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CN-122011253-A - Sieber resin and preparation method and application thereof

CN122011253ACN 122011253 ACN122011253 ACN 122011253ACN-122011253-A

Abstract

The application relates to the technical field of synthesis, in particular to Sieber resin and a preparation method and application thereof. The preparation method comprises the following steps of carrying out a first reaction of (9H-xanthene-9-ketone-3-oxymethyl) resin and fluorenylmethoxycarbonyl amide in a first solvent under the catalysis of a first catalyst to prepare Sieber resin, wherein the first catalyst comprises triacetoxyborohydride alkali metal salt and acetic acid, the triacetoxyborohydride salt has a general formula of M [ BH (OAc) 3 ], and M is selected from Li, na, K, rb, cs. The preparation method of Sieber resin provided by the embodiment of the application simplifies the reaction steps, improves the synthesis efficiency, has mild and controllable reaction conditions, and is good in swelling performance and stable in product performance, thereby being suitable for large-scale industrial production.

Inventors

  • CAI JIANGUO
  • SHI HONGYAN
  • BAI FAN

Assignees

  • 江苏海普功能材料有限公司

Dates

Publication Date
20260512
Application Date
20260225

Claims (10)

  1. 1. The preparation method of Sieber resin is characterized by comprising the following steps: Under the catalysis of a first catalyst, carrying out a first reaction on (9H-xanthene-9-ketone-3-oxymethyl) resin and fluorenylmethoxycarbonyl amide in a first solvent to prepare Sieber resin; Wherein the structural formula of the (9H-xanthen-9-one-3-oxymethyl) resin is shown as follows: ; P is a polymer resin; The first catalyst comprises an alkali metal triacetoxyborohydride and acetic acid, the triacetoxyborohydride having the general formula M [ BH (OAc) 3 ], M being selected from Li, na, K, rb, cs.
  2. 2. The method of claim 1, wherein the (9H-xanthen-9-one-3-oxymethyl) resin is prepared by the steps of: under the catalysis of a second catalyst, carrying out a second reaction on chloromethyl resin and 3-hydroxy-9H-xanthen-9-one in a second solvent to prepare (9H-xanthen-9-one-3-oxymethyl) resin; wherein the structural formula of the chloromethyl resin is shown as follows: 。
  3. 3. The method of manufacturing according to claim 2, wherein at least one of the following conditions is satisfied: (1) The second catalyst is selected from at least one of sodium tert-butyl alcohol, sodium methoxide and sodium ethoxide; (2) The second solvent is at least one selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1, 4-dioxane; (3) The particle size of the chloromethyl resin is 100-200 meshes; (4) The temperature of the second reaction is 60-100 ℃; (5) The second reaction time is 12-24 h.
  4. 4. The method according to any one of claims 1 to 3, wherein P is one selected from the group consisting of polystyrene-divinylbenzene copolymer resin, polyethylene-ethylene glycol-grafted polystyrene resin, and diethylene glycol dimethacrylate crosslinked polystyrene resin.
  5. 5. A method of preparing as claimed in any one of claims 1 to 3, wherein at least one of the following conditions is satisfied: (1) The mass ratio of the sodium triacetoxyborohydride to the acetic acid is (5-15) 1; (2) The mass of the first catalyst is 0.2-2 times of that of the (9H-xanthene-9-ketone-3-oxymethyl) resin; (3) The mass of the fluorenylmethoxycarbonyl amide is 0.5-1.5 times of that of the (9H-xanthene-9-ketone-3-oxymethyl) resin; (4) The first solvent is at least one selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1, 4-dioxane; (5) The temperature of the first reaction is 30-45 ℃; (6) The time of the first reaction is 16-24 hours.
  6. 6. A method of preparing as claimed in any one of claims 1 to 3, further comprising, prior to performing the first reaction: The (9H-xanthen-9-one-3-oxymethyl) resin is subjected to a first swelling treatment with a first solvent.
  7. 7. The method of claim 6, wherein the first swelling treatment is performed for 15 min to 30 min.
  8. 8. A Sieber resin prepared by the method of any one of claims 1 to 7.
  9. 9. The Sieber resin of claim 8, wherein at least one of the following conditions is satisfied: (1) The swelling degree of the Sieber resin in N, N-dimethylformamide is 4.0 mL/g-7.0 mL/g; (2) The sufficient swelling time of the Sieber resin in N, N-dimethylformamide is 2-6 h; (3) The swelling degree of the Sieber resin in methylene dichloride is 4.5 mL/g-8.0 mL/g; (4) The sufficient swelling time of the Sieber resin in dichloromethane is 2-6 h; (5) The substitution degree of the Sieber resin is 0.2 mmol/g-1 mmol/g.
  10. 10. Use of the Sieber resin of claim 8 or 9 as a carrier in solid phase synthesis of polypeptides.

