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CN-121974787-A - Preparation method of (3, 5-difluorophenoxy) -1-propanol

CN121974787ACN 121974787 ACN121974787 ACN 121974787ACN-121974787-A

Abstract

The invention belongs to the technical field of carbon-oxygen bond coupling, and relates to a preparation method of (3, 5-difluorophenoxy) -1-propanol, which comprises the steps of reacting a compound of formula 1 with 1, 3-propanediol in an organic solvent in the presence of Pd catalyst, ligand and alkali at a certain temperature under the condition of nitrogen atmosphere to obtain the compound of formula 2, wherein the method has mild reaction conditions, has cost advantage and is easy for industrial production.

Inventors

  • LI MINLIANG
  • XIE LIANGHUI
  • LI SHUO
  • ZHENG LONGSHENG

Assignees

  • 深圳格林凯特医药技术有限公司
  • 南方科技大学坪山生物医药研究院

Dates

Publication Date
20260505
Application Date
20260129

Claims (10)

  1. 1. A preparation method of (3, 5-difluorophenoxy) -1-propanol is characterized by comprising the steps of reacting a compound of formula 1 with 1, 3-propanediol in the presence of a palladium catalyst, a ligand and a base in an organic solvent under an inert atmosphere to obtain a compound of formula 2; 。
  2. 2. The method of claim 1, wherein the palladium catalyst is at least one of Pd (OAc) 2 、PdCl 2 、Pd 2 (dba) 3 and Pd (dba) 2 ; preferably, the molar ratio of the compound of formula 1 to the palladium catalyst is (15000-40000): 1.
  3. 3. The preparation method according to claim 1, wherein the ligand is a phosphorus-containing ligand, preferably the molar ratio of the compound of formula 1 to the ligand is (5000-25000): 1.
  4. 4. The method of claim 1, wherein the ligand is , wherein, R 1 is alkoxy, aryl, heteroaryl or carbazolyl which are monosubstituted or polysubstituted by R 4 ; r 2 is alkyl; Each R 4 and R 3 is independently hydrogen, alkoxy, alkyl or aryl, n is selected from 0, 1, 2, 3, 4 or 5.
  5. 5. The method of claim 1, wherein the ligand is , wherein, R 1 is C 1-6 alkoxy, C 6-12 aryl which is monosubstituted or polysubstituted or unsubstituted by R 4 , C 1-6 heteroaryl or carbazolyl; r 2 is C 1-6 alkyl; Each R 4 and R 3 is independently hydrogen, C 1-6 alkoxy, C 1-6 alkyl or C 6-12 aryl, n is selected from 0, 1, 2, 3, 4 or 5.
  6. 6. The method of claim 1, wherein the ligand is , wherein, R 1 is methoxy, ethoxy, propoxy, phenyl which is singly or multiply substituted or unsubstituted by R 4 , naphthyl which is singly or multiply substituted or unsubstituted by R 4 or carbazolyl; R 2 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-hexyl or n-pentyl; Each R 4 and R 3 is independently hydrogen, methoxy, ethoxy, propoxy, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-hexyl, n-pentyl or phenyl, n is selected from 0, 1,2, 3,4 or 5.
  7. 7. The method of claim 1, wherein the ligand is selected from one of the following structures: 、 、 、 、 、 、 、 、 。
  8. 8. The process according to claim 1, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, potassium t-butoxide, sodium t-butoxide, triethylamine, potassium acetate, sodium acetate; Preferably, the molar ratio of the base to the compound of formula 1 is (0.5-2.5): 1.
  9. 9. The preparation method according to claim 1, wherein the reaction is carried out at 60-105 ℃ for 6-42 hours; preferably, the molar ratio of the 1, 3-propanediol to the compound of formula 1 is (0.5-2.5): 1; Preferably, the inert atmosphere is at least one selected from nitrogen and argon.
  10. 10. The process according to claim 1, wherein the organic solvent is selected from the group consisting of toluene, xylene, dioxane, t-butanol, tetrahydrofuran and 2-methyltetrahydrofuran.

