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Product Details of [ 147118-37-4 ]

CAS No. :147118-37-4
Formula : C16H18FN3O3S
M.W : 351.40
SMILES Code : CS(=O)(N(C1=NC(C(C)C)=C(C=O)C(C2=CC=C(F)C=C2)=N1)C)=O
MDL No. :MFCD08458342
Boiling Point : No data available
InChI Key :WOCOTUDOVSLFOB-UHFFFAOYSA-N
Pubchem ID :10473133

Safety of [ 147118-37-4 ]

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

Computational Chemistry of [ 147118-37-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 24
Num. arom. heavy atoms 12
Fraction Csp3 0.31
Num. rotatable bonds 5
Num. H-bond acceptors 6.0
Num. H-bond donors 0.0
Molar Refractivity 90.56
TPSA ?

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

88.61 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.22
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

2.07
Log Po/w (WLOGP)?

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

4.12
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.

0.8
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

2.56
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.35

Water Solubility

Log S (ESOL):?

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

-3.36
Solubility 0.152 mg/ml ; 0.000434 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.

-3.56
Solubility 0.0968 mg/ml ; 0.000275 mol/l
Class?

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

-5.22
Solubility 0.00214 mg/ml ; 0.00000608 mol/l
Class?

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

Moderately 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

Yes
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

Yes
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.

-6.97 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

0.0
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

1.0 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)

2.91

Application In Synthesis of [ 147118-37-4 ]

* 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.

  • Upstream synthesis route of [ 147118-37-4 ]
  • Downstream synthetic route of [ 147118-37-4 ]

