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Chemical Structure| 52481-41-1

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Product Details of [ 52481-41-1 ]

CAS No. :52481-41-1
Formula : C12H18N2O2
M.W : 222.28
SMILES Code : NC1=CC=C(OCCN2CCOCC2)C=C1
MDL No. :MFCD04970981
InChI Key :ZHFFNLQQANCJEQ-UHFFFAOYSA-N
Pubchem ID :6484711

Safety of [ 52481-41-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302+H312+H332-H315-H319
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312+P330-P302+P352+P312+P362+P364-P304+P340+P312-P305+P351+P338+P337+P313-P501

Computational Chemistry of [ 52481-41-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 6
Fraction Csp3 0.5
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 67.16
TPSA ?

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

47.72 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.23
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

1.03
Log Po/w (WLOGP)?

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

0.61
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.

0.55
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

1.41
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.17

Water Solubility

Log S (ESOL):?

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

-1.88
Solubility 2.93 mg/ml ; 0.0132 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.

-1.62
Solubility 5.31 mg/ml ; 0.0239 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

-2.78
Solubility 0.367 mg/ml ; 0.00165 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

Yes
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.

-6.92 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.

1.0 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)

1.76

Application In Synthesis of [ 52481-41-1 ]

* 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 [ 52481-41-1 ]

