WO2018099424A1 - Procédé de préparation d'un dérivé de pyridinone et son intermédiaire - Google Patents

Procédé de préparation d'un dérivé de pyridinone et son intermédiaire Download PDF

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WO2018099424A1
WO2018099424A1 PCT/CN2017/113902 CN2017113902W WO2018099424A1 WO 2018099424 A1 WO2018099424 A1 WO 2018099424A1 CN 2017113902 W CN2017113902 W CN 2017113902W WO 2018099424 A1 WO2018099424 A1 WO 2018099424A1
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compound
formula
group
membered
acid
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PCT/CN2017/113902
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Chinese (zh)
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贾君磊
边林
高晓晖
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江苏恒瑞医药股份有限公司
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Priority to CN201780020531.9A priority Critical patent/CN108884048B/zh
Publication of WO2018099424A1 publication Critical patent/WO2018099424A1/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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

Definitions

  • the present invention relates to a pyridone derivative, a pharmaceutically acceptable salt thereof, a process for preparing the same, an intermediate for the preparation thereof, and a process for the preparation thereof, the pyridone derivative, a pharmaceutically acceptable salt thereof and a drug containing the same
  • Silk/threonine mitogen-activated protein kinases are cells associated with tyrosine kinase receptors (such as EGF receptors) and/or G-protein heterotrimers Factor receptor activation interacts with a variety of intracellular signals evoked by different second messengers, phosphorylating and modulating the activity of various enzymes and transcription factors (eg NF- ⁇ B, Rsk 90, phospholipase A2, c- Myc, CREB, Ets-1, AP-1 and c-jun, etc.).
  • tyrosine kinase receptors such as EGF receptors
  • G-protein heterotrimers Factor receptor activation interacts with a variety of intracellular signals evoked by different second messengers, phosphorylating and modulating the activity of various enzymes and transcription factors (eg NF- ⁇ B, Rsk 90, phospholipase A2, c- Myc, CREB, Ets-1, AP-1 and c-jun, etc.).
  • MEKs also known as MAP kinases (MAPKK or Erk kinase) are bispecific kinases that phosphorylate the silk/threonine residues and tyrosine residues of MAPK (p44 MAPK (Erk1) and p42 MAPK (Erk2) (Erk1)
  • the phosphorylation sites are T202 and Y204, the Erk2 phosphorylation sites are T183 and Y185), and the MEK family contains five genes: MEK1, MEK2, MEK3, MEK4 and MEK5.
  • the N-terminus of MEKs is a negative regulatory region, C-terminal
  • the catalytic domain has the function of binding to Erks and activating Erks. It was found that knocking out the regulatory region of MEK1 leads to inhibition of the intrinsic activity of MEK1 and Erk.
  • sorafenib (Bay 43-9006) was launched in 2006 and is a non-specific silk/threonine and tyrosine kinase inhibitor. Its target includes Raf, MEK, VEGFR2/3, Flt-3, PDGFR, c. -Kit and so on.
  • B-Raf-specific inhibitors such as dabrafenib (GSK2118436) and vemurafenib (PLX4032) showed good clinical outcomes, but the duration was not long. At the same time, clinical studies found that patients who received PLX4032 were most likely to relapse with symptoms.
  • Example 1 and Example 31 of WO2015058589A1 disclose the preparation of compound 31 in a total of eleven steps, the specific reactions are as follows:
  • the method finally obtains the target product by preparative separation, and the yield is 30.3%.
  • the method has more reaction steps, longer reaction time, high temperature reaction (the seventh reaction temperature is 230 ° C), low yield, etc.
  • the problem is not conducive to industrial expansion.
  • the technical problem to be solved by the present invention is to provide a method for preparing a compound of the formula (II) which is completely different from the prior art, and to change the starting materials and intermediates to prepare the target product, by shortening the reaction step, starting materials, etc.
  • the reactants are simple and easy to purchase, the reaction conditions are simple and controllable, the high temperature reaction is avoided, the post-reaction treatment method is simple, and the like, the preparation method is optimized, the yield is improved, and the industry is expanded.
  • the present invention provides a process for the preparation of a compound of the formula (II), which is a process for preparing a compound of the formula (II) from a compound of the formula (6).
