CN114591302B - Compounds and methods for preparing compounds - Google Patents

Compounds and methods for preparing compounds Download PDF

Info

Publication number
CN114591302B
CN114591302B CN202210500289.8A CN202210500289A CN114591302B CN 114591302 B CN114591302 B CN 114591302B CN 202210500289 A CN202210500289 A CN 202210500289A CN 114591302 B CN114591302 B CN 114591302B
Authority
CN
China
Prior art keywords
methyl
formula
compound
acid
mmol
Prior art date
Legal status (The legal status 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 status listed.)
Active
Application number
CN202210500289.8A
Other languages
Chinese (zh)
Other versions
CN114591302A (en
Inventor
魏伟业
杨建楠
吴小涛
赵涛涛
王浩
李超
曲蕾
王斌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Gritpharma Co ltd
Beijing Grand Johamu Pharmaceutical Co Ltd
Original Assignee
Nanjing Gritpharma Co ltd
Beijing Grand Johamu Pharmaceutical Co Ltd
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 Nanjing Gritpharma Co ltd, Beijing Grand Johamu Pharmaceutical Co Ltd filed Critical Nanjing Gritpharma Co ltd
Priority to CN202210500289.8A priority Critical patent/CN114591302B/en
Publication of CN114591302A publication Critical patent/CN114591302A/en
Priority to US17/900,071 priority patent/US11840526B2/en
Application granted granted Critical
Publication of CN114591302B publication Critical patent/CN114591302B/en
Priority to US18/463,112 priority patent/US20240083884A1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a preparation method of a compound of formula (I) or a salt thereof，
Figure 312725DEST_PATH_IMAGE001
Formula (I) wherein R 1 、R 2 X and n are as defined herein; and a compound of formula (I) in high purity. The preparation method can obtain the target product with high yield and high purity.

