WO2024022483A1 - Intermédiaire pharmaceutique bifonctionnel, son procédé de préparation et son utilisation - Google Patents

Intermédiaire pharmaceutique bifonctionnel, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024022483A1
WO2024022483A1 PCT/CN2023/109822 CN2023109822W WO2024022483A1 WO 2024022483 A1 WO2024022483 A1 WO 2024022483A1 CN 2023109822 W CN2023109822 W CN 2023109822W WO 2024022483 A1 WO2024022483 A1 WO 2024022483A1
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formula
compound
halogens
optionally substituted
reaction
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PCT/CN2023/109822
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Youzhi Tong
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Suzhou Kintor Pharmaceuticals, Inc.
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Publication of WO2024022483A1 publication Critical patent/WO2024022483A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention belongs to the technical field of pharmaceutical synthesis and relates to a bifunctional pharmaceutical intermediate and its preparation method and use.
  • the androgen receptor belongs to the family of nuclear hormone receptors activated by androgens; AR is responsible for the development of male sex characteristics and is also a well-documented oncogene in certain cancers, such as prostate cancer.
  • AR antagonists have been approved and marketed, such as Enzalutamide and Abatacept, which have been successfully used in the treatment of castration-resistant prostate cancer and have become the main treatment for prostate cancer.
  • Enzalutamide and Abatacept which have been successfully used in the treatment of castration-resistant prostate cancer and have become the main treatment for prostate cancer.
  • most patients develop drug resistance after 0.5 to 2 years of treatment, which leads to further progression of the disease.
  • PROTAC PROteolysis TArgeting Chimera
  • PROTAC is a bifunctional compound containing two different ligands in its structure: one is a ubiquitin ligase E3 ligand and the other is a target protein-binding ligand, and the two ligands are connected by a linker.
  • PROTAC forms the target protein-PROTAC-E3 ternary complex, and then the E3 ubiquitin ligase marks the target protein with the ubiquitinated protein tag, which then initiates the powerful ubiquitination-proteasome system in the cell to specifically degradation of the target protein.
  • PROTAC can inhibit the signaling pathways of the corresponding proteins (Cell Biochem Funct. 2019, 37, 21-30) .
  • PROTAC has unique advantages: 1) PROTAC does not need to bind to the target proteins for a long period of time and with high intensity, and the degradation of the target proteins is similar to a catalytic reaction, which can circulate the binding and degradation of target proteins, thus reducing the systemic exposure to the drug and reducing the incidence of toxic side effects; 2) the target proteins need to be resynthesized after being degraded in order to regain their functions, thus degradation of target protein shows more efficient and long-lasting anti-tumor effect than inhibition of its activity, without the development of drug resistance due to the mutation of the target protein.
  • CN202110246427 discloses a novel bifunctional compound to achieve androgen receptor degradation or inhibition; it also discloses a preparation method for the bifunctional compound (for example, Example A46) , wherein Intermediates 46-9 and Intermediates 46-11 are prepared as shown below:
  • TMSCN trimethylsilyl cyanide
  • the purpose of the invention is to provide an intermediate for bifunctional drugs and a preparation method thereof, and for use in the preparation of bifunctional drugs (especially for use in the preparation of compounds of formula (C) -1) , in order to solve the defects of the prior art in which the raw material is highly toxic, the nature of the intermediate is unstable, the reaction yield is low, and it is unsuitable for scaled-up production.
  • the present invention provides a compound of formula (A) or a pharmaceutically acceptable salt thereof:
  • a is an integer selected from 1 to 6;
  • b is an integer selected from 0 to 6, preferably 1 to 3;
  • each c is independently selected from an integer of 1 to 6;
  • a is 1, b is 1 and c is 4;
  • R 1 , R 2 are each independently selected from C1-C6 alkyl
  • R 1 , R 2 are selected from C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, and more preferably any of methyl, ethyl, isobutyl, or tert-butyl; further preferably, R 1 is tert-butyl and R 2 is methyl.
