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CAS No. : | 146474-00-2 | MDL No. : | MFCD01073617 |
Formula : | C8H9F3N2O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YNHKVOGCDPODMT-UHFFFAOYSA-N |
M.W : | 254.16 | Pubchem ID : | 16212752 |
Synonyms : |
N-(2-Aminoethyl)maleimide (trifluoroacetate salt);2-Maleimidoethylamine
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 51.98 |
TPSA : | 100.7 Ų |
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) : | -9.06 cm/s |
Log Po/w (iLOGP) : | 0.76 |
Log Po/w (XLOGP3) : | -1.71 |
Log Po/w (WLOGP) : | 0.38 |
Log Po/w (MLOGP) : | -0.41 |
Log Po/w (SILICOS-IT) : | -0.46 |
Consensus Log Po/w : | -0.29 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.14 |
Solubility : | 184.0 mg/ml ; 0.724 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.11 |
Solubility : | 326.0 mg/ml ; 1.28 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.06 |
Solubility : | 222.0 mg/ml ; 0.873 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.34 |
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: |
* 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 |
---|---|---|
65% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 1.16667h; | 1.e 0.4 g (0.45 mmol) of the title compound of Example Id) and 45 mg (0.45 mmol) of triethylamine are dissolved in 10 ml of dimethylformamide, mixed at 00C with 0.15 g (0.45 mmol) of TBTU and stirred for 10 minutes. Then, a solution of 0.17 g (0.68 mmol) of N-(2- aminoethyl)maleimide-trifluoroacetate (Int J Pept Protein Res 1992, 40, 445) and 68 mg (0.68 mmol) of triethylamine in 0.5 ml of dimethylformamide is added, and it is stirred for 1 hour at room temperature. After 10 ml of diethyl ether is added, the solid is centrifuged off, dried and purified by means of chromatography (RP C- 18 silica gel, gradient methanol/water) . Yield: 0.30 g of a blue lyophilizate (65% of theory). Elementary analysis: CId.: C 47.24 H 4.26 N 5.51 S 12.61 Na 6.78 Fnd.: C 47.74 H 4.47 N 5.40 S 11.99 Na 7.02 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In dichloromethane at 20℃; for 18h; | 29 M-PEOZ p-nitrophenylcarbonate (Mn 2150 Da, 0.500 g, 0.232 mmol), prepared as described above, was added to a mixture of N-(2-aminoethyl)maleimide trifluoroacetate salt (0.065 g, 0.255 mmol) and triethylamine (0.097 mL, 0.696 mmol) in methylene chloride (5 mL). After stirring for 18 hours at room temperature, the mixture was filtered and then added dropwise into diethyl ether to give a light yellow precipitate. The solvent was decanted and the solid dried under vacuum to give quantitative yield. 1H NMR spectra showed the terminal methylene protons (-CH2-OCO-NU-) at 4.15 ppm (br s, 2H) and the protons associated with maleimide at 6.72 ppm (s, 2H) in addition to the usual backbone peaks. The yield was determined to be -80% by comparison of integrations of the initiating methyl group and maleimide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: trisodium 3,3-dimethyl-2-{7-[3,3-dimethyl-5-sulfonato-1-(2-sulfonatoethyl)-3H-indolium-2-yl]-4-(2-carboxyethyl)hepta-2,4,6-trien-1-ylidene}-1-(2-sulfonatoethyl)-2,3-dihydro-1H-indole-5-sulfonate With tributyl-2-thiourea; triethylamine In DMF (N,N-dimethyl-formamide) at 0℃; for 0.166667h; Stage #2: N-(2-aminoethyl)maleimide trifluoroacetate With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 1h; | 1.e e) Trisodium 3, 3-dimethyl-2- {7- [3, 3-DIMETHYL-5-SULFONATO-1- (2-SULFONATOETHYL)-3H- indolium-2-yl]-4- (2- { [2- (2, 5-dioxo-2, 