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CN-122010773-A - Synthesis method of alpha-total substituted large-steric-hindrance aldehyde

CN122010773ACN 122010773 ACN122010773 ACN 122010773ACN-122010773-A

Abstract

The invention relates to a synthesis method of alpha-total substituted large steric hindrance aldehyde. The invention provides a preparation method of a compound B, which comprises the following steps of reacting a compound shown as a formula I with a compound A to generate the compound B. The synthesis method has the advantages of simple operation, no need of transition metal catalysis, no need of additives, economy of atoms, environmental friendliness, good reactivity, higher yield, simple post-reaction treatment and capability of amplifying production.

Inventors

  • XUE XIAOSONG
  • YU CUI
  • CAI LIU
  • LAI XIAOYU

Assignees

  • 中国科学院上海有机化学研究所

Dates

Publication Date
20260512
Application Date
20260122

Claims (10)

  1. 1. The preparation method of the compound B is characterized by comprising the following steps of reacting a compound shown as a formula I with a compound A to generate the compound B; ; when the compound A is XN 3 , the compound B is a compound B-1 ; When the compound A is H-R 3 , the compound B is a compound B-2 ; When the compound A is PhSY, the compound B is a compound B-3 ; X is Na or K; Y is Na or K; R 1 is C 1-10 alkyl, C 5-16 cycloalkyl, C 1-10 alkyl substituted with one or more R 1-1 , or C 5-16 cycloalkyl substituted with one or more R 1-2 ; R 2 is C 5-16 cycloalkyl, C 3-12 cycloalkyl and C 6-12 aryl, C 1-10 alkyl substituted with one or more R 2-1 , or C 5-16 cycloalkyl substituted with one or more R 2-2 ; R 1-1 and R 2-1 are each independently C 6-12 aryl; R 1-2 and R 2-2 are each independently halogen or C 1-6 alkyl; Or R 1 and R 2 together with the carbon atom to which they are attached form a C 5-24 cycloalkyl group, or a C 5-24 cycloalkyl group substituted with one or more R a ; R a is independently C 1-10 alkyl or C 1-10 alkoxy; R 3 is C 1-6 alkoxy, 5-16 membered heterocycloalkyl substituted by one or more R 3-1 , -S-R 3-2 、-NR 3-3 R 3-4 or 5-16 membered heteroaryl, wherein in the 5-16 membered heterocycloalkyl and the 5-16 membered heterocycloalkyl in the 5-16 membered heterocycloalkyl substituted by one or more R 3-1 , the heteroatom is one or more of N, O and S, the number of heteroatoms is 1,2 or 3, and in the 5-16 membered heteroaryl, the heteroatom is one or more of N, O and S, the number of heteroatoms is 1,2 or 3; R 3-1 is independently 5-16 membered heteroaryl, or 5-16 membered heteroaryl substituted with one or more R 3-1-1 , wherein in the 5-16 membered heteroaryl and the 5-16 membered heteroaryl in the 5-16 membered heteroaryl substituted with one or more R 3-1-1 , the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 3-2 is 5-16 membered heteroaryl, or 5-16 membered heteroaryl substituted with one or more R 3-2-1 , wherein in the 5-16 membered heteroaryl and the 5-16 membered heteroaryl in the 5-16 membered heteroaryl substituted with one or more R 3-2-1 , the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1,2 or 3; R 3-1-1 and R 3-2-1 are each independently C 1-6 alkyl or oxo; R 3-3 is H or C 1-6 alkyl; r 3-4 is ; L 1 is -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 - or- (CH 2 ) 6 -,L 1 ) -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 - and- (CH 2 ) 6 -) one or two of-CH 2 -optionally replaced by-X 1 -; X 1 is-O-, -S-or-CHR 3-4-1 -; R 3-4-1 is C 6-12 aryl, or C 6-12 aryl substituted with one or more R 3-4-1-1 ; Ring a is C 6-12 aryl, or C 6-12 aryl substituted with one or more R 3-4-2 ; R 3-4-1-1 and R 3-4-2 are each independently halogen, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more halogens.
