WO2023029979A1 - Procédé de préparation d'un intermédiaire agoniste du récepteur de glp-1 - Google Patents

Procédé de préparation d'un intermédiaire agoniste du récepteur de glp-1 Download PDF

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WO2023029979A1
WO2023029979A1 PCT/CN2022/112721 CN2022112721W WO2023029979A1 WO 2023029979 A1 WO2023029979 A1 WO 2023029979A1 CN 2022112721 W CN2022112721 W CN 2022112721W WO 2023029979 A1 WO2023029979 A1 WO 2023029979A1
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acid
compound
reaction
post
phenyl
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PCT/CN2022/112721
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English (en)
Chinese (zh)
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胡范
周鑫洁
刘东舟
胡海文
刘克楠
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杭州中美华东制药有限公司
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Priority to CN202280058903.8A priority Critical patent/CN117897387A/zh
Publication of WO2023029979A1 publication Critical patent/WO2023029979A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system

Definitions

  • the invention belongs to the technical field of drug synthesis, in particular to an intermediate (S,Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy) of a GLP-1 receptor agonist Phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-hydroxyacrylic acid and (S)-3-((S)-2-(4- ((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S) - a preparation method of 1-phenylpropyl) amino) propionic acid.
  • Invention patent CN102378574B discloses a method for preparing compound I free base by using 4-hydroxyacetophenone as a raw material through 14 steps of nucleophilic substitution, bromination, asymmetric reduction, condensation, and hydrolysis.
  • the preparation of the free base of compound I from compound A requires catalytic hydrogenation and multiple deprotection processes, making the reaction steps longer.
  • the present invention uses intermediate 3 to replace intermediate compound A, and then compound 3 can be prepared by five steps of hydrolysis, reduction, condensation and other reactions to obtain free base I.
  • the preparation of compound 2 from compound 3 requires a hydrolysis process.
  • the literature (US6211235 B1; J.Am.Chem.Soc.2018,140,32,10263) adopts Strong acid hydrolysis. Since the ether bond in compound 3 may be hydrolyzed under acidic conditions, applying this method to the preparation of compound 2 will result in the inversion of the chiral configuration of the generated compound 2, thereby affecting the quality of the product. Therefore, it is urgent to develop a preparation process route of compound 2 with good yield and controllable quality.
  • compound (S,S,S)-1 compound 1 of the new route has 3 chiral centers, and the preparation of compound 1 is an ammoniation reduction reaction. Two chiral centers will be introduced here, and there will be 8 non- Enantiomers, in the actual process development process, there are mainly three isomer impurities (S, R, S)-1, (R, S, S)-1, (S, S, R)-1.
  • Its isomer content is mainly affected by the chiral purity of the starting material and the reduction reaction, wherein compound 1 reacts with S-phenylpropylamine to generate imine first, and then under the action of a reducing agent, compound 1 is asymmetrically synthesized, due to the reaction Selectivity, the main side reaction impurity is (R, S, S)-1 introduced by asymmetric reduction reaction.
  • the formation of impurity (R,S,S)-1 is mainly affected by the reducing agent, and when a single boron reducing agent (such as sodium borohydride) is used, the product is a racemate.
  • the urgent problem to be solved at present is to increase the conversion rate of the reaction without affecting the chiral purity, so as to obtain compound 1 with high yield and high purity.
  • the present invention provides a novel intermediate (S,Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzene of compound I [b][1,4]dioxin-6-yl)-2-hydroxyacrylic acid (compound 2), an economical and effective preparation method, which has the advantages of low cost, high yield and controllable quality, It is more suitable for industrialized production.
  • the inorganic base used in the step a-1) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide; preferably sodium hydroxide.
  • organic acid and inorganic acid aqueous solution are added in batches.
  • the organic acid used in step a-2) is selected from oxalic acid, citric acid, malic acid, succinic acid, maleic acid, fumaric acid, acetic acid, trifluoroacetic acid or propionic acid; preferably acetic acid.
  • the inorganic acid used in step a-22) is selected from hydrochloric acid or sulfuric acid.
  • the organic acid is added first, and then the aqueous solution of the inorganic acid is added twice.
  • the concentration of the inorganic acid is selected from 2-8 mol/L.
  • the reaction temperature of step a-2) is 50-100°C.
  • post-reaction treatment is performed, and the post-treatment includes cooling the reaction liquid, transferring it to water, stirring and crystallizing, and filtering to obtain the crude compound 2.
  • the crude product in the post-treatment, can be further beaten with an organic solvent, the temperature of the beating can be controlled, and the pure compound 2 can be obtained after filtration.
  • the crystallization temperature in post-treatment is 0-40°C.
  • the organic solvent used in the post-treatment is selected from dichloromethane, chloroform, ethyl acetate, methanol, 1,2-dichloroethane, preferably dichloromethane.
  • the beating temperature in post-treatment is selected from 0-40°C, preferably 10-20°C.
  • the present invention also provides a novel intermediate of compound I (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-
  • the method has the advantages of low cost, high yield and controllable quality, and is more suitable for industrial production.
  • the present invention further provides the preparation of (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b]
  • the organic base in the step b-1) is selected from isopropylamine, triethylamine, N-methylmorpholine, piperazine, and N,N-diisopropylethylamine.
  • the reaction temperature in the step b-1) is 5-45°C, preferably 15-35°C.
  • the molar ratio of compound 2, S-phenylpropylamine and organic base in the step b-1) is 1:1.1:1.1 ⁇ 1:4:6.
  • the reaction solvent in step b-1 is selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane.
  • the reducing agent in step b-2) is a combination of MBH(RCOO) 3 and zinc borohydride.
  • the feeding ratio of compound 2, MBH(RCOO) 3 and zinc borohydride in step b-2) is 1:1.1:0.1 ⁇ 1:6:0.6.
  • M is selected from lithium, sodium, and potassium; R is a C6-C10 saturated alkyl group.
  • the reaction solvent in the step b-22) is selected from toluene, xylene, and chlorobenzene.
  • the reaction temperature in step b-22) is 0-40°C.
  • post-reaction treatment is carried out, and the post-treatment includes adding methanol to quench the reaction, then adding DMF to distill off the low-boiling reaction solvent, and then drop Add an alcoholic solvent, crystallize, filter and dry to obtain Compound 1; wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, and n-propanol.
  • the beneficial effects of this technical solution are: increasing the reducing agent component, and adding lithium chloride to promote the reaction, increasing the reaction conversion rate from 80% to 95%, thereby increasing the yield from 70% to 85%, and isomerization
  • the volume content does not increase, and the product quality is guaranteed while improving the yield.
  • the experimental method that does not indicate specific condition in the embodiment is conventional condition usually, or according to the condition suggested by raw material or commodity manufacturer;
  • Known reagents are prepared by conventional methods.
  • Embodiment 1 the preparation of compound 3
  • Embodiment 2 the preparation of compound 2
  • Embodiment 3 the preparation of compound 1 (purity detection is used)
  • Embodiment 4 Comparative example of compound 2 preparation (compound 2 is prepared by one-step acid hydrolysis method)
  • step-by-step hydrolysis method can significantly reduce the content of isomer impurities, thereby improving product quality.
  • Embodiment 5 the preparation of compound 1
  • Preparation of reducing agent add NaBH 4 (2.4g), dioxane (36g), xylene (28.8g) to the reaction flask, and stir at 15°C under temperature control; dropwise add isooctanoic acid (27.42g), dropwise After adding, keep warm and stir. Add a THF solution (8 mL) of zinc borohydride, continue to insulate and stir for 3-4 h, and set aside.
  • Embodiment 6 the comparative example of compound 1 preparation (do not add zinc borohydride and lithium chloride to prepare compound 1)
  • Preparation of reducing agent add NaBH 4 (2.4g), dioxane (36g), xylene (28.8g) to the reaction flask, and stir at 15°C under temperature control; dropwise add isooctanoic acid (27.42g), dropwise After adding, keep warm and stir, set aside.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de l'acide (S,Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy)phényl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-hydroxyacrylique et de l'acide (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phényl)-2,3-dihydrobenzo[b][1,4]dioxine-6-yl)-2-(((S)-1-phénylpropyl)amino)propanoïque. Le procédé de préparation présente les avantages d'un faible coût, d'un rendement élevé et d'une qualité contrôlable, et est plus approprié pour la production industrielle.
PCT/CN2022/112721 2021-09-03 2022-08-16 Procédé de préparation d'un intermédiaire agoniste du récepteur de glp-1 WO2023029979A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280058903.8A CN117897387A (zh) 2021-09-03 2022-08-16 Glp-1受体激动剂中间体的制备方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202111030690.1 2021-09-03
CN202111030690 2021-09-03
CN202210251625 2022-03-15
CN202210251625.X 2022-03-15

