1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide

Carbodiimide cross-linking reagent.

General procedure: To the reaction vessel, 0.3 mmol of the thiourea compound shown in Table 2, 0.9 mmol of CpFe(CO)2Me identical to Example 1-1 as an iron compound and 9 mL of tetrahydrofuran were added, and the reaction was carried out at 60 C. for 24 hours under a nitrogen atmosphere . However, only in Example 2-4, each charged amount was multiplied by 100/3, and it was carried out.After completion of the reaction, the obtained reaction solution was analyzed with a gas chromatograph mass spectrometer (GC-MS), and it was found that the product shown in Table 2 was produced at the yield shown in Table 2.The reaction solutions obtained in Examples 2-1 to 2-4 were cooled to room temperature, water was added, and the product was extracted with ethyl acetate. Subsequently, the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product, and the crude product was used in Examples 2-1 to 2-3, silica gel (Developing solvent: ethyl acetate / hexane (mixing ratio was appropriately adjusted)), and purified by distillation in Example 2-4 to obtain the respective products. The isolated yield of the product obtained in Example 2-3 was 35%3-(((3S)-1-(2-fluoropropanoyl)piperidin-3-yl)methyl)-6-((5-fluoropyridin-2-yl)oxy)-2-(o-tolyl)quinazolin-4(3H)-one (5j, JQ-2-113) 2-fluoropropionic acid (18.4 mg, 0.22 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (38.4 mg, 0.22 mmol) and hydroxybenzotriazole (HOBt) (5 mg, 0.033 mmol) were added into DCM (5 ml). The solution was stirred for 5 minutes. Compound 4b (44 mg, 0.099 mmol) was then added. The resulting solution was stirred at room temperature for 24 hours. The solvent was removed and the product was subjected to reverse phase chromatography (Isolera One, HS-C18-30 g cartridge) with a gradient elution of 0-75% acetonitrile in water. The purified compound was lyophilized to give 35 mg white power with 69% yield. UP LC-MS (waters) method: 5-95% acetonitrile (0.1% TFA) in water (0.1% TFA), 3 mins run, RT (min) 2.09, Found m/z (MH+): 519.1. HRMS (ESI+) for C29H28F2N4O3Na (M+Na+), calcd 541.2027, found 541.2031. 1H NMR (400 MHz, methanol-d4) delta ppm 7.94 (d, J=2.9 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H), 7.65-7.56 (m, 2H), 7.52 (dd, J=8.8, 2.7 Hz, 1H), 7.45-7.36 (m, 2H), 7.34-7.26 (m, 2H), 7.05 (dd, J=8.9, 2.9 Hz, 1H), 5.37-4.98 (m, 1H), 4.23-3.87 (m, 2H), 3.75-3.32 (m, 2H), 2.97-2.23 (m, 2H), 2.19-2.09 (m, 3H), 1.74-1.00 (m, 8H). 19F NMR (376 MHz, methanol-d4) delta ppm -134.46--135.77 (m, 1F), -177.27--179.90 (m, 1F).Add 1100 g of triethylamine hydrochloride to a 3000 ml reaction flask.1000g of acetonitrile, wherein the mass ratio of triethylamine to HCL is 5:1, EDC213.6g was slowly added dropwise, and the temperature was controlled at 15 C.The dropping time is controlled at 60 min, filtered, EDC hydrochloride was obtained with a purity of 99.5% and a yield of 92%.(1) 4.3 kg of a dichloromethane solvent was added to a reaction vessel, and 1.0 kg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide was added.Start stirring evenly, pass through chilled brine, and start to cool down to obtain mixed solution A.(2) When the temperature of the solution A to be mixed drops below 15 C, 0.91 kg of methyl iodide is added dropwise. During the dropwise addition, the control temperature is between 15 C and 25 C. After the dropwise addition of methyl iodide, the reaction is continued for 1 hour. During the reaction, The temperature was controlled below 25 C to obtain a mixed solution B.The reaction procedure for adding methyl iodide to the mixed solution A is:(3) After the completion of the reaction, 2.15 kg of petroleum ether solvent was added to the mixed solution B, and the temperature was kept at 25 C or lower for 2 hours.(4) The material produced by the reaction in the third step is placed in a bag, centrifuged in a centrifuge and dried to obtain 1.55 kg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide methyl iodide. The yield was 81.2%.Step one, adding 4.0 kg of organic solvent to a reactor, and inputting 1-ethyl-3-(3-dimethylaminopropylBase) - 1.0 kg of carbodiimide, start stirring, pass into chilled brine, and start to cool down.Step 2: When the temperature drops below 15 C, 0.850 kg of n-butyl sulfonic acid is added dropwise. During the dropwise addition, the temperature is controlled at 15 C to 25 C, and the reaction is continued for 1 hour after the dropwise addition of n-butyl sulfonic acid. During the reaction, the temperature is controlled below 25 C.In the second step, the chemical reaction formula of the mixed solution A dropwise adding the alkylsulfonic acid. Step 3, after the reaction is completed, 2.8 kg of an organic solvent is added, the temperature is kept for 2 hours, and the temperature is controlled below 25 C.Step 4, the contents of the reaction in the third step are loaded into a bag, centrifuged in a centrifuge and dried to obtain 1-B.The finished product of -3-(3-dimethylaminopropyl)-carbodiimide n-butyl sulfonate was 1.772 kg, and the yield was 95.8%.Step one, adding 4.0 kg of organic solvent to a reactor, and inputting 1-ethyl-3-(3-dimethylaminopropylBase) - 1.0 kg of carbodiimide, start stirring, pass into chilled brine, and start to cool down.Step two, when the temperature drops below 15 C, Start adding 0.619 kg of methanesulfonic acid.During the addition process, The control temperature is between 15 C and 25 C.The reaction was continued for 1 hour after the dropwise addition of methanesulfonic acid.During the reaction, The temperature is controlled below 25 C. In step 2, the chemical reaction formula of the mixed solution A dropwise addition of alkylsulfonic acid. Step 3, after the reaction is completed, 2.8 kg of an organic solvent is added, the temperature is kept for 2 hours, and the temperature is controlled below 25 C.Step 4, the material produced by the reaction in the third step is placed in a bag, centrifuged in a centrifuge and dried to obtain 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide methanesulfonate. The finished product was 1.553 kg, and the yield was 95.5%.Step one, adding 4.0 kg of organic solvent to a reaction kettle.Put 1.0 kg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, Start stirring, Pass the frozen brine and start to cool down.Step two, When the temperature drops below 15 C, Start adding 1.990 kg of hexadecyl sulfonic acid.During the addition process, The control temperature is between 15 C and 25 C.The reaction was continued for 1 hour after the dropwise addition of cetylsulfonic acid.During the reaction, The temperature is controlled below 25 C. In step 2, the chemical reaction formula of the mixed solution A dropwise addition of alkylsulfonic acid. Step 3, after the reaction is completed, 2.8 kg of an organic solvent is added, the temperature is kept for 2 hours, and the temperature is controlled below 25 C.Step 4, the material produced by the reaction in the third step is put into a bag, centrifuged in a centrifuge and dried to obtain 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide cetyl group. The finished sulfonate product was 2.810 kg, and the yield was 94.0%.

Molecular Weight:155.24
XLogP3:1.9
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:155.142247555
Monoisotopic Mass:155.142247555
Topological Polar Surface Area:28
Heavy Atom Count:11
Complexity:134
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:No