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Structure of 75985-45-4

Chemical Structure| 75985-45-4

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Product Citations

Product Citations

Walczak, Juliusz Maksymilian ; Iwaszkiewicz-Grzes, Dorota ; Ziomkowska, Michalina ; Sliwka-Kaszynska, Magdalena ; Dasko, Mateusz ; Trzonkowski, Piotr , et al.

Abstract: The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.

Keywords: Mycophenolic acid ; amide derivatives ; heterocycles ; benzoxazole ; IMPDH inhibition

Alternative Products

Product Details of [ 75985-45-4 ]

CAS No. :75985-45-4
Formula : C5H7N3
M.W : 109.13
SMILES Code : N1=C(N=CC=C1)CN
MDL No. :MFCD06212857
InChI Key :ROSKZJGILXBSFM-UHFFFAOYSA-N
Pubchem ID :4658047

Safety of [ 75985-45-4 ]

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

Computational Chemistry of [ 75985-45-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 29.71
TPSA ?

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

51.8 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.96
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

-0.9
Log Po/w (WLOGP)?

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

-0.22
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.

-0.99
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

0.55
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.12

Water Solubility

Log S (ESOL):?

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

-0.44
Solubility 39.8 mg/ml ; 0.364 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.

0.29
Solubility 215.0 mg/ml ; 1.97 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Highly 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

-1.63
Solubility 2.53 mg/ml ; 0.0232 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.

-7.6 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)

1.24

Application In Synthesis of [ 75985-45-4 ]

* 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 [ 75985-45-4 ]

[ 75985-45-4 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 330785-84-7 ]
  • [ 75985-45-4 ]
  • [ 330784-47-9 ]
YieldReaction ConditionsOperation in experiment
99% With dicyclohexyl-carbodiimide; 1-hydroxy-1,2,3-benzotriazine-4(3H)-one; In N,N-dimethyl-formamide; at 0℃; In the reaction flask, anhydrous DMF 3930 mL, compound 5 (393 g, 1.0 mol), 2-aminopyrimidine (163.5 g,1.5 mol), DCC (210 g, 1.02 mol) and 1-hydroxy-1,2,3-benzotriazine-4(3H)-one (166 g, 1.02 mol) at 0 CThe reaction was stirred, monitored until Compound 5 was completely reacted, filtered, and the filtrate was added to water, extracted with chloroform, washed with organic phase and dried.After the filtrate is too short, the silica gel layer is spin-dried to obtain crude avervavir, and the crude avervavir is purified by methanol to obtain pure avenue.The yield was 99.0% and the purity was 99.85%.
91.2% With 5,10,15,20-tetrakis[4-(dihydroxyboryl)phenyl]-21H,23H-porphine; In toluene; for 16h;Reflux; Green chemistry; 4-[(3-Chloro-4-methoxyphenyl)methylamino]-2-[(S)-2-hydroxymethylpyrrol-1-yl]pyrimidine-5-carboxylic acid(39.3g, 100mmol, 1.0eq),2-Aminomethylpyrimidine (12.0 g, 110 mmol, 1.1 eq) and porphyrin borate (7.9 g, 10 mmol, 0.1 eq) were added to 500 mL of toluene.The mixture was heated to reflux to carry out a reaction for 16 hours.After the reaction,Slowly cool the reaction solution to 10-20 C.1000 mL of a 2 wt% aqueous hydrochloric acid solution was added dropwise.The temperature of the control system does not exceed 20 C,Stir for 30min,The boric acid porphyrin catalyst was recovered by filtration.Dispensing the lower aqueous phase,Add 500 mL of dichloromethane to wash the aqueous phase.Slowly add solid NaOH to adjust the pH of the aqueous phase to 7.0, and stir and crystallize for 2 h at room temperature.FiltrationThat is not crude, the filter cake is washed twice with purified water.Add the crude afarafatin to 1000 mL of anhydrous methanol and heat to reflux.After adding 3.0g of activated carbon, stirring and decolorizing for 30min,Hot filtered,The filtrate was stirred and cooled to 30 C, and crystallization was carried out for about 3 hours.filter,After ice-washing with methanol twice, it was dried at 50 C to obtain 44.1 g of a white needle solid (yield 91.2%, purity: 99.63%).
90% With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 20℃; for 4h; To is equipped with a thermometer and constant pressure dropping funnel a 250 ml three-mouth bottle by adding 20g a compound represented by the formula VI, 6.9gHOBT, 6 g2-amine methyl pyrimidine and 100 ml dimethyl sulfoxide; at room temperature to the reaction system under the conditions of adding dropwisely 11g DCC, after dropping, stirring the mixture at room temperature for 4 hours; after the reaction, the reaction system into the dumping 200g ice water, a large amount of solid precipitated, filtered, the filter cake is washed with ethyl acetate to recrystallize, that shall be atorvastatin non -22g, white solid, molar yield is 90%, HPLC purity 99.8%.
57% With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; In dichloromethane; at 20℃; add M6, EDCI, HOBT, DCM and SM5 into a three-necked flask, and react at room temperature for 10-15h. The reaction was quenched, the organic phase was separated and evaporated to dryness, a solvent was added for crystallization, and a large amount of white solid was obtained by filtration and drying, and the yield was 57%.
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 8h; (5) A mixture of the compound (600 mg) obtained in the above (4), 2-aminomethylpyrimidine (217 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (323 mg), 1-hydroxybenzotriazole monohydrate (227 mg) and N,N-dimethylformamide (12 ml) is stirred at room temperature for 8 hours, and the reaction mixture is poured into aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue is purified by a column chromatography on silica gel (solvent: chloroform:methanol = 50:1) to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine (610 mg).

