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[ CAS No. 2418-95-3 ] {[proInfo.proName]}

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Chemical Structure| 2418-95-3
Chemical Structure| 2418-95-3
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Product Details of [ 2418-95-3 ]

CAS No. :2418-95-3 MDL No. :MFCD00037221
Formula : C11H22N2O4 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 246.30 Pubchem ID :-
Synonyms :
(S)-2-Amino-6-((tert-butoxycarbonyl)amino)hexanoic acid

Calculated chemistry of [ 2418-95-3 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.82
Num. rotatable bonds : 9
Num. H-bond acceptors : 5.0
Num. H-bond donors : 3.0
Molar Refractivity : 63.98
TPSA : 101.65 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) : -8.42 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.96
Log Po/w (XLOGP3) : -0.87
Log Po/w (WLOGP) : 1.09
Log Po/w (MLOGP) : -1.61
Log Po/w (SILICOS-IT) : 0.29
Consensus Log Po/w : 0.17

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.22
Solubility : 147.0 mg/ml ; 0.596 mol/l
Class : Very soluble
Log S (Ali) : -0.78
Solubility : 40.6 mg/ml ; 0.165 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.52
Solubility : 7.44 mg/ml ; 0.0302 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 2.71

Safety of [ 2418-95-3 ]

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

Application In Synthesis of [ 2418-95-3 ]

* 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 [ 2418-95-3 ]
  • Downstream synthetic route of [ 2418-95-3 ]

