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Chemical Structure| 127828-22-2
Chemical Structure| 127828-22-2
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Product Details of [ 127828-22-2 ]

CAS No. :127828-22-2 MDL No. :MFCD12031501
Formula : C9H20N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :VULKFBHOEKTQSF-UHFFFAOYSA-N
M.W : 204.27 Pubchem ID :12106198
Synonyms :
Chemical Name :tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate

Calculated chemistry of [ 127828-22-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.89
Num. rotatable bonds : 8
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 53.68
TPSA : 73.58 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.66 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.44
Log Po/w (XLOGP3) : -0.16
Log Po/w (WLOGP) : 0.49
Log Po/w (MLOGP) : 0.12
Log Po/w (SILICOS-IT) : 0.17
Consensus Log Po/w : 0.61

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.48
Solubility : 68.0 mg/ml ; 0.333 mol/l
Class : Very soluble
Log S (Ali) : -0.93
Solubility : 24.0 mg/ml ; 0.117 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.84
Solubility : 2.97 mg/ml ; 0.0145 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 2.59

Safety of [ 127828-22-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 127828-22-2 ]

* 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 [ 127828-22-2 ]
  • Downstream synthetic route of [ 127828-22-2 ]

[ 127828-22-2 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 176220-30-7 ]
  • [ 127828-22-2 ]
YieldReaction ConditionsOperation in experiment
100% With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 8 h; Compound 16 (1.7 g, 7.7 mmol) was dissolved in MeOH (25 mL) and the solution was degassed several times with Ar before adding a catalytic amount of Pd/C 10percent. The atmosphere was filled with H2 and the reaction was stirred 8 h at 25 °C. The mixture was filtered and the solvent was removed under reduced pressure. No further purification was needed (quantitative yield). 1H NMR (300 MHz, CDCl3) δ 5.08 (br s, 1H), 3.66-3.47 (m, 4H), 3.37-3.22 (m, 2H), 3.22-3.10 (m, 2H), 3.02-2.84 (m, 2H), 1.43 (s, 9H); ESI-MS m/z 205 [M+H]+, 227 [M+Na]+.
79%
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 2 h;
Stage #2: With water In tetrahydrofuran at 20℃;
A solution of 0.82 g (3.1 mmol) of triphenylphosphine in 10 ml of tetrahydrofurane was added to a solution of 0.6 g (2.6 mmol) of 2c in 20 ml of tetrahydrofurane.
The resulting solution was stirred for 2 h at room temperature.
Subsequently, 200 ml of water was added, and the mixture was stirred overnight at room temperature.
Then the mixture was evaporated to 75 ml and filtered.
The filtrate was washed with 25 ml of dichloromethane and evaporated to get the product. Yield: 0.5 g (79percent).
1H NMR (CDCl3): δ 3.50 (m, 4H, H2+ H3), 3.33 (m, 2H, H4), 2.86 (t, 2H, H1). ESI-MS: m/z 205.2 (M+H).
3 g With palladium 10% on activated carbon; hydrogen In methanol at 20℃; Inert atmosphere Step 4:
Synthesis of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (58)
A solution of tert-butyl (2-(2-azidoethoxy)ethyl)carbamate 57 (5.0 g, 0.0217 mol) in methanol (100 mL) was added 10percent Pd/C (2.5 g) under Ar.
The mixture was stirred under H2 (50 psi) at room temperature overnight.
After filtration through a pad of celite, the organic layer was concentrated under reduced pressure to provide tert-butyl (2-(2-aminoethoxy)ethyl)carbamate 58 (3.0 g).
The product was used in the next step without further purification. 1H NMR (400 MHz, MeOD) δ 3.48-3.45 (m, 4H), 3.23-3.20 (t, 2H), 2.77-2.75 (m, 2H), 1.43 (s, 9H).
Reference: [1] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 301 - 320
[2] Patent: EP1745802, 2007, A1, . Location in patent: Page/Page column 17
[3] Patent: US6664265, 2003, B2, . Location in patent: Page column 23
[4] Patent: US2003/130518, 2003, A1,
[5] Patent: US2003/139441, 2003, A1,
[6] Patent: US2003/187016, 2003, A1,
[7] Patent: US6677347, 2004, B2,
[8] Patent: US6660735, 2003, B2, . Location in patent: Page column 21
[9] Patent: US2004/10007, 2004, A1, . Location in patent: Page 75; 98
[10] Patent: US2011/269965, 2011, A1, . Location in patent: Page/Page column 34
[11] Patent: US2013/116263, 2013, A1, . Location in patent: Paragraph 0697
[12] Patent: WO2009/113828, 2009, A2, . Location in patent: Page/Page column 46-47
  • 2
  • [ 24424-99-5 ]
  • [ 60792-79-2 ]
  • [ 127828-22-2 ]
YieldReaction ConditionsOperation in experiment
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH3CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (280 mg, 44percent). MS calculated for C15H23N3O4: 309.17; found: [M+H]+310.tert-Butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (140 mg, 0.453 mmol) was taken up in 25percent TFA in CH2Cl2 (10 mL). The reaction mixture was allowed to stand at room temperature for 2 h and then concentrated under reduced pressure to afford the TFA salt of N-(2-(2-aminoethoxy)ethyl)nicotinamide. This material was then taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (148 mg, 0.453 mmol), HATU (190 mg, 0.498 mmol) and DIEA (0.24 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (9:1 CH2Cl2/MeOH) afforded N-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethoxy)ethyl)nicotinamide (75 mg, 31percent). MS calculated for C31H46N2O5: 526.34; found: [M+H]+527.
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
Example 6
Preparation of N-(2-(2-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamidoethoxy)ethyl)-5-methyl-4-oxo-5-phenyl-4,5-dihydrofuran-2-carboxamide (I-3)
In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added.
The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min.
The resulting reaction mixture was stirred at room temperature for 18 h.
It was then concentrated under reduced pressure.
The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h.
The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
Example 6
Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide
In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added.
The resulting reaction mixture is stirred at room temperature for 30 min.
A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min.
The resulting reaction mixture was stirred at room temperature for 18 h.
It was then concentrated under reduced pressure.
The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h.
The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
Example 3
Preparation of 2-hydroxy-N-(2-(2-(2-((2Z,5Z,8Z,11Z,14Z,17Z)-eicosa-2,5,8,11,14,17-hexaenylthio)acetamido)ethoxy)ethyl)benzamide (1-1)
In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added.
The resulting reaction mixture is stirred at room temperature for 30 min.