5-dihydro-1 H-pyrrol-1- yl) ethyl] carbamoyl} ethyl) hepta-2,4, 6-TRIEN-1-YLIDENE}-1- (2-SULFONATOETHYL)-2, 3- DIHYDRO-LH-INDOLE-5-SULFONATE, internal salt 0.4 g (0.45 mmol) of the title compound of Example ld) and 45 mg (0.45 mmol) of triethyla- mine are dissolved in 10 ml OF DIMETHYLFORMAMIDE, mixed at 0°C with 0.15 g (0.45 mmol) of TBTU and stirred for 10 minutes. Then, a solution of 0.17 g (0.68 mmol) of N- (2- aminoethyl) maleimide-trifluoroacetate (INT JPEPT PROTEIN RES 1992, 40, 445) and 68 mg (0.68 mmol) of triethylamine in 0.5 ml OF DIMETHYLFORMAMIDE is added, and it is stirred for 1 hour at room temperature. After 10 ml of diethyl ether is added, the solid is centrifuged off, dried and purified by means of chromatography (RP C-18 silica gel, gradient methanol/water). Yield: 0. 30 g of a blue lyophilizate (65% of theory). Elementary analysis : Cld. : C 47.24 H4. 26 N 5. 51 S 12.61 NA6. 78 Fnd.: C 47.74 H 4. 47 N 5. 40 S 11.99 Na 7. 02 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile at 20℃; for 3h; | 16 Preparation of (E)-methyl 4-((R)-3-(1-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2,5-dioxopyrrolidin-3-ylthio)-1-methoxy-1-oxopropan-2-ylamino)-4-oxobut-2-enoate (Compound I-39) Example 16 Preparation of (E)-methyl 4-((R)-3-(1-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2,5-dioxopyrrolidin-3-ylthio)-1-methoxy-1-oxopropan-2-ylamino)-4-oxobut-2-enoate (Compound I-39) The TFA salt of 1-(2-aminoethyl)-1H-pyrrole-2,5-dione (Aldrich, 280 mg, 1.10 mmol) was taken up in 10 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 360 mg, 1.1 mmol), HATU (460 mg, 1.2 mmol) and DIEA (0.58 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 350 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2,5-dioxo-2H-pyrrol-1(5H)-yl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (70% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | N1-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethyl)-N5-(6-(6-(pyridin-2-yl)-To a flame dried flask was added 0.03 g (0.065 mmol, 1 eq.) of 2,5- dioxopyrrolidin-l-yl 5-oxo-5-((6-(6-(pyridin-2-yl)-l,2,4,5-tetrazin-3-yl)pyridin-3- yl)amino)pentanoate (13), followed by 0.02 g (0.078 mmol, 1.2 eq.) of 2-(2,5-dioxo- 2,5-dihydro-lH-pyrrol-l-yl)ethanaminium trifluoroacetate. The flask was evacuated and then refilled with nitrogen. DMF (1 ml) was added and the mixture was stirred.Diisopropylethyl amine (0.032 ml, 0.195 mmol, 3 eq.) was added dropwise to the mixture. The reaction mixture was stirred for 24 hours at room temperature. The reaction was condensed in vacuo and then loaded onto a silica gel column using the minimum amount of MeOH required along with CH2CI2. The column was then run using a gradient of 0-10% MeOH in CH2CI2 to yield 48% (0.015 g, 0.031 mmol) of N1-(2-(2,5- dioxo-2,5-dihydro-lH-pyrrol- l-yl)ethyl)-N5-(6-(6-(pyridin-2-yl)- l,2,4,5-tetrazin-3- yl)pyridin-3-yl)glutaramide.H NMR (400 MHz, CD3OD) δ 9.06 (d, J = 2.3 Hz, 1H), 8.92-8.88 (m, 1H), 8.82- 8.75 (m, 2H), 8.51 (dd, J = 8.8, 2.6 Hz, 1H), 8.19 (dt, J = 1.7, 7.8 Hz, 1H), 7.80 - 7.69 (m, 1H), 6.84 (s, 2H), 5.51 (s, 1H), 4.60 (s, 2H), 3.72 - 3.56 (m, 2H), 3.42-3.36 (m, 2H), 2.68 (s, 1H), 2.53 (t, J = 7.3 Hz, 2H), 2.27 (t, J - 7.4 Hz, 2H), 2.08 - 1.90 (m, 2H). |
