WO2018210336A1 - Procédé de préparation de glyx-13 et composant intermédiaire de celui-ci - Google Patents

Procédé de préparation de glyx-13 et composant intermédiaire de celui-ci Download PDF

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Publication number
WO2018210336A1
WO2018210336A1 PCT/CN2018/087487 CN2018087487W WO2018210336A1 WO 2018210336 A1 WO2018210336 A1 WO 2018210336A1 CN 2018087487 W CN2018087487 W CN 2018087487W WO 2018210336 A1 WO2018210336 A1 WO 2018210336A1
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Prior art keywords
compound
group
formula
organic solvent
dichloromethane
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PCT/CN2018/087487
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English (en)
Chinese (zh)
Inventor
刘经建
张亮仁
张桂森
王国海
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江苏恩华药业股份有限公司
北京大学
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Publication of WO2018210336A1 publication Critical patent/WO2018210336A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of pharmaceutical compounds, and the present invention relates to a method for preparing GLYX-13 and an intermediate compound thereof.
  • Rapastinel is a novel antidepressant drug candidate developed by Naurex, a small biotechnology company in the United States. It is a tetrapeptide derivative whose structure is shown below. The drug is a partial agonist of the N-methyl-D-aspartate receptor glycine site. Due to its rapid onset of antidepressant effects in the early stage of development, the company has obtained fast-track approval from the US FDA and is now in clinical phase III research.
  • a synthesis process of GLYX-13 is disclosed in CN104109189A. As shown in the following synthetic scheme, the method of this patent application uses Fmoc-O-tert-butyl-L-threonine, Fmoc-valine and valine methyl ester hydrochloride as starting materials, using chlorine. Isobutyl formate is a condensation reagent, and GLYX-13 is synthesized through a primary hydrolysis reaction of a carboxylic acid, a tertiary peptide condensation reaction, and a five-step deprotection reaction in a total of nine steps.
  • a process for the preparation of GLYX-13 which comprises the steps of: removing a compound of formula VII (also referred to as intermediate VII) by an action of a deprotecting agent in an organic solvent. Fmoc (fluorenylmethoxycarbonyl) protecting group, thereby producing GLYX-13.
  • the deprotecting agent is selected from t-butylamine (TBA) and one or two thiol (C 8 -SH) of n-octyl.
  • the organic solvent is one or more selected from the group consisting of methanol, ethanol, dichloromethane, DMSO (dimethyl sulfoxide), and DMF (N,N-dimethylformamide). And preferably dichloromethane.
  • the compound of formula VII is prepared by a process comprising the steps of:
  • Step 1) in aprotic polar organic solvent, in a presence of a condensing agent, a base, a compound of formula III (also referred to as intermediate III) is subjected to a condensation reaction with a compound of formula V to prepare a compound of formula VI (also known as intermediate VI);
  • Step 2 The compound of formula VII is prepared by removing the tert-butyl protecting group from the compound of formula VI in an organic solvent under the action of a deprotecting reagent.
  • the aprotic organic solvent used in the step 1) is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, DMF, and Preferably, it is DMF;
  • the condensing agent used is selected from the group consisting of EDCI (1-ethyl-(3-dimethylaminopropyl) carbonyl diimide hydrochloride), p-toluenesulfonyl chloride, cyanuric chloride, and methylene chloride.
  • NMM N-methylmorpholine
  • N-methylimidazole N,N- One or more of diisopropylethylamine
  • imidazole imidazole
  • imidazole imidazole
  • the deprotecting agent used in the step 2) is selected from the group consisting of 85% aqueous phosphoric acid (the mass of phosphoric acid is 85% by mass of the total solution), sodium iodide/ One or more of antimony trichloride or zinc bromide, and preferably zinc bromide; and the organic solvent used therein is one of dichloromethane, methanol, ethyl acetate, methyl acetate, ethyl formatekind or several, and preferably ethyl acetate.
  • the compound of formula III is prepared by a process comprising the steps of: removing a compound of formula II (also referred to as intermediate II) under conditions of a deprotecting reagent and an organic solvent. Fmoc protecting group.
