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Chemical Structure| 18997-19-8 Chemical Structure| 18997-19-8

Structure of Pivaloyloxymethyl chloride
CAS No.: 18997-19-8

Chemical Structure| 18997-19-8

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Product Details of [ 18997-19-8 ]

CAS No. :18997-19-8
Formula : C6H11ClO2
M.W : 150.60
SMILES Code : CC(C)(C)C(OCCl)=O
MDL No. :MFCD00000884
InChI Key :GGRHYQCXXYLUTL-UHFFFAOYSA-N
Pubchem ID :87885

Safety of [ 18997-19-8 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H226-H314
Precautionary Statements:P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405
Class:3(8)
UN#:2924
Packing Group:

Computational Chemistry of [ 18997-19-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 0
Fraction Csp3 0.83
Num. rotatable bonds 3
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 36.78
TPSA ?

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

26.3 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

2.21
Log Po/w (WLOGP)?

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

1.77
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.

1.63
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

1.37
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.84

Water Solubility

Log S (ESOL):?

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

-1.97
Solubility 1.62 mg/ml ; 0.0108 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.

-2.4
Solubility 0.604 mg/ml ; 0.00401 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

-1.78
Solubility 2.49 mg/ml ; 0.0165 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

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.

-5.65 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

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)

1.65

Application In Synthesis of [ 18997-19-8 ]

* 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 [ 18997-19-8 ]