In N,N-dimethyl-formamide at 20℃; for 24h; Alkaline conditions; Inert atmosphere; | Compound 5 (60mg, 0.13mmol) and 2-(2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethanaminium trifluoroacetate (40mg, 0.156mmol) were added to a flame dried flask. The flask was evacuated and then filled with N2. DMF (1ml) was added and the mixture was stirred. Diisopropylethyl amine (0.064ml, 0.39mmol) was added dropwise to the mixture. The reaction mixture was stirred overnight at room temperature. The reaction was condensedin vacuoand then loaded onto a silica gel column using the minimum amount of MeOH required along with DCM. The column was then run using a gradient of 0-10% MeOH in CH2CI2 to yield 40% (24mg) as purple solid. 1H NMR (600MHz, d6-DMSO) δ 10.56 (s, 1H), 9.06 (d, J=2.5Hz, 1H), 8.93 (ddd, J=4.7, 1.7, 0.9Hz, 1H), 8.67-8.52 (m, 2H), 8.43 (dd, J=8.7, 2.5Hz, 1H), 8.15 (td, J=7.7, 1.8Hz, 1H), 7.95 (t, J=6.0Hz, 1H), 7.73 (ddd, J=7.6, 4.7, 1.1Hz, 1H), 7.01 (s, 2H), 3.46 (t, J=5.9Hz, 2H), 3.20 (dd, J=11.8, 6.0Hz, 2H), 2.42 (t, J=7.4Hz, 2H), 2.08 (t, J=7.4Hz, 2H), 1.87-1.76 (m, 2H). 13C NMR (151MHz, d6-DMSO) δ 172.10, 171.87, 171.07, 162.77, 162.77, 150.59, 150.20, 143.71, 141.27, 141.27, 138.53, 137.79, 134.52, 126.56, 126.10, 124.88, 124.18, 37.21, 36.79, 35.68, 34.49, 20.77. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: C46H64N2O16S3(2-)*2Na(1+) With O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: N-(2-aminoethyl)maleimide trifluoroacetate In N,N-dimethyl-formamide at 20℃; for 2h; | General procedure: The general procedure for synthesis of dye-maleimide was as follows: Fifty μιηοΙ dye, free acid 1 was dissolved in 4 ml DMF and cooled to 0°C. To this solution 60 μιηοΙ 0-succinimidyl-N,N,N',N'-tetramethyluronium tetrafluoroborate 2 and 60 μιηοΙ diisopropylethylamine were added. After 20 minutes at 0°C, 60 μιηοΙ N-(2-aminoethyl)-maleimide trifluoroacetate salt and 60 μιηοΙ diisopropylethylamin were added. The reaction mixture was warmed to room temperature and stirred for two hours. The solvents were distilled off in high vacuum. The residue was purified by column chromatography (RP-18 silica gel; acetonitrile/water).The following compound according to general formula la is synthesized according to general procedure for compound I and general procedure for dye-maleimide. (PEG4-682-maleimide) yield : 46 mg (79%) UV-vis (ethanol): abs = 690 nm em = 708 nm MS (ESI-) [M/z] : 559.2 [M]2" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With trimethylpyridine In 1-methyl-pyrrolidin-2-one at 20℃; for 1.16667h; | 3 Example 3: Synthesis of Bifunctional Linker (Compound 4). Example 3: Synthesis of Bifunctional Linker (Compound 4). N-(2-aminoethyl)maleimide TFA-salt (Sigma- Aldrich; 151 mg.) and Eei-AOAc-OSu (IRIS Biotech; 77 mg) were stirred in NMP (2 mL) at ambient temperature. Trimethylpyridine (80 μ) was added, and the reaction mixture stirred at ambient temperature for 70 min. The reaction was quenched by dilution with 0.1% acetic acid (7 mL). The product was purified by preparative HPLC as follows: Detection UV at 214 nm and 254 nm Column type and size Luna C-18 (2), 5μιη, 100 A, 20 x 250 mm from Phenomenex Eluent A 0.1% v/v acetic acid in water, 1 mL/L Eluent B Acetonitrile (Lichrosolv) Gradient 15-30% B during 40 min. Flow rate 10 ml/min during gradient elution The purified Compound 4 was freeze-dried. Yield 43 mg (75%), purity: > 97% by area. The pure product was analysed by analytical LC-MS (gradient: 10-40 % B over 5 min where A = H2O/0.1 % TFA and B = ACN/0.1 % TFA, flow rate: 0.6 mL/min, column: Phenomenex Luna 3μ C18 (2) 20 x 2 mm, detection: UV 214 nm, product retention time: 1.93 min), MH+ calculated: 284.1, MH+ found: 284.1). |