  • the reaction for removing the Fmoc protecting group can be carried out at room temperature.
  • the deprotecting agent used in the method is selected from one or more of diethylamine, aluminum trichloride, dimethyl sulfoxide (DMSO), and t-butylamine (TBA) / n-octyl mercaptan (C 8 -SH). And preferably TBA/n-octyl mercaptan; and the organic solvent used therein is methanol, ethanol, toluene and TBA, preferably TBA.
  • the molar ratio of the compound of the above formula II to t-butylamine is selected from the group consisting of 1:1 to 1:3, preferably 1:1, 1:1.5, 1:2, more preferably 1:1.5;
  • the molar ratio of the compound of formula II to n-octyl mercaptan is selected from 1:1 to 1:5, preferably 1:1.5, 1:2, 1:2.5, 1:3, more preferably 1:2.5.
  • the compound of formula V (also referred to as intermediate V) is prepared by a process comprising the steps of:
  • Step 1) in an organic solvent, in the presence of a condensing agent or a base, Fmoc-O-tert-butyl-L-threonine and L-valine benzyl ester hydrochloride are condensed to form an intermediate Body IV;
  • Step 2 in an organic solvent, using palladium on carbon as a catalyst and in the presence of a hydrogen donor, the intermediate IV is highly selectively deprotected from the benzyl ester protecting group to prepare a compound of formula V.
  • the condensation reagent used in the step 1) is selected from one of EDCI, p-toluenesulfonyl chloride, cyanuric chloride and pivaloyl chloride or a plurality of, and preferably pivaloyl chloride; wherein the base used is selected from one of N-methylmorpholine, triethylamine, N-methylimidazole, N,N-diisopropylethylamine and imidazole or a plurality of, and preferably imidazole; wherein the organic solvent used is one or more selected from the group consisting of tetrahydrofuran, acetonitrile, N,N-dimethylformamide (DMF) and dichloromethane, and preferably tetrahydrofuran and/or Methyl chloride.
  • the base used is selected from one of N-methylmorpholine, triethylamine, N-methylimidazole, N,N-diisopropylethy
  • the hydrogen donor used in step 2) is selected from the group consisting of formic acid, amine formate, hydrogen and triethylsilane (Et 3 SiH), and preferably It is triethylsilane; and the organic solvent used therein is one or more selected from the group consisting of methanol, ethanol, tetrahydrofuran, and ethyl acetate; and preferably ethanol.
  • the compound of formula II (also referred to as intermediate II) is prepared by a process comprising the steps of:
  • Step 1) under the palladium carbon catalysis, N-benzyloxycarbonyl-L-threonamide is hydrogenated to remove the protective benzyloxycarbonyl group (Cbz) in an organic solvent to obtain a compound of the formula I;
  • Step 2 A compound of formula II is formed by subjecting Fmoc-L-proline to a compound of formula I (also referred to as intermediate I) under condensing agent conditions in an organic solvent.
  • the organic solvent in step 1) are selected from C 1 ⁇ C 5 alcohols, preferably methanol, ethanol.
  • the organic solvent used in the step 2) is selected from one or more of tetrahydrofuran, acetonitrile, dichloromethane or DMF, and preferably a solvent.
  • Is DMF the condensing agent used is selected from the group consisting of isobutyl chloroformate (IBCF), EDCI (1-ethyl-(3-dimethylaminopropyl) carbonyl diimide hydrochloride), p-toluenesulfonyl chloride, One or more of cyanuric chloride and pivaloyl chloride, and preferably isobutyl chloroformate (IBCF).
  • IBCF isobutyl chloroformate
  • EDCI 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide hydrochloride
  • p-toluenesulfonyl chloride One or more of cyanuric chloride and pivaloyl chloride,
  • the method for producing GLYX-13 according to the present invention can be, for example, as shown in the following synthetic route map:
  • GLYX-13 can be produced on an industrial scale in a high yield by an easy-to-follow and economical synthesis step in eight steps.
