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Chemical Structure| 98760-08-8

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Product Details of [ 98760-08-8 ]

CAS No. :98760-08-8
Formula : C15H21NO3
M.W : 263.33
SMILES Code : O=C(N[C@@H](CC1=CC=CC=C1)[C@@H]2CO2)OC(C)(C)C
MDL No. :MFCD00671705
InChI Key :NVPOUMXZERMIJK-STQMWFEESA-N
Pubchem ID :9813904

Safety of [ 98760-08-8 ]

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

Computational Chemistry of [ 98760-08-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 19
Num. arom. heavy atoms 6
Fraction Csp3 0.53
Num. rotatable bonds 7
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 73.35
TPSA ?

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

50.86 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.79
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

2.64
Log Po/w (WLOGP)?

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

2.52
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.

1.93
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

2.83
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.54

Water Solubility

Log S (ESOL):?

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

-2.91
Solubility 0.326 mg/ml ; 0.00124 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.

-3.36
Solubility 0.115 mg/ml ; 0.000438 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

-3.87
Solubility 0.0359 mg/ml ; 0.000136 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

Yes
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.

-6.03 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<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)

3.13

Application In Synthesis of [ 98760-08-8 ]

* 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 [ 98760-08-8 ]

[ 98760-08-8 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 162536-40-5 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydroxide; In water; isopropyl alcohol; at 0℃; for 4h;Product distribution / selectivity; To (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (45.1 g) obtained in Example 3 were added isopropanol (120 ml) and water (45 ml), and the mixture was cooled to 0C. 29%. Aqueous sodium hydroxide solution was added, and the mixture was stirred for 4 hours. Aqueous citric acid solution (a mixed solution of citric acid (6.73 g) and water (14 ml)) was added to the reaction mixture, and acetone (35 ml) and water (59.5 ml) were further added. A seed crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was added, and this mixture was stirred for 1 hour. Water (200 ml) was added dropwise to the mixture over 1 hour, and the mixture was stirred overnight. The slurry solution was filtered, and the crystals were washed twice with aqueous acetone solution (a mixed solution of acetone (50 ml) and water (350 ml)). Wet crystals were dried under reduced pressure at room temperature to give (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane as white crystals (37.1 g, 100 wt%, yield 93%). As a result of HPLC analysis, it was found that the peak area ratio of the compound was 99.9%, and the diastereomer ((2S,3S)-form) was not detected.
