Methotrexate EP Impurity A | Other Aromatic Heterocycles

CAS No. :	945-24-4
Formula :	C₇H₈N₆O
M.W :	192.18
SMILES Code :	OCC1=NC2=C(N)N=C(N)N=C2N=C1
MDL No. :	MFCD00006711
InChI Key :	CYNARAWTVHQHDI-UHFFFAOYSA-N
Pubchem ID :	70347

Safety of [ 945-24-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 945-24-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	10
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	5.0
Num. H-bond donors	3.0
Molar Refractivity	50.06
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	123.83 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.72
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	-1.72
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-1.06
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.	-1.48
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	-0.66
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.84

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.41
Solubility	74.7 mg/ml ; 0.389 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.	-0.37
Solubility	82.6 mg/ml ; 0.43 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	-1.7
Solubility	3.84 mg/ml ; 0.02 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	No
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.	-8.69 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	1.0
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)	2.19

Application In Synthesis of [ 945-24-4 ]

* 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 [ 945-24-4 ]

[ 945-24-4 ] Synthesis Path-Downstream 1~54

1
[ 945-24-4 ]
[ 10541-83-0 ]
[ 19741-14-1 ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 5146 - 5154.
[2]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 3503 - 3515.

2
[ 945-24-4 ]
[ 112113-84-5 ]
[ 112113-77-6 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 763 - 768.

3
[ 945-24-4 ]
[ 158090-74-5 ]
[ 1053629-25-6 ]

References: [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 2167 - 2174.

4
[ 945-24-4 ]
[ 52853-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine dibromide; N,N-dimethyl acetamide; at 20℃; for 200h;	<strong>[945-24-4]2,4-diamino-6-(hydroxymethyl)pteridine</strong> hydrochloride (4.40 g; 19.19 mmol) was dissolved in hot water (150 mL) and the solution was neutralized by addition of 1 M NaOH (ca. 20 mL). The precipitate was filtered, washed with water, and dried in vacuo over P2O5. Subsequently, this was suspended in DMAc (25 mL), and triphenylphosphine dibromide (18.12 g; 42.92 mmol) was added. The turbid reaction mixture was stirred for 20 hr at 200C. 4-(Methylamino)benzoic acid (2.95 g; 19.50 mmol) and DIPEA (5.04 g; 39.00 mmol) were added, and the turbid reaction mixture was stirred for 3 days at 200C. Then, it was poured in 0.33 M NaOH-solution (250 mL), the precipitate was filtered off, and the filtrate was neutralized by addition of 10% acetic acid in water (ca. 20 mL). The precipitate was filtered, washed with water, triturated with methanol (30 mL), and dried in vacuo over P2O5, to yield the product as a beige/orange powder (3.48 g; 56%).1H-NMR (DMSO): delta 8.59 (s, IH), 7.53 (d, 2H, 8.8 Hz), 7.7 (br. s, IH), 7.5 (br. s, IH), 6.83 (d, 2H, 8.8 Hz), 4.79 (s, 2H), 3.23 (s, 3H) ppm. FT-IR (ATR): V 3335, 3194, 2964, 1651, 1597, 1292, 1187 cm"1.

References: [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 660 - 667.
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 3455 - 3462.
[3]Patent: WO2007/110811,2007,A2 .Location in patent: Page/Page column 23.

5
[ 73978-41-3 ]
[ 945-24-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water;	2,4-diamino-6-(hydroxymethyl)pteridine hydrochloride (4.40 g; 19.19 mmol) was dissolved in hot water (150 mL) and the solution was neutralized by addition of 1 M NaOH (ca. 20 mL). The precipitate was filtered, washed with water, and dried in vacuo over P2O5. Subsequently, this was suspended in DMAc (25 mL), and triphenylphosphine dibromide (18.12 g; 42.92 mmol) was added. The turbid reaction mixture was stirred for 20 hr at 200C. 4-(Methylamino)benzoic acid (2.95 g; 19.50 mmol) and DIPEA (5.04 g; 39.00 mmol) were added, and the turbid reaction mixture was stirred for 3 days at 200C. Then, it was poured in 0.33 M NaOH-solution (250 mL), the precipitate was filtered off, and the filtrate was neutralized by addition of 10% acetic acid in water (ca. 20 mL). The precipitate was filtered, washed with water, triturated with methanol (30 mL), and dried in vacuo over P2O5, to yield the product as a beige/orange powder (3.48 g; 56%).1H-NMR (DMSO): delta 8.59 (s, IH), 7.53 (d, 2H, 8.8 Hz), 7.7 (br. s, IH), 7.5 (br. s, IH), 6.83 (d, 2H, 8.8 Hz), 4.79 (s, 2H), 3.23 (s, 3H) ppm. FT-IR (ATR): V 3335, 3194, 2964, 1651, 1597, 1292, 1187 cm"1.