A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 min.
The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure.
The resulting residue is taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h.
The mixture is filtered and the filtrate is concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
Example 7
Preparation of 5-((2-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethoxy)ethyl)carbamoyl)-2-methylpyrazine 1-oxide (I-4)
In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added.
The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min.
The resulting reaction mixture was stirred at room temperature for 18 h.
It was then concentrated under reduced pressure.
The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h.
The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
Example 13
Preparation of (E)-methyl 4-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethoxy)ethylamino)-4-oxobut-2-enoate (Compound I-3)
Sodium hydroxide (400 mg, 10 mmol) was dissolved in 70 mL of MeOH and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added.
The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in 15 mL of THF was then added dropwise, at room temperature, over a period of 15 min.
The resulting reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure.
The resulting residue was taken up in 200 mL of CH2Cl2 and stirred vigorously at room temperature for 4 h.
The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74percent yield).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
Example 6
Preparation of (S)-N-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethoxy)ethyl)-2-hydroxybenzamide (I-3)
In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)-ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added.
The resulting reaction mixture was stirred at room temperature for 30 minutes.
A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 minutes.
The resulting reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure.
The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h.
The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74% With sodium hydroxide In methanol at 20℃; for 18 h; Example 6; Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-((E)-6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-2); In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min The resulting reaction mixture was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (1.47 mmol) was then taken up in CH3CN (10 mL) along with mycophenolic acid (470 mg, 1.47 mmol) and EDCI (310 mg, 1.62 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It is then diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 620 mg of (E)-tert-butyl 2-(2-(6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethoxy)ethylcarbamate (83percent yield).(E)-tert-Butyl 2-(2-(6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamido)ethoxy)ethylcarbamate (620 mg, 1.22 mmol) was taken up in 10 mL of 4 M HC1 in dioxane and allowed to stir at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of (E)-N-(2-(2-aminoethoxy)ethyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide This material was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (400 mg, 1.22 mmol), HATU (510 mg, 1.34 mmol) and DIEA (640 μL, 3.66 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5percent MeOH in CH2Cl2) afforded 600 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2- (2-((E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4- methylhex-4-enamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (68percent yield). MS (EI) calcd for C43H60N2O7: 716.44; found 717 (M+1).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
The same procedure outlined in example 8 was used, substituting tert-butyl (2-(2-aminoethoxy)ethyl)carbamate for tert-butyl 2-aminoethylcarbamate. tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate, in turn, could be prepared as follows: Sodium hydroxide (400 mg, 10 mmol) was dissolved in 70 mL of MeOH and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in 15 mL of THF was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. The resulting residue was taken up in 200 mL of CH2Cl2 and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74percent yield). Compound I-32: MS (EI) calcd for C30H49N5O3 527.38; found 528 [M+H]+.
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
Preparation of 1-((3R,5R)-7-(2-(2-(4Z,7Z,1OZ,13Z,16Z,19Z)-docosa-4,7,1O,13,16,19- hexaenamidoethoxy)ethylamino)-3 ,5-dihydroxy-7-oxoheptyl)-5-(4-fluorophenyl)-2- isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (1-32):1) EDCIH2N°NH2 H2N°NHBoc2) HCIOH OH 0H / N NH2\/[0239j In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 mm. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 mm. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH2C12 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2- aminoethoxy)ethylcarbamate (74percent yield).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18 h;
[0241j In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 mm. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 mm. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2C12 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tertbutyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18.25 h;
[0329] In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc20 (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2C12 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2- aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%
Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h;
Stage #2: at 20℃; for 18 h;
Example 6 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-13) (0371) (0372) In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 L) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74percent yield). (0373) tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150 mg, 0.735 mmol) was then taken up in CH3CN (10 mL) along with indomethacin (263 mg, 0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 310 mg of tert-butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate (78percent). (0374) tert-Butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate was taken up in 10 mL of 4 M HCl in dioxane and allowed to stand at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of N-(2-(2-aminoethoxy)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide. This material was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (187 mg, 0.57 mmol), HATU (238 mg, 0.63 mmol) and DIEA (300 μL, 1.71 mmol). The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5percent MeOH—CH2Cl2) afforded (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide. MS (EI) calcd for C45H56ClN3O5: 753.39; found 754 (M+1).