  • a is 1, b is 1, c is 4, R 1 is tert-butyl, and R 2 is methyl; That is, the compound of formula (A) is structured as
  • the present invention provides a preparation method for a compound of formula (A) (method 1) , method 1 which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (II) by substitution reaction to obtain a compound of formula (A) ;
  • R 1 , R 2 , a, b, and c are as defined in the first aspect
  • X is Cl, Br or I, preferably Cl or Br, more preferably Br.
  • a is 1
  • b is 1
  • c is 4
  • R 1 is tert-butyl
  • R 2 is methyl
  • X is Br.
  • the substitution reaction is carried out in the presence of an organic alkali; further, the organic alkali is an alkali metal alkoxide or a nitrogenous organic alkali; wherein: the alkali metal alkoxide is sodium tert-butanol, potassium tert-butanol, etc., and the nitrogenous organic alkali is a high boiling nitrogenous organic alkali, and the high boiling nitrogenous organic alkali is any one or more of N, N-diisopropylethylamine (DIPEA) , N, N-diisopropylethylaniline, 4-dimethyl aminopyridine (DMAP) , dimethylpyridine, imidazole, triethylamine or pyridine.
  • DIPEA N-diisopropylethylamine
  • DMAP 4-dimethyl aminopyridine
  • the substitution reaction is carried out in the presence of a high boiling point nitrogenous organic alkali, either solvent free or in the presence of an organic solvent, and it is further preferred that the reaction is taken solvent free.
  • the solvent free reaction means that only the compound of formula (I) or its pharmaceutically acceptable salt, the compound of formula (II) and nitrogenous organic base are added, and no additional solvent is added.
  • TLC thin layer chromatography
  • the reason for the formation of products in the pyridine system may be that pyridine itself is a nitrogen-containing organic base with a high boiling point.
  • the reaction temperature of the substitution reaction is 80-135°C, preferably 90-110°C, further preferably 90-100°C.
  • the experimental results during the applicant's preliminary research and development process showed that under the solvent free system, too low a temperature will lead to incomplete reaction of formula (I) and low conversion rate; however, if the temperature is higher than 135°C or above, the impurities will increase significantly, and the reaction temperature is a key control index for the reaction of the present invention.
  • the molar ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the compound of formula (II) in the substitution reaction is 1: (1-6) ; further preferably 1: (2-5) , for example 1: 2, 1: 3, 1: 4, 1: 5.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof reacts with a compound of formula (II) by a substitution reaction.
  • X is Br
  • R 1 is tert-butyl
  • R 2 is methyl
  • the substitution reaction being carried out in the presence of a high boiling nitrogenous organic alkali.
  • the present invention provides a preparation method for a compound of formula (A) (method 2) , method 2 which comprises a substitution reaction of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a compound of formula (III) in the presence of an organic solvent to obtain a compound of formula (IV) or a pharmaceutically acceptable salt thereof, and esterification reaction with R 2 OH to obtain the compound of formula (A) ;
  • R 1 , R 2 , a, b, and c are as defined in the first aspect
  • X is Cl, Br or I, preferably Cl or Br, more preferably Br.
  • the substitution reaction is carried out in the presence of an alkali; further, the alkali is an alkali metal alkyd, an alkali metal carbonate, an alkali metal hydroxide or a nitrogenous organic alkali, wherein: the alkali metal alkyd comprises sodium methanol, sodium ethanol, sodium tert-butanol, potassium tert-butanol, etc.; the alkali metal carbonate is sodium carbonate, potassium carbonate, cesium carbonate or lithium carbonate; the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; the nitrogenous organic alkali includes triethylamine, N, N-diisopropylethylamine (DIPEA) , 4-dimethylaminopyridine (DMAP) , etc.; the alkali is preferably a nitrogenous organic alkali such as triethylamine.
  • DIPEA N-diisopropylethylamine
  • the organic solvent is a chain or cyclic C1-C6 aliphatic alcohol (for example methanol, ethanol, isopropanol, tert-butanol) , an aromatic hydrocarbon (for example benzene, toluene, dimethylbenzene) , preferably isopropanol.
  • a chain or cyclic C1-C6 aliphatic alcohol for example methanol, ethanol, isopropanol, tert-butanol
  • an aromatic hydrocarbon for example benzene, toluene, dimethylbenzene
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof reacts with a compound of formula (III) by a substitution reaction.
