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Structure of 14464-30-3

Chemical Structure| 14464-30-3

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Product Details of [ 14464-30-3 ]

CAS No. :14464-30-3
Formula : C12H19NO4
M.W : 241.28
SMILES Code : CCCCCCCC(ON1C(CCC1=O)=O)=O
MDL No. :MFCD00050404
InChI Key :PEJVSXYBFAVPAQ-UHFFFAOYSA-N
Pubchem ID :3542774

Safety of [ 14464-30-3 ]

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

Computational Chemistry of [ 14464-30-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 17
Num. arom. heavy atoms 0
Fraction Csp3 0.75
Num. rotatable bonds 8
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 66.18
TPSA ?

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

63.68 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.66
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

2.22
Log Po/w (WLOGP)?

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

1.57
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.

1.62
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

2.06
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.03

Water Solubility

Log S (ESOL):?

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

-2.21
Solubility 1.5 mg/ml ; 0.00622 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.

-3.19
Solubility 0.155 mg/ml ; 0.000642 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

-2.62
Solubility 0.586 mg/ml ; 0.00243 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.

-6.2 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<2.0
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)

2.69

Application In Synthesis of [ 14464-30-3 ]

* 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 [ 14464-30-3 ]

[ 14464-30-3 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 14464-30-3 ]
  • [ 491833-28-4 ]
  • [ 491833-29-5 ]
YieldReaction ConditionsOperation in experiment
75% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18 h; A compound of formula (VII) (60 mg, 0.22 mmol) in 5 mL of N, N dimethylformamide,Add DIPEA (0.065 mL, 0.38 mmol),Then intermediate A (60 mg, 0.24 mmol),Room temperature 18h,After the TLC is displayed completely,Extracted with 20 mL of ethyl acetate and washed with water.Wash with saturated sodium chloride and dry over anhydrous sodium sulfate.Filtration, evaporation of the solvent, and column chromatography (PE: EA = 10: 1-DCM: MeOH = 10:1) afforded product 65mg, yield 75percent.
74% at 10 - 20℃; Inert atmosphere (1 R, 2R)-2-Amino-1 -(2', 3'-dihydro-benzo [1 , 4] dioxin-6'-yl)-3-pyrrolidin-1 -yl-propan- 1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15° C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15° C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45°C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74percent, Mass (m/zj: 404.7 HPLC (percent Area Method): 97.5 percent, ELSD (percent Area Method): 99.78percent, Chiral HPLC (percent Area Method): 99.78 percent.
55% at 20℃; for 20 h; Inert atmosphere At 25 ~ 30 °C, the raw material EGS-SMA2.5g (1 eq) was dissolved in 50 ml of anhydrous DCM and the raw material EGS-SMB2.2g (1 eq) was dissolved in 25 ml of anhydrous DCM and replaced with nitrogen twice. Under nitrogen, the EGS-SMA solution was slowly added dropwise to the EGS-SMB solution at room temperature for 30 min. After the addition was completed, the reaction was continued for 20 hours at room temperature. 35 ml of 1 M NaOH was added to the reaction system and stirred for 45 min. After the completion of the reaction, the reaction system was separated, the organic phase was washed twice with 20 ml of 1 M NaOH, washed twice, and dried to dryness to obtain a viscous yellow liquid. And further adding 100 ml of a 5percent EA n-hexane solution to the reaction system, heating and refluxing to dissolve most of the crude product, cooling to 40 ° C, and pouring the liquid into another reaction flask. The remaining yellow viscous yellow liquid was further added to 20 ml of a 5percent EA solution of n-hexane, heated to reflux to dissolve most of the crude product, cooled to 40 ° C, poured out and repeated. The resulting n-hexane solution was stirred at room temperature for 4 h, filtered, and 10 ml of 5percent EA of n-hexane was washed twice to give 2 g of a white product as EGS-API in 55percent yield.
39% at 20℃; Inert atmosphere Compound 6 (1R,2R)-Octanoic acid [2-(2',3'-dihydro-benzo[1,4]dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide
To Intermediate 5 (22.36 g, 80.33 mmol) dissolved in anhydrous methylene chloride (300 mL) was added a solution of octanoic acid N-hydroxysuccinimide ester (19.4 g, 80.39 mmol) dissolved in anhydrous methylene chloride (150 mL) over 15-30 minutes under nitrogen at room temperature.
