WO2021121270A1 - Procédé de purification d'un inhibiteur des sglt et utilisation associée - Google Patents

Procédé de purification d'un inhibiteur des sglt et utilisation associée Download PDF

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Publication number
WO2021121270A1
WO2021121270A1 PCT/CN2020/136812 CN2020136812W WO2021121270A1 WO 2021121270 A1 WO2021121270 A1 WO 2021121270A1 CN 2020136812 W CN2020136812 W CN 2020136812W WO 2021121270 A1 WO2021121270 A1 WO 2021121270A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
diethylamine
preparing
purification method
Prior art date
Application number
PCT/CN2020/136812
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English (en)
Chinese (zh)
Inventor
王元
何训贵
王海边
Original Assignee
上海研健新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海研健新药研发有限公司 filed Critical 上海研健新药研发有限公司
Priority to CN202080009907.8A priority Critical patent/CN113330017B/zh
Publication of WO2021121270A1 publication Critical patent/WO2021121270A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a purification method and application of SGLTs inhibitors.
  • Diabetes is a metabolic disorder, recurrent or persistent hyperglycemia.
  • diet control and exercise therapy are the first choice for blood sugar control.
  • insulin or oral hypoglycemic drugs are needed for treatment.
  • GLUTs glucose-promoting transporters
  • SGLTs sodium-dependent glucose cotransporters
  • members of the SGLTs family with glucose transport function are mainly distributed in the proximal tubules of the intestine and kidney, and it is inferred that they play a key role in the process of intestinal glucose absorption and renal glucose reuptake.
  • an SGLTs inhibitor it is possible to regulate its glucose transport function, on the one hand, it can control the absorption of intestinal glucose, and on the other hand, it can inhibit kidney glucose.
  • the re-intake of diabetics strengthens the excretion of glucose from the urine and exerts a more systematic hypoglycemic effect, thus becoming an ideal medicine for the treatment of diabetes.
  • SGLTs inhibitors have good development prospects. Therefore, there is an urgent need to develop a compound with good efficacy, pharmacokinetic properties and high safety for the treatment of diabetes and related metabolic disorders.
  • An amorphous compound of formula (A) is disclosed in Example 9 of patent application WO2015/032272A1. It contains many impurities and is difficult to remove in subsequent development. Therefore, there is an urgent need to develop a method that can purify the compound of formula (A) for industrial production, and prepare qualified APIs to meet the needs of clinical research and the production of marketed pharmaceutical preparations.
  • the purpose of the present invention is to provide a purification method for SGLTs inhibitors, so as to meet the needs of clinical research and the production of marketed pharmaceutical preparations.
  • the first aspect of the present invention provides a method for purifying a compound of formula (A), which comprises the following steps:
  • Step 1) The compound of formula (A) is reacted to produce the compound of formula (B);
  • Step 2) The compound of formula (B) is hydrolyzed to produce the compound of formula (A), and the reaction route is as follows:
  • step 1) of the purification method the compound of formula (A) is reacted with p-nitrobenzoic acid or its derivative to produce the compound of formula (B).
  • the p-nitrobenzoic acid derivative is p-nitrobenzoyl chloride, p-nitrobenzoyl chloride or p-nitrobenzoic anhydride.
  • step 1) of the purification method the molar ratio of the compound of formula (A) to p-nitrobenzoic acid is 1.0: (1.0-6.0).
  • step 1) of the purification method the molar ratio of the compound of formula (A) to p-nitrobenzoic acid is 1.0: (3.0-4.0).
  • step 1) of the purification method the molar ratio of the compound of formula (A) to p-nitrobenzoic acid is 1.0:4.0.
  • step 1) and/or step 2) of the purification method the organic layer is washed with sodium bicarbonate during the treatment after the reaction is completed.
  • adding sodium bicarbonate solution to wash can remove the excess or generated p-nitrobenzoic acid or its derivatives as much as possible.
  • step 1) of the purification method the product of formula (B) is obtained and then purified with acetonitrile, isopropanol, dichloromethane or a mixture thereof.
  • step 1) of the purification method the product of formula (B) is obtained and then purified with acetonitrile and/or isopropanol.
  • step 1) of the purification method the product of the compound of formula (B) is obtained and then purified with dichloromethane.
  • the second aspect of the present invention provides an intermediate compound of formula (B) in the method for purifying the compound of formula (A), the structure is as follows:
  • the third aspect of the present invention provides a method for preparing a compound of formula (I), which comprises the following steps:
  • Step 1) Contacting the compound of formula (A) prepared by the aforementioned purification method with diethylamine;
  • Step 2) Add seed crystals and/or anti-solvent until the solution appears turbid or a combination, and continue to crystallize;
  • the diethylamine described in step 1) in the method for preparing the compound of formula (I) is pure liquid diethylamine, an aqueous solution of diethylamine or a mixed liquid of diethylamine and an organic solvent.
  • step 1) of the method for preparing the compound of formula (I) the compound of formula (A) is dissolved in diethylamine or the compound of formula (A) is dissolved in an organic solvent, and then the two Ethylamine.
  • the anti-solvent is selected from water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, and cyclopentane. Alkane, ether and mixtures thereof.
  • the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, and dioxane.
  • step 3) after solid-liquid separation further includes the step of further drying to obtain the compound of formula (I), and the drying process specifically includes drying at room temperature. Then, the temperature is controlled at 30-60°C and dried, preferably at 35-45°C.
  • the present invention has the following technical advantages:
  • the present invention is an industrialized purification method that solves the problem of drug accessibility.
  • the present invention adopts simple raw materials or reagents, mild reaction conditions and strong operability.
  • the present invention develops a key intermediate compound of formula (B), which has stable physical and chemical properties and is not easily degraded.
  • step 1) of the purification method can increase the purity of the compound of formula (B), thereby increasing the purity of the compound of formula (I) and improving the appearance of the product.
  • the inventor of the present application developed a purification method for the SGLTs inhibitor of the compound structure of formula (A) for the first time.
  • p-nitrobenzoic acid or its derivatives are used to react the compound of formula (A), and the compound of formula (A) with high purity is obtained after post-treatment.
  • diethylamine amine solvate (compound of formula (I)), which can be widely used in the treatment or delay of diabetes and diabetic retina Disease, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, Diabetes complications, atherosclerosis or hypertension and other diseases are expected to be developed into a new generation of SGLTs inhibitors. On this basis, the present invention has been completed.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR).
  • NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
  • ppm parts per million
  • NMR was measured with Bruker BioSpin Gmbh 600 nuclear magnetic resonance instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ) and deuterated acetone ((CD 3 ) 2 CO), and the internal standard was tetramethylsilane ( TMS).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications used by TLC are 0.15mm ⁇ 0.20mm.
  • the starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de purification d'un inhibiteur des SGLT et une utilisation associée. L'inhibiteur des SGLT est (1S,2S,3S,4R,5S)-5-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)méthyl)-4- éthyl phényl)-1-(hydroxyméthyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol. L'acide nitrobenzoïque ou un dérivé de celui-ci est utilisé pour réagir avec un composé de formule (A), puis est hydrolysé pour obtenir un composé de pureté élevée. L'invention concerne en outre la réaction du composé purifié pour obtenir un solvate d'amine de diéthylamine, et le solvate est prévu pour être développé en une nouvelle génération d'inhibiteur des SGLT.
PCT/CN2020/136812 2019-12-19 2020-12-16 Procédé de purification d'un inhibiteur des sglt et utilisation associée WO2021121270A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080009907.8A CN113330017B (zh) 2019-12-19 2020-12-16 一种SGLTs抑制剂的纯化方法及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911323674 2019-12-19
CN201911323674.4 2019-12-19