  2. 2. The method of claim 1, wherein one or more of the following conditions are satisfied: (1) The C 1-10 alkyl is C 1-8 alkyl, preferably C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or heptyl, and such as methyl or heptyl; (2) The C 5-16 cycloalkyl group is a C 5-12 cycloalkyl group, preferably a C 5-6 monocycloalkyl group or a C 8-12 bridged cycloalkyl group, for example Or (b) ; (3) The C 3-12 cycloalkyl and C 6-12 aryl radicals are C 3-6 cycloalkyl and C 6-12 aryl radicals, preferably C 5-6 cycloalkyl and C 6-10 aryl radicals, e.g ; (4) The C 6-12 aryl is phenyl or naphthyl; (5) The halogen is fluorine, chlorine, bromine or iodine; (6) The C 5-24 cycloalkyl is C 5-17 monocycloalkyl or C 8-20 and cycloalkyl, for example 、 Or (b) ; (7) The C 1-10 alkoxy group is a C 1-6 alkoxy group, preferably methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy or ethoxy; (8) The C 1-6 alkoxy group is a C 1-4 alkoxy group, preferably methoxy, ethoxy, propoxy, isopropoxy or n-butoxy, for example methoxy or ethoxy; (9) The C 1-6 alkyl is C 1-4 alkyl, preferably methyl, ethyl, propyl, isopropyl or n-butyl; (10) The 5-16 membered heterocycloalkyl group is a 5-12 membered heterocycloalkyl group, preferably a 5-6 membered heterocycloalkyl group, the hetero atom in the 5-16 membered heterocycloalkyl group is preferably one or both of N and O, the number of hetero atoms is preferably 1 or 2, for example ; (11) The 5-16 membered heteroaryl group is a 5-12 membered heteroaryl group, preferably a 5-10 membered heteroaryl group, the heteroatom in the 5-16 membered heteroaryl group is preferably one or both of N and O, the number of heteroatoms is preferably 1 or 2, for example Or (b) 。
  3. 3. The method of claim 1, wherein one or more of the following conditions are satisfied: (1) R 1 is methyl, ethyl or ; (2) R 2 is 、 、 Or (b) ; (3) R 1 and R 2 together form 、 Or (b) ; (4) R 3 is 、 、 Or (b) 。
  4. 4. The method of claim 1, wherein one or more of the following conditions are satisfied: (1) The compound shown in the formula I is any one of the following compounds: 、 、 、 、 、 、 Or (b) ; (2) The compound A is any one of NaN 3 , phSK, etOH, 、 Or (b) ; (3) The compound B-1 is any one of the following compounds: 、 、 、 、 、 、 Or (b) ; (4) The compound B-2 is any one of the following compounds: 、 、 Or (b) ; (5) The compound B-3 is 。
  5. 5. The method of claim 1, wherein one or more of the following conditions are satisfied: (1) The reaction is carried out in the presence of a solvent; (2) The molar ratio of the compound of formula I to the compound A is 1 (0.8-4), preferably 1 (1-3), for example 1:1.2, 1:1.25, 1:1.3, 1:1.6, 1:1.8 or 1:2.5; (3) The reaction temperature is 60-120 ℃; (4) When the compound B is the compound B-1, the reaction further comprises the following post-treatment steps of cooling the reaction liquid after the reaction is finished, adding an ester solvent and water for extraction, washing, drying, filtering, concentrating the obtained organic phase, and carrying out column chromatography on the obtained crude product to obtain the compound B-1; (5) When the compound B is the compound B-2 or the compound B-3, the reaction further comprises the following post-treatment steps of cooling and concentrating the reaction liquid after the reaction is finished, and performing column chromatography on the obtained crude product to obtain the compound B-2 or the compound B-3.