[ 2418-95-3 ] Synthesis Path-Upstream   1~27

  • 1
  • [ 2418-95-3 ]
  • [ 75-36-5 ]
  • [ 23500-04-1 ]
YieldReaction ConditionsOperation in experiment
87.7% With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 4 h; Example A73 Preparation of Ar2-acetyl-L-lysyl-L-valyl-A^-carbamoyl-Ar-[4-([(2-[(3i?,51S',7i?,8i?)-8-hydroxy-7- {(l£,3£)-5-[(21S,,35',5i?,6i?)-5-[(2Z,41S)-4-hydroxypent-2-enoyl]amino}-3,6-dimethyltetrahydro- 2H-pyran-2-yl]-3-methylpenta-l,3-dien-l-yl}-l,6-dioxaspiro[2.5]oct-5- yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-L-ornithinamide, acetate salt (B222). B227 Step 1. Synthesis of N2-acetyl-N6-(teri-butoxycarbonyl)-L-lysine (B223). To a mixture of N6- (fert-butoxycarbonyl)-L-lysine (22.5 g, 91.5 mmol, 1 eq.) and K2CO3 (63.1 g, 0.457 mol, 5 eq.) in tetrahydrofuran/water (200 mL/200 mL) at 0 °C was added acetyl chloride (8.62 g, 0.109 mol, 1.2 eq.), and the mixture was stirred at rt for 4 h. The mixture was concentrated in vacuo to remove the tetrahydrofuran, and the aqueous layer was adjusted to pH = 1 with 2 M HCI and extracted with EtOAc (100 mL) three times. The extract was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford B223 (23.1 g, 87.7 percent) as a yellow oil. Step 2. Synthesis of N2-acetyl-L-lysine hydrochloride salt (B224). To a solution of B223 (23.1 g, 0.080 mmol, 1 eq.) in ethyl acetate (400 mL) at 0 °C was added HC1 (g) in ethyl acetate (250 mL) under nitrogen. The mixture was stirred at rt for 4 h and filtered. The solid was washed with ethyl acetate and dried in vacuo to afford B224 (18.5 g, >100 percent) as a white solid which was used without further purification. Step 3. Synthesis of N2-acetyl-N6-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysine (B225). To a mixture of B224 (8 g, 35.6 mmol, 1 eq.) and NaHC03 (5.99 g, 71.3 mmol, 2 eq.) in acetone/water (80 mL/80 mL) at 0 °C was added a solution of Fmoc-Cl (9.41 g, 36.3 mmol, 1.02 eq.) in acetone (80 mL), and the mixture was stirred at rt for 2 h. The mixture was adjusted to pH = 3-4 with 2 N HC1 and extracted with ethyl acetate (100 mL) three times. The extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give the crude product (7 g) as a yellow oil. To the crude product was added dichloromethane and fert-butylmethyl ether (100 mL), and the suspension was stirred for 30 min and then filtered. The filter cake was dried in vacuo to afford B225 (3.25 g, 22.2 percent) as a white solid. Step 4. Synthesis of N2-acetyl-N6-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysyl-L-valyl-N5- carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (B226). To a mixture of B225 (1.04 g, 2.54 mmol, 1 eq.) in NN-dimethylformamide (20 mL) at 0 °C was added N-methylmorpholine (769 mg, 7.61 mmol, 3 eq.), l -ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl (632 mg, 3.30 mmol, 1.3 eq.), 1 -hydroxybenzotriazole hydrate (445 mg, 3.30 mmol, 1.3 eq.) and L-valyl-N5-carbamoyl-N-[4- (hydroxymethyl)phenyl]-L-ornithinamide (From WO04010957, 1.01 g, 2.66 mmol, 1.05 eq.) under nitrogen, and the mixture was stirred at rt for 2 h. the mixture was poured into teri-butylmethyl ether (300 mL) and filtered. The solid was washed with dichloromethane (50 mL) and water (50 mL) and dried in vacuo to afford B226 (1.87 g, 95.6percent) as a white solid. Step 5. Synthesis of N2-acetyl-N6-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysyl-L-valyl-N5- carbamoyl-N-[4-( [(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (B227). To a mixture of B226 (1.87 g, 2.43 mmol, 1 eq.) and bis-(4-nitrophenyl)carbonate (2.21 g, 7.28 mmol, 3 eq.) in NN-dimethylformamide (30 mL) at 0 °C was added NN-diisopropylethylamine (313 mg, 2.43 mmol, 1 eq.) under nitrogen, and the mixture was stirred at rt overnight. The mixture was poured into teri-butylmethylether (50 mL) and filtered. The solid (1.95 g) was purified by prep HPLC to give B227 (580 mg, 25.7 percent) as a white solid. lU NMR (400Hz, DMSO-dg): 10.1 (s, 1 H), 8.29 (d, 2 H), 8.00 (d, 1 H), 7.86 (d, 1 H), 7.65 (d, 2 H), 7.64 (d, 1 H), 7.61 (m, 4 H), 7.40 (m, 2 H), 7.38 (m, 4 H), 7.30 (m, 3 H), 6.01 (br, 1 H), 5.21 (s, 2 H), 4.35 (br, 1 H), 4.27-4.15 (m, 5 H), 2.96 (m, 4 H), 1.98 (m, 1 H), 1.82 (s, 3 H), 1.65 (br, 3 H), 1.43-1.24 (m, 7 H), 0.83 (m, 6 H). Step 6. Synthesis ofN2-acetyl-N6-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysyl-L-valyl-N5- carbamoyl-N-[4-( [(2-[(3R,5S,7R,8R)-8-hydroxy-7-{(l£',3£')-5-[(2S,3S,5R,6R)-5- [(2Z,4S)-4- hydroxypent-2-enoyl]amino}-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-l,3-dien-l -yl} - 1.6- dioxaspiro [2.5] oct-5-yl] acetyl} hydrazinyl)carbonyl] oxy } methyl)phenyl] -L-ornithinamide (B228) . To a solution of B209 (8.1 mg, 0.016 mmol, 1 eq.) in NN-dimethylformamide (0.4 mL) at rt was added 2,6-lutidine (7.5 \L, 0.064 mmol, 4 eq.), NN-diisopropylethylamine (11.3 \L, 0.064 mmol, 4 eq.) and 4-NN-dimethylamino pyridine (2 mg, 0.016 mmol, 1 eq.) followed by B227 (17.8 mg, 0.019 mmol, 1.2 eq.), and the reaction was stirred for 5 h. The reaction was purified by reverse phase chromatography (Method A) to give B228 as a white solid. Yield: 5.5 mg, 0.004 mmol, 26percent. LCMS (Protocol D): m/z 1306.1 [M+H]+, retention time = 0.81 minutes. Step 7. Synthesis of N2-acetyl-L-lysyl-L-valyl-N5-carbamoyl-N-[4-([(2- [(3R,5S,7R,8R)-8- hydroxy-7-{(l£',3£')-5-[(2S,3S,5R,6R)-5-[(2Z,4S)-4-hydroxypent-2-enoyl]amino}-3,6- dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-l,3-dien-l -yl} -l,6-dioxaspiro[2.5]oct-5- yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-L-ornithinamide, acetate salt (B222). The title compound was prepared in 79percent yield from 9.5 mg (0.007 mmol, 1.0 eq.) of B228 and 11.9 mg (0.14 mmol, 20.0 eq.) of piperidine using the procedure described for preparation of compound B47. LCMS (Protocol D): m/z 1084.1 [M+H]+, retention time = 0.58 minutes. lU NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.22-8.12 (m, 1 H), 8.03 (d, J= 7.8 Hz, 1 H), 7.87-7.74 (m, 2 H), 7.64-7.53 (m, 2 H), 7.34-7.18 (m, 2 H), 6.31 (d, J= 15.9 Hz, 1 H), 6.09-6.01 (m, 1 H), 5.98 (d, J= 11.8 Hz, 1 H), 5.86 (dd, J= 11.8 and 7.1 Hz, 1 H), 5.66-5.56 (m, 1 H), 5.55-5.49 (m, 1 H), 5.44 (br s, 1 H), 5.23-4.91 (m, 3 H), 4.43-4.33 (m, 1 H), 4.30-4.21 (m, 2 H), 4.20-4.12 (m, 1 H), 3.69-3.59 (m, 1 H), 3.53-3.45 (m, 1 H), 3.07- 2.88 (m, 2 H), 2.76-2.71 (m, 1 H), 2.61-2.56 (m, 1 H), 2.35-2.14 (m, 4 H), 2.04-1.53 (m, 18 H), 1.52-1.18 (m, 10 H), 1.11 (d, J= 6.4 Hz, 3 H), 1.06 (d, J= 6.4 Hz, 3 H), 0.95 (d, J= 7.3 Hz, 3 H), 0.85 (d, J= 6.9 Hz, 3 H), 0.82 (d, J= 6.9 Hz, 3 H).
Reference: [1] Patent: WO2014/68443, 2014, A1, . Location in patent: Page/Page column 202; 203; 204
[2] Journal of the American Chemical Society, 2018, vol. 140, # 5, p. 1572 - 1575
  • 2
  • [ 2418-95-3 ]
  • [ 108-24-7 ]
  • [ 23500-04-1 ]
Reference: [1] Organic Letters, 2006, vol. 8, # 15, p. 3215 - 3217
[2] Journal of Agricultural and Food Chemistry, 1996, vol. 44, # 9, p. 2531 - 2537
  • 3
  • [ 2418-95-3 ]
  • [ 2212-75-1 ]
Reference: [1] Journal of the American Chemical Society, 1982, vol. 104, # 16, p. 4446 - 4450
  • 4
  • [ 2418-95-3 ]