Description

Compound and preparation method of compound
Technical Field
The present invention relates to a process for the preparation of inclusion compounds, in particular to a process for the preparation of high purity compounds.
Background
Coronaviruses belong to the phylogenetic genus coronaviruses (Coronavirus), which are positive-strand RNA viruses with an envelope. Coronaviruses are becoming a research hotspot in the field of virology due to the outbreaks of Severe Acute Respiratory Syndrome (SARS) in 2003 and Middle East Respiratory Syndrome (MERS) in 2012. The novel coronavirus pneumonia (Corona Virus Disease 2019) is a new acute respiratory infectious Disease, is caused by SARS-CoV-2 (also called 2019-nCoV), and has outbreak at the end of 12 months in 2019, so that more than 2 hundred million people in the world are infected and more than 400 million people die, and the coronavirus pneumonia becomes a global important public health event at present and also has a great influence on the global social economy.
2019 novel coronavirus (2019-nCoV) is a novel strain of coronavirus that has not previously been found in humans. At present, aiming at novel coronavirus infection, clinically supportive treatment is mainly performed, and no specific antiviral medicine is available. In view of the severe situation of epidemic situation, there is an urgent need for effective treatment.
Disclosure of Invention
The prior art (Yuto Unoh et al, "Discovery of S-217622, a Noncovent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical code for Treating CODV-19",J. Med. Chem.2022) discloses that the candidate compound S-217622 may be used in the treatment of COVID-19. However, the inventors found that the yield (25%) in step d of the production method of the compound S-217622 was low, and it was not suitable for industrial mass production.
In addition to the above problems of the prior art, the present inventors have found, after repeated experiments, that the purity of the target product of step d disclosed in the above document is about 86%, and pharmaceutical requirements cannot be satisfied.
Based on the above, the present invention provides a technical solution to the above-mentioned problems.
In a first aspect of the invention, there is provided a process for the preparation of a compound of formula (I) or a salt thereof,
Figure DEST_PATH_IMAGE001
formula (I)
Wherein
R 1 And R 2 Each independently is C 1 -C 6 An alkyl group;
x is halogen;
n is 1 to 5;
the method is characterized by comprising the following steps:
(a) Reacting a compound of formula (II)
Figure 141145DEST_PATH_IMAGE002
Formula (II)
Wherein the content of the first and second substances,
r' is C 1 -C 6 An alkyl group;
R 2 x and n are as defined in formula (I);
with compounds of the formula (III)
Figure DEST_PATH_IMAGE003
Formula (III)
Wherein the content of the first and second substances,
R 1 and X is as defined for formula (I);
in the presence of a cosolvent to obtain the compound of the formula (I).
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula (I) or a salt thereof,
Figure 992426DEST_PATH_IMAGE004
formula (I)
Wherein
R 1 And R 2 Each independently is C 1 -C 6 An alkyl group;
x is halogen;
n is 1 to 5;
the method is characterized by comprising the following steps:
(a') reacting a compound of formula (II)
Figure DEST_PATH_IMAGE005
Formula (II)
Wherein the content of the first and second substances,
r' is C 1 -C 6 An alkyl group;
R 2 x and n are as defined in formula (I);
with compounds of the formula (III)
Figure 641844DEST_PATH_IMAGE006
Formula (III)
Wherein the content of the first and second substances,
R 1 and X is as defined for formula (I);
in the presence of a base which is added in portions, to give the compound of the formula (I).
In a third aspect of the invention, there is provided a high purity compound of formula (I), wherein the purity of the compound of formula (I) is 90.0% or more.
In a fourth aspect of the invention, there is provided the use of a compound of formula (I) prepared by a process as described herein or a highly pure compound of formula (I) as described herein, in the manufacture of a medicament for the treatment of a disease caused by a coronavirus in a subject.
Compared with the prior art, the preparation method can obtain the target product, namely the compound shown in the formula (I), with high yield and high purity. The high-purity target compound of the formula (I) has good fluidity and anti-caking property, and is beneficial to the development requirement of preparations.
Drawings
FIG. 1 is an HPLC chromatogram of the compound prepared in comparative example 1.
FIG. 2 is an HPLC chromatogram of the compound prepared in comparative example 2.
FIG. 3 is an HPLC chromatogram of the compound prepared in example 3.
FIG. 4 is an HPLC chromatogram of the compound prepared in example 8.
FIG. 5 is an HPLC chromatogram of the compound prepared in example 10.
Detailed Description
For the purposes of the present invention, unless otherwise indicated, the terms used herein have the following meanings:
the term "cosolvent" refers to a poorly soluble substance in a solvent with the addition of a third substanceForm soluble intermolecular complex, association, double salt, etc. to increase the solubility of the poorly soluble substance in the solvent. This third material is referred to as a co-solvent. Examples include, but are not limited to, dioxane, C 1 -C 6 Alkyl ketones, C 1 -C 6 Alkyl alcohols, dimethylacetamide, dimethylformamide, acetonitrile, dimethyl sulfoxide and/or N-methylpyrrolidone.
The terms "halogen", "halogen atom" or "halo" denote fluorine, chlorine, bromine and iodine, in particular bromine, chlorine or fluorine, preferably chlorine or fluorine.
