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Chemical Structure| 74844-91-0 Chemical Structure| 74844-91-0

Structure of Boc-Hyp-OMe
CAS No.: 74844-91-0

Chemical Structure| 74844-91-0

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Product Details of [ 74844-91-0 ]

CAS No. :74844-91-0
Formula : C11H19NO5
M.W : 245.27
SMILES Code : O=C(OC)[C@H]1N(C(OC(C)(C)C)=O)C[C@H](O)C1
MDL No. :MFCD00076981
InChI Key :MZMNEDXVUJLQAF-SFYZADRCSA-N
Pubchem ID :2734883

Safety of [ 74844-91-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501

Computational Chemistry of [ 74844-91-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 17
Num. arom. heavy atoms 0
Fraction Csp3 0.82
Num. rotatable bonds 5
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 63.85
TPSA ?

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

76.07 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.57
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

0.58
Log Po/w (WLOGP)?

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

0.15
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.

0.22
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

-0.11
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.68

Water Solubility

Log S (ESOL):?

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

-1.4
Solubility 9.85 mg/ml ; 0.0402 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.

-1.75
Solubility 4.36 mg/ml ; 0.0178 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very 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

-0.27
Solubility 131.0 mg/ml ; 0.535 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.

-7.38 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<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)

3.36

Application In Synthesis of [ 74844-91-0 ]

* 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 [ 74844-91-0 ]