  6. 6. The method of claim 5, wherein one or more of the following conditions are satisfied: (1) When the reaction is performed in the presence of a solvent, the solvent is one or more of an amide-based solvent, an alcohol-based solvent, and a nitrile-based solvent; The amide solvent is preferably DMF; the alcohol solvent is preferably ethanol; The nitrile solvent is preferably acetonitrile; (2) When the reaction is carried out in the presence of a solvent, the molar volume ratio of the compound of formula I to the solvent is (0.01-0.3) mol/L, preferably (0.01-0.2) mol/L; (3) The reaction temperature is 70-110 ℃.
  7. 7. The process according to claim 5, wherein the solvent is used in the form of compound A when the compound A is H-R 3 ,R 3 is C 1-6 alkoxy, preferably the molar volume ratio of the compound of formula I to the compound A is (0.02-0.05) mol/L, for example 0.04mol/L.
  8. 8. The method of claim 6, wherein one or more of the following conditions are satisfied: (1) When the compound A is XN 3 , the molar volume ratio of the compound of formula I to the solvent is (0.02-0.2) mol/L, for example 0.02mol/L, 0.04mol/L, 0.08 mol/L or 0.2 mol/L; (2) When the compound A is PhSY, the molar volume ratio of the compound of formula I to the solvent is (0.01-0.04) mol/L, for example 0.02mol/L; (3) When the compound A is H-R 3 ,R 3 -16 membered heterocycloalkyl, 5-16 membered heterocycloalkyl substituted with one or more R 3-1 , -S-R 3-2 、-NR 3-3 R 3-4 or 5-16 membered heteroaryl, the molar volume ratio of the compound of formula I to the solvent is (0.02-0.06) mol/L, e.g. 0.028mol/L, 0.032 mol/L or 0.04 mol/L; (4) The temperature of the reaction is 80 ℃ or 100 ℃.
  9. 9. The method of claim 6, wherein one or more of the following conditions are satisfied: (1) When the compound A is XN 3 , the preparation method is a method 1, and comprises the following steps of reacting a compound shown as a formula I with the compound A in the amide solvent to obtain the compound B-1; (2) When the compound A is H-R 3 ,R 3 -16 membered heterocycloalkyl, 5-16 membered heterocycloalkyl substituted with one or more R 3-1 , -S-R 3-2 、-NR 3-3 R 3-4 or 5-16 membered heteroaryl, the preparation method is method 2, which comprises the steps of reacting a compound of formula I with compound A in the presence of an alkaline reagent in the nitrile solvent to obtain compound B-2; The alkaline agent is preferably an alkali metal carbonate, such as K 2 CO 3 or Cs 2 CO 3 ; Preferably, the molar ratio of the compound of formula I to the basic agent is 1 (0.8-3), preferably 1 (1-2), for example 1:1.25, 1:1.6 or 1:1.8; (3) When the compound A is H-R 3 ,R 3 and C 1-6 alkoxy, the preparation method is a method 3, and comprises the following steps of reacting a compound shown as a formula I with the compound A to obtain a compound B-2; (4) When the compound A is PhSY, the preparation method is a method 4, which comprises the following steps of reacting a compound shown as a formula I with the compound A in the alcohol solvent to obtain the compound B-3.
  10. 10. The method of claim 9, characterized in that it satisfies one or more of the following conditions: (1) The reaction materials of the method 1 are the amide solvent, the compound shown in the formula I and the compound A; (2) The reaction materials of the method 2 are the nitrile solvent, the alkaline reagent, the compound shown in the formula I and the compound A; (3) The reaction materials of the method 3 are the compound shown in the formula I and the compound A; (4) The reaction materials of the method 4 are the alcohol solvent, the compound shown in the formula I and the compound A.