  • X is Br.
  • the substitution reaction is carried out in the presence of a nitrogenous organic alkali to obtain a compound of formula (IV) or a pharmaceutically acceptable salt thereof.
  • the molar ratio of the compound of formula (III) to the compound of formula (I) or pharmaceutically acceptable salt thereof is (1.1-2.0) : 1, for example 1.1: 1, 1.35: 1, 1.5: 1, 1.8: 1.
  • the molar ratio of the nitrogenous organic alkali to the compound of formula (I) is (1-6) : 1, for example 1.5: 1, 2: 1, 3: 1, 4: 1, 5: 1.
  • the esterification reaction is carried out in the presence of a catalyst
  • the catalyst may be selected from a chlorinated reagent, an alkylating reagent or an inorganic acid;
  • the chlorinated reagent is a reagent such as SOCl 2 , POCl 3 , PCl 5 or COCl 2 ;
  • the alkylating reagent is a reagent such as methyl iodide, dimethyl sulfate or dimethyl carbonate;
  • the inorganic acid is sulfuric acid, phosphoric acid or hydrochloric acid.
  • the person having ordinary skill in the art may select the most suitable catalyst in combination with the reaction rate and product yield.
  • the present invention provides a preparation method for a compound of formula (A) (method 3) , method 3 which comprises a Jocic reaction of a compound of formula (I) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof to obtain a compound of formula (IV) or a pharmaceutically acceptable salt thereof. Then the compound of formula (A) was obtained by esterification reaction with R 2 OH;
  • R 1 , R 2 , a, b, and c are as defined in the first aspect; n is 0, 0.5 or 1.
  • the Jocic reaction is carried out in the presence of a solvent and an alkali, and at the end of the reaction, an acid is employed for post-treatment;
  • the solvent may be any one or more of a non-protonic solvent or a protonic solvent, wherein: the non-protonic solvent comprises a chained or cyclic C1-C6 aliphatic ketone (for example acetone, butanone) , a chained or cyclic C1-C6 aliphatic ether (for example tetrahydrofuran, dimethyl ether) etc.;
  • the protonic solvent comprises chained or cyclic C1-C6 aliphatic alcohols (for example methanol, ethanol, isopropanol, tert-butanol) ;
  • the solvent preferably any one or more of acetone, tetrahydrofuran, tert-butanol;
  • the alkali may be an alkali metal hydroxide; and the acid
  • the esterification reaction is carried out in the presence of a catalyst, and the catalyst being selectable with reference to the type of catalyst in the esterification reaction in method 2.
  • the present invention provides a preparation method for a compound of formula (VI) (Method A) .
  • Method A which comprises a compound of formula (A) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (B-1) and a thio source reagent in an organic solvent to obtain a compound of formula (VI) by a one-pot reaction;
  • R 1 , R 2 , a, b, and c are as defined in the first aspect
  • Z 1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted with one or more halogens and C1-C4 alkoxy optionally substituted with one or more halogens; preferably C1-C4 alkyl optionally substituted with one or more halogens; more preferably CF 3 ;
  • Z 2 is selected from halogen, hydroxyl, cyano and C1-C4 alkoxy optionally substituted with one or more halogens; preferably halogen; more preferably F.
  • a is 1
  • b is 1
  • c is 4
  • R 1 is tert-butyl
  • R 2 is methyl
  • Z 1 is CF 3
  • Z 2 is F.
  • the thio source reagent is selected from:
  • the thio source reagent is selected from:
  • the compound of formula (VI) reacts in an organic solvent and under acidic conditions by a hydrolysis reaction to obtain a compound of formula (VII) ; further preferably, the compound of formula (VI) is obtained by the one-pot reaction without post-treatment, and an acid is directly added to carry out the hydrolysis reaction to obtain a compound of formula (VII) .