[ 74844-91-0 ] Synthesis Path-Downstream   1~15

  • 4
  • [ 574745-97-4 ]
  • [ 74844-91-0 ]
  • [ 849345-89-7 ]
YieldReaction ConditionsOperation in experiment
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 25℃; for 1h; Example 12 (4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methyl-N- PROP-2-VN-1-VL-L-PROLINAMIDE Example 12 HATU (0.34g) was added to an agitated solution of (4R)-4-({4-[(3-CHLORO-2- fluorophenyl) amino]-7-methoxyquinazolin-6-yl} oxy)-1-methyl-L-proline (0.2g), propargylamine (49.3mg) and DIPEA (231mg) in DIMETHYLACETAMIDE (10ML). THE MIXTURE was stirred at 50C for 10 minutes then allowed to stand at room temperature overnight. The reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (0/100-12/88). The fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 067G). LH NMR Spectrum (DMSO D6) 2.08-2. 22 (M, 1H), 2.25-2. 62 (M, 2H + DMSO), 2.31 (s, 3H), 3.06 (s, 1H), 3.15 (t, 1H), 3.62-3. 72 (M, 1H), 3.78-4. 02 (M, 2H), 3.93 (s, 3H), 5.06 (M, 1H), 7.16-7. 32 (M, 1H), 7.21 (s, 1H), 7.43- 7.56 (M, 2H), 7.67 (s, 1H), 8.28 (M, 1H), 8.36 (s, 1H), 9.63 (s, 1H); Mass Spectrum : (M+H) + 484. The starting material was prepared as follows: 1-TERT-BUTYL 2-methyl (2S, 4S)-4-HYDROXYPYRROLIDINE-1, 2-dicarboxylate (1), (Boc-cis- Hyp-OMe) is commercially available. Di-ethyl azodicarboxylate (12.4g) was added slowly to a stirred suspension of 1-TEST- butyl 2-methyl (2S, 4S)-4-HYDROXYPYRROLIDINE-1, 2-dicarboxylate (1) (17.46g), 4-chloro-7- methoxyquinazolin-6-ol (2) (10g) [prepared as described in Example 1 above (compound 3)] and TRIPHENYLPHOSPHINE (L8. 67G) INMETHYLENE chloride (300 ML) at 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 1 hours. The reaction mixture was then evaporated to ½ volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (0/100-3.5/96. 5). The desired product fractions were combined and evaporated to give 1-TERT-BUTYL 2-methyl (2S, 4R)-4- [ (4- CHLORO-7-METHOXYQUINAZOLIN-6-YL) oxy] pyrrolidine-1, 2-dicarboxylate (3) as a pale yellow foam Mass Spectrum : (M+H) + 438. This was used in the preparation of (4) without further purification. The starting material (4) was prepared as follows: 4. 0M HCl in Dioxane (39.2 ML) was added to a suspension of 1-tert-butyl 2-methyl (2S, 4R)-4- [ (4-chloro-7-methoxyquinazolin-6-yl) oxy] pyrrolidine-1, 2-dicarboxylate (3) and 3- CHLORO-2-FLUOROANILINE (7.61g) in acetonitrile (300 ML) and the reaction mixture was stirred and heated at 50C for 1 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4R)-4-({4-[(3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-L-PROLINATE HYDROCHLORIDE (4) as an off- white solid, (23. 05G). 1H NMR Spectrum : (DMSO D6) 2.46-2. 74 (M, 2H), 3.24-3. 68 (m, 1H), 3.78 (s, 3H), 3.95-4. 07 (M, 1H), 4.00 (s, 3H), 4.61 (t, 1H), 5.50 (M, 1H), 7.35 (t, 1H), 7.47-7. 57 (M, 1H), 7.49 (s, 1H), 7.63 (t, 1H), 8.73 (s, 1H), 8.83 (s, 1H), 12.38 (bs, LH)-, MASS SPECTRUM : (M+H) + 447. Methyl (4R)-4-({4-[(3-CLZLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)- L-PROLINATE HYDROCHLORIDE (4) (22.9g), paraformaldehyde (14.25g), sodium cyanoborohydride (11.97g) and magnesium sulphate (11.4g) were suspended in methanol (600ML) and heated at 45C for 3 hours under an atmosphere of nitrogen. The reaction mixture was filtered, evaporated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organics were then washed with saturated brine, dried over MgS04, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/methylene chloride (0/100-10/90) to give methyl (4R)- 4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO] -7-METHOXYQUINAZOLIN-6-YL} OXY)-L-METHYL-L-PROLINATE (5) as a yellow solid, (14. 87 G). LH NMR SPECTRUM : (DMSO d6) 2.13-2. 25 (M, 1H), 2.34 (s, 3H), 2.46-2. 61 (M, 2H + DMSO), 3.37 (t, 1H), 3.57-3. 69 (M, 1H), 3.66 (s, 3H), 3.93 (s, 3H), 5.08 (M, 1H), 7.21 (s, 1H), 7.23-7. 31 (t, 1H), 7.43-7. 58 (M, 2H), 7.69 (s, 1H), 8.37 (s, 1H), 9.62 (s, 1H) ; Mass Spectrum : (M+H) + 461. Sodium hydroxide 2M (24.2 ml) was added to a stirred solution of methyl (4R)-4- ( {4- [(3-CHLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-L-PROLINATE (5) (14.87g) in methanol (100 ml) at 25C and the reaction mixture was stirred for 1 hour. The reaction mixture was evaporated and the residue re-dissolved in water. The pH of this solution was then adjusted to 6 by the dropwise addition of 2M HCl (aq) to give (4R0-4-({4-[(3-chloro- 2-fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-L-METHYL-L-PROLINE (6) as a pale yellow solid which was filtered and washed with water and dried, (1...
  • 5
  • [ 24424-99-5 ]
  • [ 32968-78-8 ]
  • [ 74844-91-0 ]
YieldReaction ConditionsOperation in experiment
