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CN-122010850-A - Synthesis method of 3- (5-bromopyrimidinyl) benzyl alcohol

CN122010850ACN 122010850 ACN122010850 ACN 122010850ACN-122010850-A

Abstract

The invention discloses a synthesis method of 3- (5-bromopyrimidinyl) benzyl alcohol, and relates to the technical field of medicine preparation. Compared with the method for synthesizing 3- (5-bromopyrimidinyl) benzyl alcohol by taking 3- (hydroxymethyl) phenylboronic acid as a raw material, the synthetic method disclosed by the invention has the advantages that the raw material is cheap and easy to obtain, and the reaction yield is high.

Inventors

  • SU QIANG
  • MAO WENJIN
  • YUAN DAN
  • BI DONGWEI
  • YE WEIPING
  • ZHOU ZHANGTAO
  • LI ZHAOFEI
  • YING LIN
  • LIU HUIQIN

Assignees

  • 广东莱佛士制药技术有限公司

Dates

Publication Date
20260512
Application Date
20241112

Claims (10)

  1. 1. The synthesis method of 3- (5-bromopyrimidinyl) benzyl alcohol is characterized in that the 3- (5-bromopyrimidinyl) benzyl alcohol is synthesized by using m-methylbenzonitrile as a raw material through the following steps:
  2. 2. The synthetic method according to claim 1, wherein the step 1 further comprises performing a post-treatment operation after the end of the reaction to obtain compound II or a salt thereof; the post-treatment operation is selected from one of the following three operations: Operation a, conventional post-treatment; Adding NaOH into the reaction liquid, and performing conventional post-treatment; and c, adding acid into the reaction liquid to form salt crystals.
  3. 3. The synthetic method according to claim 2, wherein the compound II or a salt thereof is selected from at least one of 3-methylbenzamidine free base, 3-methylbenzamidine hydrochloride, 3-methylbenzamidine sulfate, 3-methylbenzamidine formate, 3-methylbenzamidine acetate, 3-methylbenzamidine trifluoroacetate.
  4. 4. The synthetic method according to claim 2, wherein the synthetic method of 3- (5-bromopyrimidinyl) benzyl alcohol comprises the steps of: Step 1, mixing an alcohol reagent and acetyl chloride, controlling the temperature of the mixture to be below 5 ℃, preserving heat for 1-4 hours, then mixing the mixture with m-methylbenzonitrile, controlling the temperature of the mixture to be 5-25 ℃, preserving heat for 17-23 hours, concentrating a reaction system, cooling to be below 0 ℃, adding NH 3 for reaction, controlling the temperature of the system in the reaction process to be 15-35 ℃, and performing post-treatment operation after the reaction is finished to obtain a compound II or salt thereof; Step 2, mixing an acid reagent with the compound II or the salt thereof, replacing with nitrogen, keeping the temperature of the mixture at 80-100 ℃, mixing the mixture with bromomalonaldehyde, keeping the temperature of the mixture at 80-100 ℃, and carrying out heat preservation for reaction to obtain a compound III after the reaction is finished; Step 3, mixing the solvent 1, the compound III, the bromination reagent and the free radical initiator, replacing nitrogen, heating to 65-85 ℃, and carrying out heat preservation reaction to obtain a compound IV after the reaction is finished; and 4, mixing the solvent 2, the compound IV, an alkali reagent and water, keeping the temperature of the mixture at 70-90 ℃, carrying out heat preservation reaction, cooling to 15-35 ℃, and quenching the reaction to obtain the compound V.
  5. 5. The method according to claim 4, wherein in step 1, the alcohol reagent is at least one selected from methanol, ethanol and isopropanol.
  6. 6. The synthetic method according to claim 4, wherein in step 1, the acid in the operation c is at least one selected from sulfuric acid, formic acid, acetic acid, and trifluoroacetic acid.
  7. 7. The method according to claim 4, wherein in step2, the acid reagent is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, formic acid, acetic acid and trifluoroacetic acid.
  8. 8. The synthesis method according to claim 4, wherein in step 3, The solvent 1 is at least one selected from acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, tetrahydrofuran, isopropyl acetate, propylene glycol and pyridine; The free radical initiator is at least one selected from AIBN and BPO.
  9. 9. The method according to claim 4, wherein in step 3, the brominating reagent is at least one selected from NBS, DBH, DBI, NBSac, NBP.
  10. 10. The method of synthesis according to claim 4, wherein in step 4, The solvent 2 is at least one selected from acetone, dioxane, n-butanol, n-amyl alcohol, isopropanol and ethyl acetate; The alkali reagent is at least one selected from sodium carbonate, potassium carbonate, sodium acetate, potassium tert-butoxide, sodium methoxide, sodium ethoxide and triethylamine.