  • R 1 is selected from an optionally substituted phenyl or pyridyl group selected from a C 1-6 alkyl group, a halogen, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, C 1-6 Alkylaminocarbonyl, C 1-6 alkylcarbonylamino, 3-14 membered heterocyclyloxy, 3-14 membered cycloalkylaminocarbonyl, 3-14 membered cycloalkylcarbonylamino or C 1-6 alkyl a sulfonylamino group, a 3-14 membered heterocyclic group is preferably a 3-8 membered heterocyclic group, and a 3-14 membered cycloalkyl group is preferably a 3-8 membered cycloalkyl group;
  • the present invention provides a process for the preparation of a compound of the formula (II), which further comprises preparing a compound of the formula (6) from a compound of the formula (5),
  • the present invention provides a process for the preparation of a compound of the formula (II), which further comprises preparing a compound of the formula (4) from a compound of the formula (3),
  • the present invention provides a process for the preparation of a compound of the formula (II), which further comprises preparing a compound of the formula (2) from a compound of the formula (1),
  • the invention further relates to a compound as shown in formula (6),
  • R a , R 1 and R 2 are as defined in the formula (II).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (6), which comprises preparing a compound of the formula (6) from a compound of the formula (5),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (6), which process further comprises preparing a compound of the formula (5) from a compound of the formula (4),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (6), which process further comprises preparing a compound of the formula (4) from a compound of the formula (3),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (6), which process further comprises preparing a compound of the formula (3) from a compound of the formula (2),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (6), which process further comprises preparing a compound of the formula (2) from a compound of the formula (1),
  • the invention further relates to a compound as shown in formula (5),
  • R a , R 1 and R 2 are as defined in the formula (II).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (5), which comprises preparing a compound of the formula (5) from a compound of the formula (4),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (5), which process further comprises preparing a compound of the formula (4) from a compound of the formula (3),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (5), which process further comprises preparing a compound of the formula (3) from a compound of the formula (2),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (5), which process further comprises preparing a compound of the formula (2) from a compound of the formula (1),
  • the invention further relates to a compound as shown in formula (4),
  • R a , R 1 and R 2 are as defined in the formula (II).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (4), which comprises preparing a compound of the formula (4) from a compound of the formula (3),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (4), which process further comprises preparing a compound of the formula (3) from a compound of the formula (2),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (4), which process further comprises preparing a compound of the formula (2) from a compound of the formula (1),
  • the invention further relates to a compound as shown in formula (3),
  • R 1 and R 2 are as defined in formula (II).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (3), which comprises preparing a compound of the formula (3) from a compound of the formula (2),
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (3), which process further comprises preparing a compound of the formula (2) from a compound of the formula (1),
  • the present invention provides a compound of the formula (3-1),
  • the present invention also provides a process for producing a compound of the formula (3-1), which is produced in the same manner as the compound of the formula (3).
  • Another aspect of the invention relates to a process for producing a compound of the formula (6), characterized in that the compound has a structure represented by the following formula (6-1),
  • R a is preferably an F atom
  • R 1 is preferably an optionally substituted phenyl or pyridyl group, and the substituent is selected from a methyl group;
  • R 2 is preferably a hydrogen atom.
  • the present invention also provides a process for producing a compound of the formula (6-1), which is produced in the same manner as the compound of the formula (6).
  • the present invention provides a compound of the formula (6-2),
  • the present invention also provides a process for producing a compound of the formula (6-2), which is produced in the same manner as the compound of the formula (6) or (6-1).
  • Another aspect of the invention relates to a process for producing a compound of the formula (5), characterized in that the compound has a structure represented by the following formula (5-1),
  • R a is preferably an F atom
  • R 1 is preferably an optionally substituted phenyl or pyridyl group, and the substituent is selected from a methyl group;
  • R 2 is preferably a hydrogen atom.
  • the present invention also provides a process for producing a compound of the formula (5-1), which is produced in the same manner as the compound of the formula (5).
  • the present invention provides a compound of the formula (5-2),
  • the present invention also provides a process for producing a compound of the formula (5-2), which is produced in the same manner as the compound of the formula (5) or (5-1).
  • Another aspect of the invention relates to a process for producing a compound of the formula (4), characterized in that the compound has a structure represented by the following formula (4-1),
  • R a R 1, R 2 , as defined in formula (4);
  • R a is preferably an F atom
  • R 2 is preferably a hydrogen atom.
  • the invention also provides a preparation method of the compound represented by the formula (4-1), the method and the compound of the formula (4)
  • the preparation method is the same.
  • the present invention provides a compound of the formula (4-2),
  • the present invention also provides a process for producing a compound of the formula (4-2), which is produced in the same manner as the compound of the formula (4) or (4-1).