The term "C 1 -C 6 Alkyl "means a straight-chain or branched-chain alkyl group having a specifically specified number of carbon atoms (e.g., one, two, three, four, five or six carbon atoms), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl. The term "alkyl" generally denotes, if the number of carbon atoms is not specified, a straight-chain or branched alkyl group having 1 to 9, in particular 1 to 6, preferably 1 to 4 carbon atoms. In particular, the alkyl group has 1,2, 3, 4,5 or 6 carbon atoms ("C) 1 -C 6 Alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl. Preferably, the alkyl group has 1,2 or 3 carbon atoms ("C) 1 -C 3 -an alkyl group "), methyl, ethyl,N-propyl or isopropyl.
The term "C 1 -C 6 Alkyl ketone "means a straight or branched alkyl alcohol containing 1 to 6 carbon atoms, i.e. C with a ketone group (C = O) 1 -C 6 An alkyl group. Examples include, but are not limited to, acetone, methyl isobutyl ketone.
The term "C 1 -C 6 Alkyl alcohol "means a straight or branched chain alkyl alcohol containing 1 to 6 carbon atoms, i.e. C having a hydroxyl group (OH) 1 -C 6 An alkyl group. Examples include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, 2-pentanol, 3-pentanol, n-hexanol, and the like.
The term "C 1 -C 6 Haloalkane "means a halogen-substituted straight or branched chain alkane containing 1 to 6 carbon atoms, i.e. C 1 -C 6 One or more hydrogen atoms in the alkane are replaced by a halogen. Examples include, but are not limited to, those selected from the group consisting of dichloromethane, trichloromethane, carbon tetrachloride, bromoethane, 1, 2-dichloroethane, and the like.
The term "di C 1 -C 6 Alkyl ether "means a straight or branched chain alkyl ether containing from 1 to 6 carbon atoms, i.e. C with an ether group (-O-) 1 -C 6 An alkyl group. Examples include, but are not limited to, methyl ether, ethyl ether, methyl butyl ether, n-propyl ether, isopropyl ether, 1, 2-ethylene oxide, cis-2, 3-butylene oxide, trans-2, 3-butylene oxide, and the like.
The compounds mentioned herein may be present in free form, e.g. as a free base or as a free acid or as a zwitterion, or may be present in the form of a salt. The salts may be any of the salts, organic or inorganic addition salts, in particular any physiologically acceptable organic or inorganic addition salt, commonly used in pharmacy.
For the purposes of the present invention, preferred salts are the physiologically acceptable salts of the compounds mentioned in the present application. However, salts which are not suitable per se for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds described herein are also included.
The term "physiologically acceptable Salts" refers to the relatively non-toxic, inorganic or organic acid addition Salts of the compounds described herein, see, e.g., s.m. Berge et al, "Pharmaceutical Salts", j. Pharm. Sci. 1977, 66, 1-19.
Physiologically acceptable salts of the compounds mentioned herein encompass the acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid, sulfamic acid, phosphoric acid, nitric acid, or salts with organic acids, for example formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, undecanoic acid, dodecanoic acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, diglucosic acid, octylic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, pivalic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, pantothenic acid, mucic acid, succinic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, aspartic acid, succinic acid, fumaric acid, ascorbic acid, fumaric acid, or ascorbic acid. Particularly preferred are the fumarate salts. Examples thereof include all possible salts of the compounds mentioned herein, as single salts or any mixture of said salts in any ratio, such as 3.
The term "subject" refers to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. Specifically, the subject is 0 years or older, 1 year or older, 2 years or older, 4 years or older, 5 years or older, 10 years or older, 12 years or older, 13 years or older, 15 years or older, 16 years or older, 18 years or older, 20 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 55 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, 95 years or older, 100 years or older, or 105 years or older.
The term "Coronavirus" belongs phylogenetically to the family Coronaviridae (Coronaviridae) genus coronaviruses (Coronavirus). One variant of coronavirus is the causative agent of atypical pneumonia. Coronaviruses include, but are not limited to, 2019 novel coronaviruses (2019-nCoV or SARS-CoV-2, causing novel coronavirus pneumonia COVID-19), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (causing severe acute respiratory syndrome), and MERS-CoV (causing middle east respiratory syndrome). The disease caused by coronaviruses is mainly respiratory infection (including severe acute respiratory syndrome, SARS).
The term "novel coronavirus" refers to 2019 novel coronavirus (2019-nCoV) or SARS-CoV-2 (segment acid respiratory syndrome coronavirus 2) published by the International Committee of viral Classification in 2 months 2020. SARS-CoV-2 has the same meaning as 2019-nCoV in the present application, and includes all variants of the new coronavirus 2019, such as all variants included in NCBI or GISAID (Global shared influenza data initiative), especially important variants with strong transmission, pathogenicity or immune evasion, such as WHO-designated Alpha, beta, gamma, delta, eta, iota, kappa or Lambda variants, and important variants designated later.
In a specific embodiment, in the preparation method of the present invention, the compound of formula (II) is synthesized by the following steps:
(ii) Reacting a compound of formula (IV)
Figure DEST_PATH_IMAGE007
Formula (IV)
Wherein, the first and the second end of the pipe are connected with each other,
r', X and n are as defined in formula (II);
with a compound of formula (V) or a salt thereof
Figure 945787DEST_PATH_IMAGE008
Formula (V)
Wherein the content of the first and second substances,
R 2 and X is as defined in formula (II);
reacting to obtain the compound of formula (II).