Description

Synthesis method of 3- (5-bromopyrimidinyl) benzyl alcohol Technical Field The invention relates to the technical field of medicine preparation, in particular to a synthetic method of 3- (5-bromopyrimidinyl) benzyl alcohol. Background The structure of the topotinib is shown as the following formula, and the topotinib is used for treating non-small cell lung cancer (NSCLC) patients carrying MET exon 14 (METex 14) skipping. Non-small cell lung cancer is the most common type of lung cancer, accounting for approximately 85% of the total lung cancer patients. MET is one of the driving genes for cancer, and cases with MET mutations account for approximately 3% -4% of the total number in NSCLC patients. These patients are generally older and the prognosis is often poor. Furthermore, MET signaling pathway also plays an important role in driving lung cancer resistance to other targeted therapies. The purpose of terpetinib is to inhibit oncogenic MET receptor signaling caused by MET genetic variation, including METex jump changes, MET amplification, or MET protein overexpression. It is designed to improve prognosis of invasive tumors with poor prognosis and these specific mutations, and the indications to be developed include NSCLC, hepatocellular carcinoma, colorectal cancer and other solid tumors with MET mutations. 3- (5-Bromopyrimidinyl) benzyl alcohol as a key synthetic block for terpotinib, literature 1(Dorsch D,Schadt O,Stieber F,et al.Identification and optimization ofpyridazinones as potent and selective c-Met kinase inhibitors[J].Bioorganic&Medicinal Chemistry Letters,2015,25(7):1597-1602.DOI:10.1016/j.bmcl.2015.02.002.) discloses a method for synthesizing 3- (5-bromopyrimidinyl) benzyl alcohol by adding an aqueous solution of sodium carbonate to a solution of 5-bromo-2-iodopyrimidine in toluene under nitrogen and heating to 80 ℃. Palladium chloride bis (triphenylphosphine) was added followed by dropwise addition of an ethanol solution of 3- (hydroxymethyl) phenylboronic acid. The reaction mixture was stirred at 89 ℃ for 18 hours. The reaction mixture was cooled to room temperature and filtered, ethyl acetate and water were added to the filtrate, the organic phase was separated off, dried over sodium sulfate and evaporated. The residue was recrystallized from 2-propanol to give [3- (5-bromo-pyrimidin-2-yl) -phenyl ] -methanol as pale yellow crystals in 72% yield, as shown in the following formula. In the synthesis process, the Suzuki coupling reaction has poor selectivity and complicated post-treatment, so that the process yield of 3- (5-bromopyrimidinyl) benzyl alcohol is low, and the palladium catalyst is expensive. The raw material of the synthesis method is 3- (hydroxymethyl) phenylboronic acid, and foreign patent WO2014201073A1 discloses that 3- (hydroxymethyl) phenylboronic acid is obtained by reacting 3-bromobenzyl alcohol with triisopropyl borate and butyl lithium, and the triisopropyl borate is expensive and difficult to obtain. In view of the above, the invention provides a novel synthesis method of 3- (5-bromopyrimidinyl) benzyl alcohol in order to solve the defects in the prior art. The 3- (5-bromopyrimidinyl) benzyl alcohol prepared by the invention can be applied to the preparation of the terponinib, and has good research and development prospects. Disclosure of Invention The invention aims to provide a synthesis method of 3- (5-bromopyrimidinyl) benzyl alcohol, which has the advantages of cheap and easily obtained raw materials and high reaction yield, and is suitable for large-scale industrial production. In order to achieve the above purpose, the technical scheme of the invention is as follows: the invention provides a method for synthesizing 3- (5-bromopyrimidinyl) benzyl alcohol, which is synthesized by using m-methylbenzonitrile as a raw material through the following steps: preferably, the step 1 further comprises performing a post-treatment operation after the end of the reaction to obtain compound II or a salt thereof; the post-treatment operation is selected from one of the following three operations: Operation a, conventional post-treatment; Adding NaOH into the reaction liquid, and performing conventional post-treatment; and c, adding acid into the reaction liquid to form salt crystals. Further preferably, the compound II or a salt thereof is selected from at least one of 3-methylbenzamidine free base, 3-methylbenzamidine hydrochloride, 3-methylbenzamidine sulfate, 3-methylbenzamidine formate, 3-methylbenzamidine acetate, 3-methylbenzamidine trifluoroacetate. Further preferably, the synthesis method of the 3- (5-bromopyrimidinyl) benzyl alcohol comprises the following steps: Step 1, mixing an alcohol reagent and acetyl chloride, controlling the temperature of the mixture to be below 5 ℃, preserving heat for 1-4 hours, then mixing the mixture with m-methylbenzonitrile, controlling the temperature of the mixture to be 5-25 ℃, preserving heat for 17-23 hours, concentrating a reaction