Description

Sieber resin and preparation method and application thereof Technical Field The application relates to the technical field of polypeptide solid-phase synthesis, in particular to Sieber resin and a preparation method and application thereof. Background Polypeptide Solid phase synthesis (Solid-PHASE PEPTIDE SYNTHESIS, SPPS) is a high-efficiency polypeptide synthesis technology, which sequentially connects amino acids to a Solid phase carrier, and gradually constructs a target polypeptide chain through repeated deprotection and coupling reactions. SPPS simplifies the complicated purification steps in the traditional liquid phase synthesis, remarkably improves the synthesis efficiency and the product purity, and becomes a key means in polypeptide research and drug development. In SPPS, the choice of resin solid phase carrier directly affects the synthesis efficiency, product purity and yield. Although the conventional Rink amide resin is widely used for synthesizing peptide amide, the reaction efficiency is easily reduced due to steric hindrance problem in the case of high-load synthesis and the like. Sieber resin has smaller steric hindrance due to side chain functional groups, is favorable for reducing racemization side reaction in synthesis, can be cracked under mild acidic conditions, does not influence the activity of polypeptide, has higher reaction efficiency and product purity, and has obvious advantages in the production of polypeptide medicines. However, the conventional Sieber resin synthesis method is generally cumbersome in steps, low in efficiency, and requires reduction with lithium borohydride or sodium borohydride. Such materials are prone to severe reactions in humid air and release hydrogen, with the risk of burning and explosion, increasing safety risks and management costs. Disclosure of Invention Based on the above, the main purpose of the application is to provide a preparation method of Sieber resin, which simplifies the reaction steps, improves the synthesis efficiency and improves the process safety. In a first aspect of the application, a preparation method of Sieber resin is provided, which comprises the following steps of carrying out a first reaction of (9H-xanthene-9-ketone-3-oxymethyl) resin and fluorenylmethoxycarbonyl amide in a first solvent under the catalysis of a first catalyst to prepare Sieber resin, wherein the structural formula of the (9H-xanthene-9-ketone-3-oxymethyl) resin is shown as follows: Wherein P is a polymer resin, and the first catalyst comprises an alkali metal triacetoxyborohydride and acetic acid, wherein the triacetoxyborohydride has a general formula of M [ BH (OAc) 3 ], and M is selected from Li, na, K, rb, cs. In some embodiments, the (9H-xanthen-9-one-3-oxymethyl) resin is prepared by subjecting chloromethyl resin and 3-hydroxy-9H-xanthen-9-one to a second reaction in a second solvent under the catalysis of a second catalyst to prepare the (9H-xanthen-9-one-3-oxymethyl) resin, wherein the structural formula of the chloromethyl resin is as follows:。 In some embodiments, the preparation method meets at least one of the following conditions (1) the second catalyst is selected from at least one of tert-butyl sodium alkoxide, sodium methoxide and sodium ethoxide, (2) the second solvent is selected from at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1, 4-dioxane, (3) the particle size of chloromethyl resin is 100-200 meshes, (4) the temperature of the second reaction is 60-100 ℃, and (5) the time of the second reaction is 12-24 h. In some embodiments, P is selected from one of a polystyrene-divinylbenzene copolymer resin, a polyethylene-ethylene glycol-grafted polystyrene resin, and a diethylene glycol dimethacrylate crosslinked polystyrene resin. In some embodiments, the preparation method meets at least one of (1) a mass ratio of sodium triacetoxyborohydride to acetic acid of (5-15) 1, (2) a mass of the first catalyst of 0.2-2 times that of (9H-xanthen-9-one-3-oxymethyl) resin, (3) a mass of the fluorenylmethoxycarbonyl amide of 0.5-1.5 times that of (9H-xanthen-9-one-3-oxymethyl) resin, and (4) at least one of the first solvent selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1, 4-dioxane, wherein the temperature of the first reaction is 30-45 ℃ and the time of the first reaction is 16-24H. In some embodiments, the swelling treatment of the (9H-xanthen-9-one-3-oxymethyl) resin with a first solvent is also included before the first reaction. In some embodiments, the first swelling treatment is for 15 min to 30 min. In a second aspect of the present application, there is provided a Sieber resin prepared by the preparation method provided in the first aspect. In some embodiments, the Sieber resin satisfies at least one of (1) a degree of swelling of the Sieber resin in N, N-dimethylformamide of 4.0 mL/g to 7.0 mL/g, (2) a sufficient degree of swelling