[ 147118-37-4 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 380460-37-7 ]
  • [ 147118-37-4 ]
  • [ 289042-12-2 ]
YieldReaction ConditionsOperation in experiment
91% With potassium <i>tert</i>-butylate In tetrahydrofuran; water at -15 - 42℃; for 1 h; Inert atmosphere The present embodiment of rosuvastatin calcium intermediate preparation,which is 6 - [(1E) -2- [4- (4- fluorophenyl) -6-isopropyl- 2- [methyl (methylsulfonyl) amino] -5-pyrimidinyl] ethenyl] -dimethyl-l, 3-dioxane-4-acetic acid tert-butyl ester comprises the following steps: (1) under the protection of N2,To a 1000 mL reaction flask was added 36 g of compound of formula 3,21 g of compound of formula 2 and 620 mL of tetrahydrofuran,Heated to 42 ° C and stirred until clear,Then cooled to -15 ° C, added 1.8mL of water, 20g of potassium tert-butoxide, the reaction was incubated for 60 minutes after the addition; (2) The reaction was quenched with 105mL saturated ammonium chloride, quenched after the addition of 600mL water, and then 600mL ethyl acetate extraction, washed with brine, dried and concentrated to give a pale yellow solid,Add 288mL of methanol and 48mL water recrystallization,Filtration and drying gave 31 g of a white solid, which was the target product.
120 g With sodium hydride In tetrahydrofuran at 0 - 35℃; To a solution of N-[4-(4-fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N- methyl-methane sulfonamide (100 gms) and compound III (wherein Rl=l-phenyl-lH- tetrazol-5-yl, X=0 and R2= tert-butyl; 130 gms) in tetrahydrofuran (2000 mL) was added sodium hydride (34 gms) lot wise at 0°C to 5°C. The reaction mass was stirred for 30 min at 0°C to 5°C and then the temperature was gradually allowed to raise to 25 °C to 35 °C and stirred till reaction completion. The reaction mass was quenched with 10percent potassium carbonate solution (lOOOmL) and extracted with ethyl acetate. The organic layer was washed with 10 percent NaCl solution and concentrated under vacuum. The obtained residue was triturated with methanol (500mL) ; the precipitated white solid was filtered and dried at 55°C to afford 120 gms of the title compound. HPLC purity: >98percent and Z-isomer content: <0.2percent.
References: [1] Patent: CN107298675, 2017, A, . Location in patent: Paragraph 0023-0026; 0027-0030; 0031-0034.
[2] Patent: WO2016/125086, 2016, A1, . Location in patent: Page/Page column 26-27.
  • 2
  • [ 1054627-26-7 ]
  • [ 147118-37-4 ]
  • [ 289042-12-2 ]
YieldReaction ConditionsOperation in experiment
64% With sodium hexamethyldisilazane In tetrahydrofuran at -75 - -10℃; for 2 h; Example 6b Using NaHMDS N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (0.5 g, 1.4 mmol) and 2-((4 ,6S)-6-((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate te/f-butyl ester (0.7 g, 1.6 mmol) were added to 10 mL of dry THF. After stirring for 10 min at 20°C, the reaction mixture was cooled to -70°C. At this temperature 1.9 mL of NaHMDS solution (1 M in THF, total 3.8 mmol) was added in 60 min keeping the temperature between -70 and -75°C. When dosing was completed, the temperature of the reaction mixture was allowed to increase to -10°C. After stirring at this temperature for 1 h, the reaction was quenched with 10percent aqueous NaHC03 (5 mL). The phases were separated. The aqueous layer was extracted with 2 x 20 mL of ethyl acetate. The combined organic phases were washed with 5percent aqueous Na2C03 and concentrated under vacuum. H PLC analysis indicated an E to Z ratio of >99: 1 . The residue was crystallized from methanol to give 2-((4f?,6S)-6-((E)-2-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan- 4-yl)acetate, te/f-butyl ester as a solid (0.52 g, 0.9 mmol, 64percent yield).
65 g With potassium <i>tert</i>-butylate In tetrahydrofuran at -80 - 45℃; for 1.75 h; EXAMPLE-6PREPARATION OF tert-BUTYL 2-[(4R,6-2,2-DIMETIIYL-6-[(E)-2-[4-(4- FLUOROPHENYL)-6-ISOPROPYL-2-[N-METHYL(N-METHYLSULFONYL)-AMINOIPYRIMIDIN-5-YL]VINYLI-1,3-DIOXAN-4-YLIACETATE [DIPROTECTED ROSUVASTATIN)A mixture of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl arnino)pyrimidine-5-ylcarboxaldehyde (50 g, 0.142 mole) and chiral diol sulphone (62.82 g, 0.142 mole) was dissolved in tetrahydrofuran (750 ml) at 40-45°C. The above reaction mass was cooled to -75 to -80°C and thereafter potassium tertbutoxide (22.33 g, 0.199 mole) was dissolved in tetrahydrofuran (100 ml) slowly at -80°C to -75°C over a period of 45 mi Stirring was continued till pyrimidine carboxaldehyde was consumed (—1 h) and the progress of reaction was monitored by HPLC. After completion of the reaction, 20percent aqueous ammonium chloride solution (500 ml) was added to the reaction mass at -75° to -80°C. Thereafter, temperature was raised to 20-30°C. The product was extracted with ethyl acetate (2 x 250 ml), washed with 10percent w/w aqueous sodium chloride (500 ml) and solvent was evaporated under reduced pressure at 40-45°C. Thereafter, methanol (750 ml) was added to the concentrated mass and heated to 60-65°C to obtain a clear solution. It was cooled to 0-5°C and the title compound was isolated by filtration.Yield: 65 gChroinatographic Purity (by HPLC): 99percent
References: [1] Patent: WO2012/98048, 2012, A1, . Location in patent: Page/Page column 18-19.
[2] Patent: WO2014/108795, 2014, A2, . Location in patent: Page/Page column 17.
[3] Patent: WO2016/125086, 2016, A1, . Location in patent: Page/Page column 28.
  • 3
  • [ 1054627-26-7 ]
  • [ 147118-37-4 ]
  • [ 289042-12-2 ]
YieldReaction ConditionsOperation in experiment
52% With lithium hexamethyldisilazane In tetrahydrofuran at -75 - -10℃; for 2.33333 h; Example 6 Preparation of 2-((4 ?,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan-4- yl)acetate, ferf-butyl ester (P) from N-(4-(4-fluorophenyl)-5-formyl-6- isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (J) and 2-((4 ?,6S)-6- ((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate ferf- (E) (J) (P)Example 6a Using Li HMDS N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfon ( J , 1 . 0 g, 2.9 mmol) and 2-((4ft,6S)-6-((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2- dimethyl-1 ,3-dioxan-4-yl)acetate te/f-butyl ester (E, 1.4 g, 3.1 mmol) were added to dry THF (12 mL). After stirring for 10 min at 20°C, the reaction mixture was cooled to -70°C and 3.8 mL of Li HM DS solution (1 M in TH F, total 3.8 mmol) was added in 80 min keeping the temperature between -70 and -75°C. When dosing was completed, the temperature of the reaction mixture was allowed to increase to -10°C. After stirring at this temperature for 1 h, the reaction was quenched with 10percent aqueous NaHC03 (5 mL). The phases were separated. The aqueous layer was extracted with 2 x 20 mL of ethyl acetate. The combined organic phases were washed with 5percent aqueous Na2C03 and concentrated under vacuum. H PLC analysis indicated an E to Z ratio of 70:30. The residue was crystallized from methanol to give 2-((4f?,6S)-6-((E)-2-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan- 4-yl)acetate, te/f-butyl ester as a solid (P, 0.87 g, 1.5 mmol, 52percent yield).
References: [1] Patent: WO2012/98048, 2012, A1, . Location in patent: Page/Page column 17-18.
 

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