In one embodiment, the preparation method of the present invention comprises the steps of: reacting a compound of formula (II) with a compound of formula (III) in the presence of a co-solvent, optionally in the presence of a base added in portions, to give a compound of formula (I); alternatively, the preparation method of the invention comprises the following steps: reacting a compound of formula (II) with a compound of formula (III) in the presence of a base added in portions, optionally in the presence of a co-solvent, to give a compound of formula (I). Preferably, the preparation method of the present invention comprises the steps of: reacting a compound of formula (II) with a compound of formula (III) in the presence of a co-solvent and a base added in portions to give a compound of formula (I).
In a particular embodiment, the co-solvent is selected from dioxane, C 1 -C 6 Alkyl ketones, C 1 -C 6 Alkyl alcohol, dimethylacetamide, dimethylformamide, acetonitrile, dimethylsulfoxide, N-methylpyrrolidone or any mixture thereof.
In a specific embodiment, the co-solvent is anhydrous.
In one embodiment, the co-solvent is a mixture of water and another solvent selected from the group consisting of: dioxane, C 1 -C 6 Alkyl ketones, C 1 -C 6 Alkyl alcohol, dimethylacetamide, dimethylformamide, acetonitrile, dimethylsulfoxide, N-methylpyrrolidone or any mixture thereof. Preferably, the mixing ratio of water and other solvents may be any ratio.
In a specific embodiment, in the preparation method of the present invention, the addition in portions is carried out in more than two (e.g., two, three or more) times, and preferably, each addition amount may be the same or different. Preferably, the addition in portions is carried out in more than two additions of the same or different amounts at different time points.
In a particular embodiment, in the preparation process of the invention, step (a) or (a') is carried out in a solvent, for example an organic solvent, which may be chosen from ethyl acetate, methyl formate, di-C 1 -C 6 Alkyl ether, tetrahydrofuran, toluene or a mixture thereof, preferably tetrahydrofuran. Preferably, the volume ratio of co-solvent to solvent is in the range 1.
In one embodiment, in the preparation method of the present invention, the volume of the co-solvent is 5% to 35%, preferably 10% to 30%, more preferably 15% to 25% of the total volume of the reaction system of step (i).
In a particular embodiment, in the preparation process according to the invention, step (a) is carried out in the presence of a catalyst. Preferably, the molar ratio of compound of formula (II) to catalyst is in the range 1 to 1. Preferably, the catalyst is a base, such as Lithium Hexamethyldisilazide (LHMDS), potassium tert-butoxide, or lithium diisopropylamide.
Specifically, in the preparation method of the invention, the base is Lithium Hexamethyldisilazide (LHMDS), potassium tert-butoxide or lithium diisopropylamide. Preferably, the molar ratio of the compound of formula (II) to the base is in the range 1 to 1. Preferably, the base is added dropwise, more optionally, the base is added slowly dropwise.
In a specific embodiment, in the preparation process of the present invention, step (a) or (a') is carried out at a temperature in the range of 0 to 55 ℃; preferably, step (a) or (a') is carried out first at low temperature (0-5 ℃) and subsequently at elevated temperature (e.g. room temperature or higher, such as 20-25 ℃ or higher). Alternatively, it is preferred that step (a) or (a') is carried out at elevated temperature (e.g. 20-30 ℃).
In one particular embodiment, in the preparation process of the invention, the molar ratio of the compound of formula (II) to the compound of formula (III) is in the range from 1 to 1.5, preferably in the range from 1.1 to 1.4, for example 1.
In a particular embodiment, the preparation process of the invention further comprises a purification step. Preferably, the purification step is a column chromatography and/or recrystallization step.
Specifically, column chromatography is performed using C 1 -C 6 Halogenated alkanes and C 1 -C 6 Alkyl alcohol, preferably the mixed solvent is graded, more preferably C 1 -C 6 The volume percentage of the alkyl alcohol in the mixed solvent is 0-20%.
In particular, recrystallization in water and C 1 -C 6 And a mixed solvent of alkyl ketones. Preferably, the volume ratio of the two solvents in the mixed solvent is in the range of 5.
In a specific embodiment, the preparation process of the invention herein further comprises the steps of:
(iii) The compound of formula (I) is salified with an acid.
Preferably, step (iii) is carried out in a solvent (such as ethyl acetate); and/or step (iii) is carried out at room temperature (e.g.20-25 ℃). Preferably, the acid in step (iii) is fumaric acid. For example, in the salt, the ratio of free base to fumaric acid is 3, 2, 1 or 1.
In one embodiment, X is fluoro or chloro; and/or n is 2 to 4, for example 3.
In one embodiment, the compound of formula (I) is
Figure DEST_PATH_IMAGE009
。
In one embodiment, the purity of the compound of formula (I) is 95.0% or more.
In a specific embodiment, the purity is HPLC purity.
In a specific embodiment, the coronavirus is a novel coronavirus.
In a specific embodiment, the subject is a human, e.g., a child, an adult, or an elderly human.
The embodiments or different preferred grades of the embodiments described herein may be combined in any combination, unless otherwise indicated.
The present invention is illustrated below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. The compounds or reagents used in the following examples are commercially available or may be prepared by conventional methods known to those skilled in the art; the laboratory instruments used are commercially available.
Examples
