Search

CN-122010826-A - Preparation method of high-purity 2-bromo-5-aldehyde pyridine

CN122010826ACN 122010826 ACN122010826 ACN 122010826ACN-122010826-A

Abstract

The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of high-purity 2-bromo-5-aldehyde pyridine, which comprises the following steps that S1 takes 2, 5-dibromopyridine and butyllithium as raw materials to react to obtain an intermediate I; S2, reacting the intermediate I obtained in the step S1 with DMF to obtain an intermediate II, and reacting the intermediate II obtained in the step S2 with acetic acid to obtain 2-bromo-5-aldehyde pyridine. The preparation method of the invention synthesizes the 2-bromo-5-aldehyde pyridine through the micro-channel reactor, has simple and convenient operation, can directly react without separation in the intermediate state, and has high yield and high purity.

Inventors

  • GUO HENGJIE
  • CHE JIN
  • ZHOU XINHUA

Assignees

  • 山东丰金制药有限公司

Dates

Publication Date
20260512
Application Date
20260317

Claims (7)

  1. 1. The preparation method of the high-purity 2-bromo-5-aldehyde pyridine is characterized by comprising the following steps: s1, taking 2, 5-dibromopyridine and butyllithium as raw materials, and reacting to obtain an intermediate I; s2, reacting the intermediate I obtained in the step S1 with DMF to obtain an intermediate II; s3, reacting the intermediate II obtained in the step S2 with acetic acid to obtain 2-bromo-5-aldehyde pyridine.
  2. 2. The preparation method of claim 1, wherein in the step S1, the reaction temperature is-80 to-70 ℃, and the molar ratio of the 2, 5-dibromopyridine to the butyllithium is 1 (1.5-3.0).
  3. 3. The method according to claim 1, wherein in step S1, the reaction is performed in a microchannel reactor for 1 to 5 minutes.
  4. 4. The preparation method according to claim 1, wherein in the step S2, the reaction temperature is-10-0 ℃, and the molar ratio of 2, 5-dibromopyridine to DMF is 1 (1.1-2.0).
  5. 5. The method according to claim 1, wherein in step S2, the reaction is performed in a microchannel reactor for 1-3 min.
  6. 6. The preparation method according to claim 1, wherein in the step S3, the reaction temperature is-10-0 ℃, and the molar ratio of 2, 5-dibromopyridine to acetic acid is 1 (1.0-3.0).
  7. 7. The preparation method according to claim 1, wherein in the step S3, the reaction is performed in a microchannel reactor, and the reaction time is 0.5-2 min.

Description

Preparation method of high-purity 2-bromo-5-aldehyde pyridine Technical Field The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of high-purity 2-bromo-5-aldehyde pyridine. Background Abeli (abemaciclib), chemical name N- [5- [ (4-ethyl-1-piperazine) methyl ] -2-pyridinyl ] -5-fluoro-4- [ 4-fluoro-1- (1-isopropyl) -2-methyl-1H-benzimidazol-6-yl ] -2-pyrimidinamine, approved by the U.S. FDA for use in 2017, 9, trade name Verzenio. It is used to treat advanced or metastatic breast cancer, shows better tolerability than previously approved CDK drugs, rebamactinib (Kisqali) and palbociclib (Ibrance), and also has less adverse effects of lowering neutrophils, which is more advantageous for patients with weaker immune system. 2-Bromo-5-aldehyde pyridine is of great interest as a key intermediate to arbelide. The synthesis method mainly comprises the following steps: (1) Chinese patent CN107698497a discloses a method for preparing 2-bromo-5-aldehyde pyridine, the synthetic route is as follows: the first step of the route needs distillation and purification, has complex operation, and the second step needs heating and sealing reaction, has certain potential safety hazard, and is not suitable for industrial production. (2) The literature "synthesis of 2-bromo-5-pyridinecarboxaldehyde, chemical reagent 2006,28 (7), 433-434" discloses a method for preparing 2-bromo-5-aldehyde pyridine, the synthetic route is as follows: the reaction of the route is not thorough, the second step uses column chromatography for purification, the yield is only 40%, the conversion rate is too low, the industrialization cost is high, and the method is not suitable for industrial production. Disclosure of Invention The invention provides a preparation method of high-purity 2-bromo-5-aldehyde pyridine aiming at the defects of the prior art. The invention takes 2, 5-dibromopyridine and butyllithium as raw materials to prepare lithium salt solution through halogen-lithium exchange reaction, then reacts with DMF to prepare a solution similar to hemiacetal, and finally hydrolyzes with acetic acid to obtain 2-bromo-5-aldehyde pyridine. The specific scheme is as follows: A preparation method of high-purity 2-bromo-5-aldehyde pyridine comprises the following steps: s1, taking 2, 5-dibromopyridine and butyllithium as raw materials, and reacting to obtain an intermediate I; s2, reacting the intermediate I obtained in the step S1 with DMF to obtain an intermediate II; s3, reacting the intermediate II obtained in the step S2 with acetic acid to obtain 2-bromo-5-aldehyde pyridine. The synthetic route (examples) is as follows: 。 in the step S1, the reaction temperature is-80 to-70 ℃, and the molar ratio of the 2, 5-dibromopyridine to the butyllithium is 1 (1.5-3.0). Preferably, in step S1, the reaction is performed in a microchannel reactor. Specifically, 2, 5-dibromopyridine and an organic solvent are utilized to prepare a2, 5-dibromopyridine solution, butyl lithium and an organic solvent are utilized to prepare a butyl lithium solution, and the 2, 5-dibromopyridine solution and the butyl lithium solution are introduced into a micro-channel reactor for reaction to obtain an intermediate I solution. The organic solvent is preferably toluene, diethyl ether or tetrahydrofuran, the concentration of the 2, 5-dibromopyridine solution is preferably 20-30wt%, the flow rate is preferably 10-30 mL-min -1, the concentration of the butyl lithium solution is preferably 15-25wt%, and the flow rate is preferably 10-20mL-min -1. In step S1, the reaction time is preferably 1 to 5 minutes. In the step S2, the reaction temperature is-10-0 ℃, and the molar ratio of the 2, 5-dibromopyridine to the DMF is 1 (1.1-2.0). Preferably, in step S2, the reaction is performed in a microchannel reactor. And (3) preparing a DMF solution by using DMF and an organic solution, and introducing the intermediate I solution obtained in the step (S1) and the DMF solution into a microchannel reactor for reaction to obtain an intermediate II solution. The organic solvent is preferably toluene, diethyl ether or tetrahydrofuran, the concentration of the intermediate I solution is preferably 20-30wt%, the flow rate is preferably 25-35 mL-min -1, the concentration of the DMF solution is preferably 60-70wt%, and the flow rate is preferably 2-5 mL-min -1. In step S2, the reaction time is preferably 1 to 3 minutes. In the step S3, the reaction temperature is-10-0 ℃, and the molar ratio of 2, 5-dibromopyridine to acetic acid is 1 (1.0-3.0). Preferably, in step S3, the reaction is performed in a microchannel reactor. Specifically, preparing an acetic acid aqueous solution, and introducing the intermediate II solution obtained in the step S2 and the acetic acid aqueous solution into a microchannel reactor for reaction to obtain the 2-bromo-5-aldehyde pyridine. The concentration of the intermediate II solution is preferably 20-30wt%, the flow