  • the invention provides a method for preparing GLYX-13 and its key intermediates which is easy to control on a safe and industrial scale, and can be prepared by a simple process operation in a good yield and at a low cost without expensive use. Peptide condensation reagents and deprotecting agents that are susceptible to manufacturing or corrosive.
  • the compound of the formula VII can directly obtain GLYX-13 by the de-Fmoc reaction, thereby avoiding potential problems such as cumbersome operation and reduced yield due to re-dissociation after salt formation.
  • the condensation reagent for example, pivaloyl chloride used in the preparation of the intermediate IV and the intermediate VI is inexpensive, and no by-products are formed in the reaction, and the yield is high.
  • N-Cbz-L-threonamide (2 mol, 504 g), palladium carbon (50.4 g) and anhydrous methanol 3000 mL were added to a 5 L autoclave, and N-Cbz-L-threonamide was dissolved by mechanical stirring.
  • the reaction kettle was purged with hydrogen gas and maintained at a pressure of 1 MPa, and reacted at room temperature for 12 hours.
  • the palladium carbon was removed by filtration, and the filtrate was evaporated on a rotary evaporator to afford crude crude oil.
  • N-Fmoc-proline (1.5 mol, 505 g) was added to a 3 L four-necked flask, and 1500 mL of anhydrous DMF was added under a nitrogen stream, dissolved by mechanical stirring, and N-methylmorpholine (152 g) was added.
  • the bottom of the reaction flask was placed in a low temperature reactor, isobutyl chloroformate (205 g) was slowly added dropwise and the temperature of the reaction solution was maintained below -15 ° C.
  • the intermediate I (243 g) was added as a solid, followed by slow N-methylmorpholine (152 g) was added dropwise, and the reaction solution was gradually returned to room temperature after the dropwise addition.
  • reaction liquid was transferred to a plastic drum and purified water (9 L) was added thereto, and 1500 mL of ethyl acetate was added dropwise thereto under mechanical stirring, and a white solid was precipitated, suction filtered and dried in vacuo to yield 585 g of white solid. 89.2%.
  • N-Fmoc-proline (1.5 mol, 505 g) was added to a 3 L four-necked flask, and 3 L of anhydrous tetrahydrofuran was added under a nitrogen stream, dissolved by mechanical stirring, and N-methylmorpholine (152 g) was added.
  • the bottom of the reaction flask was placed in a low temperature reactor, isobutyl chloroformate (205 g) was slowly added dropwise and the temperature of the reaction solution was maintained below -15 ° C.
  • the intermediate I (243 g) was added as a solid, followed by slow N-methylmorpholine (152 g) was added dropwise, and the reaction solution was gradually returned to room temperature after the dropwise addition.
  • reaction liquid was transferred to a plastic drum and purified water (9 L) was added thereto, and 1500 mL of ethyl acetate was added dropwise thereto under mechanical stirring, and a white solid was precipitated, suction filtered and dried in vacuo to yield 585 g of white solid. 89.2%.
  • N-Fmoc-O-tert-butyl-L-threonine (1 mol, 397 g) was added to a 5 L four-necked flask, and 1 L of anhydrous tetrahydrofuran was added under a nitrogen stream, dissolved by mechanical stirring and 68 g of imidazole was added.
  • the reaction flask was placed in a low temperature reactor, 120.5 g of pivaloyl chloride was slowly added dropwise and the temperature of the reaction solution was maintained below -15 ° C, and 245 g of L-valine benzyl ester hydrochloride and 68 g of imidazole were dissolved in 2 L of dichloromethane.
  • the obtained solution was slowly dropped into a four-necked flask and the temperature of the reaction solution was maintained below -15 ° C. After the completion of the dropwise addition, the reaction solution was gradually returned to room temperature.
  • the reaction mixture was suction filtered to remove some of the by-products, and the solvent was evaporated to give a pale yellow oil.
  • the oil was dissolved in ethyl acetate and transferred to a 5 L separatory funnel, using dilute hydrochloric acid and saturated. The organic phase was washed with sodium hydrogencarbonate, and then evaporated, evaporated, evaporated
  • the obtained crude product was dissolved in absolute ethanol, transferred to a 3 L four-necked flask, and palladium carbon was added thereto, and an appropriate amount of triethylsilane was slowly added dropwise under a nitrogen stream, and the temperature of the reaction solution was maintained below 10 using an ice water bath. °C, the reaction was continued for about 2 hours after the addition was completed.
