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Structure of N-(Chloroacetoxy)succinimide
CAS No.: 27243-15-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 27243-15-8 |
Formula : | C6H6ClNO4 |
M.W : | 191.57 |
SMILES Code : | O=C(N1OC(CCl)=O)CCC1=O |
MDL No. : | MFCD11044492 |
InChI Key : | OWZGNRBFMASABS-UHFFFAOYSA-N |
Pubchem ID : | 12535337 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H314 |
Precautionary Statements: | P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅲ |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 42.13 |
TPSA ? Topological Polar Surface Area: Calculated from |
63.68 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.16 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.15 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.55 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.5 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.46 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.28 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.74 |
Solubility | 35.2 mg/ml ; 0.184 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.73 |
Solubility | 35.4 mg/ml ; 0.185 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.82 |
Solubility | 29.3 mg/ml ; 0.153 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.58 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.2 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With triethylamine; In chloroform; at 0℃; for 0.416667h; | To a solution of N-hydroxysuccinimide (640.3 mg, 5.56 mmol) in chloroform (8.5 mL) was added triethylamine (861.6 mu, 6.18 mmol) 0 C. Then, a-chloroacetyl chloride was added dropwise over a 5 minute period and stirred for an additional 20 minutes at 0C. The reaction mixture was washed with ice-cold water (15 mL) and brine (15 mL), concentrated to a volume of 1.7 mL in vacuo, then dried with sodium sulfate and filtered. To the resulting solution were added ethyl acetate (170 mu) and hexanes (1.2 mL), and the mixture was cooled down to 0 C stirred for 2 h, and a white solid was precipitated. It was filtered and washed first with ice-cold 10 mL portion of hexanes/ethyl acetate (4: 1), then with 10 mL hexanes/ethyl acetate (9: 1), and finally with hexanes (10 mL, twice). The resulting white solid was dried under house vacuum to yield 2,5-dioxopyrrolidin-l-yl 2-chloroacetate (563.9 mg, 53%). NMR 400 MHz (CDC13) delta 4.37 (s, 2H), 2.87 (s, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | In dichloromethane; at 20℃; | 3-Trifluoromethyl-4- (2-chlorocarbamoylmethyl)methoxyethoxymethylbenzene; 3-Trifluoromethyl-4-amino-methoxyethoxymethylbenzene (0.5 g, 0.2 mmol), and N-hydroxysuccinimidyl chloroacetate(0.36 g, 0.2 mmol) were dissolved in dichloromethane (10 cm3), and stirred at room temperature overnight. Solvent was removed and the product purified using column chromatography on silica, (DCM/MeOH, Rf = 0.6, 5% MeOH/DCM) , followed by recrystallisation from hexane/EtOAc to give a white solid, (0.25 g, 52%), m.p. 72-740C, Found C, 45.76%,H, 4.63%, N, 4.21%. C13Hi5NO4F3Cl requires C, 45.72%, H,4.43%, N, 4.13%, m/z (ES+) :341 (M+), 364 [(M+Na)+], deltaH <n="42"/>(CDCl3, 400MHz) : 3.37(s, 3H, 0-CH3) , 3.55(t, J = 4.8 Hz, 2H,0-CH2), 3.81(t, J = 4.8Hz, 2H, O- CH2), 4.22 (s, 2H, CH2Cl),5.28 (s, 2H, 0-CH2-O)7 7.27 (d, J H-H«» = 8Hz, IH, Ar H ortho) , , 7.34 (s, IH, Ar H ortho) . 7.96 (d, JH-H(O) = 8Hz, IH, Ar H meta) , 8.57 (br s, IH, NH) . deltac (CDCl3, ' 100.6Hz) : 43.10(CH2C1), 59.25 (0-CH3), 68.09(0-CH2), 71.68 (0-CH2), 93.82(0-CH2-O), 114.65 (q, 2JCF = 18Hz, CCF3), 120.37(Ar CH),122.97 ( q, 1J0F = 162 Hz, CF3), 126.89 (Ar CH), 127.96 ( ArC), 154.82 (Ar C), 164.63 (Ar CH), 178.54 (C=O)], deltaF(CDCl3, 188MHz) : 61.5 (s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetonitrile; at 23℃; for 1h; | Step A: 2-Chloro-N-{2-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide A mixture of (R)-N2-(1,2,3,4-tetrahydro-naphthalen-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 33) (293 mg, 1 mmol) and chloro-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (CAS 27243-15-8) (192 mg, 1 mmol) in acetonitrile (2 ml) was stirred at 23 C. for 1 h. Poured onto water and extracted with ethyl acetate, dried the combined organic layers over sodium sulfate, filtered off and evaporated totally to give the title compound as a light red oil (370 mg, 100%, HPLC 1.185 min), MS (ISP) m/e=370.1 [(M+H)+] and 372 [(M+2+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | In acetonitrile; at 20℃; for 24h;pH 7.4; | Compound 8 (30 mg, 29 ?mol) was dissolved in PBS-CH3CN (15 mL, 1:1, v/v). The mixture was added halo (I, Br, Cl) acetic acid NHS ester (12 mg, 42 ?mol in case of I) and stirred at rt for 