83% With sodium hydroxide; In water; isopropyl alcohol; at 0℃; for 8.5h;Product distribution / selectivity; The organic layer (26.5 g) obtained in Comparative Example 2, step (2'g), was concentrated under reduced pressure, isopropanol (2 ml) was added to the residue, and the mixture was concentrated again to dryness. Isopropanol (21.8 ml) and water (3.0 ml) were added to the residue and the mixture was cooled to 0C. Then, 6 M aqueous sodium hydroxide solution (2.7 ml) and water (1.2 ml) were added to the solution, and the mixture was reacted for 8.5 hours. An aqueous solution (36.6 ml) of citric acid (351 mg) was added to the reaction mixture, and the mixture was cooled from 0C to -10C over 3 hours. A seed crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was added, and the mixture was stirred at -10C for 3 days and filtered. The obtained crystals were dried under reduced pressure to give adhesive orange crystals (2.47 g). As a result of HPLC analysis, it was found that the content of the object compound, (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane, was 2.07 g, 83.8 wt%, and the yield was 83%. In addition, the crystals contained 0.071 g of a diastereomer ((2S,3S)-form)), and the diastereomer ratio (2R,3S)/(2S,3S) was 96.7/3.3. Moreover, the peak area ratio of other byproduct was 10% relative to the object compound, (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane.
81.4 mg (93.5%) With potassium carbonate; citric acid; In methanol; water; ethyl acetate; Example 6 Production of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (100 mg) and potassium carbonate (91.5 mg) were added to methanol (2.0 ml) for agitation at ambient temperature for 4 hours. Aqueous 10% citric acid solution (0.204 ml) and water (0.408 ml) were added to the resulting mixture, from which the solvent was evaporated under reduced pressure. To the residue were added water (1 ml) and ethyl acetate (1 ml) for extraction; the organic phase was concentrated under reduced pressure, to afford (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane {(2R,3S) yield: 81.4 mg (93.5%)}. 1H-NMR (CDCl3, 300 MHz) delta ppm: 1.38 (s, 9H), 2.59 (bs, 1H), 2.69 (t. J=4.4 Hz, 1H), 2.83-3.04 (m, 3H), 4.12 (bs, 1H), 4.48 (bs, 1H), 7.17-7.37 (m, 5H) Mass spectrum m/e: 286 (M+Na+)
191 mg (71.6%) With potassium carbonate; citric acid; In ethanol; water; Example 7 Production of crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane To (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 300 mg; (2S,3S) content of 6.67 mg} obtained in the same manner as in Example 1 were added ethanol (3.40 ml), water (0.109 ml) and potassium carbonate (755 mg), for agitation at ambient temperature for 5 hours and further agitation at 30 C. for one hour. After cooling to 5 C., aqueous 17.5% citric acid solution (3.99 g) was added. After phase separation at 0 C., the ethanol layer was cooled to -10 C., followed by addition of the seed crystal and overnight agitation, to crystallize (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. The resulting slurry was filtered, to afford (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. {(2R,3S) yield: 191 mg (71.6%) The dried crystal was analyzed by HPLC. (2R,3S): (2S,3S)-96.8:3.2.
64.2 mg (75%) With sodium hydroxide; In water; acetone; Example 8 Production of crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane Acetone (0.8 ml) and aqueous 2.5 mol/l sodium hydroxide solution (0.2 ml) were added to (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 97.8 mg; (2S,3S) content of 2.2 mg} obtained in the same manner as in Example 1, for agitation at ambient temperature for 2 hours and 50 minutes. The resulting mixture was separated into phases. To the resulting acetone layer was added water (1.18 ml), which was then cooled to -10 C., followed by addition of the seed crystal and overnight agitation, to crystallize (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. The resulting slurry was filtered, to recover the crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane {(2R,3S) yield: 64.2 mg (75%)}. The dried crystal was analyzed by HPLC. (2R,3S): (2S,3S)=97.9:2.1.