[ 52481-41-1 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 65300-53-0 ]
  • [ 52481-41-1 ]
YieldReaction ConditionsOperation in experiment
99% With 5%-palladium/activated carbon; hydrogen; In tetrahydrofuran; methanol; under 2068.65 Torr; for 17h; A solution of 22 (33.3 g, 132 mmol) in MeOH (170 mL) and THF (50 mL) with Pd/C (5%, ca. 3 g) was hydrogenated at 40 psi overnight (17 h). The mixture was filtered through Celite and the Celite plug was washed with CH2Cl2:MeOH (5:1) several times. The combined filtrates were evaporated to give 23 as a pink solid (29.0 g, 99%); δH (CDCl3) 6.77-6.72 (m, 2H), 6.65-6.60 (m, 2H), 4.04 (t, J = 5.8 Hz, 2H), 3.76-3.70 (m, 4H), 3.41 (br s, 2H), 2.76 (t, J = 5.8 Hz, 2H), 2.60-2.54 (m, 4H); consistent with that reported [11]. [Found: C, 64.94; H, 8.08; N, 12.66. C12H18N2O2 requires C, 64.84; H, 8.16; N, 12.60].
96% With palladium 10% on activated carbon; hydrogen; In ethanol; at 25℃; under 760.051 Torr; for 18h; Under hydrogen (1 atm), to a solution of compound 8-b (900 mg, 3.57 mmol) in ethanol (50 mL) was added 10% Pd-C (0.5 g). The mixture was stirred at 25 C. for 18 hours, and then filtrated. The filtrate was concentrated under reduced pressure to give light yellow oil 8-a (760 mg, yield: 96%), which was used directly for the next step without purification.
95% With palladium on activated charcoal; hydrogen; In methanol; at 20℃; the compound 4-[2-(4-Nitrophenoxy) ethyl] morpholine (5) 1.12g (5mmol) dissolved in 60mL of Methanol, added the 0.20g of Palladium on carbon, then passes through the hydrogen at room temperature for reduction reaction, TLC monitors the reaction process, then obtained the compound 4-[2-(4-aminophenoxy) ethyl] morpholine (6) 0.92g, yield 95%.
94% With palladium 10% on activated carbon; hydrogen; for 3.5h;Reflux; A mixture of compound 10 (10.10 g, 40 mmol) and Pd/C (1.01 g, 10% (w/w)) were added in ethanol (50 mL). The reaction mixture was stirred reflux for 3.5 h under the action of H2. The mixture was filtered under the action of diatomaceous earth and the filtrate was concentrated at 50 C to obtain compound 11. Red solid. Yield: 94.0%; 1H NMR (400 MHz, DMSO-d6) δ: 6.63, (d, J =8.8 Hz, 2H), 6.48, (d, J =8.8 Hz, 2H), 4.57, (s, 2H), 3.92, (t, J =6.0 Hz, 2H), 3.57, (t, J =4.8 Hz, 4H), 2.61, (t, J =5.6 Hz, 2H), 2.44, (t, J =4.4 Hz, 4H). MS [ESI]: m/z, 223.2 [M+H]+.
92% With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; Into a Round bottom flask, [A] 4-[2-(4-Nitro-phenoxy)-ethyl]-morpholine (3.70 g,0.0147 mol), 10 % Pd/C(10:90, Palladium: carbon black, 1.6 g, 0.0015 mol), and Ethanol (100 niL, 2 mol) were added. The mixture was evacuated under house vacuum and charged with ahydrogen balloon (3X). The reaction was stired at room temperature under an atmosphere of Hydrogen via a balloon. The solid was filtered. The solvent was removed under vacuum to give 4-(2-Morpholin-4-yl-ethoxy)-phenylamine a white solid (3.0Og, 92%). NMR 1H (DSMO-d6)- 6.63 (dd, IH, J= 1.92, 4.76 Hz), 6.49 (dd, 2H, J= 1.97, 4.72 Hz), 4.52 (bs, 2H), 3.91 (t, 2H, J= 5.84 Hz), 3.56 (t, 4H, J= 4.60 Hz), 2.60 (t, 2H, J= 4.580 Hz), 2.47 (t, 4H, J= 4.48 Hz)
63% With hydrogen;palladium dihydroxide; In ethanol; under 3750.38 Torr; for 2h; Step 1 4-(2-Morpholιn-4-yl-ethoxy)-phenylamιne[00307] To a solution of 4-[2-(4-nitro-phenoxy)-ethyl]-morpholme (2 25g, 8 93mmol) m ethanol(4OmL) is added palladium hydroxide (0 313g, 0 45mmol) and the mixture is stirred in a Parr-apparatus under hydrogen pressure (5 bars) for 2 hours Filtration over Celite 521 and evaporation gave a red oil puϖfed by silica gel column chromatography Elution with DCM and a mixture 90 10 DCM MeOH affords the title compound as a white solid (1 256g, 63%) 1H-NMR (400MHz, CDCl3) δ (ppm) 2 52 2 63 (4H, m), 2 71-2 80 (2H, t), 3 46 (2H, br s), 3 70-3 78 (4H, m), 4 00-4 10 (2H, m), 6 65 (2H, d), 6 77 (2H, d)