Description

Synthesis method of alpha-total substituted large-steric-hindrance aldehyde Technical Field The invention relates to a synthesis method of alpha-total substituted large steric hindrance aldehyde. Background Alpha-fully substituted large sterically hindered aldehyde refers to an aldehyde in which the alpha carbon of the aldehyde group (the tertiary carbon center substituted by alpha oxygen, nitrogen, sulfur) is fully substituted by a large sterically hindered group. Aldehyde groups are key pharmacophores and are widely used in anti-infective and anti-tumour drugs. However, despite the inherent reactivity that imparts therapeutic activity, the toxicity of such compounds, which is associated with metabolic instability and the risk of off-target covalent binding, limits the use of such compounds in the medical field. The introduction of steric hindrance at the alpha position by methyl substitution in drug design can effectively inhibit off-target interactions while retaining therapeutic functions (j. Med. Chem 2020, 63, 14357). Meanwhile, literature (J. Am. chem. Soc. 2025, 147, 31662) discloses sterically hindered aldehydes, including tertiary aldehydes and Ji Quan alkyl substituted derivatives, which are ubiquitous in pharmaceuticals, such as anti-tumor drugs peruvian glycoside and antifeedant diterpenoids. Despite the pharmacological relevance of sterically hindered aldehydes, the current general approach to directly synthesizing this structure is relatively lacking, which limits their discovery and use in drug discovery. In addition, aldehyde groups serve as a very basic organic functional group, and subsequent conversion, including classical reduction, oxidation, reductive amination, and the like, can efficiently convert the product to other high value products. The current methods for preparing alpha-fully substituted, highly hindered aldehydes are mainly divided into two types, the first type is alpha-functionalization of aldehydes, including enamine activation, bronsted base activation, metal catalysis, enamine-metal bi-catalysis activation, etc. (Molecules 2023, 28, 2694), and the second type is free radical hydroformylation of olefins (j. Am. chem. Soc. 2025, 147, 31662). However, the former enamine catalyst has high usage amount, poor compatibility of a double catalytic system, dependence of partial reaction on toxic reagents or expensive metals and ligands, and the latter requires light irradiation, catalyst and the like to initiate a radical process to promote the reaction, has poor atom economy and is not friendly to the environment, and in addition, the two methods have greatly reduced yield or are difficult to synthesize when synthesizing the alpha-larger steric hindrance group (such as adamantyl) substituted aldehyde, so that development of an efficient, environment-friendly and substrate-friendly synthesis method is urgent. Disclosure of Invention The invention aims to overcome the defects that the yield is greatly reduced or the synthesis is difficult to realize when the alpha-aldehyde substituted by a larger steric hindrance group is synthesized in the prior art, thereby providing a synthesis method of the alpha-full substituted aldehyde with large steric hindrance. The synthesis method has the advantages of simple operation, no need of transition metal catalysis, no need of additives, economy of atoms, environmental friendliness, good reactivity, higher yield, simple post-reaction treatment and capability of amplifying production. The invention solves the technical problems by the following technical scheme: The invention provides a preparation method of a compound B, which comprises the following steps of reacting a compound shown as a formula I with a compound A to generate the compound B; ; when the compound A is XN 3, the compound B is a compound B-1 ; When the compound A is H-R 3, the compound B is a compound B-2; When the compound A is PhSY, the compound B is a compound B-3; X is Na or K; Y is Na or K; R 1 is C 1-10 alkyl, C 5-16 cycloalkyl, C 1-10 alkyl substituted with one or more R 1-1, or C 5-16 cycloalkyl substituted with one or more R 1-2; R 2 is C 5-16 cycloalkyl, C 3-12 cycloalkyl and C 6-12 aryl, C 1-10 alkyl substituted with one or more R 2-1, or C 5-16 cycloalkyl substituted with one or more R 2-2; R 1-1 and R 2-1 are each independently C 6-12 aryl; R 1-2 and R 2-2 are each independently halogen or C 1-6 alkyl; Or R 1 and R 2 together with the carbon atom to which they are attached form a C 5-24 cycloalkyl group, or a C 5-24 cycloalkyl group substituted with one or more R a; R a is independently C 1-10 alkyl or C 1-10 alkoxy; R 3 is C 1-6 alkoxy, 5-16 membered heterocycloalkyl substituted by one or more R 3-1, -S-R 3-2、-NR3-3R3-4 or 5-16 membered heteroaryl, wherein in the 5-16 membered heterocycloalkyl and the 5-16 membered heterocycloalkyl in the 5-16 membered heterocycloalkyl substituted by one or more R 3-1, the heteroatom is one or more of N, O and S, the number of het