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Chemical Structure| 1206102-07-9

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Product Details of [ 1206102-07-9 ]

CAS No. :1206102-07-9
Formula : C17H19NO6
M.W : 333.34
SMILES Code : O=C(C1=C(OCC2=CC=CC=C2)C(C=CN1CC(O)CO)=O)OC
MDL No. :MFCD22741605
InChI Key :JUVSRACZYLMJQD-UHFFFAOYSA-N
Pubchem ID :58277222

Safety of [ 1206102-07-9 ]

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

Computational Chemistry of [ 1206102-07-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 24
Num. arom. heavy atoms 12
Fraction Csp3 0.29
Num. rotatable bonds 8
Num. H-bond acceptors 6.0
Num. H-bond donors 2.0
Molar Refractivity 86.16
TPSA ?

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

97.99 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.42
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

0.71
Log Po/w (WLOGP)?

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

0.42
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.

-0.21
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

1.76
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.02

Water Solubility

Log S (ESOL):?

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

-2.2
Solubility 2.12 mg/ml ; 0.00637 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.

-2.35
Solubility 1.5 mg/ml ; 0.00451 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

-3.52
Solubility 0.0995 mg/ml ; 0.000299 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.

-7.83 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

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)

3.47

Application In Synthesis of [ 1206102-07-9 ]

* 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 [ 1206102-07-9 ]

