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WO2025087220A1 - Procédé de préparation d'amino-3-hydroxy-3-(4-méthoxyphényl)propionate (2s,3r)-2-substitué - Google Patents

Procédé de préparation d'amino-3-hydroxy-3-(4-méthoxyphényl)propionate (2s,3r)-2-substitué Download PDF

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Publication number
WO2025087220A1
WO2025087220A1 PCT/CN2024/126369 CN2024126369W WO2025087220A1 WO 2025087220 A1 WO2025087220 A1 WO 2025087220A1 CN 2024126369 W CN2024126369 W CN 2024126369W WO 2025087220 A1 WO2025087220 A1 WO 2025087220A1
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molar amount
preparation
compound
methoxyphenyl
hydroxy
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PCT/CN2024/126369
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English (en)
Chinese (zh)
Inventor
牛德强
李旭珂
朱振东
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Artivila Shenzhen Innovation Center Ltd
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Artivila Shenzhen Innovation Center Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present application belongs to the field of organic synthesis, and specifically relates to a method for preparing (2S, 3R)-2-substituted amino-3-hydroxy-3-(4-methoxyphenyl) propionate, and in particular to a method for preparing (2S, 3R)-2-substituted amino-3-hydroxy-3-(4-methoxyphenyl) propionate with high yield.
  • KZR-616 (Zetomipzomib) is a selective immunoproteasome inhibitor pioneered by Kezar Life Sciences. It selectively targets immunoproteasome subunits. Its inhibitory activity against LMP7/PSMB5 subunits in MOLT-4 cells is IC 50 : 39nM/688nM, and against LMP2/PSMB6 subunits is IC 50 : 131nM/>10600nM. The selective inhibition of different proteasome subunits can treat immune-related diseases without causing immunosuppression. KZR-616 has been approved by the US FDA to enter Phase II clinical trials, becoming the first selective immunoproteasome inhibitor to enter clinical trials.
  • autoimmune diseases including the treatment of patients with dermatitis/dermatomyositis (PM/DM), autoimmune hepatitis (AIH), and active proliferative lupus nephritis (LN).
  • PM/DM dermatitis/dermatomyositis
  • AIH autoimmune hepatitis
  • LN active proliferative lupus nephritis
  • KZR-616 is a tripeptide compound composed of three amino acids, and the synthesis process involves more than 15 steps. Compound I is an important synthetic fragment. Johnson, Henry WB et al. reported the synthesis steps of the intermediate compound I in the discovery document of KZR-616 published in 2018 (J. Med. Chem. 2018, 61, 11127-11143), as shown in the figure below:
  • the synthetic route has the following shortcomings: 1) There are many steps and the operation process is extremely complicated. The total yield of the five-step reaction is only 2.6%, which makes industrial production extremely difficult; 2) The first step reaction obtains the racemic intermediate V, and recrystallization and chiral resolution methods are required to obtain the chiral intermediate VII; 3) It involves the conversion of multiple protecting groups, which does not meet the requirements of green chemistry.
  • the present application provides a method for preparing (2S, 3R)-2-substituted amino-3-hydroxy-3-(4-methoxyphenyl) propionate, and in particular provides a method for preparing (2S, 3R)-2-substituted amino-3-hydroxy-3-(4-methoxyphenyl) propionate with high yield.
  • the method provided in the present application can realize the preparation of the product in only one step, and has the advantages of simple operation steps, high yield, high selectivity, and mild reaction conditions.
  • the present application provides a method for preparing (2S, 3R)-2-substituted amino-3-hydroxy-3-(4-methoxyphenyl) propionate, the preparation method comprising the following steps:
  • Compound II is mixed with a chiral ligand, a nitrogen source PG 2 NH 2 , an oxidant, a catalyst, and an alkaline reagent to react to obtain compound I, namely the (2S, 3R)-2-substituted amino-3-hydroxy-3-(4-methoxyphenyl) propionate.
  • PG 1 is selected from methyl, ethyl, isopropyl, tert-butyl, phenyl or benzyl
  • PG 2 is selected from Boc (tert-butoxycarbonyl), Cbz (benzyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Tfa (trifluoroacetyl).
  • the above method realizes the one-step preparation of the product by adopting a chiral ligand, and has the advantages of simple operation steps, high yield, high selectivity and mild reaction conditions.
  • the chiral ligand is (DHQD) 2 AQN.
  • the PG 1 is selected from benzyl
  • the PG 2 is selected from Boc
  • the nitrogen source is tert-butyl carbamate.
  • the oxidant comprises trichloroisocyanuric acid and/or tert-butyl hypochlorite, preferably trichloroisocyanuric acid.
  • the above specific oxidants can significantly improve the optical purity of the product.
  • the catalyst comprises osmium tetroxide and/or osmate.
  • the alkaline reagent includes any one of potassium hydroxide, sodium hydroxide or lithium hydroxide, or a combination of at least two of them, such as a combination of potassium hydroxide and sodium hydroxide, a combination of sodium hydroxide and lithium hydroxide, or a combination of potassium hydroxide and lithium hydroxide, but is not limited to the combinations listed above. Other combinations not listed within the above combination range are also applicable.
  • the reaction is carried out in a solvent
  • the solvent is a mixed solvent of water and an organic solvent.