With hydrogen;palladium 10% on activated carbon; In ethanol; water; at 20℃; under 2999.54 Torr; for 1h; Example 6 4-(2-(Morpholin-4-yl)ethoxy)phenylamine (11): A solution of 10 (6.00 g, 23.8 mmol) in 95% EtOH (40 mL) was hydrogenated over Pd/C (10%, 350 mg) at 58 psi H2 for 1 h at room temperature. The formed solid was removed by filtration through Celite, which was washed thoroughly with EtOH (100 mL) and MeOH (50 mL); the filtrate was concentrated in vacuo to give 11 (5.29 g, quant.) as a reddish brown oil, which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 2.57 (mc, 4H, 3"-H2, 5"-H2), 2.76 (t, J=5.8 Hz, 2H, 2'-H2), 3.40 (sbr, 2H, NH2), 3.73 (mc, 4H, 2"-H2, 6"-H2), 4.03 (t, J=5.8 Hz, 2H, 1'-H2), 6.59-6.66 (m 2H, 2-H, 6-H), 6.71-6.78 (m, 2H, 3-H, 5-H) ppm; 13C NMR (50.3 MHz, CDCl3): δ=54.0 (C-3", C-5"), 57.7 (C-2'), 66.3 (C-1'), 66.8 (C-2", C-6"), 115.7 (C-3, C-5), 116.2 (C-2, C-6), 140.2 (C-1), 151.7 (C-4) ppm; MS (70 eV, EI): i/z (%) 222 (17) [M]+, 100 (100) [M-CH2OC6H4-NH2]+.
With hydrogen;palladium 10% on activated carbon; In methanol; under 22801.5 Torr; b. EPO <DP n="66"/>The nitro compound (prepared as in step a, 80 g, 0.32 mole) was dissolved in MeOH (1.5 L) and added to a 4 L autoclave. To this was added 10% Pd/C (5 g) and the autoclave charged with hydrogen (30 atmospheres). The reaction was stirred overnight, then filtered to remove the catalyst. The filtrate was concentrated and distilled under vacuum to give an oil. The oil was taken up in hot cylohexane. The excess solvent was decanted off, and the solution cooled, and filtered. The solids were washed with hexanes to give the product (23.7 g)IH NMR (300 MHz, DMSO-d6) δ ppm 6.67 (d, 2H, J = 8.7), 6.53 (d, 2H, J = 8.7), 4.62 (s, 2H), 3.95 (t, 2H, J = 5.9), 3.6 (m, 4H), 2.64 (t, 2H, J = 5.7), 2.47 (m, 4H)
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2999.54 Torr; for 24h; A solution of 10 (6.00 g, 23.8 mmol) in 95% EtOH (40 mL) was hydrogenated over Pd/C (10%, 350 mg) at 58 psi H2 for 1 h at room temperature. The formed solid was removed by filtration through Celite, which was washed thoroughly with EtOH (100 mL) and MeOH (50 mL); the filtrate was concentrated in vacuo to give 11 (5.29 g, quant.) as a reddish brown oil, which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): 5 = 2.57 (m, 4 H, 3"-H2, 5"-H2), 2.76 (t, J= 5.8 Hz, 2 H, 2'-H2), 3.40 (sbr, 2 H, NH2), 3.73 (In0, 4 H, 2"-H2, 6"-H2), 4.03 (t, J= 5.8 Hz, 2 H, 1'-H2), <n="88"/>6.59-6.66 (m, 2 H, 2-H, 6-H), 6.71-6.78 (m, 2 H, 3-H, 5-H) ppm; 13C NMR (50.3 MHz, CDCl3): δ = 54.0 (C-3", C-5"), 57.7 (C-21), 66.3 (C-I1), 66.8 (C-2", C-6"), 115.7 (C-3, C-5), 116.2 (C-2, C-6), 140.2 (C-I), 151.7 (C-4) ppm; MS (7O eV, EI): m/z (%) = 222 (17) [M]+, 100 (100) [M-CH2OC6H4-NH2]+.
With hydrogen;palladium over charcoal; In ethanol; at 20℃; Step B: 8.1 g (32 [MMOL)] of [4- [2- (4-NITRO-PHENOXY)-ETHYL]-MORPHOLINE] is dissolved in 100 mL of ethanol and subjected to catalytic hydration at rt using 681 mg of [PD/C.] After filtration trough HYFLO and removal of the solvent under reduced pressure, the crude product is purified by bulb-to-bulb distillation (0.13 mbar; [200C)] to obtain 4- (2-morpholin-4-yl-ethoxy)- phenylamine. Title compound: ES-MS: 223 [M+H] [+] ; single peak at [TR=] 3 min (System 2).
With 5%-palladium/activated carbon; hydrogen; In methanol; at 20℃; for 4h; General procedure: N,N-Dimethyl-3-(4-nitrophenoxy) propan-1-amine (d14) (3.92 mmol) was dissolved in 30 mL anhydrous methanol, and then 0.1 g Pd/C (5%) was added to this solution. After that, the mixture was reacted at room temperature under N2 for 4 h. The mixture was filtered, and Pd/C was washed with methanol for 3-4 times. The organic phases were combined and methanol was removed by reduced pressure distillation to give the crude product. The residue was reserved for the next step.
