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CN-122010821-A - Adaglazecloth Synthesis method of intermediate

CN122010821ACN 122010821 ACN122010821 ACN 122010821ACN-122010821-A

Abstract

The invention provides a preparation method of an adagransie intermediate compound, which comprises the step of reacting a compound with a result shown as a formula III with a compound with a result shown as a formula IV to obtain the intermediate compound with a result shown as a formula V. The preparation method provided by the invention can obtain the intermediate compound with high quality, the intermediate does not need to be separated and purified by a silica gel column, and complicated post-treatment operation is not needed, so that complicated separation and purification steps are avoided, the waste of raw materials is avoided, the production cost is reduced, and the preparation method is more suitable for industrial production.

Inventors

  • LI SHANGLI
  • GUO WEI
  • ZHANG PENGFEI
  • TANG XIANHAO

Assignees

  • 上海博氏医药科技有限公司

Dates

Publication Date
20260512
Application Date
20260128

Claims (10)

  1. 1. Use of a palladium salt in combination with a ligand as a catalyst system for the reaction of a compound having the structure shown in formula II with 1-bromo-8-chloronaphthalene to produce a compound having the structure shown in formula III.
  2. 2. The preparation method of the compound shown in the formula III is characterized in that the compound shown in the formula II is adopted to carry out coupling reaction with 1-bromo-8-chloronaphthalene, and the reaction route is as follows: 。
  3. 3. The synthesis method according to claim 2, wherein the molar ratio of the compound of formula II to 1-bromo-8-chloronaphthalene is 1 (1-1.1); And/or the reaction system of the coupling reaction also comprises a catalyst, wherein the catalyst is one or two selected from palladium acetate or DBA palladium; and/or the reaction system of the coupling reaction further comprises an alkaline auxiliary agent, wherein the alkaline auxiliary agent is one or two selected from cesium carbonate or potassium tert-butoxide; And/or the reaction system of the coupling reaction further comprises a ligand which is one or two selected from XantPhos or 2- (dicyclohexylphosphino) biphenyl; and/or the reaction system of the coupling reaction further comprises a second organic solvent, wherein the second organic solvent is one or more selected from toluene, DMF and 1, 4-dioxane; and/or the reaction temperature of the coupling reaction is 90-100 ℃; and/or, the coupling reaction further comprises the post-treatment steps of extraction and concentration after the coupling reaction is finished.
  4. 4. The method according to claim 3, wherein the molar ratio of the catalyst to the compound of formula II is (0.02-0.05): 1; And/or the molar ratio of the alkaline auxiliary agent to the compound shown in the formula II is (1-2) 1; and/or the molar ratio of the ligand to the compound of the formula II is (0.04-0.1): 1; And/or, the extraction is to add water and MTBE and stir and then separate and preserve an organic phase; And/or, the concentration is reduced pressure distillation of the organic phase.
  5. 5. The synthesis method according to claim 2, wherein the compound with the structure shown in formula II is prepared by deprotection reaction of the compound with the structure shown in formula I, and the reaction route is as follows: 。
  6. 6. The synthesis method according to claim 5, wherein the reaction system of the deprotection reaction further comprises an acidic auxiliary agent, and the acidic auxiliary agent is one or more of trifluoroacetic acid, p-toluenesulfonic acid or ethyl acetate hydrochloride; and/or the reaction system of the deprotection reaction further comprises a third organic solvent, wherein the third organic solvent is one or two selected from methanol or ethyl acetate; and/or the reaction temperature of the deprotection reaction is 10-40 ℃; and/or, after the deprotection reaction is finished, a post-treatment step is further included, wherein the post-treatment step is suction filtration and purification.
  7. 7. The method according to claim 6, wherein the molar ratio of the acidic auxiliary to the compound of formula I is (4-6): 1.
  8. 8. The synthesis method of the adaglazepan intermediate compound comprises the steps of carrying out a ring condensation reaction on a compound with a structure shown in a formula III and a compound with a structure shown in a formula IV to obtain an intermediate compound with a structure shown in a formula V, wherein the reaction route is as follows: 。
  9. 9. the synthesis method according to claim 8, wherein the molar ratio of the compound of formula III to the compound of formula IV is 1 (1.05-1.2); And/or the reaction system of the ring condensation reaction also comprises an alkaline auxiliary agent, wherein the alkaline auxiliary agent is one or two selected from potassium tert-butoxide or sodium methoxide; And/or the reaction system of the cyclocondensation reaction further comprises a first organic solvent, wherein the first organic solvent is one or two selected from methanol or THF; And/or the reaction temperature of the cyclic condensation reaction is 20-65 ℃; And/or, the cyclic condensation reaction is finished and then the extraction, concentration and purification are further carried out.
  10. 10. The method according to claim 9, wherein the molar ratio of the basic auxiliary to the compound of formula III is (3-5): 1; And/or, the extraction is to add water and MTBE and stir and then separate and preserve an organic phase; and/or, said concentrating to distill the organic phase under reduced pressure; and/or, the purification is to add ethyl acetate to dissolve the crude product, drop n-heptane, suction filtration and drying.