  • reaction solution was transferred to a 5 L beaker, and purified water (about 5 times volume) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate. , used directly in the next reaction.
  • the obtained crude product was dissolved in ethyl acetate, and 562.5 g of zinc bromide was added, and the reaction was stirred at room temperature for 12 h. After the completion of the reaction, purified water was added and stirred for 1 hour, and the white solid was gradually precipitated by standing, suction filtered and dried in vacuo to yield 228 g of white solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de GLYX-13 et d'un composé intermédiaire de celui-ci. Selon le procédé de l'invention, Fmoc-O-tert-butyl-L-thréonine, Fmoc-L-proline, N-carboxybenzyl-L-thréonine amide et le chlorhydrate de proline ester benzylique sont utilisés en tant que matières premières; grâce à huit étapes synthétiques faciles à mettre en oeuvre et économiques, le GLYX-13 peut être préparé à l'échelle commerciale, avec un rendement élevé, sans utiliser d'agent de condensation peptidique coûteux ou tout précurseur contrôlé ou agent de déprotection agressif.
PCT/CN2018/087487 2017-05-18 2018-05-18 Procédé de préparation de glyx-13 et composant intermédiaire de celui-ci WO2018210336A1 (fr)

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Application Number Priority Date Filing Date Title
CN201710355328.9 2017-05-18
CN201710355328.9A CN107474107B (zh) 2017-05-18 2017-05-18 Glyx-13的制备方法及用于制备glyx-13的化合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107474107B (zh) * 2017-05-18 2023-01-17 江苏恩华药业股份有限公司 Glyx-13的制备方法及用于制备glyx-13的化合物
CN108276414B (zh) * 2018-01-26 2019-07-23 齐鲁天和惠世制药有限公司 一种枸橼酸托法替尼的制备方法
CN108864252B (zh) * 2018-07-24 2020-07-28 中国人民解放军军事科学院军事医学研究院 制备nrx-1074的方法
CN110878119B (zh) * 2018-09-06 2021-05-07 深圳翰宇药业股份有限公司 一种阿巴帕肽的固相合成方法
CN113557028A (zh) * 2019-01-11 2021-10-26 诺雷克斯股份有限公司 雷帕替奈的盐和晶型

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013063120A2 (fr) * 2011-10-24 2013-05-02 Northwestern University Modulateurs des récepteurs nmda et utilisations de ceux-ci
CN104109189A (zh) * 2013-04-18 2014-10-22 中国人民解放军军事医学科学院毒物药物研究所 Thr-Pro-Pro-Thr四肽的液相合成方法
WO2016014982A1 (fr) * 2014-07-24 2016-01-28 Naurex, Inc. Modulateurs du récepteur de n-méthyl-d-aspartate et leurs procédés d'élaboration et d'utilisation
CN107474107A (zh) * 2017-05-18 2017-12-15 江苏恩华药业股份有限公司 Glyx‑13的制备方法及用于制备glyx‑13的化合物

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CN104098650B (zh) * 2013-04-15 2019-04-09 中国医学科学院药物研究所 阿托西班的中间体的合成与应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013063120A2 (fr) * 2011-10-24 2013-05-02 Northwestern University Modulateurs des récepteurs nmda et utilisations de ceux-ci
CN104109189A (zh) * 2013-04-18 2014-10-22 中国人民解放军军事医学科学院毒物药物研究所 Thr-Pro-Pro-Thr四肽的液相合成方法
WO2016014982A1 (fr) * 2014-07-24 2016-01-28 Naurex, Inc. Modulateurs du récepteur de n-méthyl-d-aspartate et leurs procédés d'élaboration et d'utilisation
CN107474107A (zh) * 2017-05-18 2017-12-15 江苏恩华药业股份有限公司 Glyx‑13的制备方法及用于制备glyx‑13的化合物

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