All commercial reagents and solvents were not further purified. The reaction was monitored by thin layer chromatography on a Yangtze friend silica gel plate (HSGF 254) or analytical liquid chromatography/mass spectrometry (LC/MS). The column chromatography is completed by silica gel prepackaged by Dingkang silica gel and a chromatographic column. The purity was determined by HPLC method on Agilent Technologies 1260 Infinity under the following test conditions: and (3) chromatographic column: a C18 column; sample introduction volume: 10. mu.l; fluidity: water + acetonitrile; 95 for 25min → 10; flow rate: 1.0 ml/min; column temperature: 30 ℃; detection wavelength: 254nm.
Preparation examples
Comparative example 1
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]To a solution of-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF, 1.46mL, 1.46 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2.5 h, then at room temperature for 40min. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino as a brown solid]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl)) Methyl radical]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (146.0 mg, yield 38.3%, purity 80.1%).
Comparative example 2
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]To a solution of-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF, 1.46mL, 1.46 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2.5 h, followed by 40min at room temperature. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Dried and concentrated under reduced pressure. The residue was chromatographed on silica gel (CHCl) 3 MeOH gradient, 0-20% MeOH). The solid is treated with acetone/H 2 O (volume ratio 1]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (95.3 mg, yield 25.0%, purity 86.2%).
Example 1
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL), LHMDS (1M in THF, 0.97mL, 0.97 mmol) was added first dropwise at 0 deg.C, stirred for 30min, and then LHMDS (1M in THF, 0.49mL, 0.49 mmol). The reaction mixture was stirred at 0 ℃ for 2.5 h, followed by 40min at room temperature. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino as a yellow solid]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (296.6 mg, yield 77.8%, purity 90.2%).
Example 2
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1-(2,4,To a solution of 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF, 0.49mL, 0.49 mmol) first dropwise at 0 deg.C, stirred for 30min, and then LHMDS (1M in THF, 0.97mL, 0.97 mmol) was added dropwise. The reaction mixture was stirred at 0 ℃ for 2.5 h, followed by 40min at room temperature. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] as a yellow solid]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (299.2 mg, yield 78.5%, purity 90.6%).
Example 3
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL), LHMDS (1M in THF, 0.49mL, 0.49 mmol) was added dropwise first at 0 deg.C, LHMDS (1M in THF, 0.49mL, 0.49 mmol) was added dropwise after stirring for 30 min. The reaction mixture was stirred at 0 ℃ for 2.5 h, followed by 40min at room temperature. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino as a yellow solid]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (301.5 mg, yield 79.1%, purity 91.9%).
Example 4
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) in solution LHMDS (1M in THF, 0.49mL, 0.49 mmol) was added dropwise first at 20-30 deg.C, stirred for 30min and then LHMDS (LHMDS: (6 mL)0.49mL, 0.49 mmol of 1M in THF) and stirring is continued for 30min before LHMDS (0.49 mL, 0.49 mmol of 1M in THF) is added dropwise. The reaction mixture was stirred at 20-30 ℃ for 3.7 h. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] as a yellow solid]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (303.1 mg, yield 79.5%, purity 92.8%).
Example 5
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]To a solution of-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF, 1.46mL, 1.46 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2.5 h, then at room temperature for 40min, and 1.2 mL of isopropanol was added and stirring was continued until the reaction was substantially complete. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino as a yellow solid]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (300.8 mg, yield 78.9%, purity 92.5%).
Example 6
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]To a solution of-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF, 1.46mL, 1.46 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2.5 h, then at room temperature for 40min, and 1.2 mL of acetone was added and stirring was continued until the reaction was substantially complete. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to obtain (6E) -6- [ (6-chloro-2-methyl-2H-indole) as a yellow solidAzol-5-yl) imino]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (287.0 mg, yield 75.3%, purity 91.3%).
Example 7
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL), first potassium tert-butoxide (1M in THF, 0.49mL, 0.49 mmol) was added dropwise at 0 deg.C, stirring 30min, and then potassium tert-butoxide (1M in THF, 0.97mL, 0.97 mmol) was added dropwise. The reaction mixture was stirred at 0 ℃ for 2.5 h, then at room temperature for 40min. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino as a yellow solid]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (292.4 mg, yield 76.7%, purity 90.4%).
Example 8
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL), LHMDS (1M in THF, 0.49mL, 0.49 mmol) was added first dropwise at 0 deg.C, stirred for 30min, and then LHMDS (1M in THF, 0.97mL, 0.97 mmol). The reaction mixture was stirred at 0 ℃ for 2.5 h, then at room temperature for 40min, 1.2 ml of N-methylpyrrolidone was added and stirring was continued until the reaction was substantially complete. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Drying and concentrating under reduced pressure to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino as a yellow solid]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (304.6 mg, yield 79.9%, purity 93.1%).