75% | With trimethylpyridine In 1-methyl-pyrrolidin-2-one at 20℃; for 1.16667h; | 8 Example 8: Synthesis of Bifunctional Linker (Compound 4). Example 8: Synthesis of Bifunctional Linker (Compound 4). Compound 4 N-(2-aminoethyl)maleimide TFA-salt (Sigma- Aldrich; 151 mg.) and Eei-AOAc-OSu (IRIS Biotech;77 mg) were stirred in NMP (2 mL) at ambient temperature. Trimethylpyridine (80 μ) was added, and the reaction mixture stirred at ambient temperature for 70 min. The reaction was quenched by dilution with 0.1% acetic acid (7 mL). The product was purified by preparative HPLC as follows: The purified Compound 4 was freeze-dried. Yield 43 mg (75%), purity: > 97% by area. The pure product was analysed by analytical LC-MS (gradient: 10-40 % B over 5 min where A = H2O/0.1 % TFA and B = ACN/0.1 % TFA, flow rate: 0.6 mL/min, column: Phenomenex Luna 3μ C18 (2) 20 x 2 mm, detection: UV 214 nm, product retention time: 1.93 min), MH+ calculated: 284.1, MH+ found: 284.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 2-amino-6-(4-carboxy-phenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; Stage #2: N-(2-aminoethyl)maleimide trifluoroacetate In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere; | 2-Amino-6-{4-N(2-aminoethyl)maleimido)-phenyl}-3,7-dihydro-pyrrolo [2,3-d] pyrimidin-4-one (3o). To a suspension of the starting material 3m (54mg, 0.2mmol) in 1 ml DMF was added N-methylmorfoline(0.12 ml, 1mmol) followed by 2-chloro-4,6-dimethoxy-1,3,5 triazine. The reaction mixture was stirred for 2 hours at room temperature. Another 0.1 ml of N-methylmorfoline was added followed by N-(2-Aminoethyl)-maleimide trifluoroacetate salt (44mg, 0.25mmol), and the solution was stirred at room temperature over two days. Upon completion, the reaction was quenched with 20 ml of water, and stirred for 10min. The precipitate was filtered under vacuum and dried. 85 mg of product in 95 % yield was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h; | 2,5-Di(methylamino)terephthalic Acid 1-[2-(2,5-Dioxo-2,5-dihydropyrrol-1-yl)ethyl]amide 4-Methylester (3). HATU (96 mg, 0.25 mmol) and DIPEA (33 mg, 0.25 mmol)were added to a solution of diaminoterephthalic acid 1 (50 mg,0.21 mmol) and maleimide 2 (160 mg, 0.630 mmol) in CH2Cl2(2 mL). The reaction mixture was stirred for 16 h at ambienttemperature and subsequently washed with water (5 mL), asaturated aq NaHCO3 solution (5 mL), and brine (5 mL). Theorganic layer was dried over MgSO4 and filtered, and thesolvent was removed under reduced pressure. After purification by column chromatography (SiO2, 1/5 hexane/MTBE , Rf =0.19), the title compound 3 (63 mg, 0.18 mmol, 85%) wasobtained as a yellow solid. Mp: 173 °C. 1H NMR (500 MHz,DMSO-d6): δ 2.67 (d, J = 5.2 Hz, 3 H), 2.82 (d, J = 5.1 Hz, 3H), 3.38 (q, J = 5.8 Hz, 2 H), 3.57 (t, J = 5.3 Hz, 2 H), 3.80 (s,3 H), 5.95 (q, J = 5.0 Hz, 1 H), 6.71 (s, 1 H), 6.81 (q, J = 4.8Hz, 1 H), 7.00 (s, 1 H), 7.02 (s, 2 H), 8.59 (t, J = 6.0 Hz, 1 H).13C{1H} NMR (125 MHz, DMSO-d6): δ 29.96 (CH3), 30.32(CH3), 37.27 (CH2), 37.31 (CH2), 51.77 (CH3), 111.71 (CH),111.89 (CH), 112.23 (C), 125.22 (C), 134.68 (2 CH), 138.80(C), 142.84 (C), 167.88 (C), 168.70 (C), 171.22 (2 C). IR(ATR): 1/λ 3354 (m), 3219 (br, w), 2925 (br, m), 1698 (s),1684 (s), 1645 (m), 1522 (s), 1440 (s), 1400 (s), 1368 (s),1224 (vs), 1136 (s), 826 (m), 696 (s) cm-1. MS (EI, 70 eV):m/z (%) 360 (100) [M+], 329 (3) [M+ - OMe], 220 (11), 188(4), 160 (12). UV-vis (CH2Cl2): λmax (log ε) 454 nm (3.53).Fluorescence (CH2Cl2): λem 568 nm, λex 454 nm, Φ 