  • the invention further relates to a compound as shown in formula (2),
  • the 6-14 membered aryl group is preferably a 6-8 membered aryl group, and the 5-15 membered heteroaryl group is preferably a 5-8 membered heteroaryl group; and R 2 is preferably a hydrogen atom;
  • X is selected from a halogen, preferably a chlorine atom.
  • the present invention provides a compound of the formula (2-1),
  • the invention further relates to a compound as shown in formula (1),
  • R 2 is selected from a hydrogen atom, a halogen or an optionally substituted C 1-6 alkyl group selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-6 alkoxy, 3-14 membered cycloalkane a 3-14 membered heterocyclic group, a 6-14 membered aryl group or a 5-15 membered heteroaryl group, and the 3-14 membered cycloalkyl group is preferably a 3-8 membered cycloalkyl group, and a 3-14 membered heterocyclic group is preferred.
  • the 3-8 membered heterocyclic group, the 6-14 membered aryl group is preferably a 6-8 membered aryl group, and the 5-15 membered heteroaryl group is preferably a 5-8 membered heteroaryl group; and R 2 is preferably a hydrogen atom.
  • the present invention provides a compound of the formula (1-1),
  • Dimethyl malonate and malononitrile are added to an ether organic solvent, reacted with an aqueous solution of methylamine under the action of a base, and a sodium hydroxide solution is added dropwise, filtered, and dried to obtain an intermediate (1-1).
  • the ether organic solvent includes, but is not limited to, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether or tetrahydrofuran, preferably tetrahydrofuran, and the base is selected from 1,8-diaza Ring [5.4.0] undec-7-ene (DBU) or liquid ammonia.
  • an intermediate (2-1) selected from the group consisting of phosphorus oxychloride and N-chloro Succinimide, phosphorus trichloride or phosphorus pentachloride, preferably phosphorus oxychloride.
  • the intermediate (2-1) and 3-hydroxy-6-methylpyridine are added to a polar aprotic organic solvent, and under the protection of an inert gas, the substitution reaction is carried out under the action of a base, water is added, and the solid is precipitated and filtered. After washing, drying, the intermediate (3-1) is obtained.
  • the inert gas is selected from nitrogen or argon.
  • the polar aprotic organic solvent includes but is not limited to dimethyl sulfoxide and 1,4-dioxane.
  • the base is selected from organic or inorganic bases, preferably inorganic bases, including but not limited to sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, carbonic acid Anthraquinone, potassium t-butoxide, sodium t-butoxide, sodium hydroxide or potassium hydroxide, preferably cesium carbonate.
  • the organic phase is concentrated under reduced pressure to give the intermediate (4-2), the inert gas is selected from nitrogen or argon, and the polar aprotic organic solvent includes, but is not limited to, dimethyl sulfoxide, 1 , 4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide, the extraction organic solvent includes but is not limited to ethyl acetate, propyl acetate, isopropyl acetate, Methylene chloride, chloroform or methyl tert-butyl ether, the base is selected from an organic base or an inorganic base, preferably an inorganic base, including but not limited to sodium carbonate, potassium carbonate, sodium hydrogencarbonate, carbonic acid Potassium hydrogen, cesium carbonate, potassium t-butoxide, sodium t-butoxide, sodium hydroxide or potassium hydroxide, preferably cesium carbonate.
  • the inert gas is selected from nitrogen or argon
  • the intermediate (4-2) is subjected to an oxidation reaction under the action of a strong oxidizing agent to remove excess oxidizing agent, and is subjected to crystallization, filtration, and drying to obtain an intermediate (5-2) including but not limited to sulfuric acid and hydrogen peroxide. , potassium permanganate, manganese dioxide, preferably sulfuric acid.
  • the reduction reaction may be selected from the group consisting of iron powder reduction (iron powder mixed with hydrochloric acid, acetic acid or ammonium chloride), Reduction of zinc powder (mixed zinc powder with hydrochloric acid, acetic acid or ammonium chloride), catalytic hydrogenation of metal catalyst (Rannickel, palladium carbon, etc.
  • the compound of formula (6-2) forms a diazo compound under low temperature conditions, an aqueous acid solution and sodium nitrite, and then iodide reacts with potassium iodide. After the reaction is finished, it is filtered, and the filter cake is added to a weakly reducing aqueous solution for beating and filtering.
  • the target product IIA is obtained, wherein the aqueous acid solution is selected from hydrochloric acid or sulfuric acid, preferably hydrochloric acid, the hydrochloric acid comprises dilute hydrochloric acid and concentrated hydrochloric acid, preferably concentrated hydrochloric acid, and the low temperature is selected from 0-5 ° C, the weak reduction
  • the aqueous solution is selected from the group consisting of aqueous sodium sulfite solution, aqueous sodium hydrogen sulfite solution, aqueous sodium thiosulfate solution and the like.