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 4h; General procedure: In 100 mL flask, 4-nitrophenol (1.39 g, 10 mmol) was dissolved in 20 mL anhydrous DMF. Then 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (1.57 g, 10 mmol) and Cs2CO3 (5.29 g, 15 mmol) were added to the solution. Under nitrogen, the mixture was heated to 100 C, and reacted for 2.5 h. The mixture was filtered, and the filtrate was poured to ice water (200 mL). The aqueous phase was extracted by EtOAc. The combined organic phase was washed by Na2CO3, water, saturated sodium chloride. The organic layer was dried over Na2SO4 to afford (8). N,N-dimethyl-3-(4-nitrophenoxy) propan-1-amine (8) (3.92 mmol) was dissolved in 30 mL anhydrous methanol, then 0.10 g Pd/C (5%) was added to this solution. After that, the mixture was reacted at room temperature under H2 for 4 h. The mixture was filtered, and Pd/C was washed with methanol for 3-4 times. The organic phases were combined and methanol was removed by reduced pressure distillation to yield (9a) for next step without purification.
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 1h; Compound 4a was synthesized in the same manner as in Reaction Scheme 1 above.Compound 3a and 10% palladium were added to methanol, stirred at room temperature under hydrogen for 1 hour, and filtered. The filtrate was concentrated in vacuo and the crude product was used in the next reaction without further purification.
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; To a solution of 10a-f (0.1 mmol) in dry methanol (10 mL) was added catalytic amount ofPd-C, and then the mixture was stirred under hydrogen atmosphere at room temperature for 12hours. The Pd-C was filtered and the filtrate was evaporated to dryness under reduced pressure toafford final basic chains 11a-f, which were used without further purification.
With hydrogen;palladium 10% on activated carbon; In methanol; To a solution of 18c (160mg, 0.63mmola) in methanol (1OmL) was added 10% Pd/C (140mg). The mixture was hydrogenated under H2 atmosphere overnight. Pd/C was filtered off and the filtrate was evaporated to provide crude 18d (135mg, 96%) which was used for next step without purification.
2 g With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 12h; General procedure: PdeC (0.27 g, 10% m/m) wasadded to a solution of 8a (2.7 g, 13.0 mmol) in ethanol (20 ml) andhydrogenated for 12 h at room temperature. The resultant wasfiltered, washed with ethanol and concentrated. 2.2 g of 9a aspurple solid was obtained; yield: 94%.
With ammonium chloride; zinc; In water; at 20 - 70℃; for 1h;Inert atmosphere; General procedure: 11a-b (50 mmol), 2,4,5-trichloropyrimidine (50 mmol) andDIPEA (100 mmol) in acetonitrile, it was gradually heated to 80 Cand stirred for 10 h. The precipitate was filtrated and washed withwater, and the acquired production could directly be used withoutfurther purification. 13a-k was prepared according to the reportedprocess [20e22,24]. Ar atmosphere, a mixture of 13a-k (15 mmol),ammonium chloride (20 mmol) and zinc powder (120 mmol) inethanol/water (100/20 mL) was reacted at 70 C for 1 h. After thereaction, the solvent was distilled off and the residuewas dispersedin dichloromethane. The zinc powder was removed by filtration,and the organic layer was washed with dilute ammonia and driedover anhydrous sodium sulfate. The organicwas vacuum distilled to give the crude which was purified by silica-gel column separationto get the 14a-k. A mixture of 12a-b (5.0 mmol), 14a-k (5.0 mmol), and p-TsOH(7.5 mmol) in ethyl alcohol was gradually heated to 70 C andstirred for 3 h. After reaction, the solvent was vacuum distilled andthe residuum was dispersed with saturated sodium bicarbonate/ethyl acetate. The crude product was purified using flash chromatographywith dichloromethane/methanol as eluents.Ar atmosphere,15a-k (2.0 mmol) and hydroxylamine (40 mmol)in anhydrous methanol, sodium methoxide (25 mmol) in methanolsolution was slowly added to the mixture. After the addition, thereaction was allowed to warm room temperature and stirred for2 h. Adjusted pH to 6 with dilute hydrochloric acid, the inorganicsalt was removed by filtration and the rest of organic phase wasvacuum distilled to produce the 9~a k.

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