  • the organic solvent comprises any one of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol or acetonitrile, or a combination of at least two thereof, preferably a combination of n-propanol and acetonitrile.
  • the above-mentioned specific solvent combination can effectively promote the reaction and improve the yield and selectivity.
  • the volume ratio of water to organic solvent is 1:5-5:1, preferably 1:2-2:1.
  • the molar amount of the chiral ligand is 0.1%-5% of the molar amount of compound II.
  • the molar amount of the oxidant is 0.3-5 times the molar amount of compound II.
  • the molar amount of the catalyst is 0.1%-5% of the molar amount of compound II.
  • the molar amount of the alkaline agent is 2-5 times the molar amount of compound II.
  • the molar amount of the nitrogen source is 1-5 times the molar amount of compound II.
  • the volume ratio of water to organic solvent can be 1:5, 2:4, 3:3, 4:2 or 5:1, etc.
  • the molar amount of the solvent can be 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% of the molar amount of Compound II
  • the molar amount of the oxidant can be 0.3 times, 1 times, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times or 5 times the molar amount of Compound II
  • the molar amount of the catalyst can be 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% of the molar amount of Compound II
  • the molar amount of the alkaline agent is 2 times, 3 times, 4 times or 5 times the molar amount of Compound II
  • the molar amount of the nitrogen source is 1 times, 2 times, 3 times, 4 times or 5 times the m
  • the reaction temperature is 0-100°C, for example 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C, but is not limited to the above-listed values. Other unlisted values within the above numerical range are also applicable, preferably 10-30°C, and more preferably 20-30°C.
  • the reaction time is 1-5 h, for example 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h or 5 h, but is not limited to the above-listed values, and other unlisted values within the above numerical range are also applicable.
  • the present application provides a method for preparing (2S, 3R)-2-substituted amino-3-hydroxy-3-(4-methoxyphenyl) propionate, which realizes the one-step preparation of the product by adopting a chiral ligand, and has the advantages of simple operation steps, high yield, high selectivity, and mild reaction conditions; and by selecting a specific catalyst and solvent combination, the reaction can be effectively promoted to improve the yield and selectivity.
  • This embodiment provides a method for preparing benzyl (2S, 3R)-2-((tert-butyloxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propionate, and the specific steps are as follows:
  • the product was analyzed by chirality (chromatographic column: CHIRALPAK AD-H, mobile phase was a n-hexane solution containing 30% isopropanol), wherein the content of (2S, 3R)-2-((tert-butyloxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl) propionic acid benzyl ester was 96%, and the content of other chiral isomers was 4%.
  • This embodiment provides a method for preparing benzyl (2S, 3R)-2-((tert-butyloxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propionate.
  • the specific steps are the same as those in Example 1 except that trichloroisocyanuric acid is replaced with three times the molar amount of tert-butyl hypochlorite.
  • This embodiment provides a method for preparing benzyl (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propionate.
  • the specific steps are the same as those in Example 1 except that sodium hydroxide is replaced by an equimolar amount of potassium hydroxide.
  • This embodiment provides a method for preparing benzyl (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propionate.
  • the specific steps are the same as those in Example 1 except that the n-propanol-acetonitrile mixed solution is replaced with an equal amount of n-propanol.
  • This embodiment provides a method for preparing benzyl (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propionate.
  • the specific steps are the same as those in Example 1 except that the n-propanol-acetonitrile mixed solution is replaced with an equal amount of acetonitrile.
  • This embodiment provides a method for preparing benzyl (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propionate.
  • the specific steps are the same as those in Example 1 except that the n-propanol-acetonitrile mixed solution is replaced with an equal amount of ethanol.
  • This embodiment provides a method for preparing methyl (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propionate.
  • the specific steps are the same as those in Example 1 except that benzyl 4-methoxycinnamate is replaced by an equimolar amount of methyl 4-methoxycinnamate.
  • This embodiment provides a method for preparing methyl (2S, 3R)-2-((benzyloxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propionate.
  • tert-butyl carbamate is replaced by an equal molar amount of benzyl carbamate
  • benzyl 4-methoxycinnamate is replaced by an equal molar amount of methyl 4-methoxycinnamate
  • the preparation method provided in the present application can effectively prepare (2S, 3R)-2-substituted amino-3-hydroxy-3-(4-methoxyphenyl) propanoate, and has the advantages of simple operation steps, mild reaction conditions, high yield and good selectivity.
  • the present application can effectively promote the reaction by selecting a specific solvent combination and a specific oxidant, thereby further improving the yield and selectivity.