  • [ 501-53-1 ]
  • [ 2389-60-8 ]
Reference: [1] Journal of the American Chemical Society, 1982, vol. 104, # 16, p. 4446 - 4450
[2] Bulletin of the Chemical Society of Japan, 1964, vol. 37, p. 1471 - 1477
[3] Patent: WO2018/51197, 2018, A1, . Location in patent: Paragraph 0088; 0174
  • 5
  • [ 13139-17-8 ]
  • [ 2418-95-3 ]
  • [ 2389-60-8 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 10, p. 1489 - 1490
  • 6
  • [ 2389-60-8 ]
  • [ 2418-95-3 ]
Reference: [1] Synthetic Communications, 1981, vol. 11, # 4, p. 303 - 314
[2] Tetrahedron Letters, 2003, vol. 44, # 27, p. 4981 - 4984
[3] Organic and Biomolecular Chemistry, 2011, vol. 9, # 8, p. 2597 - 2601
[4] Chemische Berichte, 1972, vol. 105, # 2, p. 740 - 742
[5] Journal of the American Chemical Society, 1965, vol. 87, p. 99 - 104
[6] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 9, p. 2592 - 2597
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 3, p. 550 - 565
  • 7
  • [ 71989-26-9 ]
  • [ 2418-95-3 ]
YieldReaction ConditionsOperation in experiment
95% With piperidine In dichloromethane at 20℃; for 16 h; Step 1. To a stirred solution of compound 20-1 (5 g, 10.7 mmol) in DCM was added compound 20-2 (5.5 ml, 53 mmol) at r.t. The mixture was stirred at r.t. for 16 h. The reaction mixture was extracted with H20 and the combined aqueous layers were concentrated to give 20-3. (Yield: 95 percent)
Reference: [1] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 103; 104
[2] Organic and Biomolecular Chemistry, 2011, vol. 9, # 4, p. 987 - 993
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
  • 8
  • [ 657-27-2 ]
  • [ 2418-95-3 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With copper (II) carbonate hydroxide; sodium carbonate In methanol; water; acetone at 25℃; for 24 h;
Stage #2: With disodium ethylenediamine tetraacetic acid In water at 80 - 90℃; for 1 h;
L-Lysine monohydrochloride (3.0 g, 16.4 mmol), sodium carbonate (2.09g, 19.7 mmol) and Copper (II) carbonate hydroxide [Cu3 (CO3)2(OH) 2] (1.81 g, 8.2 mmol) were added to water (30 mL) and stirred for 15 min. To this solution was added a solution of 2 (5.37g, 18.1 mmol) in acetone (20 mL). The reaction mixture and stirred for 18h at room temperature. Methanol (5 mL) was added and further stirred for 6h. The solid obtained was filtered and washed with acetone (20 mL). Solid was suspended in water (30 mL), added disodium EDTA (3.60 g, 9.67 mmol) and heated to 80-90°C for 1h. The reaction mixture was cooled to 5-10°C and neutralized with dilute HCl carefully. The obtained solid was filtered and dried to give H-Lys (Boc)-OH (3.15g, 78percent yield). mp: 247-250°C (lit.3 250°C); [α]D 20 = +17.2° (c 1, AcOH) {lit.3 [α]D 20 = +18° (c 1, AcOH)}; IR (KBr, cm-1): vmax 3375, 2979, 2937, 2865, 1687, 1604, 1583, 1528, 1444, 1412, 1366, 1350, 1325, 1294, 1275, 1250, 1180, 1063, 1038, 1017, 994, 979, 925, 871, 810, 781, 765, 737, 663, 528; 1H NMR (300 MHz, CD3OD): δ 3.52 (t, 1H), 3.06-3.02 (t, 2H), 1.85-1.80 (m, 2H), 1.50-1.42 (m, 13H); 13C NMR (300 MHz, CD3OD): δ 174.49, 158.60, 79.91, 56.24, 41.02, 32.04, 30.65, 28.80, 23.59; MS: m/z 246.93 [M+H]+.
Reference: [1] Synthetic Communications, 2017, vol. 47, # 22, p. 2127 - 2132
  • 9
  • [ 56-87-1 ]
  • [ 24424-99-5 ]
  • [ 2418-95-3 ]
Reference: [1] Chemistry of Natural Compounds, 1979, vol. 15, p. 471 - 476[2] Khimiya Prirodnykh Soedinenii, 1979, vol. 15, p. 543 - 548
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2175 - 2179
[4] Journal of Materials Chemistry B, 2015, vol. 3, # 1, p. 119 - 126