6-24 h. The reaction mixture was diluted with EtOAc and washed with H2O. The organic solution was dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography eluted with CHCl3-MeOH (10:1) to give 9 (17 mg, 63% : case of I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | To a solution of (2S)-2-propylpentyl 2-(((((((2R,3S,4R,5R)-5-(2-amino-6-oxo- 1H- purin-9(6H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)(2- aminoethoxy)phosphoryl)amino)propanoate (15.0 mg, 0.019 mmol) in DMF (1 mL) were added DIPEA (16.7 mu, 0.096 mmol) and 2.17 (7.3 mg, 0.038 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 30 min. It was diluted with water (10 mL) and washed with dichloromethane (10 mL). The aqueous layer was concentrated in vacuo, diluted with water (1 mL), and directly purified by preparative reverse-phase HPLC (methanol/water gradient) to provide (2S)-2-propylpentyl 2-(((((((2R,3S,4R,5R)-5-(2-amino- 6-oxo-lH-purin-9(6H)-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(hydroxy)phosphoryl)oxy)(2-(2-chloroacetamido)ethoxy)phosphoryl)amino)- propanoate. MS m/z: 746.41 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 2-(((((((2R,3S,4R,5R)-5-(2-amino-6-oxo-lH-purin-9(6H)-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)(hydroxy)phosphoryl)oxy)(hydroxy)phosphoryl)oxy)ethylamine (7.8 mg, 0.013 mmol) in DMF (1 mL) were added DIPEA (11.3 mu, 0.065 mmol) and 2,5-dioxopyrrolidin-l- yl 2-chloroacetate (5.0 mg, 0.026 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h. It was diluted with water (10 mL) and washed with dichloromethane (10 mL). The aqueous layer was concentrated in vacuo, diluted with water (1 mL), and directly purified by preparative reverse-phase HPLC (methanol/water gradient) to provide (2-chloroacetamido)-(((((((2R,3S,4R,5R)-5-(2-amino-6-oxo-lH-purin-9(6H)-yl)- 3 ,4-dihydroxytetrahydrofuran-2- yl)methoxy)(hydroxy)phosphoryl)oxy)(hydroxy)phosphoryl)-oxy)ethane (4.3 mg, 49%). 1H 400 MHz NMR (D20) delta 8.47 (s, 1H), 8.01 (s, 1H), 5.94 (d, J = 6.6 Hz, 1H), 4.52 (del, J = 5.4, 3.0 Hz, 1H), 4.34-4.36 (m, 1H), 4.20-4.22 (m, 2H), 4.11 (s, 2H), 4.00-4.03 (m, 2H), 3.43-3.46 (m, 2H); MS m/z: 563.07 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | To a stirred solution of 22 (154 mg, 0.16 mmol) in dry DMF (3 mL) were added DIEA (83.2 muL, 0.48 mmol), and alpha-chloroacetylsuccinimidyl ester (36.5 mg, 0.19 mmol). The reaction mixture we stirred for 1.5 hrs at rt. After dilution with water, the reaction mixture was extracted with AcOEt (x2). The extracts were washed with sat. NaHCO3 aq. and brine followed by drying over Na2SO4. After removal of the solvent in vacuo, the residue was purified by column chromatography on SiO2 (chloroform : methanol = 30 : 1) to give 23 (159 mg, 96 %) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | Compound 26 (110 mg, 0.09 mmol) was used as a starting material. By the same synthetic procedure as that for 23, 27 (106 mg, 94%) was obtained as a colorless amorphous powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | To a stirred solution of 2b (130 mg, 0.164 mmol) in CH2Cl2 (3.0 mL) was added TFA(2.0 mL) at room temperature. The mixture was allowed to stir for 1 h. The solvent wasco-evaporated twice with toluene (2 mL) to yield deprotected 2b (quantitative). To astirred solution of deprotected 2b (20 mg, 25 mumol) in dry DMF (2.0 mL) was addedEt3N (27.4 muL, 0.20 mmol) and <strong>[27243-15-8](2,5-dioxopyrrolidin-1-yl) 2-chloroacetate</strong> (7.0 mg, 37mumol) at room temperature. The mixture was allowed to stir for 1 h. After removing thesolvent in vacuo, the residue was purified by RP-HPLC (CH3CN (0.1% TFA) : H2O(0.1% TFA) = 10 : 90 (0 min) > 40 : 60 (30 min) > 100 : 0 (40 min) > 10 : 90 (45 min),detection: UV (220 nm)) to yield 2 (14 mg, 61%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.2 mg | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere; | To a stirred solution of 3c (130 mg, 0.164 mmol) in CH2Cl2 (3.0 mL) was added TFA(2.0 mL) at room temperature. The mixture was allowed to stir for 1 h. The solvent wasco-evaporated twice with toluene (2 mL) to yield deprotected 3c (quantitative). To astirred solution of deprotected 3c (14.7 mumol) in dry DMF (2.0 mL) was added Et3N(16.3 muL, 0.117 mmol) and <strong>[27243-15-8](2,5-dioxopyrrolidin-1-yl) 2-chloroacetate</strong> (5.2 mg, 27mumol) at room temperature. The mixture was allowed to stir for 2 h. After removing thesolvent in vacuo, the residue was purified by RP-HPLC (CH3CN (0.1% TFA) : H2O(0.1% TFA) = 10 : 90 (0 min) > 40 : 60 (30 min) > 100 : 0 (40 min) > 10 : 90 (45 min),detection: UV (220 nm)) to yield 3 (6.2 mg, 45%) as yellow oil. |
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