  • the organic solvent is an alkyl acid ester, a straight or branched alkyl ether, a cyclic ether, an aryl ether, a halogenated hydrocarbon, an aryl hydrocarbon, a halogenated aromatic hydrocarbon, an alkyl ketone, a straight or branched C2-C6 nitrile, a sulfoxide solvent, or an amide in the form of a chain or a cyclic amide;
  • the alkyl acid ester is ethyl acetate, isopropyl acetate or n-propyl acetate;
  • the cyclic ether is 1, 4-dioxane, tetrahydrofuran or 2-methyltetrahydrofuran;
  • the aryl ether is anisole;
  • the chlorinated hydrocarbon is dichloromethane
  • the organic solvent is a chlorinated hydrocarbon, a cyclic ether, a straight or branched chain C2-C6 nitrile or an aromatic hydrocarbon.
  • the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, toluene or 1, 4-dioxane.
  • the molar ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof, the compound of formula (B-1) and the thio source reagent is 1: (1-5) : (1-5) ; further preferably 1: (1-3) : (2-4) .
  • the compound of formula (A) or a pharmaceutically acceptable salt thereof, compound of formula (B-1) and the thio source reagent are added simultaneously to the organic solvent for stirring and reaction; or the compound of formula (A) or a pharmaceutically acceptable salt thereof and the compound of formula (B-1) are first added to the organic solvent for stirring, and then the thio source reagent is added in batches for reaction; or the compound of formula (A) or a pharmaceutically acceptable salt thereof and a thio source reagent are first added to the organic solvent with stirring, and then the compound of formula (B-1) is added in batches for reaction.
  • the reaction temperature is from 0°C to below the boiling point, preferably from 20°C to below the boiling point, for example, 20-100°C, 30-90°C, 40-80°C or 50-70°C, 70-80°C, 35-40°C, and a person having ordinary skill in the art can determine a suitable reaction temperature in conjunction with the rate of the reaction and the specific reaction solvent.
  • the acid for the hydrolysis reaction is an inorganic acid or an organic acid
  • the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid etc.
  • the organic acid is sulfonic acid, formic acid, trifluoroacetic acid etc.; preferably hydrochloric acid.
  • the compound of formula (A) (R 1 is tert-butyl, R 2 is methyl, a is 1, b is 1, c is 4) or a pharmaceutically acceptable salt thereof reacts with 4-amino-3-fluoro-2-trifluoromethylbenzonitrile, and in the presence of halogenated hydrocarbons to obtain the compound of formula (VI) (R 1 is tert-butyl, Z 1 is CF 3 , Z 2 is F, a is 1, b is 1, c is 4) , and then acid hydrolysis reaction is carried out at 70-80°C to obtain the compound of formula (VII) (Z 1 is CF 3 , Z 2 is F, a is 1, b is 1, c is 4) .
  • the present invention provides a preparation method for a compound of formula (VI) (method B) .
  • the method B which comprises a compound of formula (A) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (B-2) by a ring closure reaction in an organic solvent to obtain a compound of formula (VI) ;
  • R 1 , R 2 , a, b, and c are as defined in the first aspect; Z 1 and Z 2 are as defined in the fifth aspect.
  • a is 1
  • b is 1
  • c is 4
  • R 1 is tert-butyl
  • R 2 is methyl
  • Z 1 is CF 3
  • Z 2 is F.
  • the compound of formula (VI) reacts by a hydrolysis reaction in an organic solvent and under acidic conditions to obtain a compound of formula (VII) ; Further preferably, without post-treatment, the compound of Formula (VI) is obtained by the ring closing reaction, and the compound of formula (VII) is obtained by direct addition of acid to the hydrolysis reaction.
  • the ring closure reaction and/or hydrolysis reaction is carried out in the presence of an organic solvent; further, the organic solvent may be one or more of an ether solvent, an amide solvent, a sulfoxide solvent, an ester solvent; the ether solvent is a reagent such as ethyl ether, methyl tert-butyl ether, 1, 4-dioxane, 2-methyltetrahydrofuran, anisole etc.; the amide solvent is N, N-dimethylformamide, N, N-dimethylacetamide, N-ethylformamide and other reagents; the sulfoxide solvent is dimethyl sulfoxide, diethyl sulfoxide, n-propyl sulfoxide and other reagents; the ester solvent is ethyl acetate, propyl acetate, isopropyl acetate and other reagents.