Description

Adaglazecloth Synthesis method of intermediate Technical Field The invention relates to the field of drug synthesis, in particular to a synthesis method of an adaglazeb intermediate compound. Background Adaglazepine is a highly selective, irreversible KRAS G12C small molecule inhibitor that is effective in inhibiting downstream oncogenic signaling pathways by covalently binding and locking the KRAS G12C protein in an inactive state. The drug has been approved by the U.S. FDA in 2022 for the treatment of previously treated KRAS G12C mutant non-small cell lung cancer (NSCLC), providing an important targeted therapeutic option for this mutant population, accounting for about 13% of NSCLC patients. Besides lung cancer, the compound also has therapeutic potential in colorectal cancer, pancreatic cancer and other KRAS G12C mutant solid tumors, and the application range is expected to be continuously expanded. According to industry analysis, the global KRAS inhibitor market scale is expected to rapidly increase to the billion dollar magnitude in the next few years, and the market prospect is wide. The adaglazepine intermediate compound has the following chemical name ：(S)-7-(8-chloronaphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(1H)-one; and the structural formulaThe molecular formula is C 23H25ClN4O2, the molecular weight is 424.92, and the CAS number is 2408250-15-5. The adaglazeb has the following structural formula: 。 CAS registry number 2326521-71-3, molecular formula C 23H35ClFN7O2. The product has been reported to be synthesized by literature, but all of the methods have obvious defects. The synthetic route of the method of patent CN119072477a is as follows: 。 from the route Compounds toThe compound underwent 3 steps of reaction. The method also uses highly toxic high-risk chemical triphosgene in the reaction process, has potential toxic gas risk, needs strict quenching and protection, and has the molecular weight of triphosgene as high as 296.75 g/mol, but the molecular weight of an effective part (one carbonyl group) of the triphosgene is only 28 g/mol, so that the raw material utilization rate of the triphosgene is low, and the atom economy is poor. Disclosure of Invention In view of the above-mentioned drawbacks of the prior art, an object of the present invention is to provide a synthesis method of adaglazeb intermediate compounds, which is suitable for industrial production. To achieve the above and other related objects, the present invention is achieved by the following technical means. The first aspect of the invention provides a synthesis method of an intermediate compound of adaglazeb, which comprises the steps of carrying out a ring condensation reaction on a compound with a structure shown in a formula III and a compound with a structure shown in a formula IV to obtain the intermediate compound of adaglazeb with a structure shown in a formula V, wherein the reaction route is as follows: 。 Preferably, the molar ratio of the compound of formula III to the compound of formula IV is 1 (1.05-1.2), such as 1:1.05, 1:1.1, 1:1.15 or 1:1.2. When the ratio is too small, the compound of the formula IV is excessive, so that the subsequent separation and purification are difficult, and when the ratio is too large, the reaction is incomplete, and the yield of the target product is reduced. More preferably 1:1.06. Preferably, the reaction system of the ring condensation reaction further comprises an alkaline auxiliary agent, wherein the alkaline auxiliary agent is one or two selected from potassium tert-butoxide or sodium methoxide. The role of the basic promoter in the ring condensation reaction is to provide an alkaline environment. More preferably, the alkaline auxiliary is sodium methoxide. More preferably, the molar ratio of the alkaline auxiliary agent to the compound of formula III is (3-5): 1. Such as 3:1, 4:1, or 5:1. Preferably 3:1. Preferably, the reaction system of the ring condensation reaction further comprises a first organic solvent, wherein the first organic solvent is one or two selected from methanol or tetrahydrofuran (abbreviated as THF), and other solvents can cause poor solubility. More preferably, the first organic solvent is methanol. Preferably, the reaction temperature of the ring condensation reaction is 20 to 65 ℃, such as 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃ and 65 ℃. More preferably, the reaction temperature is 60-65 ℃. The impurity of the product increases when the reaction temperature is too high (such as over 70 ℃), the reaction is very slow when the reaction temperature is lower than 50 ℃, the reaction temperature is too low (such as lower than 10 ℃), and the reaction does not proceed. Preferably, the reaction time of the ring condensation reaction is 18-22 h, such as 18h, 19h, 20h, 21h or 22h. More preferably, the reaction time is 20h. Preferably, the reaction is finished and further comprises a post-treatme