Electric Literature of 20485-43-2,Some common heterocyclic compound, 20485-43-2, name is 1-Methyl-1H-imidazole-2-carboxylic acid, molecular formula is C5H6N2O2, traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
(a)Resin swelling: 400 mg of Fmoc-protected phenylhydrazine (0.66 mmol / g, 0.264 mmol) and 3 mL of CH2CI2 were added to a 10 mL solid phase reactor, the resin was swollen for 30 min, CH2CI2 was withdrawn, (b)Remove Fmoc protecting group: A solution of 3 mL of 20% piperidine / DMF was added to the swollen resin in step (a), N2 After bubbling, lOmin, the solvent was extracted, then 3 mL of 20% piperidine / DMF solution was added, N2 was bubbled and mixed. After lOmin, the resin was washed with DMF (4 x 3 mL) and the resin was washed with 3 mL of anhydrous DMF ,spare; (c) Amino acid condensation: A solution of 4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carboxylic acid (254 mg, 1.056 mmol) and triphosgene (BTC, 128 mg, 0.433 mmol) in 2 mL of anhydrous THF was added to the solution Slowly dropwise trimethyl P-pyridine (Col 1 idine, 488yL, 3.696mmol), the reaction immediately produced a large number of white precipitate, added reaction 3min, (5%, nu / nu), the white precipitate was completely disappeared, and the reaction solution was transferred to the phenylhydrazine resin in which the protecting group was removed in step (b), N2 was bubbled and mixed, and the condensation reaction was 0.5 ~ Lh, the reaction solution was extracted, and the resin was washed with DMF (4 x 3 mL),(d)Removal of tert-butoxycarbonyl protecting group: Washed with CH2C12 (2 X 3 mL) Extraction of CH2C12, adding 3. OmLTFA / benzoic acid / Eta2Omicron (nu: nu: nu = 92: 5: 2.5) mixed solution removal step (b) The reaction was carried out for 2 min and the mixture was stirred for 2 min. After adding the solvent to 3. OmL TFA / phenol / H20 (nu: nu: nu = 92: 5: 2.5) for 20 min, the mixture was treated with CH2C12 (2 X 3 mL) and DMF (4 x 3 mL), and the resin was washed with 3 mL of anhydrous DMF,Repeating the above condensation and deprotection steps (c) and (d) Until the synthesis of the peptide supported on the phenylhydrazine resin as shown in formula (8).(e)Amino acid condensation: A solution of 4-tert-butoxycarbonylamino-1-methyl-1H-imidazole-2-carboxylic acid (254 mg, 1.056 mmol) and triphosgene (BTC, 128 mg, 0.433 mmol) in 2 mL of anhydrous THF was added to the solution (Col 1 idine, 488yL, 3.696 mmol) was slowly added and the reaction immediately resulted in a large amount of white precipitate. After the reaction was added for 3 min, (5%, nu / nu), the white precipitate completely disappeared, and the reaction solution was transferred to the phenylhydrazine resin in which the protecting group was removed in step (b), N2 was bubbled and mixed, and the condensation reaction was carried out for 0.5 to 11 hours , The reaction solution was extracted, and the resin was washed with DMF (4 X 3 mL), Repeat the above condensation and deprotection steps () and (d), Until the synthesis of the peptide supported on the phenylhydrazine resin as shown in formula (9) is completed;(G) Gamma-amino acid condensation: A solution of R-2- (9-fluorenylmethoxycarbonylamino) -4-tert-butoxycarbonylaminobutyric acid (465 mg, 1.056 mmol) And triphosgene (128 mg, 0.433 mmol) Dissolved in 2 mL of anhydrous THF, To this solution was slowly added dropwise trimethylpyridine (488yL, 3.696 mmol) The reaction immediately resulted in a large amount of white precipitate, added to the reaction lmin, added HOAt (144 mg, 1.056 mmol) Then add 2mL DIEA / DMF solution (5%, nu / nu), reaction 5min, The white precipitate completely disappeared, and the reaction solution was transferred to a linear peptide supported on the phenylhydrazine resin represented by the formula (9) (NH2-Im-Im-Py-Py-phenylhydrazine resin), N2 bubbling, the condensation reaction was carried out for 0.5 to 11 hours, the reaction solution was extracted, The resin was washed with DMF (4 X 3 mL) to give a peptide supported on the phenylhydrazine resin represented by the formula (10)H) repeating the condensation and deprotection guard step (d) and (C), wherein the load until the completion of the synthetic peptides to give formula (11) in a phenylhydrazine of the resin;I) repeating the condensation and deprotection guard step (d) and (E), wherein the load until the completion of peptide synthesis to give the formula (12) in the resin phenylhydrazineJ) Condensation of terminal amino acids: 1-methyl-1H-imidazole-2-carboxylic acid (132 mg, 1.56pimol) and PyBOP (550 mg, 1.056 mmo 1) was dissolved in 3 mL of anhydrous DMF, DIEA (350 yL, 2.112 mmol) was added, and the reaction was carried out for 5 min. The reaction solution was transferred to the reaction represented by the formula (12) obtained in step (h) (2), and the reaction was carried out for 2 hours. The reaction solution was purged with N2, and the resin was washed with DMF (4 X 3 mL), and the compound represented by the formula (12) was removed by the step (b) in Example 1 A Fmoc protecting group supported on a phenylhydrazine resin to obtain a peptide supported on the phenylhydrazine resin represented by the formula (13)
These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 1-Methyl-1H-imidazole-2-carboxylic acid, its application will become more common.
Reference:
Patent; Shenzhen Advanced Technology Institute; Su Wu; Wang Wei; Pan Zhengyin; Cheng Zhehong; Wu Chunlei; Fang Lijing; (36 pag.)CN106674209; (2017); A;,
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