  • the organic solvent may be one or more of an ether solvent, an amide solvent
  • the organic solvent may be selected from one or more of 1, 4-dioxane, N, N-dimethylformamide (DMF) , dimethylsulfoxide (DMSO) , more preferably from one or more of 1, 4-dioxane, DMF.
  • DMF N, N-dimethylformamide
  • DMSO dimethylsulfoxide
  • the reaction temperature of the ring closure reaction is 15-70°C, more preferably 30-60°C, further preferably 35-40°C.
  • the acid for the hydrolysis reaction is an inorganic acid or an organic acid;
  • the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid etc.;
  • the organic acid is sulfonic acid, formic acid, trifluoroacetic acid etc.; preferably hydrochloric acid.
  • the compound of formula (A) or a pharmaceutically acceptable salt thereof reacts by a ring closure reaction with the compound of formula (B-2) in the presence of 1,4-dioxane and/or DMF to obtain the compound of formula (VI) . And then followed by an acidic hydrolysis reaction at 60-80°C to obtain the compound of formula (VII) , wherein R 1 is tert-butyl, R 2 is methyl, Z 1 is CF 3 , Z 2 is F, a is 1, b is 1, and c is 4; further, the molar ratio of the compound of formula (A) or pharmaceutically acceptable salt thereof to the compound of formula (B-2) is 1: (1.0-5.0) ; preferably 1: (1.5-3.0) .
  • the present invention provides a preparation method for a compound of formula (VII) which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (II) by substitution reaction to obtain a compound of formula (A) ; a compound of formula (A) reacts with a compound of formula (B-2) by a ring closing reaction in an organic solvent to obtain a compound of formula (VI) ; and the compound of formula (VI) reacts in the presence of organic solvents and in an acidic condition by a hydrolysis reaction to obtain a compound of formula (VII) ;
  • R 1 , R 2 , a, b, and c are as defined in the first aspect;
  • Z 1 and Z 2 are as defined in the fifth aspect;
  • X is Cl, Br or I, preferably Cl or Br, more preferably Br;
  • a is 1
  • b is 1
  • c is 4
  • R 1 is tert-butyl
  • R 2 is methyl
  • Z 1 is CF 3
  • Z 2 is F.
  • substitution reaction is carried out according to the preparation method described in the second aspect;
  • the ring closure reaction and hydrolysis reaction are carried out according to the preparation method described in the sixth aspect.
  • the present invention provides the use of compounds of formula (A) for the preparation of compounds of formula (VII) or for use as impurity controls and/or reference standards for the analysis of compounds of formula (VII) ;
  • the present invention provides a preparation method for a bifunctional compound of formula (C) which comprises a condensation reaction of a compound of formula (VII) or a pharmaceutically acceptable salt thereof with a compound of formula (VIII) or a pharmaceutically acceptable salt thereof in the presence of an alkali, an organic solvent, an amide condensing agent, at low temperature, to obtain a compound of formula (C) .
  • a, b, and c are as defined in the first aspect;
  • Z 1 and Z 2 are as defined in the fifth aspect;
  • a is 1
  • b is 1
  • c is 4
  • Z 1 is CF 3 and Z 2 is F.
  • ULM is a hydroxycerebroside E3 ubiquitin ligase binding portion (CLM) or a VHLE3 ligase binding portion (VLM) .
  • the CLM is a
  • the VLM is as defined in paragraphs [0167] - [0295] of the specification CN113387930A, with the following exemplary structure:
  • the VLM is a VLM
  • the alkali is an organic alkali; further, the organic alkali is an alkali metal alkyd or a nitrogenous organic alkali, wherein: the alkali metal alkyd is sodium tert-butanol, potassium tert-butanol, etc., and the nitrogenous organic alkali is N, N-diisopropylethylamine (DIPEA) , N, N-diisopropylethylaniline, 4-dimethylaminopyridine (DMAP) , dimethylpyridine, imidazole, triethylamine, etc.; preferably the nitrogenous organic alkalis such as N, N-diisopropylethylamine.
  • DIPEA N-diisopropylethylamine
  • DMAP 4-dimethylaminopyridine
  • the nitrogenous organic alkalis such as N, N-diisopropylethylamine.
