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Chemical Structure| 99469-99-5 Chemical Structure| 99469-99-5

Structure of Repaglinide Related Compound B
CAS No.: 99469-99-5

Chemical Structure| 99469-99-5

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Product Details of [ 99469-99-5 ]

CAS No. :99469-99-5
Formula : C13H16O5
M.W : 252.26
SMILES Code : O=C(O)CC1=CC=C(C(OCC)=O)C(OCC)=C1
MDL No. :MFCD08704233
InChI Key :OTGSESBEJUHCES-UHFFFAOYSA-N
Pubchem ID :10131212

Safety of [ 99469-99-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H319
Precautionary Statements:P305+P351+P338

Computational Chemistry of [ 99469-99-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 6
Fraction Csp3 0.38
Num. rotatable bonds 7
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 65.37
TPSA ?

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

72.83 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.41
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

1.94
Log Po/w (WLOGP)?

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

1.89
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.

1.83
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

2.31
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.08

Water Solubility

Log S (ESOL):?

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

-2.41
Solubility 0.979 mg/ml ; 0.00388 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.

-3.09
Solubility 0.203 mg/ml ; 0.000806 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

-3.19
Solubility 0.161 mg/ml ; 0.000638 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.

-6.46 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.

0.56

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<0.0
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)

2.24

Application In Synthesis of [ 99469-99-5 ]

* 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 [ 99469-99-5 ]