  • Another aspect of the invention relates to a process for the preparation of a pharmaceutically acceptable salt of a compound of the formula (II) or a compound of the above formula IIA, comprising the preparation of the formula (II) as described in the above scheme a step of compounding, further comprising the step of reacting with an acid to obtain a compound of formula (II) or a pharmaceutically acceptable salt of a compound of formula IIA, said acid being selected from the group consisting of organic or inorganic acids, preferably organic acids;
  • the organic acid is selected from p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid, preferably p-toluenesulfonic acid;
  • the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
  • the "beating" as used in the present invention refers to a method in which the solubility of a substance in a solvent is poor, but the solubility of the impurity in a solvent is good, and the beating and purifying can remove the color, change the crystal form or remove a small amount of impurities.
  • the "C 1-6 alkyl group” of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, "C 1-4 alkyl group", "C 1-3 alkyl group", and the like. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methyl Butyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl 2,2-Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl , 2-
  • the "3-14 membered cycloalkyl” as used herein means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 14 carbon atoms, preferably from 3 to 12 carbon atoms, more Preferably, the cycloalkyl ring contains from 3 to 8 carbon atoms, most preferably the cycloalkyl ring contains from 5 to 6 carbon atoms, most preferably a cyclopropyl group.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the "3-14 membered heterocyclic group" as used in the present invention means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 14 ring atoms, wherein one or more ring atoms are selected from nitrogen a heteroatom of oxygen or S(O) m (where m is an integer from 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains from 3 to 8 ring atoms, more preferably the heterocyclyl ring contains from 5 to 6 ring atoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the "6-14 membered aryl group" as used in the present invention means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (that is, a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably
  • the aryl group is 6 to 8 members, more preferably a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the "5-15 membered heteroaryl group” as used in the present invention means a 5- to 15-membered all-carbon monocyclic or fused polycyclic group having a conjugated ⁇ -electron system, further comprising 1 to 4 hetero atoms, wherein The heteroatoms are selected from one or more of oxygen, sulfur or nitrogen. It is preferably a 5- to 8-membered heteroaryl group, more preferably a 5- to 6-membered heteroaryl group, even more preferably a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, and a pyridyl group.
  • heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
  • C 1-6 alkoxy group as used in the present invention means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the C 1-6 alkyl group is as defined above.
  • Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.
  • halogenated C 1-6 alkyl group as used in the present invention means that the hydrogen atom on the alkyl group is substituted by one or more halogens, wherein the alkyl group is as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • ether solvent means a chain compound or a cyclic compound having an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, methyl tert-butyl ether, Ethylene glycol dimethyl ether, ethylene glycol monomethyl ether or tetrahydrofuran.
  • polar aprotic organic solvent as used in the present invention means a liquid compound which is composed of a polar molecule having an asymmetric structure and does not contain an active hydrogen atom; specific examples include, but are not limited to, dimethyl sulfoxide, 1 , 4-dioxane, N,N-dimethylformamide or N,N-dimethylacetamide.
  • halogenating agent refers to a compound which provides a halogen during the reaction in which a halogen atom is introduced into a simple substance or a compound molecule to produce a halide.
  • the specific examples include, but are not limited to, chlorine gas, liquid bromine, and tribromination.
  • the "metal catalyst” as used in the present invention refers to a chemical reaction which can change the chemical reaction rate (increasing or decreasing) of a reactant without changing the chemical equilibrium, and the quality and chemical properties of the catalyst are not changed before and after the chemical reaction.
  • the metal material is generally a transition metal, and specific examples include, but are not limited to, Raney-Ni, palladium carbon (Pd/C), platinum (Pt), ruthenium (Ru), and the like.
  • the “acid” as used in the present invention means an organic acid or an inorganic acid
  • the “organic acid” means a compound which can accept an electron pair according to the broad acid-base theory.
  • the organic acid includes a carboxylic acid, a halogenated acid, a hydroxy acid, a keto acid, an amino acid, a sulfonic acid, a sulfinic acid, a sulfuric acid, a phenolic acid, etc., preferably a sulfonic acid, and specific examples of the sulfonic acid include, but are not limited to, methanesulfonic acid.
  • inorganic acid refers to an inorganic compound capable of dissociating hydrogen ions. According to the composition, the inorganic acid can be divided into oxygen.