  • the organic solvent is an amide, a chlorinated hydrocarbon or a mixture thereof;
  • the amide solvent is a reagent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-ethylformamide etc.;
  • the chlorinated hydrocarbon is a reagent such as methylene chloride, ethylene chloride, chloroform etc..
  • the amide condenser is one or two or more of carbonyldiimidazole (CDI) , dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) , 1- (-3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) , 2- (7-azobenzotriazolyl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) , benzotriazolyl-N, N, .
  • CDI carbonyldiimidazole
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1- (-3-dimethylaminopropyl) -3-ethylcarbodiimide
  • N', N'-tetramethylurea hexafluorophosphate HBTU
  • 6-chlorobenzotriazole-1, 1, 3, 3-tetramethylurea hexafluorophosphate HCTU
  • O-benzotriazole-N, N, N', N'-tetramethylurea tetrafluoroborate TBTU
  • 6-chlorobenzotriazole-1, 1, 3, 3-tetramethylurea tetrafluoroborate TCTU
  • 2-succinimidyl -1, 1, 3, 3-tetramethyluronium tetrafluoroborate TSTU
  • 2- (5-norbornene-2, 3-dicarboximido) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate quaternary TNTU
  • the condensation reaction is carried out at low temperature means that the condensation reaction is carried out at -40°C to 10°C; further preferably, the reaction is carried out at -30°C to 10°C, and even more preferably, at -30°C to -10°C.
  • the charging sequence of the condensation reaction is as follows: to the system of compound of formula (VII) or pharmaceutically acceptable salt thereof and organic solvent, an amide condenser, an alkali is added for stirring, then compound of formula (VIII) or pharmaceutically acceptable salt thereof is added, and the reaction is carried out.
  • the compound of formula (VII) or a pharmaceutically acceptable salt thereof reacts with the compound of formula (VIII) or a pharmaceutically acceptable salt thereof by a condensation reaction to prepare a compound of formula (C) , wherein Z 1 is CF 3 , Z 2 is F, a is 1, b is 1, and c is 4.
  • the ratio of the molar ratio of the compound of formula (VII) or a pharmaceutically acceptable salt thereof to the compound of formula (VIII) or a pharmaceutically acceptable salt is 1.0: (1.0-2.0) , such as 1.0: 1.2, 1.0: 1.5, 1.0: 1.6.
  • the compound of formula (VII) is prepared by the method A or method B.
  • the compound of formula (A) in the Method A or Method B is prepared by either of the Methods 1 to 3.
  • the compound of formula (A) is prepared by the method 1.
  • the present invention provides the use of compounds of formula (VII) for the preparation of compounds of formula (C) or for use as impurity controls and/or reference standards for the analysis of compounds of formula (C) ;
  • a, b, and c are as defined in the first aspect; Z 1 and Z 2 are as defined in the fifth aspect; and ULM is as defined in the ninth aspect.
  • a is 1
  • b is 1
  • c is 4
  • Z 1 is CF 3
  • Z 2 is F
  • ULM is
  • a post-processing step can be taken to further separate and/or purify the product, and the reaction solution can be extracted and concentrated;
  • the separated products are crystallized, pulped, activated carbon/silica gel decolorization, impurity adsorption, filtration assistance and other unit operations;
  • the organic solvent is used to dissolve the product by heating and cool the crystallization; Or use good solvent to dissolve, and then add bad solvent for crystallization; Or use solvent in the case of insoluble products, stirring for a certain time after filtration; Or a salt-forming operation can be used for purification.
  • the present invention has the following excellent effects:
  • the invention provides a bifunctional pharmaceutical intermediate, the compound of formula (A) , which can be used to prepare bifunctional pharmaceutical as shown in Formula (C) , and solves the defects of unstable intermediates and low yield in the existing production process; Compared with the preparation method 1n CN202110246427. X, this method eliminates the use of dangerous raw materials such as trimethylsilyl cyanide, and the ring closing reaction and condensation reaction yields are significantly improved, up to 77%and 98%.