Publications (1)

Publication Number Publication Date
WO2021121270A1 true WO2021121270A1 (fr) 2021-06-24

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PCT/CN2020/136812 WO2021121270A1 (fr) 2019-12-19 2020-12-16 Procédé de purification d'un inhibiteur des sglt et utilisation associée

Country Status (2)

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CN (1) CN113330017B (fr)
WO (1) WO2021121270A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102149717A (zh) * 2008-08-28 2011-08-10 辉瑞大药厂 二氧杂-双环[3.2.1]辛烷-2,3,4-三醇衍生物
CN102372722A (zh) * 2010-08-10 2012-03-14 江苏恒瑞医药股份有限公司 C-芳基葡萄糖苷衍生物、其制备方法及其在医药上的应用
CN103748090A (zh) * 2011-04-14 2014-04-23 诺瓦提斯公司 糖苷衍生物及其用于治疗糖尿病的用途
WO2015032272A1 (fr) * 2013-09-09 2015-03-12 江苏豪森药业股份有限公司 Dérivé de glucoside de type c-aryle, son procédé de préparation, et ses applications médicales
CN108239123A (zh) * 2016-12-27 2018-07-03 广东东阳光药业有限公司 吡喃葡萄糖基衍生物的共晶、制备方法和应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016173425A1 (fr) * 2015-04-30 2016-11-03 Sunshine Lake Pharma Co., Ltd. Dérivé de glucopyranosyle, son procédé de préparation et ses utilisations
CN109988161A (zh) * 2017-12-29 2019-07-09 徐州万邦金桥制药有限公司 一种适合工业化生产恩格列净的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
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CN102149717A (zh) * 2008-08-28 2011-08-10 辉瑞大药厂 二氧杂-双环[3.2.1]辛烷-2,3,4-三醇衍生物
CN102372722A (zh) * 2010-08-10 2012-03-14 江苏恒瑞医药股份有限公司 C-芳基葡萄糖苷衍生物、其制备方法及其在医药上的应用
CN103748090A (zh) * 2011-04-14 2014-04-23 诺瓦提斯公司 糖苷衍生物及其用于治疗糖尿病的用途
WO2015032272A1 (fr) * 2013-09-09 2015-03-12 江苏豪森药业股份有限公司 Dérivé de glucoside de type c-aryle, son procédé de préparation, et ses applications médicales
CN108239123A (zh) * 2016-12-27 2018-07-03 广东东阳光药业有限公司 吡喃葡萄糖基衍生物的共晶、制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MASCITTI V, MAURER T S, ROBINSON R P, BIAN J, BOUSTANY-KARI C M, BRANDT T, COLLMAN B M, KALGUTKAR A S, KLENOTIC M K, LEININGER M T: "Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 54, no. 8, 28 April 2011 (2011-04-28), pages 2952 - 2960, XP002758834, ISSN: 0022-2623, DOI: 10.1021/jm200049r *

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CN113330017B (zh) 2023-01-31

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