References: [1]Chemische Berichte,1980,vol. 113,p. 1514 - 1523.
[2]Patent: WO2007/110811,2007,A2 .Location in patent: Page/Page column 23.
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 3503 - 3515.

6
[ 52-89-1 ]
[ 5392-28-9 ]
[ 945-24-4 ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 5146 - 5154.

7
[ 945-24-4 ]
(S)-2-[4-(2,4-Diamino-pteridin-6-ylmethoxycarbonyl)-benzoylamino]-pentanedioic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 3455 - 3462.

8
[ 945-24-4 ]
[ 581785-35-5 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 3455 - 3462.

9
[ 712-29-8 ]
[ 945-24-4 ]

References: [1]Helvetica Chimica Acta,2003,vol. 86,p. 1 - 12.

10
[ 32363-58-9 ]
[ 945-24-4 ]

References: [1]Helvetica Chimica Acta,2003,vol. 86,p. 1 - 12.

11
[ 945-24-4 ]
1,12-d-[4-(4S)-carboxy-4-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}butyrylamino]dodecane [ No CAS ]

References: [1]Journal of the American Chemical Society,2003,vol. 125,p. 1501 - 1507.

12
[ 945-24-4 ]
[ 56892-87-6 ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 5146 - 5154.

13
[ 945-24-4 ]
[ 357933-50-7 ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 5146 - 5154.

14
[ 945-24-4 ]
2-[[[3-carboxy-3-[[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]amino]propyl]hydroxyphosphinyl]methyl]pentane-1,5-dioic acid tetra(triethylamine) salt [ No CAS ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 5146 - 5154.

15
[ 945-24-4 ]
(S)-2-{4-[(3-Carboxy-propyl)-(2,4-diamino-pteridin-6-ylmethyl)-amino]-benzoyloxy}-pentanedioic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1463 - 1468.

16
[ 945-24-4 ]
(S)-2-{4-[(4-Carboxy-butyl)-(2,4-diamino-pteridin-6-ylmethyl)-amino]-benzoyloxy}-pentanedioic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1463 - 1468.

17
[ 945-24-4 ]
(S)-2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-(3-ethoxycarbonyl-propyl)-amino]-benzoyloxy}-pentanedioic acid diethyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1463 - 1468.

18
[ 945-24-4 ]
(S)-2-{4-[(5-Carboxy-pentyl)-(2,4-diamino-pteridin-6-ylmethyl)-amino]-benzoyloxy}-pentanedioic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1463 - 1468.

19
[ 945-24-4 ]
(S)-2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-(4-ethoxycarbonyl-butyl)-amino]-benzoyloxy}-pentanedioic acid diethyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1463 - 1468.

20
[ 945-24-4 ]
(S)-2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-(5-ethoxycarbonyl-pentyl)-amino]-benzoyloxy}-pentanedioic acid diethyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1463 - 1468.

21
[ 945-24-4 ]
[ 156579-02-1 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1997,vol. 39,p. 363 - 368.

22
[ 945-24-4 ]
[ 156579-01-0 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1997,vol. 39,p. 363 - 368.

23
[ 52853-40-4 ]
[ 945-24-4 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1997,vol. 39,p. 363 - 368.

24
[ 191786-01-3 ]
[ 945-24-4 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1997,vol. 39,p. 363 - 368.

25
[ 191786-03-5 ]
[ 945-24-4 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1997,vol. 39,p. 363 - 368.

26
[ 191786-02-4 ]
[ 945-24-4 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1997,vol. 39,p. 363 - 368.

27
[ 945-24-4 ]
[ 67022-39-3 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.
[2]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.

28
[ 945-24-4 ]
[ 79640-75-8 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.
[2]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.

29
[ 945-24-4 ]
[ 79648-88-7 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.

30
[ 945-24-4 ]
[ 121788-83-8 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.
[2]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.

31
[ 945-24-4 ]
[ 121788-84-9 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.
[2]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431.

32
[ 945-24-4 ]
[ 43111-51-9 ]