  • the present invention for the first time adopts a compound of formula (A) and an isothiocyanate compound of formula (B-2) for ring closure and hydrolysis to obtain a compound of formula (VII) with a yield of 77.4%, which is a significant increase in the yield of the present invention compared to CN202110246427. X (with a yield of 38%) .
  • the compound of formula (VII) is prepared by the method of the present invention, the compound of formula (A) can also be used as a key organic impurity for quality control analysis.
  • the present invention for the first time uses a compound of formula (A) with a compound of formula (B-1) and a thio source reagent to prepare an intermediate compound of formula (VI) of a bifunctional drug by a one-pot reaction.
  • the method does not need to prepare isothiocyanate, and overcome the defects of poor stability of isothiocyanate and disadvantages of preservation and transportation. At the same time, it greatly shortens the production period and reduces the production cost.
  • RRT refers to the ratio of the corrected retention time of a component to the corrected retention time of the corresponding reference standard sample, and in the present invention refers to the ratio of the retention time of an impurity in a condensation reaction to the retention time of a compound of formula (C) -1 (Z 1 is CF 3 , Z 2 is F, a is 1, b is 1, c is 4) .
  • a “good solvent” in the present invention refers to a solvent having good solubility for a substance, and vice versa for a “bad solvent” for the substance.
  • HPLC assay conditions used for assay or purity analysis in the examples are as follows:
  • Method 1 A compound of formula (I) -1 and a compound of formula (II) -1 (X is Br, R 2 is methyl) were used as raw materials, and a substitution reaction was carried out to prepare a compound of formula (A) -1
  • formula (I) -1 compound (12.0 g, 32 mmol) , DIPEA (16.8 g, about 4 eq) and methyl 2-bromoisobutyrate (24.0 g, about 4 eq) were added to the reaction bottle, and the temperature was raised to 95-100 °C under stirring for 48-56 hours. HPLC monitored the reaction control results (area normalization method) until the compound of formula (I) -1 ⁇ 5.0%, the end of the reaction.
  • Post-treatment The temperature of the system was controlled at 0-10 °C, and the mixture was poured into the solution of ethyl acetate and water under stirring, and then for standing and phase separation.
  • the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with saturated brine, and 2 times the volume of n-heptane was added, stirred, and then for standing and phase separation, and the lower layer was black oil.
  • the separated lower layer was dissolved by adding ethyl acetate, then 2 times the volume of n-heptane was added and stirred, and then for standing and phase separation.
  • Method 2 A compound of formula (I) -1 reacted with a compound of formula (III) -1 (X was Br) by substitution reaction to obtain a compound of formula (IV) -1; a compound of formula (IV) -1 reacted with CH 3 OH by esterification reaction to obtain a compound of formula (A) -1
  • the pH was adjusted to 5 by adding (2M) HCl aqueous solution, and 100 mL of water was added, extracted with ethyl acetate (100 mL*4) , washed with saturated sodium chloride (300 mL*3) , dried with anhydrous sodium sulfate, pumped and filtered, and the ethyl acetate was removed by rotary evaporation.
  • Silica gel mixing was added, and column chromatography was carried out to obtain 0.7 g of the compound of formula (IV) -1 in a yield of 26.0%.
  • the compound of formula (A) -1 (R is methyl) can be prepared by the esterification reaction of the compound of formula (IV) -1 with methanol; the person having ordinary skill in the art is familiar with the fact that the esterification reaction is carried out in the presence of a catalyst, and the catalyst can be selected from among the well-known catalysts by experimentation in order to obtain suitable yields and rates; for example, the catalyst can be selected from a chlorination reagent, an alkylation reagent or an inorganic acid; the chlorination reagent can be a reagent such as SOCI 2 , POCl 3 , PCl 5 or COCl 2 ; the alkylation reagent can be a reagent such as methyl iodide, dimethyl sulphate or dimethyl carbonate; and the inorganic acid can be sulfuric acid, phosphoric acid or hydrochloric acid.