  • 2
  • [ 24424-99-5 ]
  • [ 75985-45-4 ]
  • [ 1260843-26-2 ]
YieldReaction ConditionsOperation in experiment
34% With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 6h; tert-Butyl (pyrimidin-2-ylmethyl) carbamate (25):To a stirred solution of compound 24 (370 mg, 3.39 mmol) in THF (1 mL) at 0 C, Et3N (0.562 mL, 4.07 mmol) was added followed by (Boc)20 (0.86 mL, 3.73 mmol). The reaction mixture was stirred at RT for 6 h and the solvent from the reaction was removed under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 3:7) to furnish compound 25 (240 mg, 34%).TLC: 50% EtOAc Hexane (Rf: 0.3)1H NMR (400MHz, CDC13): δ 8.71 (d, J = 4.8 Hz, 2H), 7.19 (d, J = 4.8 Hz, 1H), 5.69 (br s, 1H), 4.61 (d, J = 4.4 Hz, 2H), 1.48 (s, 9H).
  • 3
  • [ 75985-45-4 ]
  • [ 2972-52-3 ]
  • 2,4-dichloro-N-(pyrimidin-2-ylmethyl)-5-pyrimidinecarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
25.5g With triethylamine; In dichloromethane; at -10 - 20℃; At room temperature, take 21.1g 2,4-dichloro-5-pyrimidine carboxylic acid chloride was added to the reaction mixture of the reaction flask was dissolved in 180mL of dichloromethane is first reaction mixture was formed, and 11. 4g 2-methylamino-pyrimidin 10. 6g triethylamine were dissolved in 100mL of dichloromethane second reaction mixture is formed, the first reaction mixture to cool -10 C, at this temperature, slowly adding the second reaction liquid to the first reaction mixture, the addition was complete after slowly warming to room temperature, 300mL water was added, layers were separated and the organic phase was washed three times 100mL were washed with water, dried over anhydrous sodium sulfate, suction filtered, the organic phase evaporated to dryness under reduced pressure to give an oil that non 25. 5g of intermediate iva A2, 4- dichloro -N- (2- methyl-pyrimidinyl) -5-pyrimidinecarboxamide.
 

Historical Records

Technical Information

Categories

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