Description

Preparation method of (3, 5-difluorophenoxy) -1-propanol Technical Field The invention relates to a preparation method of (3, 5-difluorophenoxy) -1-propanol, belonging to the technical field of carbon-oxygen bond coupling. Background Tergolian (Tegoprazan) is also called agoraphane, is a brand new medicine for treating gastroesophageal reflux disease and erosive esophagitis, has the characteristics of quick acting, strong lasting acid inhibition, convenient administration and the like, and is marketed in China in 2022. The (3, 5-difluorophenoxy) -1-propanol is an intermediate for synthesizing tergolian, most of the currently reported synthesis methods are prepared by reacting 3, 5-difluorophenol with 3-chloro-1-propanol or 3-bromo-1-propanol (org. Process Res. Dev. 2024, 28, 1159-1169), but the raw material 3, 5-difluorophenol adopted by the method is expensive, high in cost, high in safety risk and unfavorable for industrial production because of the need of using high-risk reagent sodium hydride. Patent WO2022016309 reports that the use of 3, 5-difluorobromobenzene and 1, 3-propanediol for carbon-oxygen bond coupling over copper catalyst yields (3, 5-difluorophenoxy) -1-propanol, which, although using relatively inexpensive starting materials, is not efficient in the coupling reaction. And the reaction needs to use 1, 3-propylene glycol as a reaction solvent, and the 1, 3-propylene glycol is high in price and high in boiling point, so that the 1, 3-propylene glycol is difficult to recycle in industrial production, and the comprehensive cost is high. Meanwhile, the copper catalyst is high in dosage, the copper ion content in the wastewater is high, and the wastewater treatment difficulty is high. In view of this, it is of great importance to develop a process for the preparation of (3, 5-difluorophenoxy) -1-propanol. Disclosure of Invention Based on the existing problems and needs, the invention provides a preparation method of (3, 5-difluorophenoxy) -1-propanol, which has the advantages of high coupling reaction yield, low catalyst consumption, easy recovery of solvent, mild reaction conditions, cost advantage and easy industrial production. In a first aspect, a process for preparing (3, 5-difluorophenoxy) -1-propanol is provided, comprising reacting a compound of formula 1 with 1, 3-propanediol in the presence of a palladium catalyst, a ligand and a base in an organic solvent under an inert atmosphere to obtain a compound of formula 2; 。 in some embodiments, the palladium catalyst is at least one of Pd (OAc) 2、PdCl2、Pd2(dba)3 and Pd (dba) 2. In some embodiments, the molar ratio of the compound of formula 1 to the palladium catalyst is (15000-40000): 1, preferably any one of 15000:1, 16000:1, 20000:1, 25000:1, 30000:1, 40000:1, and any two of the above values. In some embodiments, the ligand is a phosphorus-containing ligand. In some embodiments, the ligand is, wherein, R 1 is alkoxy, aryl, heteroaryl or carbazolyl which are monosubstituted or polysubstituted by R 4; r 2 is alkyl; Each R 4 and R 3 is independently hydrogen, alkoxy, alkyl or aryl, n is selected from 0, 1, 2, 3, 4 or 5. In some embodiments, the ligand is, wherein, R 1 is C 1-6 alkoxy, C 6-12 aryl which is monosubstituted or polysubstituted or unsubstituted by R 4, C 1-6 heteroaryl or carbazolyl; r 2 is C 1-6 alkyl; Each R 4 and R 3 is independently hydrogen, C 1-6 alkoxy, C 1-6 alkyl or C 6-12 aryl, n is selected from 0, 1, 2, 3, 4 or 5. In some embodiments, the ligand is, wherein, R 1 is methoxy, ethoxy, propoxy, phenyl which is singly or multiply substituted or unsubstituted by R 4, naphthyl which is singly or multiply substituted or unsubstituted by R 4 or carbazolyl; R 2 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-hexyl or n-pentyl; Each R 4 and R 3 is independently hydrogen, methoxy, ethoxy, propoxy, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-hexyl, n-pentyl or phenyl, n is selected from 0, 1,2, 3,4 or 5. In some embodiments, the ligand is selected from one of the following structures: 、、、、、、、、。 In some embodiments, the molar ratio of the compound of formula 1 to the ligand is (5000-25000): 1, preferably any one of 5000:1, 8000:1, 10000:1, 15000:1, 20000:1, 25000:1, and any two of the above values. According to the present invention, in some embodiments, the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, potassium t-butoxide, sodium t-butoxide, triethylamine, potassium acetate, sodium acetate, and the like. In some embodiments, the molar ratio of the base to the compound of formula 1 is (0.5-2.5): 1, preferably 0.5:1, 0.8:1, 1:1, 1.2:1, 1.5:1, 1.6:1, 1.8:1, 2.0:1, 2.5:1, and any two of the above values constitute any one of the ranges. In some embodiments, the reaction is conducted at 60-105 ℃, preferably 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃ and any two of the above values constitute any one of the ranges, preferably the r