  • the catalyst can be selected from a chlorination reagent, an alkylation reagent or an inorganic acid
  • Method 1 The compound of formula (A) or a pharmaceutically acceptable salt thereof, the compound of formula (B-1) , and a thio source reagent in an organic solvent to obtain the compound of formula (VI) by the one-pot reaction, and then hydrolyzed under acidic conditions to obtain the compound of formula (VII)
  • the product was added to DCM, washed with 40 mL of 0.5N HCl, neutralized with NaHCO 3 , and washed with saturated salt water.
  • the organic phase was concentrated to obtain 11.2 g of an oily product with an HPLC purity of 79.9%.
  • the weight of the product exceeded the theoretical value, and the product contained an incompletely reacted compound of formula (A) -1, and a compound of formula (B-1) -1.
  • the compound of formula (VI) -1 (500 mg, 72.8 mmol) , DCM (5 ml) , 6N hydrochloric acid were added to the reaction bottle, and the temperature was raised to 75°C ⁇ 80°C and the reaction was stirred.
  • the results of the reaction were monitored by HPLC (area normalization method) statistically (using the HPLC test method 2) , and the compound of formula (VII) -1 was 61.2% (retention time of 12.22 min) , and the compound of formula (VI) -1 was 0.49% (retention time 27.81 min) without post-processing.
  • Method 2 A compound of formula (A) or pharmaceutically acceptable salt thereof reacted with a compound of formula (B-2) by ring closing reaction, and then hydrolyzed under an acidic condition to obtain compound of formula (VII)
  • the applicant also investigated the effect of adding the compounds of formula (B-2) -1 on the reaction.
  • the method of adding the compounds of formula (B-2) -1 was adopted, the TLC test results showed that the results were consistent with the above one-time adding reaction.
  • Step 2 A compound of formula (VII) and a compound of formula (VIII) were in the presence of solvent and HATU by a condensation reaction to obtain a bifunctional compound formula (C)
  • the compound of formula (VII) -1 (45.00 g, 0.071 mol) , DCM (450 mL, 10 mL of DCM for each gram of raw material) was added to a four-necked glass vial. The internal temperature was lowered to ⁇ -25°C. The HATU (40.7 g, about 1.5 eq) was added with stirring and DIPEA (27.6 g, about 3.0 eq) was added dropwise, and the reaction was stirred for about 1 hour.
  • the Compounds of formula (VIII) -1 (40.00g, about 1.2eq) were added in batches, added and stirred for 1-3 h, and the reaction was shown to be over by liquid chromatography. Water was added, stirring and for phase separation.

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Abstract

L'invention appartient au domaine technique de la synthèse pharmaceutique et concerne un intermédiaire pharmaceutique bifonctionnel, son procédé de préparation et son utilisation. L'invention concerne un composé de formule (A) et une variété de procédés de préparation de celui-ci, ainsi que l'utilisation du composé de formule (A) pour préparer des médicaments bifonctionnels, permettant de résoudre les défauts du procédé de production existant tels qu'une toxicité élevée de matières premières, des intermédiaires instables et un faible rendement. Les médicaments bifonctionnels préparés ont une faible teneur en impuretés et satisfont aux exigences de qualité de médicaments. Le procédé de préparation selon l'invention peut également réaliser une production à l'échelle industrielle.
PCT/CN2023/109822 2022-07-28 2023-07-28 Intermédiaire pharmaceutique bifonctionnel, son procédé de préparation et son utilisation WO2024022483A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103608333A (zh) * 2011-03-10 2014-02-26 苏州开拓药业有限公司 雄激素受体拮抗剂及其用途
CN103910679A (zh) * 2014-04-23 2014-07-09 杭州新博思生物医药有限公司 一种恩杂鲁胺的制备方法
CN113387930A (zh) * 2020-03-11 2021-09-14 苏州开拓药业股份有限公司 一种双官能化合物及其制备方法和用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103608333A (zh) * 2011-03-10 2014-02-26 苏州开拓药业有限公司 雄激素受体拮抗剂及其用途
CN103910679A (zh) * 2014-04-23 2014-07-09 杭州新博思生物医药有限公司 一种恩杂鲁胺的制备方法
CN113387930A (zh) * 2020-03-11 2021-09-14 苏州开拓药业股份有限公司 一种双官能化合物及其制备方法和用途

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