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[11] Patent: WO2013/166176, 2013, A1, . Location in patent: Paragraph 0239
[12] Patent: WO2013/177536, 2013, A2, . Location in patent: Paragraph 0241
[13] Patent: WO2014/107730, 2014, A2, . Location in patent: Paragraph 0329
[14] Patent: US9216224, 2015, B2, . Location in patent: Page/Page column 53-54
[15] Patent: US2012/252810, 2012, A1, . Location in patent: Page/Page column 31-32
[16] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5260 - 5262
[17] Patent: WO2018/5794, 2018, A2, . Location in patent: Page/Page column 213
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YieldReaction ConditionsOperation in experiment
71.5% at 0 - 20℃; This compound was synthesized according to the procedure described previously with slight modifications.25 To a cooled (0 °C) solution of 2,2'-oxybis(ethylamine) (10.0 mL, 94.1 mmol) in methanol (1000 mL) was added dropwise a solution of di-tert-butyl dicarbonate ((Boc)2O; 10.3 g, 47.0 mmol) in THF (300 mL), and the mixture was stirred for 1 h at the same temperature and additional 24 h at room temperature. After removing the solvent in vacuo, the residue was dissolved in 1 N NaOH (200 mL), and extracted with chloroform (300 mL .x. 3). The organic phases were combined, dried over anhydrous MgSO4. The solvent was removed in vacuo to provide 1 as a colorless oil (6.88 g, 71.5percent). 1H NMR (CDCl3): δ 1.39 (9H, s, Boc), 2.79-2.82 (2H, t, CH2), 3.24-3.28 (2H, dd, CH2), 3.41-3.43 (2H, t, CH2), 3.44-3.47 (2H, t, CH2), 5.00 (1H, d, NH). ESI-MS (M+H)+: m/z 205, found: 205
Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 17, p. 2915 - 2919
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 2, p. 978 - 984
[3] Journal of the American Chemical Society, 2010, vol. 132, # 21, p. 7291 - 7293
[4] Chemical Communications, 2017, vol. 53, # 62, p. 8751 - 8754
[5] Chemistry - An Asian Journal, 2012, vol. 7, # 2, p. 272 - 276
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Reference: [1] Patent: EP2123283, 2009, A1, . Location in patent: Page/Page column 15
[2] Patent: US2009/325894, 2009, A1, . Location in patent: Page/Page column 10
[3] Chemistry - A European Journal, 2010, vol. 16, # 3, p. 878 - 889
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Reference: [1] European Journal of Organic Chemistry, 2002, # 17, p. 3004 - 3014
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Reference: [1] Patent: US2011/269965, 2011, A1,
[2] Patent: US2013/116263, 2013, A1,
[3] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 301 - 320
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Reference: [1] Patent: US2011/269965, 2011, A1,
[2] Patent: US2013/116263, 2013, A1,
[3] Patent: WO2009/113828, 2009, A2,
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Reference: [1] Patent: US2011/269965, 2011, A1,
[2] Patent: US2013/116263, 2013, A1,
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