[ 99469-99-5 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 99469-99-5 ]
  • [ 147769-93-5 ]
  • [ 147770-06-7 ]
YieldReaction ConditionsOperation in experiment
93% Example 11 (S)(+)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonyl-methyl]-benzoic acid ethyl ester 20.77 g (82.4 mmol) of 2-(3-Ethoxy-4-(ethoxycarbonyl)phenyl)-acetic acid were slowly added to a solution of N,N'-carbonyldiimidazole (13.36 g, 82.4 mmol, 97%) in dichloromethane (240 ml) at room temperature. After activation for 1.5h at 20-25C a solution of (S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butan-1-amine (19.70 g, 80.0 mmol) in dichloromethane (80 ml) was added dropwise and the resulting mixture was stirred for 2h. The reaction mixture was quenched by adding water (2 x 160 ml). The organic phase was then evaporated under reduced pressure. The yield of the crude repaglinide ester product of formula IV was 35.7 g (93%; HPLC: 97.58%).
89.5% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 0 - 20℃; for 18.5h; To a mixture of (1 3-METHYL-1-(2-PIPERIDIN-1-YLPHENYL) BUTAN-1-AMINE (499, 0.2 MOL), [3-ETHOXY-4- (ETHOXYCARBONYL) PHENYL] acetic acid (50 g, 0.2 mol) and triethylamine (100 g, 0.99 mol) in ethyl acetate (1.0 L), a solution (50% w/w) of propane phosphonic acid anhydride (278 g, 0.44 mol) in ethyl acetate was added dropwise over a period of 30 minutes, maintaining the temperature at 0-5 C and stirred for 18 hours at ambient temperature. The reaction mixture was washed with 1.5 N HCI, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to give title compound. Yield : 86 g, 89.5%
89.6% With phenylboronic acid; In toluene; for 16 - 18h;Heating / reflux;Product distribution / selectivity; EXAMPLE 2 Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate In a round bottom flask fitted with a dean stark condenser, 3-Ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 mol) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 mol) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was cooled at 25-30 C. followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue after complete removal of toluene in order to precipitate the solid, with stirring for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55 C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoate (Yield=89.6%; HPLC Purity: 99.66%).
89.6% With phenylboronic acid; In toluene;Reflux; Example 8Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoateIn a round bottom flask fitted with a Dean Stark condenser, 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 moles) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 moles) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 moles). The reaction mixture was refluxed for 16-18 hours. The reaction mixture was cooled at room temperature followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution. This was followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue in order to precipitate the solid and then stirred for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55 C. under vacuum for 4-6 hours to produce ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate (Yield: 89.6%; HPLC purity: 99.46%; and Chiral purity: 99.98%).
87.2% With tetramethylorthosilicate; In toluene; for 11h;Inert atmosphere; Reflux; Under nitrogen, compound 370.3g (0.285mol, 1eq), 4- carboxy-methyl-2-ethoxy ethyl benzoate 72.0g (0.285mol ,, 1eq), tetramethoxysilane 86.8g (152.22,0.57 mol, 2eq) and 285g of toluene, heated to reflux for 11 hours, HPLC control the starting material the reaction was complete, cooled, concentrated under reduced pressure, from ethanol / MTBE to give white crystalline solid 119.4g, HPLC98.8%, yield 87.2%, 99.5% ee.
73.3% With boric acid; In toluene; for 16 - 18h;Heating / reflux;Product distribution / selectivity; EXAMPLE 1 Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate In a round bottom flask fitted with a dean stark condenser, (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol) was dissolved in toluene (100 ml), followed by the addition of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0407 mol) and boric acid (0.26 g, 0.0042 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was then cooled to 25-30 C. followed by filtration. The filtrate was washed with water and 1.0% sodium bicarbonate solution followed by complete distillation of toluene and the resulting residue was stirred with hexane (50 ml) for 1 hour. The precipitated solid was filtered and washed with hexane (10 ml). The wet product was dried at 50-55 C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonyl methyl]-benzoate (Yield=73.3%; HPLC Purity: 99.50%).
With triethylamine; triphenylphosphine; In tetrachloromethane; acetonitrile; EXAMPLE 1 Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate 0.48 g (1.91 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid, 0.60 g (2.29 mMol) of triphenylphosphine, 0.80 ml (5.73 mMol) of triethylamine and 0.18 ml (1.91 mMol) of carbon tetrachloride are added successively to a solution of 0.47 g (1.91 mMol) of (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 5 ml of anhydrous acetonitrile and the resulting mixture is stirred for 20 hours at ambient temperature. It is then evaporated down in vacuo and distributed between ethyl acetate and water. The organic extract is dried and filtered and evaporated down in vauco. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate=10/1). Yield: 0.71 g (77.3% of theory), Melting point: 110-112 C. Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.29; H 8.42; N 5.80.
With dicyclohexyl-carbodiimide; In toluene; at 25 - 40℃; EXAMPLE 5; PREPARATION OF REPAGLINIDE; 3-Ethoxy-4-(ethoxycarbonyl)benzene acetic acid (2.25 g, 0.0089 moles) was added to a solution of (alphaS)-alpha-(2-methylpropyl)-2-(1-piperidinyl)benzenemethanamine (2g, .008 moles) in toluene (20 ml). Then N,N-dicyclohexylcarbodiimide (1.95 g, 0.0094 moles) was added and the reaction mixture was stirred till completion of the reaction at 25-40C. The solid was filtered under suction and toluene filtrate was distilled under reduced pressure. The product was crystallized from ethanol / water and dried to yield ethyl 2-ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoate (3 g). 1N aqueous sodium hydroxide solution (8.0 ml) in ethanol (30 ml) was added to ethyl-2-ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoate (3 g) at 60-65C and stirred. After completion of the reaction the reaction mixture was cooled, pH was adjusted to 5 with 1N aqueous hydrochloric acid and product was filtered and dried at reduced pressure. The dried product was recrystallised from aqueous ethanol to give repaglinide. Yield: 2.27 g

  • 2
  • [ 99469-99-5 ]
  • (S)-3-Methyl-1-(2-piperidin-1-yl-phenyl)-butylamine; compound with (S)-2-acetylamino-pentanedioic acid [ No CAS ]
  • [ 147770-06-7 ]
  • 3
  • [ 99469-99-5 ]
  • [ 147770-06-7 ]
  • 4
  • [ 799255-55-3 ]
  • [ 99469-99-5 ]
  • [ 147770-06-7 ]
  • 5
  • [ 799255-59-7 ]
  • [ 99469-99-5 ]
  • [ 147770-06-7 ]
 

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