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Chemical Structure| 1801-06-5

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Product Details of [ 1801-06-5 ]

CAS No. :1801-06-5
Formula : C5H4ClFN2O
M.W : 162.55
SMILES Code : COC1=NC=C(F)C(Cl)=N1
MDL No. :MFCD09834963
InChI Key :SGXQCZHNMNMMEG-UHFFFAOYSA-N
Pubchem ID :53439896

Safety of [ 1801-06-5 ]

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

Computational Chemistry of [ 1801-06-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 33.49
TPSA ?

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

35.01 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.89
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

1.57
Log Po/w (WLOGP)?

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

1.7
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.

0.78
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

2.0
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.59

Water Solubility

Log S (ESOL):?

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

-2.21
Solubility 0.991 mg/ml ; 0.0061 mol/l
Class?

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

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.92
Solubility 1.97 mg/ml ; 0.0121 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

-2.67
Solubility 0.352 mg/ml ; 0.00216 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

Yes
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.

-6.18 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 [ 1801-06-5 ]

* 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 [ 1801-06-5 ]

[ 1801-06-5 ] Synthesis Path-Downstream   1~9

  • 2
  • [ 1480-96-2 ]
  • [ 1801-06-5 ]
YieldReaction ConditionsOperation in experiment
95% With triethylamine; trichlorophosphate; In toluene; at 50 - 80℃; The 14.4g type IV compounds add 29 ml of toluene and 15.2g in triethylamine, heating to 50-80°C, dropwise 18.4g phosphorus oxychloride, the drop finishes, preserving heat and stirring reaction 5-7 hours, cooling to room temperature, adding water, separating, collecting the organic phase, organic phase is concentrated under reduced pressure, compound III namely type (strawcoloured liquid) 15.4g, molar yield is 95.0percent, HPLC purity of 95.8percent.
34% With N,N-dimethyl-aniline; trichlorophosphate; at 110℃; for 1.5h; 43b2-Methoxy-5-fluorouracil (43a, 1.04g, 7.21 mmol) and N,N-dimethylaniline (1.80 mL) were heated in POCI3 at 11O0C for 90 minutes. After cooling, the reaction was added carefully to ice. The product was extracted with diethylether. The ether layer was washed with sequentially with 2N HCI, water, and brine followed by drying (MgSO4). The ether was carefully removed under reduced pressure to give 43b as a volatile liquid (0.39g, 34percent) which was used without further purification. Rf = 0.26 (10percent EtOAc/hexane). 1H NMR (400MHz, DMSO-d6): delta 3.91 (s, 3H), 8.79 (s, 1 H)
  • 3
  • [ 1046788-69-5 ]
  • [ 1801-06-5 ]
  • [ 1046786-73-5 ]
YieldReaction ConditionsOperation in experiment
3% With acetic acid; In water; at 80℃; for 0.5h;microwave irradiation; EXAMPLE AA1 : 5-(r(2S.5f?)-4-ethyl-2.5-dimethylpiperazin-1-vncarbonyl)-lambda/-(5-fluoro-2- methoxypyrimidin-4-yl)-6,6-dimethyl-1 ,4,5.6-tetrahvdropyrrolof3.4-clpyrazol-3-amine; A solution of 5-[(2S,5f?)-4-ethyl-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl- 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine (289 mg, 0.9 mmol) and 4-chloro-5- fluoro-2-methoxypyrimidine (257 mg, 2 eq) in 5 ml_ of 50percent acetic acid in water was heated in a microwave for 30 min at 8O0C. Purification as described in Example AJ. afforded the title compound AA1 as a white powder (13.1 mg, 3percent). See Table 1 below for NMR data.
  • 4
  • [ 898044-54-7 ]
  • [ 1801-06-5 ]
  • C23H29FN8O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% With acetic acid; In water; at 100℃; for 1h; General conditions1: Chloropyrimidine 5 (0.45 mmol) and aminopyrazole 6 (0.30 mmol) were mixed in 1:1 acetic acid/water solution (1.4 mL) or in glacial acetic acid (1.4 mL) and stirred at 100 °C in an oil bath for 1 h (or 50 °C for 4 h or 25 °C for 18 h). The mixture was neutralized by the addition of ice-cold 5percent NaOH solution (10 mL) and extracted with methylene chloride (3 .x. 25 mL). Combined organic layers were dried and concentrated. The residue was further purified by normal phase flash chromatography (Biotage, for cPropylphenyl analogs R = C) or reversed phase preparative HPLC (analogs with free amines R = A or B), affording the desired aminopyrimidines (7-30).
  • 5
  • (R)-6-isopropyl-2-(3-(methylsulfonyl)phenyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride [ No CAS ]
  • [ 1801-06-5 ]
  • C20H22FN5O3S [ No CAS ]
  • 6
  • 5-fluoro-4-hydroxy-2-methoxypyrimidine [ No CAS ]
  • [ 1801-06-5 ]
YieldReaction ConditionsOperation in experiment