Example 9
To 6-BThio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL), LHMDS (1M in THF, 0.97mL, 0.97 mmol) was added first dropwise at 0 deg.C, stirred for 30min, and then LHMDS (1M in THF, 0.49mL, 0.49 mmol). The reaction mixture was stirred at 0 ℃ for 2.5 h, then at room temperature for 40min. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Dried and concentrated under reduced pressure. The residue was chromatographed on silica gel (CHCl) 3 MeOH gradient, 0-20% MeOH). The solid is treated with acetone/H 2 O (volume ratio 1]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (244.0 mg, yield 64.0%, purity 96.5%).
Example 10
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) LHMDS (1M in THF, 0.49mL, 0.49 mmol) was added dropwise first at 0 deg.C, LHMDS (1M in THF, 0.49mL, 0.49 mmol) was added dropwise after stirring for 30 min. The reaction mixture was stirred at 0 ℃ for 2.5 h, followed by 40min at room temperature. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Dried and concentrated under reduced pressure. The residue was chromatographed on silica gel (CHCl) 3 MeOH gradient, 0-20% MeOH). The solid is treated with acetone/H 2 O (volume ratio 1]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (253.9 mg, yield 66.6%, purity 97.4%).
Example 11
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]To a solution of-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF, 1.46mL, 1.46 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2.5 h, then at room temperature for 40min, and 1.2 mL of isopropanol was added and stirring was continued until the reaction was substantially complete. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Dried and concentrated under reduced pressure. The residue was chromatographed on silica gel (CHCl) 3 MeOH gradient, 0-20% MeOH). The solid is treated with acetone/H 2 O (volume ratio 1]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (248.2 mg, yield 65.1%, purity 96.9%).
Example 12
To 6-ethylthio-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]To a solution of-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF, 1.46mL, 1.46 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2.5 h, then at room temperature for 40min, and 1.2 mL of acetone was added and stirring was continued until the reaction was substantially complete. To react with NH 4 Aqueous Cl was quenched and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, over MgSO 4 Dried and concentrated under reduced pressure. The residue was chromatographed on silica gel (CHCl) 3 MeOH gradient, 0-20% MeOH). The solid is treated with acetone/H 2 O (volume ratio 1]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione (239.0 mg, yield 62.7%, purity 95.0%).
Effects of the embodiment
Example 13
The inventor finds that (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione with the purity of more than 90.0% can be subjected to a purification step (such as the purification steps disclosed in the prior art) to obtain (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione with the purity of more than 95.0%, wherein the purity of the (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1,3, 5-triazinane-2, 4-dione can have influence on the flowability, anti-caking or agglomeration performance.
Specifically, the inventors carried out a fluidity test of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione with different purities using an intelligent powder comprehensive characteristic tester (Vigortaceae LABULK, model: HMKFlow 6393 PT1000).
The Carl index reflects the quality of the fluidity, and a smaller value indicates better fluidity, while a Carl index of more than 23% generally indicates poor fluidity. Where in resistance to caking, "good" means substantially no agglomeration or clumping, "better" means partial agglomeration or clumping, and "poor" means severe or complete agglomeration. Among them, "good" means good solid state and good fluidity, which is advantageous for formulation development, "good" means general fluidity of a part, and "poor" means poor fluidity, which cannot be used for formulation development.
Figure 283227DEST_PATH_IMAGE010
In the field of pharmacy, poor fluidity mainly affects the uniformity of material mixing, and the material is easy to delaminate and has uneven material content; meanwhile, layering is easy to occur during tabletting and blanking, so that the content of the tablets pressed at different time is inconsistent, and the tablet weight difference is easy to be large. The present inventors have unexpectedly found that, compared to comparative example 1, (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione having a purity of 90.0% or more can not only obtain the compound having a purity of 95.0% or more through a purification step, but also (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione having a purity of 90.0% or more has a good fluidity, and a purity of 95.0% or more can improve the anti-caking property. On the other hand, the (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione having a purity of 90.0% or less had poor flowability and anti-caking properties, and could not satisfy the requirements for the preparation. The (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazinane-2, 4-dione prepared in the embodiments 1 to 12 of the present invention, which has a purity of 90.0% or more, has good fluidity, and has a purity of 95.0% or more, has good anti-caking properties, and can meet the requirements of preparation development.
The above-mentioned embodiments are further described in detail for the purpose of illustrating the invention, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the invention and are not intended to limit the scope of the invention, and any modification, equivalent replacement, improvement, etc. made within the spirit and spirit of the invention should be included in the scope of the invention.