4.2 g (57%) With sodium hydroxide; In tetrahydrofuran; water; ethyl acetate; i 1-(tert-Butyl) 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate In a flask was dissolved <strong>[32968-78-8](2S,4R)-4-Hydroxy-proline hydrochloride</strong> (5.4 g, 30 mmole) in a mixture of THF (200 ml), water (170 ml) and NaOH (30 ml, 2 M in water, 60 mmole). To this emulsion was added di-tert-butyldicarbonate (Boc2O, 6.54 g, 30 mmole), and the mixture was stirred vigorously for 1 hour. Ether (100 ml) was added and the phases were allowed to separate. The aqueous phase was extracted with an additional 100 ml of ether. The aqueous phase was discarded and the combined organic phases were washed with IM HCl (aq.) and potassium carbonate (saturated, aq.) and brine. The extract was dried with Na2SO4 and was concentrated in vaccuo to give a residue, which was purified on silica (Heptane:EtOAc 5:1 to 3:1 to 1:1 stepwise gradient, spots visualized with I2/MeOH). Evaporation of pure fractions were concentrated in vaccuo to give 4.2 g (57%) of the subtitle compound as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 4.50 (1H, bs); 4.45-4.35 (1H, m); 3.74 (3H, s); 3.64 (1H, dd, J 11.7, 4.3 Hz); 3.59-3.42 (1H, m); 2.35-2.20 (1H, m); 2.14-2.03 (1H, m); 1.97 (1H, dd, J 23.3, 3.7 Hz); 1.44 (9H, d, J 18.9 Hz)
  • 6
  • [ 2832-45-3 ]
  • [ 74844-91-0 ]
  • [ 960508-09-2 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; at 60 - 65℃; for 7h; Sodium hexanesulfonate (2.96 g) was suspended in acetonitrile (18 g) under a nitrogen atmosphere, and DFI (2. 14 g) was added dropwise thereto at a temperature in a range of 20 to 30C. The reaction solution was stirred at 20 to 30C for 3 hours to obtain a solution of FMSI in acetonitrile. Subsequently, trans-N-tert-butoxycarbonyl-4-hydroxy-L-proline methylester (2.57 g) was added to the solution, and the mixture was stirred at 60 to 65C for 7 hours. The reaction solution was added dropwise to a solution obtained separately by suspending sodium hydrogen carbonate (3. 30 g) in water (33 g). The mixture was then extracted with toluene (50 g), washed with water (33 g), and subsequently, the obtained toluene layer was dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was separated by filtration, and the toluene solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel 60 g, hexane: ethyl acetate=5:1?4:1?3:1) to obtain a target compound (cis-HSBPM) as a colorless clear syrup. The retention time of 1H-NMR and HPLC was consistent with that of the cis-HSBPM obtained in Reference Example 5. Amount 3.31 g Yield 80% 1H-NMR (CD3CN, 400 MHz) delta 5.23 (bs, 1H), 4.51,4.40 (2bt, 1H, J=5.0 Hz), 3.78-3.74 (m, 2H), 3.75 (s, 3H), 3.07 (bt, 2H J=7.8 Hz), 2.54 (bs, 1H), 2.49 (bs, 1H), 1.85-1.78 (m, 2H), 1.50-1.40 (m, 2H), 1.48,1.43 (2s, 9H), 1.35-1.30 (m, 4H), 0.90 (t, 3H, J=6.9 Hz) The stereoselectivity in the reaction was determined by analysis of the reaction solution, and using the peak area ratio of cis-HSBPM and (2S,4R)-N-tert-butoxycarbonyl-4-hexanesulfonyloxypyrrolidine-2-c arboxylic acid methylester (hereinafter abbreviated as trans-HSBPM). cis-HSBPM:trans-HSBPM=99.4:0.6 HPLC analysis condition-3 Column used YMC-PACK ODS AM-312 Eluent CH3CN/10 mM NaH2PO4=60/40 Column temperature 40C Flow rate 1 ml/min Detection wavelength 210 nm
  • 7
  • [ 63521-92-6 ]
  • [ 74844-91-0 ]
  • [ 1312604-78-6 ]
  • C16H25NO6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
An oven-dried 50 mL round bottom flask was charged with N-Boc-trans-4-hydroxy-L- proline methyl ester (1 mmol), N,N-dimethylaminopyridine (0.15 mmol), pyridine (3 mmol), dry acetonitrile (5 mL), and placed under an argon atmosphere. 4-Pentenoic anhydride (3 mmol) was then added dropwise and the reaction was warmed to 50 C and stirred under argon for 44 h. The reaction mixture was then concentrated in vacuo, and the residue dissolved in THF (5 mL), deionized water (3 mL), pyridine (0.5 mL) and allowed to stir an additional 24 h at 50 C. The reaction mixture was then concentrated in vacuo, the residue dissolved in DCM (20 mL), and the DCM washed 1 M HC1 (15 mL), water (15 mL), 1 M NaOH (15 mL), and finally with water (15 mL). The organic was dried over Na2S04, filtered over Celite, and then concentrated in vacuo to yield a yellow oil (71%). Diastereomeric mixture (59:41). iHNMR (400 MHz, CDCb): delta = 5.80 (m, 1H), 5.29 (m, 1H), 5.03 (m, 2H), 4.39 (dt, 1H, JHH = 8.7 Hz), 3.71 (s, 3H), 3.70-3.05 (m, 2H), 2.37 (m, 5H), 2.17 (m, 1H), 1.46 (s, 3H), 1.41 (s, 6H) ppm. isCNMR (400 MHz, CDCb): delta = 172.9, 172.7, 172.3, 172.1, 154.0, 153.3, 136.2, 115.6, 80.3, 72.6, 71.8, 57.8, 57.4, 52.2, 52.0, 51.9, 36.5, 35.5, 33.2, 30.2, 29.6, 28.7, 28.2, 28.1 ppm. HRMS-ESI: Calculated [M+Na]+: 350.1568.
  • 8
  • [ 74844-91-0 ]
  • [ 40350-83-2 ]
  • 11
  • [ 74844-91-0 ]
  • [ 215918-38-0 ]
  • 12
  • [ 74844-91-0 ]
  • [ 1138324-46-5 ]
  • 13
  • [ 74844-91-0 ]
  • [ 1138324-46-5 ]
  • 14
  • [ 5985-24-0 ]
  • [ 74844-91-0 ]
  • 1-tert-butyl 2-methyl (2S,4R)-4-(2,4-bis(methoxycarbonyl)phenoxy)pyrrolidine-1,2-dicarboxylate [ No CAS ]
  • 15
  • [ 32968-78-8 ]
  • [ 74844-91-0 ]
 

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