[ 1206102-07-9 ] Synthesis Path-Upstream   1~13

  • 1
  • [ 1206102-06-8 ]
  • [ 77-78-1 ]
  • [ 1206102-07-9 ]
YieldReaction ConditionsOperation in experiment
84% With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one; water at 28 - 33℃; for 15 - 17 h; A reactor was charged with 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1 ,4- dihydro-2-pyridinecarboxylic acid 6 (4.302 kg, 13.47 mol) followed by charging withNaHCO3 (1.69 kg, 20.09 mol) and 242 g of deionized water. To this was added 21.4 kg of NMP and the mixture was stirred and temperature brought to 28-35 0C. Dimethyl sulfate (2.34 kg, 18.30 mol) was added dropwise via an addition funnel to the reaction mixture over 1-3 hours keeping the temperature at 28-330C. The slurry was agitated at this temperature for 14 h. When deemed complete, the reaction mixture was cooled to 5 0C or below and the mixture was neutralized to pH 6 by the addition of HCI (561 ml_ of cone HCI in 2806 g of deionized water). The reaction vessel was slowly charged with cold 20percent brine solution composed of 8.7 kg NaCI, 20 kg of deionized water and 14.8 kg of ice at a maximum temperature of 100C. The mixture was agitated at 0-100C for 2.5 h. The slurry was filtered under vacuum and the cake washed with 15 kg of deionized water two times. The wet solid product was dried at 45-55 0C under vacuum until constant weight was obtained. The desired product methyl 1-(2,3-dihydroxypropyl)-4-oxo-3- [(phenylmethyl)oxy]-1 ,4-dihydro-2-pyridinecarboxylate 7 was obtained as a light yellow solid (3.77 kg, 99.42percent purity by HPLC, 84percent). 1H NMR(300 MHz, DMSO-d6) δ 7.60 (d, J = 7.5 Hz, 1 H), 7.36 (m, 5 H), 6.28 (d, J = 7.5 Hz, 1 H), 5.23 (d, J = 5.4 Hz, 1 H), 5.10 (Abq, J = 10.8 Hz, 2 H), 4.85 (m, 1 H), 3.98 (dd, J = 14.3, 2.4 Hz, 1 H), 3.79 (s, 3 H), 3.70 (dd, J = 14.3, 9.0 Hz, 1 H), 3.58 (m, 1 H), 3.23 (m, 1 H).
84% With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one; water at 28 - 35℃; Large scale Areactor was charged with 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid 6 (4.302 kg, 13.47 mol) followed by charging with NaHCO3(1.69 kg, 20.09 mol) and 242 g of deionized water. To this was added 21.4 kg of NMP and the mixture was stirred and temperature brought to 28-35° C. Dimethyl sulfate (2.34 kg, 18.30 mol) was added dropwise via an addition funnel to the reaction mixture over 1-3 hours keeping the temperature at 28-33° C. The slurry was agitated at this temperature for 14 h. When deemed complete, the reaction mixture was cooled to 5° C. or below and the mixture was neutralized to pH 6 by the addition of HCl (561 mL of conc HCl in 2806 g of deionized water). The reaction vessel was slowly charged with cold 20percent brine solution composed of 8.7 kg NaCl, 20 kg of deionized water and 14.8 kg of ice atamaximum temperature of 10° C. The mixture was agitated at 0-10° C. for 2.5 h. The slurry was filtered under vacuum and the cake washed with 15 kg of deionized water two times. The wet solid product was dried at 45-55° C. under vacuum until constant weight was obtained. The desired product methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 7 was obtained asalight yellow solid (3.77 kg, 99.42percent purity by HPLC, 84percent).
References: [1] Patent: WO2010/68262, 2010, A1, . Location in patent: Page/Page column 31-32.
[2] Patent: JP5848595, 2016, B2, . Location in patent: Paragraph 0050.
  • 2
  • [ 1206102-06-8 ]
  • [ 74-88-4 ]
  • [ 1206102-07-9 ]
YieldReaction ConditionsOperation in experiment
95% With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one at 20℃; for 5 h; (4) 10 g of Intermediate 4, 7.9 g of sodium hydrogencarbonate and 6.7 g of methyl iodide were added to 20 mL of N-methylpyrrolidone, and the mixture was stirred at room temperature for 5 hours, and the reaction was completed.Under ice water bath, dilute hydrochloric acid adjusts the system pH=4, adding a lot of water,a yellow solid precipitates,Filtered, washed, dried,Yield 9.9 g of a white solid, intermediate 5, yield: 95percent.
89% With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one; water at 20℃; for 4 h; To a slurry of 576 g of compound 6(1.0 eq.: 5.8percent of H2O was contained) in 2.88 L of NMP were added 431 g of NaHCO3(3.0 eq.) and 160 mL of methyl iodide(1.5 eq.) and the mixture was stirred at room temperature for 4 h. After cooling to 5 0C, 1.71 L of 2N HCI and 1.15 L of 20percent NaClaq were added to the mixture at less than 10 0C to give crystal of compound 7. Filtration, washing with 1.73 L of H2O and drying provided 507 g of compound 7 (89percent yield) as a crystal.1H NMR(300 MHz, DMSO-d6) δ 7.59 (d, J = 7.5 Hz, 1 H), 7.40-7.28 (m, 5H), 6.28 (d, J = 7.5 Hz, 1 H)1 5.21 (d, J = 5.4 Hz, 1 H), 5.12 (d, J = 10.8 Hz, 1 H), 5.07 (d, J = 10.8 Hz, 1H), 4.83 (t, J = 5.7 Hz, 1H), 3.97 (dd, J = 2.4, 14.1 Hz, 1 H), 3.79 (s, 3H), 3.70 (dd, J = 9.0, 14.4 Hz, 1 H), 3.65-3.50 (m, 1 H), 3.40-3.28 (m, 1H), 3.26-3.14 (m, 1 H).
89% With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one; water at 20℃; for 4 h; f) Synthesis of methyl 1 -(2,3-dihydroxypropyl)-4-oxo-3- [(phenylmethyl)oxy]-1 ,4-dihydro-2-pyridinecarboxy- late (compound P-7). To a slurry of 576 g of compound P-6 (1.0 eq.: 5.8percent of H20 was contained) in 2.88 E ofNMP were added 431 g of NaHCO3 (3.0 eq.) and 160 mE of methyl iodide (1.5 eq.) and the mixture was stirred at room temperature for 4 h. Afier cooling to 5° C. 1.71 E of 2N HC1 and 1.15 E of 20percent NaClaq were added to the mixture at less than 10° C. to give crystal of compound 7. Filtration, washing with 1.73 E of H20 and drying provided 507 g of compound P-7 (89percent yield) as a solid. ‘H NMR (300 MHz, DMSO-d5) ö 7.59 (d, J=7.5 Hz, 1H), 7.40-7.28 (m, 5H), 6.28 (d, J=7.5 Hz, 1H), 5.21 (d, J=5.4 Hz, 1H), 5.12 (d, J=10.8 Hz, 1H), 5.07 (d, J=10.8 Hz, 1H), 4.83 (t, J=5.7 Hz, 1H), 3.97 (dd, J=2.4, 14.1 Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J=9.0, 14.4 Hz, 1H),3.65-3.50 (m, 1H), 3.40-3.28 (m, 1H), 3.26-3.14 (m, 1H).
89% With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one; water at 20℃; for 4 h; To a slurry of 576 g of compound 6(1.0 eq.: 5.8percent of H2O was contained) in 2.88 L of NMP were added 431 g of NaHCO3(3.0 eq.) and 160 mL of methyl iodide (1.5 eq.) and the mixture was stirred at room temperature for 4 h. After cooling to 5° C., 1.71 L of 2N HCl and 1.15 L of 20percent NaClaq were added to the mixture at less than 10° C. to give crystal of compound 7. Filtration, washing with 1.73 L of H2O and drying provided 507 g of compound 7 (89percent yield) as a crystal.
55% With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one at 20℃; Inert atmosphere Step E - Synthesis of Intermediate Compound A Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. This was followed by the addition of 3-(benzyloxy)-l-(2,3- dihydroxypropyl)-4-oxo-l,4-dihydropyridine-2-carboxylic acid If (200 g, 626.35 mmol, 1.00 equiv), NMP (1000 mL), sodium bicarbonate (158 g, 1.88 mol, 3.00 equiv), CH3I (133.5 g, 940.54 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was cooled to 0 °C with a water/ice bath. The resulting solution was diluted with a solution of NaCl (73 g) in 500 mL of H20. Then the pH value of the solution was adjusted to 4 with hydrogen chloride (cone). The reaction mixture was then stirred for another 2 hours. The solids were collected by filtration, washed with water (2x100 mL) and then dried in an oven in vacuo. This resulted in methyl 3-(benzyloxy)-l-(2,3-dihydroxypropyl)-4-oxo-l,4- dihydropyridine-2-carboxylate (117.6 g, 55percent yield) A as a white solid.