98.5% With trichloromethyl chloroformate; In 1,4-dioxane; N,N-dimethyl-formamide; at 5 - 25℃;Inert atmosphere; 89 g (120 molpercent) of N,N-dimethylformamide and 200 ml of 1,4-dioxane were placed in a thermometer, reflux condenser,In a dropping funnel and a mechanically stirred 1000 ml three-necked flask, the reaction system temperature was lowered to 0 ° C and stirred for 1 hour.The double phosgene gas inlet speed was maintained at 2 g/min, and the reaction temperature was maintained at not more than 5 ° C, and 1.5 mol of diphosgene was introduced in common.Then, 144 g (1.0 mol) of 2-methoxy-4-hydroxy-5-fluoropyrimidine was added in portions, and the reaction temperature was controlled to not exceed 25 °C.After the reaction is completed, nitrogen gas is removed from the system to remove residual phosgene.To the reaction solution, 200 ml of water was added in portions and stirred for 50 minutes, and then the aqueous phase was separated by liquid separation.The aqueous phase was extracted with 200 ml of dichloromethane and the organic phase was combined twice.After isolation and purification, 160 g of a yellow oily liquid was obtained, yield 98.5percent.
91% As shown in Fig. 1, 144 g (1.0 mol) of 2-methoxy-4-hydroxy-5-fluoropyrimidine, 61.1 g (50 molpercent) of 4-dimethylaminopyridine and 200 mL of nitrobenzene were charged into a single flask A three-necked 1000 mL flask equipped with a thermometer, a reflux condenser, a dropping funnel and a mechanical stirrer was slowly heated to 100 ° C and stirred for 30 minutes. Then the phosgene was started slowly, maintaining the flow rate of 7 g / min. The phosgene was introduced twice as much as the molar amount of 2-methoxy-4-hydroxy-5-fluoropyrimidine and the reaction was refluxed for 20 hours . After the reaction was completed, the phosgene was stopped and the temperature was lowered to room temperature and purged with nitrogen to remove phosgene from the system. Then, the solid was removed by filtration under reduced pressure, 100 mL of water was added to the filtrate and the mixture was stirred for 30 minutes, and then the aqueous phase was separated and separated. The aqueous phase was extracted with 100 mL of ethyl acetate and the organic phases were combined twice and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure to give 147.4 g of a yellow oily product in 91percent yield.
To 100 ml dichloroethane and 25 ml acetonitrile as a solvent. Using dichloroethane as a solvent, the first 100 ml dichloroethane and 25 ml acetonitrile is poured into the 250 ml flask is, by adding 14.4g (0.1mol) of 2-methoxy-5-fluoro-4-hydroxy-pyrimidine. After dropwise 32.2g (0.3mol) of phosphorus oxychloride, within half an hour after the dropping, the stirring 10 minutes later, start dropwise triethylamine 21.2g (0.21mol), heating to 60 °C, stirring 2 hours later, cooling. In the reaction solution is poured into the crushed ice, to be layered. Applying the organic phase is 2-methoxy-4-chloro-5-fluoro pyrimidine dichloroethane solution.Then, 15 g of water and hydrazine were added dropwise thereto, and the mixture was heated to 70 ° C and reacted 2h, and the reaction was monitored by HPLC. The product was obtained as white needle crystals. 2-Methoxy-4-hydrazino-5-fluoro pyrimidine 11.98g (0.075 mol), m.p. 187 ° -188 ° C, product content 98.5percent, yield 77percent.
  • 7
  • [ 1801-06-5 ]
  • 5-fluoro-4-hydrazino-2-methoxypyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
11.98 g With hydrazine hydrate; In 1,2-dichloro-ethane; at 70℃; for 2h; To 100 ml dichloroethane and 25 ml acetonitrile as a solvent. Using dichloroethane as a solvent, the first 100 ml dichloroethane and 25 ml acetonitrile is poured into the 250 ml flask is, by adding 14.4g (0.1mol) of 2-methoxy-5-fluoro-4-hydroxy-pyrimidine. After dropwise 32.2g (0.3mol) of phosphorus oxychloride, within half an hour after the dropping, the stirring 10 minutes later, start dropwise triethylamine 21.2g (0.21mol), heating to 60 °C, stirring 2 hours later, cooling. In the reaction solution is poured into the crushed ice, to be layered. Applying the organic phase is 2-methoxy-4-chloro-5-fluoro pyrimidine dichloroethane solution.Then, 15 g of hydrazine hydrate were added dropwise thereto, and the mixture was heated to 70 ° C and reacted 2h, and the reaction was monitored by HPLC. The product was obtained as white needle crystals. 2-Methoxy-4-hydrazino-5-fluoro pyrimidine 11.98g (0.075 mol), m.p. 187 ° -188 ° C, product content 98.5percent, yield 77percent.
  • 8
  • [ 1801-06-5 ]
  • [ 1993-63-1 ]
YieldReaction ConditionsOperation in experiment
95% With ammonia; In isopropyl alcohol; at 40 - 60℃; The 32.5g formula III compound are added 170g10wt percent of the isopropyl alcohol solution of ammonia, heating to 40-60°C, stirring reaction 3-5 hours, natural cooling to room temperature, filtered, collecting solid, washing with isopropyl alcohol, drying, the compound of formula II is obtained (kind of white solid) 27.2g, molar yield is 95.0percent, HPLC purity of 99.0percent.
  • 9
  • [ 514816-42-3 ]
  • [ 1801-06-5 ]
  • methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
<Step 1> Synthesis of methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate Using 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS No.: 514816-42-3, 2.52 g, 11.5 mmol) and <strong>[1801-06-5]4-chloro-5-fluoro-2-methoxypyrimidine</strong> (1.5 g), methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.6 g) was obtained as a pale yellow liquid using a method similar to that in <Step 1> in Working Example 3 or a method based on this method. (Physical property data) LC-MS: M=266, RT=0.91 (min), [M+H]+=267. 1H-NMR (300 MHz, CDCl3, delta ppm): 8.35 (1H, d, J=2 Hz), 7.86 (1H, d, J=1 Hz), 4.15 (3H, s), 4.00 (3H, s), 3.86 (3H, s).
 

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