Claims (4)

1. A process for the preparation of a compound of formula (I) or a salt thereof,
Figure 846079DEST_PATH_IMAGE001
formula (I)
Wherein
R 1 And R 2 Each independently is C 1 -C 6 An alkyl group;
x is halogen;
n is 1 to 5;
the method is characterized by comprising the following steps:
(a) Reacting a compound of formula (II)
Figure 119015DEST_PATH_IMAGE002
Formula (II)
Wherein, the first and the second end of the pipe are connected with each other,
r' is C 1 -C 6 An alkyl group;
R 2 x and n are as defined in formula (I);
with compounds of the formula (III)
Figure 584632DEST_PATH_IMAGE003
Formula (III)
Wherein the content of the first and second substances,
R 1 and X is as defined for formula (I);
reacting a compound of formula (II) with a compound of formula (III) in the presence of a solvent, a cosolvent and a base added in portions to give a compound of formula (I); the cosolvent is selected from C 1 -C 6 Alkyl ketones, C 1 -C 6 An alkyl alcohol, acetonitrile, N-methyl pyrrolidone, or any mixture thereof; the base is selected from Lithium Hexamethyldisilazide (LHMDS), potassium tert-butoxide or lithium diisopropylamide; the solvent is tetrahydrofuran, and the volume ratio of the cosolvent to the solvent is in the range of 1;
the structure of the compound of formula (I) is as follows:
Figure 312416DEST_PATH_IMAGE004
。
2. the process according to claim 1, wherein the cosolvent is selected from the group consisting of acetone, N-methylpyrrolidone, and isopropanol
Or any mixture thereof.
3. Preparation process according to any one of claims 1 or 2, characterized in that it further comprises a purification step.
4. The method of claim 3, wherein the purification step is a column chromatography and/or a recrystallization step.
CN202210500289.8A 2022-05-10 2022-05-10 Compounds and methods for preparing compounds Active CN114591302B (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN202210500289.8A CN114591302B (en) 2022-05-10 2022-05-10 Compounds and methods for preparing compounds
US17/900,071 US11840526B2 (en) 2022-05-10 2022-08-31 Compounds and method for preparing the same
US18/463,112 US20240083884A1 (en) 2022-05-10 2023-09-07 Compounds and method for preparing the same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210500289.8A CN114591302B (en) 2022-05-10 2022-05-10 Compounds and methods for preparing compounds