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WO2023029979A1 true WO2023029979A1 (fr) 2023-03-09

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1764647A (zh) * 2003-03-26 2006-04-26 埃科特莱茵药品有限公司 四氢异喹啉基乙酰胺衍生物作为阿立新受体拮抗剂的应用
CN102378574A (zh) * 2009-03-30 2012-03-14 转化技术制药公司 取代的偶氮蒽衍生物、药物组合物及其使用方法
WO2021242806A1 (fr) * 2020-05-28 2021-12-02 Vtv Therapeutics Llc Intermédiaires et procédés de préparation d'un agoniste du récepteur glp-1
WO2021238962A1 (fr) * 2020-05-28 2021-12-02 杭州中美华东制药有限公司 Procédé de préparation d'agoniste du récepteur glp-1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1764647A (zh) * 2003-03-26 2006-04-26 埃科特莱茵药品有限公司 四氢异喹啉基乙酰胺衍生物作为阿立新受体拮抗剂的应用
CN102378574A (zh) * 2009-03-30 2012-03-14 转化技术制药公司 取代的偶氮蒽衍生物、药物组合物及其使用方法
WO2021242806A1 (fr) * 2020-05-28 2021-12-02 Vtv Therapeutics Llc Intermédiaires et procédés de préparation d'un agoniste du récepteur glp-1
WO2021238962A1 (fr) * 2020-05-28 2021-12-02 杭州中美华东制药有限公司 Procédé de préparation d'agoniste du récepteur glp-1

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