References: [1] Patent: CN108299466, 2018, A, . Location in patent: Paragraph 0032; 0036.
[2] Patent: WO2010/68262, 2010, A1, . Location in patent: Page/Page column 17-18.
[3] Patent: US9133216, 2015, B2, . Location in patent: Page/Page column 17; 19; 20.
[4] Patent: JP5848595, 2016, B2, . Location in patent: Paragraph 0032; 0038.
[5] Patent: WO2015/39348, 2015, A1, . Location in patent: Page/Page column 24; 26.
[6] Patent: WO2010/11816, 2010, A1, . Location in patent: Page/Page column 16; 18-19.
  • 3
  • [ 1206102-06-8 ]
  • [ 1206102-07-9 ]
References: [1] Patent: US9242986, 2016, B2, .
  • 4
  • [ 118-71-8 ]
  • [ 1206102-07-9 ]
References: [1] Patent: WO2015/39348, 2015, A1, .
[2] Patent: US9133216, 2015, B2, .
[3] Patent: JP5848595, 2016, B2, .
[4] Patent: JP5848595, 2016, B2, .
[5] Patent: JP5848595, 2016, B2, .
[6] Patent: JP5848595, 2016, B2, .
[7] Patent: WO2010/11816, 2010, A1, .
[8] Patent: CN108299466, 2018, A, .
[9] Organic Process Research and Development, 2019, vol. 23, # 4, p. 565 - 570.
  • 5
  • [ 100-39-0 ]
  • [ 1206102-07-9 ]
References: [1] Patent: WO2015/39348, 2015, A1, .
[2] Patent: US9133216, 2015, B2, .
[3] Patent: JP5848595, 2016, B2, .
[4] Patent: JP5848595, 2016, B2, .
[5] Patent: JP5848595, 2016, B2, .
[6] Patent: JP5848595, 2016, B2, .
[7] Patent: WO2010/11816, 2010, A1, .
[8] Organic Process Research and Development, 2019, vol. 23, # 4, p. 565 - 570.
  • 6
  • [ 61049-69-2 ]
  • [ 1206102-07-9 ]
References: [1] Patent: WO2015/39348, 2015, A1, .
[2] Patent: US9133216, 2015, B2, .
[3] Patent: JP5848595, 2016, B2, .
[4] Patent: JP5848595, 2016, B2, .
[5] Patent: JP5848595, 2016, B2, .
[6] Patent: JP5848595, 2016, B2, .
[7] Patent: WO2010/11816, 2010, A1, .
[8] Patent: CN108299466, 2018, A, .
[9] Organic Process Research and Development, 2019, vol. 23, # 4, p. 565 - 570.
  • 7
  • [ 1206102-04-6 ]
  • [ 1206102-07-9 ]
References: [1] Patent: WO2015/39348, 2015, A1, .
[2] Patent: US9133216, 2015, B2, .
[3] Patent: JP5848595, 2016, B2, .
[4] Patent: JP5848595, 2016, B2, .
[5] Patent: WO2010/11816, 2010, A1, .
[6] Organic Process Research and Development, 2019, vol. 23, # 4, p. 565 - 570.
  • 8
  • [ 1206102-05-7 ]
  • [ 1206102-07-9 ]
References: [1] Patent: WO2015/39348, 2015, A1, .
[2] Patent: US9133216, 2015, B2, .
[3] Patent: WO2010/11816, 2010, A1, .
  • 9
  • [ 119736-16-2 ]
  • [ 1206102-07-9 ]
References: [1] Patent: WO2015/39348, 2015, A1, .
[2] Patent: US9133216, 2015, B2, .
[3] Patent: JP5848595, 2016, B2, .
[4] Patent: JP5848595, 2016, B2, .
[5] Patent: WO2010/11816, 2010, A1, .
[6] Patent: CN108299466, 2018, A, .
  • 10
  • [ 1229006-11-4 ]
  • [ 1206102-07-9 ]
References: [1] Patent: JP5848595, 2016, B2, .
[2] Patent: JP5848595, 2016, B2, .
  • 11
  • [ 500371-01-7 ]
  • [ 1206102-07-9 ]
References: [1] Patent: JP5848595, 2016, B2, .
[2] Patent: JP5848595, 2016, B2, .
  • 12
  • [ 100-44-7 ]
  • [ 1206102-07-9 ]
References: [1] Patent: CN108299466, 2018, A, .
  • 13
  • [ 616-30-8 ]
  • [ 1229006-11-4 ]
  • [ 77-78-1 ]
  • [ 1206102-07-9 ]
References: [1] Organic Process Research and Development, 2019, vol. 23, # 4, p. 565 - 570.
 