Publications (2)

Publication Number Publication Date
CN114591302A CN114591302A (en) 2022-06-07
CN114591302B true CN114591302B (en) 2022-10-28

Family

ID=81820857

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210500289.8A Active CN114591302B (en) 2022-05-10 2022-05-10 Compounds and methods for preparing compounds

Country Status (1)

Country Link
CN (1) CN114591302B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115626917B (en) * 2022-06-22 2023-03-07 北京远大九和药业有限公司 Crystal forms of compound, and composition and application thereof

Also Published As

Publication number Publication date
CN114591302A (en) 2022-06-07

Similar Documents

Publication Publication Date Title
CN114591303B (en) High purity compounds and methods for purifying or preparing compounds
TWI671310B (en) Methods of preparing substituted nucleoside analogs
CN114591304B (en) Crystal form of compound, preparation method and application thereof
JP2008510840A (en) Purification of Montelukast
CN111233929B (en) Deuterated nucleoside analogue and preparation method and application thereof
JP2010533659A (en) 2'-Fluoro-4'-substituted-nucleoside analogues, methods for their preparation and use
CN114591302B (en) Compounds and methods for preparing compounds
CN106083691B (en) A kind of preparation method of arbidol HCl monohydrate
CN106083773B (en) The preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2-
CN115650959A (en) Process for the preparation or purification of compounds
KR20240093977A (en) Crystalline form of isobutyrate nucleoside compound and method for producing the same
CN106831840B (en) One kind has small molecule compound, preparation method and its medicinal usage of anti-inflammatory activity
WO2010083722A1 (en) A process for one-pot synthesis of corey lactone
US11840526B2 (en) Compounds and method for preparing the same
US20240083884A1 (en) Compounds and method for preparing the same
CN110183446B (en) New moxifloxacin impurity and synthesis method and application thereof
CN104844604B (en) A kind of preparation method of allopurinol sodium
CN106977543A (en) The preparation technology of improved Suo Feibuwei intermediates
CN113637003A (en) Method for preparing 2-amino-6- (piperidine-4-acyl) pyridine derivative
CN111004255A (en) Preparation method of cefcapene lactone compound or hydrochloride thereof
CN111943891B (en) Rosuvastatin calcium impurity and rosuvastatin calcium quality control method
JPS59116298A (en) Preparation of 6,8-substituted-adenosine-3',5'-cyclic phosphoric acid and its salt
CN114751853B (en) Process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane compounds
CN117917241A (en) Use of compounds for the treatment of enterovirus-induced diseases
CN114292240A (en) Preparation method of trelagliptin impurity

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant