64224-60-8|5-Bromo-4-pyrimidinecarboxylic acid| Ambeed

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Quality Control of [ 64224-60-8 ] Purity: 97% SDS Specification

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Product Details of [ 64224-60-8 ]

CAS No. :	64224-60-8
Formula :	C₅H₃BrN₂O₂
M.W :	202.99
SMILES Code :	BrC1=CN=CN=C1C(=O)O
MDL No. :	MFCD09754104
InChI Key :	HZZBITVSVYFOND-UHFFFAOYSA-N
Pubchem ID :	21329200

Safety of [ 64224-60-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 64224-60-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	36.69
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	63.08 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.83
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	0.75
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.94
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.	-0.02
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	1.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.7

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.95
Solubility	2.28 mg/ml ; 0.0112 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.65
Solubility	4.5 mg/ml ; 0.0222 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	-1.88
Solubility	2.65 mg/ml ; 0.0131 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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.01 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.	0.56

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)	1.55

Application In Synthesis of [ 64224-60-8 ]

* 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 [ 64224-60-8 ]

[ 64224-60-8 ] Synthesis Path-Downstream 1~35

1
[ 64224-60-8 ]
5-bromopyrimidine-4-carboxylic acid chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;	S-bromopyrimidine^-carboxylic acid (prepared according to the procedure described in U.S patent 4,110,450) (1.0 eq, 6.14 g, 30.2 mmol) was suspended in CH2Cl2 (100 ml). Oxalylchloride (1.1 eq, 2.9 ml, 33.0 mmol) was added followed by 2 drops of DMF. The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was taken in MeOH (50 ml) and heated. After evaporation of MeOH in vacuo the compound was dissolved in CH2Cl2 and poured on a prepacked silica gel column. The material was eluted using 20% Ethyl acetate in hexanes. Evaporation of the solvent provided methyl-5- bromopyrimidine-4-carboxylate as a light orange crystalline solid (2.54 g, 39% yield). LCMS (ES): 95% pure, m/z 217 [M]+; 219 [M+2]+; 1H NMR (CDCl3, 400 MHz) delta 4.04 (s, 3H), 9.02 (s, IH), 9.21 (s, IH) ppm.
	With thionyl chloride; In N,N-dimethyl-formamide; at 90℃; for 3.0h;	<strong>[64224-60-8]5-bromopyrimidine-4-carboxylic acid</strong> (0.6 g, 2.96 mmol) was dissolved in thionyl chloride (10 mL) N, N-dimethylformamide (0.05 mL) was added, The reaction was heated to 90 C for 3 hours. The reaction solution was concentrated to dryness, Toluene (10 mL) was added, Re-concentrated to dry, The crude product was used directly in the next step.

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3071 - 3078.
[2]Patent: WO2008/28168,2008,A2 .Location in patent: Page/Page column 74.
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 635 - 654.
[4]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1687 - 1691.
[5]Patent: CN106317027,2017,A .Location in patent: Paragraph 0204; 0205; 0206.

2
[ 64224-60-8 ]
5-Bromo-pyrimidine-4-carboxylic acid phenylamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3071 - 3078.

3
[ 64224-60-8 ]
2-Phenyl-isothiazolo[4,5-d]pyrimidin-3-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3071 - 3078.

4
[ 64224-60-8 ]
5-Benzylsulfanyl-pyrimidine-4-carboxylic acid phenylamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3071 - 3078.

5
[ 64224-60-8 ]
[ 1025934-63-7 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3071 - 3078.

Yield	Reaction Conditions	Operation in experiment
		5-Bromopyrimidine-4-carboxylic acid can be prepared by heating a suspension of formamidine acetate (416 g) in ethanol (1800 cc) at 45 C, and adding simultaneously, on the one hand, a solution of sodium ethoxide obtained from sodium (138 g) and ethanol (3000 cc) and, on the other hand, a solution of mucobromic acid (516 g) in ethanol (800 cc). The addition is carried out over a period of 2 hours, the temperature being maintained between 45 C and 50 C. The reaction mixture is maintained at this temperature for 11/2 hours. The solution obtained is evaporated by dryness under reduced pressure (20 mm Hg). The residue is taken up in ice-water (1000 cc) and decolourizing charcoal (20 g) is added. After filtration the solution is washed with ethyl acetate (4000 cc). The aqueous phase is decanted and acidified with concentrated 12N hydrochloric acid (500 cc). The insoluble matter is filtered off and the filtrate is extracted with ethyl acetate (10000 cc). The organic layer is decanted and filtered over silica gel (1000 g). Elution is then carried out with ethanol (5000 cc). The resulting elude is evaporated to dryness under reduced pressure. After taking up the residue in diethyl ether (250 cc), 5-bromopyrimidine-4-carboxylic acid (74 g), melting at 200 C with decomposition, is obtained.

7
[ 144-55-8 ]
[ 64224-60-8 ]
[ 64224-61-9 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroborane diethyl ether; In ethanol; dichloromethane;	Ethyl 5-methylthiopyrimidine-4-carboxylate can be prepared by heating a solution of <strong>[64224-60-8]5-bromopyrimidine-4-carboxylic acid</strong> (3.4 g) in ethanol (34 cc) and boron trifluoride etherate (7.4 g) under reflux for 20 hours. After concentration to dryness under reduced pressure (20 mm Hg), methylene chloride (50 cc) is added to the residue and neutralisation is effected by the addition of an 8% (w/v) aqueous sodium bicarbonate solution. The aqueous phase is decanted and extracted with methylene chloride (50 cc). The combined organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure. Ethyl-5-methylthiopyrimidine-4-carboxylate (3.7 g), melting at 99-100 C, is thus obtained.

References: [1]Patent: US4110450,1978,A .

8
[ 74-93-1 ]
[ 64224-60-8 ]
5-methylthiopyrimidine-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In ethanol; water;	5-Methylthiopyrimidine-4-carboxylic acid can be prepared by heating <strong>[64224-60-8]5-bromopyrimidine-4-carboxylic acid</strong> (4.1 g), sodium methoxide (2.43 g) and methylmercaptan (2.16 g) under reflux for four and a half hours in ethanol (30 cc). After evaportion of the resulting solution to dryness under reduced pressure, the residue is dissolved in water (20 cc) and the solution acidified to pH 1 with 12N hydrochloric acid. The precipitate which forms is filtered off and washed with water (15 cc) to give 5-methylthiopyrimidine-4-carboxylic acid (2.8 g) melting at 270 C with decomposition.

References: [1]Patent: US4110450,1978,A .

9
[ 64224-60-8 ]
ethyl 5-bromopyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In N-methyl-acetamide; ethanol; dichloromethane; sodium hydrogencarbonate;	Ethyl 5-bromopyrimidine-4-carboxylate can be prepared by the addition of <strong>[64224-60-8]5-bromopyrimidine-4-carboxylic acid</strong> (45.6 g) to thionyl chloride (450 cc) and dimethylformamide (0.5 cc). The mixture is progressively heated to reflux, which is maintained until the evolution of gas ceases. Thereafter the solution is concentrated to dryness under reduced pressure. The residue is taken up in methylene chloride (100 cc) and then, after cooling in an ice-bath, in ethanol (315 cc). The solution is stirred for 11/2 hours at a temperature of about 20 C, and then heated under reflux for 30 minutes. The solution obtained is evaporated to dryness under reduced pressure. The residue is taken up in an 8% (w/v) aqueous sodium bicarbonate solution (200 cc) and diethyl ether (1500 cc). The organic phase is dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure to give ethyl 5-bromopyrimidine-4-carboxylate (31 g), b.p. 87-90 C/0.15 mm Hg.

References: [1]Patent: US4110450,1978,A .