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

Abstract

La présente demande concerne un procédé de préparation d'amino-3-hydroxy-3-(4-méthoxyphényl)propionate (2S,3R)-2-substitué. Le procédé de préparation comprend l'étape suivante consistant à : mélanger le composé II avec un ligand chiral, une source d'azote PG2NH2, un agent oxydant, un catalyseur et un réactif alcalin pour subir une réaction afin d'obtenir le composé I, c'est-à-dire l'amino-3-hydroxy-3-(4-méthoxyphényl)propionate (2S,3R)-2-substitué. Le procédé fourni par la présente demande permet de réaliser la préparation du produit en une seule étape, et le procédé présente les avantages d'étapes de fonctionnement simples, d'un haut rendement, d'une sélectivité élevée et de conditions de réaction modérées.
PCT/CN2024/126369 2023-10-27 2024-10-22 Procédé de préparation d'amino-3-hydroxy-3-(4-méthoxyphényl)propionate (2s,3r)-2-substitué Pending WO2025087220A1 (fr)

Applications Claiming Priority (2)

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CN202311417811.7A CN117466780A (zh) 2023-10-27 2023-10-27 一种(2s,3r)-2-取代氨基-3-羟基-3-(4-甲氧基苯基)丙酸酯制备方法
CN202311417811.7 2023-10-27

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WO2025087220A1 true WO2025087220A1 (fr) 2025-05-01

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* Cited by examiner, † Cited by third party
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CN117466780A (zh) * 2023-10-27 2024-01-30 科辉智药(深圳)新药研究中心有限公司 一种(2s,3r)-2-取代氨基-3-羟基-3-(4-甲氧基苯基)丙酸酯制备方法

Citations (3)

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US5767304A (en) * 1996-05-21 1998-06-16 The Scripps Research Institute Catalytic asymmetric aminohydroxylation of olefins with carbamates
WO2011159177A1 (fr) * 2010-06-18 2011-12-22 Industrial Research Limited Aminohydroxylation améliorée d'alcènes
CN117466780A (zh) * 2023-10-27 2024-01-30 科辉智药(深圳)新药研究中心有限公司 一种(2s,3r)-2-取代氨基-3-羟基-3-(4-甲氧基苯基)丙酸酯制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5767304A (en) * 1996-05-21 1998-06-16 The Scripps Research Institute Catalytic asymmetric aminohydroxylation of olefins with carbamates
WO2011159177A1 (fr) * 2010-06-18 2011-12-22 Industrial Research Limited Aminohydroxylation améliorée d'alcènes
CN117466780A (zh) * 2023-10-27 2024-01-30 科辉智药(深圳)新药研究中心有限公司 一种(2s,3r)-2-取代氨基-3-羟基-3-(4-甲氧基苯基)丙酸酯制备方法

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