[5] European Journal of Medicinal Chemistry, 2019, p. 122 - 131
  • 10
  • [ 24424-99-5 ]
  • [ 657-27-2 ]
  • [ 2418-95-3 ]
Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 22, p. 6975 - 6978
[2] Organic Letters, 2006, vol. 8, # 15, p. 3215 - 3217
[3] Synthetic Communications, 1981, vol. 11, # 4, p. 303 - 314
[4] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 10, p. 1489 - 1490
  • 11
  • [ 104669-72-9 ]
  • [ 2418-95-3 ]
Reference: [1] Tetrahedron Letters, 1986, vol. 27, # 21, p. 2365 - 2368
  • 12
  • [ 2212-75-1 ]
  • [ 2418-95-3 ]
Reference: [1] Synthetic Communications, 1981, vol. 11, # 4, p. 303 - 314
[2] Journal of the American Chemical Society, 1965, vol. 87, p. 99 - 104
  • 13
  • [ 1070-19-5 ]
  • [ 2418-95-3 ]
Reference: [1] Journal of the American Chemical Society, 1965, vol. 87, p. 99 - 104
  • 14
  • [ 56-87-1 ]
  • [ 34619-03-9 ]
  • [ 2418-95-3 ]
  • [ 13734-28-6 ]
Reference: [1] Patent: WO2008/14811, 2008, A1, . Location in patent: Page/Page column 13-14
  • 15
  • [ 71989-26-9 ]
  • [ 4425-82-5 ]
  • [ 2418-95-3 ]
Reference: [1] Chimia, 2010, vol. 64, # 3, p. 200 - 202
  • 16
  • [ 6627-89-0 ]
  • [ 2418-95-3 ]
Reference: [1] Synthetic Communications, 1981, vol. 11, # 4, p. 303 - 314
  • 17
  • [ 14511-39-8 ]
  • [ 2418-95-3 ]
Reference: [1] Synthetic Communications, 1981, vol. 11, # 4, p. 303 - 314
  • 18
  • [ 657-27-2 ]
  • [ 2418-95-3 ]
Reference: [1] Synthetic Communications, 1981, vol. 11, # 4, p. 303 - 314
  • 19
  • [ 95-14-7 ]
  • [ 6627-89-0 ]
  • [ 657-27-2 ]
  • [ 2418-95-3 ]
YieldReaction ConditionsOperation in experiment
~ 75 %Spectr. at 60℃; for 18 h; A solution of L-lysine monohydrochloride (20.0 g, 109.5 mmol) and benzotriazole (14.3 g, 120.0 mmol) in a mixture of water (66.6 mL) and THF (111.0 mL) at pH 12 was treated with t-butyl phenyl carbonate (24.3 mL, 131.4 mmol) and stirred 18 hours at 600C. The mixture, initially 2 layers, became a clear orange solution and the product was approximately 75percent (NMR) .
Reference: [1] Patent: WO2008/14811, 2008, A1, . Location in patent: Page/Page column 16
  • 20
  • [ 24424-99-5 ]
  • [ 2418-95-3 ]
Reference: [1] Synthetic Communications, 2017, vol. 47, # 22, p. 2127 - 2132
  • 21
  • [ 18595-55-6 ]
  • [ 56-87-1 ]
  • [ 2418-95-3 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1968, vol. 716, p. 216 - 218
  • 22
  • [ 24424-99-5 ]
  • [ 2418-95-3 ]
  • [ 2483-46-7 ]
Reference: [1] Organic Syntheses, 1985, vol. 63, p. 160 - 160
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 11, p. 5387 - 5397
  • 23
  • [ 2418-95-3 ]
  • [ 82911-69-1 ]
  • [ 71989-26-9 ]
Reference: [1] Journal of Peptide Science, 2017, vol. 23, # 3, p. 202 - 214
[2] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 10, p. 1489 - 1490
[3] European Journal of Organic Chemistry, 2015, vol. 2015, # 17, p. 3767 - 3770
[4] Journal of Materials Chemistry B, 2015, vol. 3, # 1, p. 119 - 126
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 2980 - 2983
  • 24
  • [ 56-87-1 ]
  • [ 34619-03-9 ]
  • [ 2418-95-3 ]
  • [ 13734-28-6 ]
Reference: [1] Patent: WO2008/14811, 2008, A1, . Location in patent: Page/Page column 13-14
  • 25
  • [ 2418-95-3 ]
  • [ 34622-39-4 ]
Reference: [1] Journal of the American Chemical Society, 1982, vol. 104, # 16, p. 4446 - 4450
  • 26
  • [ 2418-95-3 ]
  • [ 82911-69-1 ]
  • [ 159610-89-6 ]
Reference: [1] Journal of Peptide Science, 2017, vol. 23, # 3, p. 202 - 214
  • 27
  • [ 2418-95-3 ]
  • [ 148101-51-3 ]
Reference: [1] Patent: WO2014/68443, 2014, A1,
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