0.001.C17H20N4O5 (360.14): calcd C 56.66%, H 5.59%, N 15.55%;found C 56.81%, H 5.72%, N 15.24%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24h; | To a solution of <strong>[42989-85-5]2-(tert-butoxycarbonylaminooxy)acetic acid</strong> (382 mg, 2 mmol) in anhydrous dichloromethane (20 mL) was added sequentially triethylamine (307 jut, 2.2 mmol), N-(2-aminoethyl)maleimide-TFA salt (508 mg, 2 mmol), HOBT (306 mg, 2 mmol), and EDC (420 mg, 2.2 mmol). After being stirred for 24 hrs at room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (3×30 mL), water (30 mL), and brine (30 mL) The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to a pale yellow solid, which was purified by column chromatography (70% ethyl acetate in hexanes) to give the product as a white powder (500 mg, 80% yield). 1H-NMR (400 MHz, CDCl3): delta 1.50 (s, 9H), 3.55 (tt, J1=6.0 Hz, J2=6.5 Hz, 2H), 3.77 (dd, J=7.6 Hz, 2H), 4.30 (s, 2H), 6.3 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; [18F]-potassium fluoride; tetrapropylammonium hydroxide; potassium carbonate; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; sodium hydroxide Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.1% | With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile at 20℃; for 4h; | 1.S2 S2, the intermediate C28g was added to 120 ml of acetonitrile, and then 24.9 g of 2-aminoethylmaleimide trifluoroacetate salt was added.After stirring and dissolving, add 37.1 g of HATU at a time, and stir at room temperature for 4 h.The reaction was terminated by TLC, and the acetonitrile was concentrated to remove 200 ml of dichloromethane and 50 ml of water.After stirring, the liquid was separated, and the dichloromethane phase was washed once with 50 ml of water, the organic phase was dried, and concentrated to give a crude product.The crude product was heated and dissolved in 110 ml of acetonitrile, filtered while hot, and the filtrate was allowed to stand to cool and crystallize, and suction filtered.Drying to obtain 27.4 g of white crystal of compound E, the yield was 78.1%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: C57H44N8O5S2 With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.166667h; Stage #2: N-(2-aminoethyl)maleimide trifluoroacetate In dichloromethane at 20℃; for 2h; | 2.1 (1) Synthesis of compound V-4 Compound V-2 (50mg, 0.05mmoL) and HBTU (38mg, 0.10mmoL) were dissolved in 5mL dichloromethane,Add DIEA (36μL, 0.20mmoL) and stir for 10min at room temperature,Then N-(2-aminoethyl)maleimide trifluoroacetate salt (20mg, 0.08mmoL) was added to react at room temperature for 2h.The reaction solution was extracted with dichloromethane, dried, concentrated,Column chromatography yielded compound V-4 (46 mg, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 6h; | 1.2 1.2 Synthesis of Intermediate A-2 Intermediate A-1 (74.13mg), N-(2-aminoethyl)maleimide trifluoroacetate (38.12mg),2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 57.04mg) and N,N-diisopropylethylamine (DIPEA , 42μL) was added to the reaction flask, then 20mL of anhydrous dichloromethane was added, and the reaction was stirred at room temperature for 6 hours. After the reaction is over, add 20mL deionized water for extraction, collect the organic phase, use a mixed solution of dichloromethane and methanol (20:1) as the eluent, and separate by column chromatography to obtain a white powdery intermediate A-2 (74.07mg, yield 85.7%). |
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