10
[ 67-56-1 ]
[ 64224-60-8 ]
[ 1009826-93-0 ]

Yield	Reaction Conditions	Operation in experiment
55%	With thionyl chloride; at 20 - 70℃; for 3.0h;	5-Bromo-4-pyrimidine carboxylic acid 1-84 (858 mg, 4.23 mmol) was dissolved in MeOH (15 mL) and thionyl chloride (77 mu, 1 .06 mmol) added dropwise at rt. The reaction mixture was heated to 70C and stirred at this temperature for 3 h. The reaction mixture was then cooled to rt and evaporated to dryness. The residue was re-dissolved in a mixture of water (25 mL) and saturated aq. NaHCOs (25 mL) before extracting with EtOAc (3 x 50 mL). The combined organic extracts were then washed with saturated aqueous NaHCOs (40 mL) and brine (40 mL) before drying over MgS04. Concentration in vacuo provided the title compound as a brown solid (502 mg, 2.31 mmol, 55%).
39%		Process 4 5-Bromopyrimidine-4-carboxylic acid (prepared according to the procedure described in U.S. Pat. No. 4,110,450) (1.0 eq, 6.14 g, 30.2 mmol) was suspended in CH2Cl2 (100 ml). Oxalylchloride (1.1 eq, 2.9 ml, 33.0 mmol) was added followed by 2 drops of DMF. The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was taken in MeOH (50 ml) and heated. After evaporation of MeOH in vacuo the compound was dissolved in CH2Cl2 and poured on a prepacked silica gel column. The material was eluted using 20% Ethyl acetate in hexanes. Evaporation of the solvent provided methyl-5-bromopyrimidine-4-carboxylate as a light orange crystalline solid (2.54 g, 39% yield). LCMS (ES): 95% pure, m/z 217 [M]+; 219 [M+2]+; 1H NMR (CDCl3, 400 MHz) delta 4.04 (s, 3H), 9.02 (s, 1H), 9.21 (s, 1H) ppm.
39%		<strong>[64224-60-8]5-bromopyrimidine-4-carboxylic acid</strong> (prepared according to the procedure described in U.S. Pat. No. 4,110,450) (1.0 eq, 6.14 g, 30.2 mmol) was suspended in CH2Cl2 (100 ml). Oxalylchloride (1.1 eq, 2.9 ml, 33.0 mmol) was added followed by 2 drops of DMF. The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was taken in MeOH (50 ml) and heated. After evaporation of MeOH in vacuo the compound was dissolved in CH2Cl2 and poured on a prepacked silica gel column. The material was eluted using 20% Ethyl acetate in hexanes. Evaporation of the solvent provided methyl-5-bromopyrimidine-4-carboxylate as a light orange crystalline solid (2.54 g, 39% yield). LCMS (ES): 95% pure, m/z 217 [M]+; 219 [M+2]+; 1H NMR (CDCl3, 400 MHz) delta 4.04 (s, 3H), 9.02 (s, 1H), 9.21 (s, 1H) ppm.

References: [1]Patent: WO2017/93543,2017,A2 .Location in patent: Page/Page column 109.
[2]Patent: US2009/93465,2009,A1 .Location in patent: Page/Page column 32.
[3]Patent: US2009/239859,2009,A1 .Location in patent: Page/Page column 41.

11
[ 64224-60-8 ]
5-(3-chlorophenylamino)pyrimido[4,5-c]quinoline-8-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 635 - 654.
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1687 - 1691.

12
[ 64224-60-8 ]
C₁₉H₁₃ClN₄O₂ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 635 - 654.
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1687 - 1691.

13
[ 64224-60-8 ]
[ 1009826-93-0 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 635 - 654.
[2]Patent: CN106317027,2017,A .

14
[ 64224-60-8 ]
methyl 5-oxo-5,6-dihydropyrimido[4,5-c]-quinoline-8-carboxylate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 635 - 654.
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1687 - 1691.

15
[ 64224-60-8 ]
[ 1009826-97-4 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 635 - 654.
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1687 - 1691.

16
[ 64224-60-8 ]
5-(3-ethynylphenylamino)pyrimido[4,5-c]quinoline-8-carboxylic acid [ No CAS ]