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Chemical Structure| 933-80-2 Chemical Structure| 933-80-2

Structure of 933-80-2

Chemical Structure| 933-80-2

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Product Details of [ 933-80-2 ]

CAS No. :933-80-2
Formula : C5H7ClN4
M.W : 158.59
SMILES Code : NC1=NC(C)=NC(Cl)=C1N
MDL No. :MFCD00234120
InChI Key :SGPFPRGCGZLZPP-UHFFFAOYSA-N
Pubchem ID :594145

Safety of [ 933-80-2 ]

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

Computational Chemistry of [ 933-80-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 40.82
TPSA ?

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

77.82 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.32
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

0.54
Log Po/w (WLOGP)?

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

0.62
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.

-0.25
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

0.6
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.57

Water Solubility

Log S (ESOL):?

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

-1.61
Solubility 3.92 mg/ml ; 0.0247 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.

-1.75
Solubility 2.85 mg/ml ; 0.018 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

-1.93
Solubility 1.88 mg/ml ; 0.0119 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.

-6.88 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)

1.94

Application In Synthesis of [ 933-80-2 ]

* 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 [ 933-80-2 ]

[ 933-80-2 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 39906-04-2 ]
  • [ 933-80-2 ]
YieldReaction ConditionsOperation in experiment
91% With ammonia In isopropyl alcohol at 150℃; for 16 h; Sealed tube Preparation 2. 6-Chloro-4,5-diamino-2-methylpyrimidine. A 200 mL stainless steel Parr vessel was loaded with 5-amino-4,6-dichloro-2-methylpyrimidine (7.2 g, 40 mmol) and 2 M ammonia in isopropanol (100 mL), and then was sealed and heated at 150° C. for 16 h. HPLC analysis indicated complete conversion. The mixture was concentrated in vacuo, and the residue was suspended in a mixture of H2O (10 mL) and isopropanol (35 mL). This was stirred at 50° C. for 1 h and then was cooled to room temperature. The precipitate was collected by suction filtration, washed sparingly with isopropanol, then air dried on the filter to afford 6-chloro-4,5-diamino-2-methylpyrimidine (5.8 g, 91percent) as a brown powder, which was used without further purification in the next step.
63% With ammonia In water at 70 - 100℃; Preparation 19; 6-Chloro-2-methyl-pyrimidine-4,5-diamine; 2-methyl-4,6-dichloro-5-aminopyrinnidine (2. g , 11.235 mmol) was suspended in 20 ml of 37percent aqueous ammonia. The mixture was shared between 4 high pressure vials and they were heated at 100°C for 10 min. The temperature was then reduced to 7O0C and maintained overnight. LCMS indicates 80percent conversion by TIC. Upon cooling the precipitated product was filtered and washed with water to yield the title product as a yellow solid (1.125g, 63percent): LCMS (System 2): 0.30 mins (2 min run) m/z (APCI) = 159 [MH+], m/z (ES) = 159 [MH+]
38% With ammonia In ethanol at 160℃; for 4 h; Microwave irradiation Dichloropyrimidine (compound 9, Scheme 1E) was subjected to nucleophilic displacement with 4-methoxy-N-methylaniline and a catalytic amount of concentrated HC1 in the presence of i-PrOH to afford compound 2, Section E. Compound 2, section E., was hydrogenated under Pd/C at 50 psi for 3 hours (h) to afford compound 3, Section E. The synthesis of compounds 4 and 5, Section E., used trialkylaluminium in the presence of Pd catalyst and THF under reflux conditions. Compound 7, Section E., was obtained from 2 using aqueous hydriodic acid at 0 °C-rt. Compound 7 was then heated at 120 °C in the presence of DMF and copper cyanide to yield compound 8, Section E. One of the chloro groups of compound 9, Section E, was substituted with the amino group under SNAr conditions with ethanolic ammonia to produce compound 10, Section E., which was then subjected to nucleophilic displacement with 4-methoxy-N-methylaniline and a catalytic amount of concentrated HC1 in the presence of butanol to afford compound 6, Section E.
References: [1] Patent: US2011/54173, 2011, A1, . Location in patent: Page/Page column 21.
[2] Patent: WO2009/144632, 2009, A1, . Location in patent: Page/Page column 62.
[3] Patent: WO2016/22890, 2016, A1, . Location in patent: Page/Page column 64; 65.
[4] Patent: WO2010/132598, 2010, A1, . Location in patent: Page/Page column 75.
[5] Patent: WO2011/25505, 2011, A1, . Location in patent: Page/Page column 49.
[6] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5188 - 5219.
[7] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4962 - 4966.
[8] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5722 - 5733.
[9] Patent: WO2015/187684, 2015, A1, . Location in patent: Page/Page column 167.
[10] Patent: WO2018/237145, 2018, A1, . Location in patent: Paragraph 0271.
 

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Technical Information

Categories

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