Historical Records

Technical Information

• Acyl Group Substitution • Appel Reaction • Baeyer-Villiger Oxidation • Barbier Coupling Reaction • Baylis-Hillman Reaction • Bouveault-Blanc Reduction • Bucherer-Bergs Reaction • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Catalytic Hydrogenation • Chugaev Reaction • Clemmensen Reduction • Complex Metal Hydride Reductions • Corey-Bakshi-Shibata (CBS) Reduction • Corey-Chaykovsky Reaction • Corey-Kim Oxidation • Dess-Martin Oxidation • Ester Cleavage • Fischer Indole Synthesis • Grignard Reaction • Henry Nitroaldol Reaction • Horner-Wadsworth-Emmons Reaction • Hydride Reductions • Jones Oxidation • Lawesson's Reagent • Leuckart-Wallach Reaction • Martin's Sulfurane Dehydrating Reagent • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Mitsunobu Reaction • Moffatt Oxidation • Nomenclature of Ethers • Oxidation of Alcohols by DMSO • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Peterson Olefination • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Alcohols • Preparation of Aldehydes and Ketones • Preparation of Amines • Preparation of Ethers • Prins Reaction • Reactions of Alcohols • Reactions of Aldehydes and Ketones • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions of Ethers • Reactions with Organometallic Reagents • Reformatsky Reaction • Ritter Reaction • Robinson Annulation • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Sharpless Olefin Synthesis • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Stobbe Condensation • Swern Oxidation • Tebbe Olefination • Ugi Reaction • Wittig Reaction • Wolff-Kishner Reduction

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