  • 2
  • [ 102123-74-0 ]
  • [ 98760-08-8 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
(2S,3S) compound/((2S,3S) compound) + (2R,3S) compound: 99.7percent (3S)-1-Chloro-2-oxo-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane content: less than 0.1 area percent (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane: less than 0.1 area percent (2R,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane: less than 0.1 area percent Mean crystal grain diameter: ca 300 to 400 mum
  • 5
  • [ 102123-74-0 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
7.94g (80.2%) Example 20 Purification of (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane and production of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane 2-Propanol (25.3 ml) and water (8.5 ml) were added to (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 11.28 g; (2S,3S) content of 1.55 g} obtained by the same method as in Reference Example 3, to prepare a slurry, followed by addition of potassium chloride (329 mg) at 70 C., which was then agitated for 15 hours and cooled to 20 C. over 2.5 hours. The slurry was filtered at 20 C., to remove insoluble matters. 2-Propanol (58.7 ml) and water (3.2 ml) were added to the resulting mother liquor, followed by cooling at 4 C. and addition of aqueous 4 mol/l sodium hydroxide solution (14.1 ml), for agitation at 4 C. for 2.5 hours. The reaction solution was analyzed by HPLC. The objective (2R,3S) compound was at 93.6% (HPLC area ratio). The reaction was quenched by addition of aqueous 0.85% citric acid solution (142 g). After cooling from 27 C. to -10 C. for 2.5 hours, the addition of the seed crystal and overnight agitation enabled the crystallization of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. The resulting slurry was filtered; to the resulting crystal was added water (56.4 ml), to prepare a slurry, followed by agitation at 20 C. for one hour; the slurry was filtered and dried, to afford the crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane {(2R,3S) recovery yield of 7.94g (80.2%)}. The dried crystal was analyzed by HPLC. (2R,3S):(2S,3S)=98.1:1.9. Additionally, (2R,3S) purity was at 97.6% (HPLC area ratio).
  • 7
  • [ 67-63-0 ]
  • [ 162536-40-5 ]
  • [ 98760-08-8 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; citric acid; Example 9 Production of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane 2-Propanol (342 ml) and aqueous 2.5 mol/l sodium hydroxide solution (85.8 ml) were added to (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 40.6 g; (2S,3S) content of 1.66 g} obtained in the same manner as in Example 1, for agitation at 0 C. for 1.5 hours. Aqueous 13.8% citric acid solution (99.5 g) was added to the resulting mixture, and then, 2-propanol was evaporated under reduced pressure. To the resulting residue was added toluene (342 ml) for extraction; and the organic layer was concentrated under reduced pressure, to afford (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (37.2 g) {the total yield of (2R,3S) and (2S,3S): 98.3%}, which was then analyzed by HPLC. (2R,3S): (2S,3R)=96.1:3.9.
2.4 g (96.2%) With sodium hydroxide; citric acid; In water; Example 18 Production of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane 2-Propanol (12.9 ml) and aqueous 6.08 mol/l sodium hydroxide solution (2.94 g) were added to a solution containing (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane obtained in Example 17 {(2R,3S) content of 2.79 g; (2S,3S) content of 83.9 mg}, for agitation at 4 C. for 15 hours. The resulting solution was analyzed by HPLC, which indicates that the objective (2R,3S) compound was at 94.0% (HPLC area ratio). After the reaction was quenched by the addition of aqueous 4.4% citric acid solution (20.9 g), the reaction solution was cooled from 25 C. to -10 C. over 2.3 hours; then, the seed crystal was added, followed by addition of water (19.2 ml) for overnight agitation, to crystallize (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. By filtration of the resulting slurry, the crystal of the objective (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was obtained {(2R,3S) yield: 2.4 g (96.2%)}. The dried crystal was then analyzed by HPLC. (2R,3S): (2S,3S)=97.9:2.1. Additionally, the purity of (2R,3S) was at 95.4% (HPLC area ratio).
With sodium hydroxide; citric acid; In water; Example 26 Production of Crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane The solution of (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane {(2R,3S) content of 5.99 g; (2S,3S)content of 80 mg} obtained in the same manner as in Example 22 was concentrated, and then 2-propanol (30.8 ml) and water (10.3 ml) were added to the resulting residue. After cooling to 4 C., 4 mol/l sodium hydroxide solution (7.7 ml) was added, followed by agitation at 4 C. for 70 minutes. The reaction solution was analyzed by HPLC. The objective (2R,3S) compound was at 97.1% (HPLC area ratio). After the reaction was quenched by the addition of aqueous 1.5% citric acid solution, the resulting mixture was cooled to -3 C., followed by the addition of the seed crystal and agitation for 30 minutes. The mixture was cooled to -10 C. over 1 hour and was agitated for 2 hours, to crystallize (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. After filtration of the resulting slurry, water (61.6 ml) was added to the resulting crystal, for preparing slurry, which was then agitated at ambient temperature for 30 minutes, to filtrate the slurry. The resulting crystal was dried to obtain the objective crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane {the yield of (2R,3S): 4.92 g (93.5%)}. The dry crystal was analyzed by HPLC. (2R,3S):(2S,3S)=97.9:2.1. Additionally, the purity of (2R,3S) was 98.3% (HPLC area ratio).
  • 8
  • [ 99980-40-2 ]
  • [ 98760-08-8 ]
  • [(1S,2R)-1-benzyl-2-hydroxy-3-(1-methyl-1-pyridin-3-ylethylamino)propyl]carbamic acid tert-butyl ester [ No CAS ]
 

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