The solution was stirred at room temperature for 18-20 hours.
To the reaction was added 1M aqueous NaOH solution (200 mL).
The two phase system was stirred at room temperature for 45 minutes.
The layers were separated and the combined organic layers were washed twice with 1M NaOH (2*200 mL) and twice with water (2*100 mL).
The organic layer was dried with sodium sulfate, filtered and rotoevaporated to a yellow oil.
Most of the crude material was dissolved in 5percent ethyl acetate in heptane (1 L) at reflux.
After cooling to 40° C., the hazy solution was separated from the yellow oil by decanting the solution into a new flask.
The first flask was rinsed twice with 5percent ethyl acetate in heptane (2*250 mL) by the same process (reflux and cooling to 40° C. and decanting the solution from the oil).
The combined solution was heated to reflux and allowed to cool to room temperature over 4 hours.
The resulting white solid was filtered and washed with 5percent ethyl acetate in heptane (100 mL) and heptane (100 mL).
The white solid (13.9 g) was dried under vacuum for 16-24 hours.
This solid was mostly dissolved in 5percent ethyl acetate in heptane (800 mL) at reflux.
After cooling to 50° C., the hazy solution was separated from the yellow oil by decanting the solution into a new flask.
The first flask was rinsed with 5percent ethyl acetate in heptane (100 mL) by the same process (reflux and cooling to 50° C. and decanting the solution from the oil).
The combined solution was heated to reflux and allowed to cool to room temperature over 4 hours.
The resulting white solid was filtered and washed with 5percent ethyl acetate/heptane (50 mL) and heptane (50 mL).
After drying at room temperature under vacuum for 2-3 days, Compound 6 was obtained in 39percent yield (12.57 g).
Analytical chiral HPLC (column: Chirex (S)-VAL and (R)-NE, 4.6*250 mm) showed this material to be 99.9percent the desired R,R isomer.
Analytical HPLC showed this material to be 99.6percent pure. mp 87-88° C. 1H NMR (CDCl3) δ 6.86-6.73 (m, 3H), 5.84 (d, J=7.3 Hz, 1H), 4.91 (d, J=3.4 Hz, 1H), 4.25 (s, 4H), 4.24-4.18 (m, 1H), 2.85-2.75 (m, 2H), 2.69-2.62 (m, 4H), 2.10 (t, J=7.3 Hz, 2H), 1.55-1.45 (m, 2H), 1.70-1.85 (m, 4H), 1.30-1.15 (m, 8H), 0.87 (t, J=6.9 Hz, 3H) ppm.
0.3 g With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 24 h; 1 mmol of compound VIII (wherein R5 is a hydrogen atom) was dissolved in 30 ml of DMF, 1.5 mmol of DIPEA was added1.2 mmol of compound IX (wherein R6 is succinimidoyl). Plus 25, 24 hours under the reaction. After the reaction, add water quenchingAnd extracted twice with ethyl acetate. The combined organic phase was washed and dried and concentrated to give 0.3g of etilogluzide
160 mg With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18 h; Without furher purification, 7 (150 mg, 0.55 mmol) was dissolved in DMF (5 mL), DIPEA (0.16 mL, 0.95 mmol) was added to the mixture. The reaction was stirred for 5 min, then 2,5-dioxopyrrolidin-1-yl octanoate (150 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 18 h. Water was added to the reaction (15 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated. The residue was purified by flash chromatography (EtOAc/ petroleum ether, 1:10 to DCM/MeOH, 10:1) to afford 1 (160 mg, 61percent for two steps) as a white solid. mp 85–87°C; [α]eq \o(\s\up 6(20),\s\do 2( D))20 D +13 (c, 0.23, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.76-6.85 (m, 3H), 5.83 (d, J = 7.2 Hz, 1H), 4.90 (d, J = 3.6 Hz, 1H), 4.24 (s, 4H), 4.16-4.20 (m, 1H), 2.74-2.84 (m, 2H), 2.62-2.67 (m, 4H), 2.08-2.12 (m, 2H), 1.77-1.80 (m, 4H), 1.52-1.55 (m, 2H), 1.20-1.30 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 173.4, 143.4, 142.8, 134.4, 118.9, 117.0, 115.0, 75.5, 64.3, 57.8, 55.2, 52.2, 36.8, 31.6, 29.1, 29.0, 25.6, 23.6, 22.6, 14.1. HR-MS (ESI) calcd for C23H37O4 N2 (M+H)+: 405.2748, found 405.2725. [1]

References: [1] Patent: CN108822072, 2018, A, . Location in patent: Paragraph 0074; 0075.
[2] Patent: WO2015/59679, 2015, A1, . Location in patent: Page/Page column 17.
[3] Patent: CN106349210, 2017, A, . Location in patent: Paragraph 0101; 0102; 0103; 0104; 0105; 0106.
[4] Patent: US9546161, 2017, B2, . Location in patent: Page/Page column 25; 26.
[5] Patent: WO2017/68496, 2017, A1, . Location in patent: Page/Page column 27; 28; 31; 32.
[6] Patent: CN106967042, 2017, A, . Location in patent: Paragraph 0363; 0364; 0365; 0366.
[7] Synthetic Communications, 2018, vol. 48, # 5, p. 594 - 600.
 

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