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Structure of 63001-30-9

Chemical Structure| 63001-30-9

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Product Details of [ 63001-30-9 ]

CAS No. :63001-30-9
Formula : C6H6N2O3
M.W : 154.12
SMILES Code : O=C1NN=C(C=C1)C(=O)OC
MDL No. :MFCD17015975
InChI Key :REYKVZJYIFOXTI-UHFFFAOYSA-N
Pubchem ID :9124994

Safety of [ 63001-30-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 63001-30-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 2
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 36.14
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

72.05 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.06
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

-0.44
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

-0.44
Log Po/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.

-0.17
Log Po/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

0.88
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.18

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-0.79
Solubility 25.0 mg/ml ; 0.162 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.

-0.61
Solubility 38.0 mg/ml ; 0.247 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

-1.62
Solubility 3.7 mg/ml ; 0.024 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.

-7.55 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)

1.72

Application In Synthesis of [ 63001-30-9 ]

* 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.

  • Upstream synthesis route of [ 63001-30-9 ]
  • Downstream synthetic route of [ 63001-30-9 ]

[ 63001-30-9 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 67-56-1 ]
  • [ 37972-69-3 ]
  • [ 63001-30-9 ]
YieldReaction ConditionsOperation in experiment
100% for 16 h; Heating / reflux A. To a methanol solution of 6-oxo-1 ,6-dihydropyridazine-3-carboxylic acid monohydrate (5.00 g, 31.6 mmol) was added thionyl chloride (0.36 mL, 0.59 g, 4.94 mmol). The reaction mixture was heated to reflux at 800C for 16 h. The product crystallized after the reaction mixture was cooled down to ambient temperature. The crystals were collected and washed with methanol and the mother liquor was concentrated and crystallized again. The total amount of product isolated was 4.954 g (100percent yield).
92% for 2 h; Reflux e)
Synthesis of methyl 6-oxo-1,6-dihydropyridazine-3-carboxylate
10.00 g of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid, monohydrate, are suspended in 160 ml of methanol in a 500 ml flask provided with magnetic stirrer and drying tube, 5.84 ml of thionyl chloride are carefully added with stirring, and the mixture is boiled under reflux on a steam bath for 2 h, giving a clear solution.
The solution is then cooled, the crystals formed are filtered off with suction and dried (K1).
The mother liquor was stripped off to dryness, the residue was stirred with a little methanol, filtered off with suction and dried (K2). K1 and K2 are combined.
Yield: 10.72 g=56.25 mmol=92percent;
TLC: CH2Cl2: MeOH=95:5; Rf approx. 0.3
m.p. 191-193°
HPLC: RT=1.36 min.
81% Reflux The procedure described in WO2006/34440 was followed. 6-oxo-1,6-dihydropyridazine-3-carboxylic acid monohydrate (8.91 g, 56.4 mmol) was taken up in 90 mL methanol. Thionyl chloride (0.66 mL, 1.1 g, 9.0 mmol) was added, and the mixture was refluxed overnight, until LC-MS analysis indicated that most or all of the acid had been esterified. The reaction mixture was cooled to room temperature, then chilled in the fridge, and the white crystalline precipitate was collected and dried under vacuum. 7.07 g, 81percent yield: 1H NMR (DMSO-d6) δ 13.60 (br. s., 1H), 7.82 (d, J=10.1 Hz, 1H), 6.96 (d, J=9.9 Hz, 1H), 3.84 (s, 3H).
66% at 70℃; for 16 h; Inert atmosphere Method 24
Methyl 6-oxo-1,6-dihydropyridazine-3-carboxylate
To a solution of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (1.80 g, 12.85 mmol) in methanol (24 mL) was added thionyl chloride (6 mL, 82.71 mmol) at room temperature.
The resulting solution was then stirred for 16 h at 70° C.
When the reaction was done, it was quenched by the addition of water (30 mL).
The resulting mixture was extracted with ethyl acetate (60 mL*3).
The organic phases were combined, washed with brine and dried over sodium sulfate.
The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0percent to 80percent gradient) to yield methyl 6-oxo-1,6-dihydropyridazine-3-carboxylate as a light yellow solid (1.31 g, 66percent). MS: m/z=155.0 [M+H]+.

References: [1] Patent: WO2006/34440, 2006, A2, . Location in patent: Page/Page column 43.
[2] Patent: US2011/257173, 2011, A1, . Location in patent: Page/Page column 19; 21.
[3] Patent: US2011/105509, 2011, A1, . Location in patent: Page/Page column 30; 31; 32.
[4] Patent: US2016/376283, 2016, A1, . Location in patent: Paragraph 1225; 1227.
[5] Patent: WO2004/89939, 2004, A1, . Location in patent: Page 40-41.
  • 2
  • [ 89532-94-5 ]
  • [ 63001-30-9 ]
YieldReaction ConditionsOperation in experiment
58% With pyridine; manganese(IV) oxide In toluene at 65℃; Manganese dioxide (3.12 g, 35.9 mmol) was suspended as a slurry in toluene (10 mL) and pyridine (720 μL). A sample of S47 (280 mg, 1.8 mmol) was added portionwise to the stirring solution and the resulting mixture was warmed at 65 °C until the disappearance of all starting material (6 h). The warm solution was filtered through a pad of Celite that was washed with several hundred milliliters of hot EtOAc and THF. The organic wash was evaporated to afford a yellowish solid which was used without further purification (160 mg, 58percent): 1H NMR (CDCl3, 300 MHz) δ 7.92 (d, IH, J = 9.9 Hz), 7.02 (d, IH, J = 9.8 Hz), 3.99 (s, 3H); HRMS-ESI-TOF m/z 155.0450 ([M+H+, C6H6N2O3 requires 155.0451).
References: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4392 - 4403.
[2] Patent: WO2010/5572, 2010, A2, . Location in patent: Page/Page column 85.
  • 3
  • [ 19194-96-8 ]
  • [ 63001-30-9 ]
References: [1] Patent: US2014/100231, 2014, A1, . Location in patent: Page/Page column.
[2] Patent: WO2014/58747, 2014, A1, . Location in patent: Page/Page column 94; 95.
  • 4
  • [ 27372-38-9 ]
  • [ 63001-30-9 ]
References: [1] Patent: US2016/376283, 2016, A1, .
 

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