[ 18997-19-8 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 39799-77-4 ]
  • [ 18997-19-8 ]
  • 1-methyl-4-imidazolin-2-one-3-methylenepivalate [ No CAS ]
  • 2
  • [ 18997-19-8 ]
  • [ 272-97-9 ]
  • [ 105952-97-4 ]
  • [ 105952-96-3 ]
  • 3
  • [ 18997-19-8 ]
  • [ 16001-93-7 ]
  • [ 134606-34-1 ]
YieldReaction ConditionsOperation in experiment
45% With sodium iodide; In acetonitrile;Reflux; Tetramethyl methylenebisphosphonate (120 g, 0.51 mol), Nal (308 g, 2 mol), chloromethyl pivalate (387 g, 2.5 mol) and acetonitrile (400 ml) were mixed and refluxed overnight. TLC (thin-layer chromatography) in EtOAc with 5 % methanol confirmed the formation of product. The reaction mixture was diluted with ether (1000 ml) and washed with water (2 x 1000 ml), dried with Na2S03and evaporated. The solid residue was washed with cold hexane and dried in vacuum to give 148 g (45 %) of X as a pale yellow solid. NM (500 MHz, CDCI3): d 5.73-5.63 (m, 8H), 2.65 (t, 2H), 1.22 (s, 36H);31P NM (500 MHz, CDCI3): d 18.61.
  • 4
  • [ 18997-19-8 ]
  • [ 2923-28-6 ]
  • [ 133463-88-4 ]
  • 1,6-dibenzyl-1,2,5,6-tetrahydro-3,4-dioxa-7a-aza-6a-azonia-cyclopenta[<i>a</i>]pentalene; trifluoro-methanesulfonate [ No CAS ]
  • 5
  • [ 39799-77-4 ]
  • [ 18997-19-8 ]
  • 1-Methyl-4-imidazolin-2-one-3-methylenepivalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In benzene; EXAMPLE 7 Synthesis of 1-Methyl-4-imidazolin-2-one-3-methylenepivalate 1-Methyl-4-imidazolin-2-one (44 mg, 4.4*10-4 mol) and sodium hydride (20 mg) in dry benzene (20 ml) was stirred at room temperature for 2 hours. Chloromethylpivalate (71 mg) was added to the suspension and the reaction mixture was stirred for an additional 4 hours. After filtering the reaction mixture through filter paper, the filtrate was concentrated to give a liquid residue which was chromatographed through a column of silica gel to give a pure product (27 mg). T.l.c. Rf value was 0.77 using chloroform as the developing solvent system. 1 H n.m.r.(CDCl3): delta1.20(9H, s, C[CH3 ]3); 3.23(3H, s, CH3 -N); 5.55(2H, s, --NCH2 --O); 6.10 (1H, d, HC=CH); 6.38(1H, d, HC=CH). numax (film): 3190, 3150(NH); 1735, 1705(C=O); 1130 cm-1 (C-O-C). m/e 212, C10 H 16 N2)O3 requires 212.
  • 6
  • [ 18997-19-8 ]
  • [ 22246-66-8 ]
  • [ 944718-09-6 ]
YieldReaction ConditionsOperation in experiment
67% Part D: Compound 4 (2.2 g, 13.4 mmol) was dissolved in THF (250 mL) and DMPU (40 ml_). Sodium t-butoxide (1.55 g, 16.13 mmol) was added and stirred for 5 hours. Chloromethylpivalate (3.0 mL, 20.1 mmol) was added dropwise and stirred overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 25% ethyl acetate/hexanes) afforded the desired product 5 (2.5 g, 67%).
67% Compound 4 (2.2 g, 13.4 mmol) was dissolved in THF (250 mL) and DMPU (40 mL). Sodium t-butoxide (1.55g, 16.13 mmol) was added and stirred for 5 hours. Chloromethylpivalate (3.0 mL, 20.1 mmol) was added dropwise andstirred overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. Thecombined ethyl acetate layers were washed with water, brine, dried over sodium sulfate and concentrated. Purificationby column chromatography (SiO2, 25% ethyl acetate/hexanes) afforded the desired product 5 (2.5 g, 67%).
  • 7
  • [ 18997-19-8 ]
  • [ 4522-35-4 ]
  • [ 1616070-60-0 ]
YieldReaction ConditionsOperation in experiment
3-Iodo-1H-pyrazole (19.44 g, 100 mmol) was charged to a flask followed byTHF (237 mL) and the solution was cooled to -10 C. NaH (4.41 g, 110 mmol)was added in portions keeping the internal temperature below -10 C. Thereaction was stirred for 30 min, then chloromethyl pivalate (17.45 mL, 120mmol) was added and the reaction was stirred for 1 h at -1 0 C and then allowedto warm to room temperature. The reaction was cooled in an ice bath andquenched with sat. NH4Cl then diluted with EtOAc and water. The organiclayer was washed with brine, dried over MgS04 and the solvent was removed.The product was purified by flash chromatography eluting with 0-50%EtOAc/hexane to give (3-iodo-1H-pyrazol-1-yl)methyl pivalate, as a white solid.LCMS calc.= 309.01; found= 308.87 (M+H+).
3-Iodo-lH-pyrazole (19.44 g, 100 mmol) was charged to a flask followed by THF (237 mL) and the solution was cooled to -10 C. NaH (4.41 g, 110 mmol) was added in portions keeping the internal temperature below -10 C. The reaction was stirred for 30 min, then chloromethyl pivalate (17.45 mL, 120 mmol) was added and the reaction was stirred for 1 h at -10 C and then allowed to warm to room temperature. The reaction was cooled in an ice bath and quenched with sat. NH4C1 then diluted with EtOAc and water. The organic layer was washed with brine, dried over MgS04 and the solvent was removed. The product was purified by flash chromatography eluting with 0-50% EtOAc/hexane to give (3-iodo-lH-pyrazol-l-yl)methyl pivalate, as a white solid. LCMS calc. = 309.01 ; found = 308.87 (M+H+).
Step A: (3-Iodo-lH-pyrazol-l -yl)methyl pivalate To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (1.40 g) in THF (25 mL) was added NaH (0.32 g, 60%wt) at 0 C. After stirring for 10 min at 0 C, chloromethyl pivalate (1.14 g) was added to the reaction at the same temperature. The reaction mixture was stirred for 1 h at room temperature. It was diluted with sat. NaHC03 aq. and extracted with EtOAc (2 times). The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give (3-iodo-lH-pyrazol-l -yl)methyl pivalate, as a brown oil, which was used in the next step without further purification. LCMS 331 (M+Na)+. NMR (300 MHz, CDC13): 5 7.48 (1 H, d, J= 2 Hz), 6.45 (1 H, d, J= 2 Hz), 5.97 (2 H, s), 1.17 (9 H, s).
  • 8
  • [ 64-18-6 ]
  • [ 313368-91-1 ]
  • [ 18997-19-8 ]
  • (6bR,10aS)-8-(2,2-dimethyl-propionyloxymethyl)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-ium formate [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 1C - Synthesis of (6b/f,10a5)-8-(2,2-dimethyl-propionyloxymethyl)-8-[4-(4- fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-lH- pyrido[3',4':4,5]pyrrolo[l,2,3-rfe uinoxalin-8-ium formate [0100] To a solution of the 4-((6b,10a5')-3-methyl-2,3,6b,9, 10, 10a-hexahydro- lH,7H-pyrido[3',4':4,5]pyrrolo[l,2,3-(ie]quinoxalin-8-yl)-l-(4-fluorophenyl)-butan- l-one (49.0 mg, 0.12 mmol) in acetonitrile (3.0 mL) is added chloromethyl pivalate (19 muL·, 0.12 mmol), followed by adding Nal (50.0 mg, 0.33 mmol). The reaction mixture is stirred at room temperature overnight, and then filtered. The obtained filtrate is purified with a semi- preparative HPLC using a gradient of 0 - 35% B (gradient curve 4) to give (6b/?,10a5)-8- (2,2-dimethyl-propionyloxymethyl)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl- 2,3,6b,7,8,9, 10, 10a-octahydro-lH-pyrido[3',4':4,5]pyrrolo[l ,2,3-de]quinoxalin-8-ium formate. UPLC retention time: 2.48 min. ESI-MS (m/z, positive mode): 508.3.
 

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