 0310; 0313; 0314

4
[ 79-37-8 ]
[ 64321-24-0 ]
[ 938443-19-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	In toluene; at 115℃;Inert atmosphere;	Intermediate 65; 7-Chloropyridor2,3-?pyrimidine-2,4-diolTo a stirred solution (0.06 M) of <strong>[64321-24-0]2-amino-6-chloronicotinamide</strong> (Intermediate 66, 1.86 g, 10.84 mmol) in anhydrous toluene (181 ml) under N2 atmosphere was added oxalyl chloride (1.651 g,13.01 mmol) in a drop-wise manner. The resulting mixture was heated at reflux (115 C) for 4 hours whereupon it was cooled and stirred for a further 16 hours. The crude reaction mixture was concentrated to half its volume in vacuo and filtered to give the desired product (1.740 g, 81 %) in suitably pure form to be used without any further purification LCMS: 200.1 [M+H]+. 103496-1P

Reference： [1]Patent: WO2010/38060,2010,A1 .Location in patent: Page/Page column 99

5
[ 38496-18-3 ]
[ 938443-19-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1212 - 1216
[2]Patent: US2020/339568,2020,A1
[3]Patent: WO2021/133509,2021,A1

6
[ 938443-19-7 ]
KU-63794 [ No CAS ]