  • the “base” as used in the present invention refers to an organic base or an inorganic base, and the “organic base” refers to a compound which can give an electron pair according to the general theory of acid-base.
  • the organic base is classified into an amine, an amide or an alcohol.
  • An alkali metal salt, an alkyl metal lithium compound, a lithium amide compound, a sodium amide compound, a nitrogen-containing heterocyclic compound, an organic base providing a hydroxide, an amino acid, etc. and specific examples include, but are not limited to, dimethylamine, triethyl ethane Amine, ethylenediamine, colchicine, sodium methoxide, potassium ethoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, n-butyl lithium, lithium diisopropylamide (LDA), 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), sodium amide, pyrrolidine, pyridine, tetramethylammonium hydroxide, lysine (Lys), and the like.
  • dimethylamine triethyl ethane Amine, ethylenediamine, colchicine, sodium methoxide, potassium ethoxide, lithium t-
  • Inorganic base refers to an inorganic compound capable of dissociating a hydroxide ion. According to the composition, the inorganic base can be classified into a metal hydroxide, ammonia or ammonia monohydrate, a salt capable of dissociating the hydroxide ion, and the like. These include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate (soda ash), potassium carbonate, sodium hydrogencarbonate (sodium bicarbonate), potassium hydrogencarbonate, cesium carbonate, and the like.
  • the "strong oxidizing agent" as used in the present invention means a substance having a strong electron-acquisition ability in a redox reaction, and specific examples include, but are not limited to, sulfuric acid, hydrogen peroxide, potassium permanganate, manganese dioxide, and the like.
  • the "pharmaceutically acceptable salt or pharmaceutically acceptable salt” as used herein means a salt of a compound of the present invention which is safe and effective for use in a mammal and which has the desired biological activity.
  • Specific examples of the compound of the present invention and a mineral acid or an organic acid include, but are not limited to, hydrohalide, carbonate, sulfate, hydrogen sulfate, phosphate, acetate, oxalate, tartaric acid Salt, maleate, fumarate, sulfonate, amino acid salt, and the like.
  • reaction step is reduced, the reaction step disclosed in the prior art is 11 steps, and the reaction step of the present invention is 7 steps.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard was tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • TMS tetramethylsilane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Agilent Plus C18 150 x 4.6 mm column).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un dérivé de pyridinone et d'un intermédiaire de celui-ci. Plus particulièrement, la présente invention concerne la préparation d'un composé représenté par la formule (6) pour obtenir un dérivé de pyridinone représenté dans la formule (II), un procédé de préparation d'un sel pharmaceutiquement acceptable de celui-ci, et un intermédiaire de celui-ci dans le procédé de préparation, et un procédé de préparation associé.
PCT/CN2017/113902 2016-12-01 2017-11-30 Procédé de préparation d'un dérivé de pyridinone et son intermédiaire WO2018099424A1 (fr)

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CN113423398A (zh) * 2019-01-29 2021-09-21 贝达药业股份有限公司 Mek抑制剂及其在医药上的应用

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CN102216274A (zh) * 2008-11-18 2011-10-12 武田药品工业株式会社 (R)-3-(2,3-二羟基丙基)-6-氟-5-(2-氟-4-碘苯基氨基)-8-甲基吡啶并[2,3-d]嘧啶-4,7(3H,8H)-二酮及其中间体的制备方法
WO2015058589A1 (fr) * 2013-10-25 2015-04-30 上海恒瑞医药有限公司 Dérivés pyridiques de cétone, leur procédé de préparation et leur application pharmaceutique
CN105121443A (zh) * 2013-04-18 2015-12-02 上海复尚慧创医药研究有限公司 蛋白激酶抑制剂
WO2016155473A1 (fr) * 2015-03-27 2016-10-06 江苏恒瑞医药股份有限公司 P-toluènesulfonate pour inhibiteur de kinase mek, forme cristalline de celui-ci et procédé de préparation de celui-ci

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Publication number Priority date Publication date Assignee Title
CN102216274A (zh) * 2008-11-18 2011-10-12 武田药品工业株式会社 (R)-3-(2,3-二羟基丙基)-6-氟-5-(2-氟-4-碘苯基氨基)-8-甲基吡啶并[2,3-d]嘧啶-4,7(3H,8H)-二酮及其中间体的制备方法
CN105121443A (zh) * 2013-04-18 2015-12-02 上海复尚慧创医药研究有限公司 蛋白激酶抑制剂
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113423398A (zh) * 2019-01-29 2021-09-21 贝达药业股份有限公司 Mek抑制剂及其在医药上的应用

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