WO2018099424A1 - 一种吡啶酮类衍生物的制备方法及其中间体 - Google Patents

一种吡啶酮类衍生物的制备方法及其中间体 Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
group
membered
acid
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.)
Ceased
Application number
PCT/CN2017/113902
Other languages
English (en)
French (fr)
Inventor
贾君磊
边林
高晓晖
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.)
Jiangsu Hengrui Medicine Co Ltd
Original Assignee
Jiangsu Hengrui Medicine 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 Jiangsu Hengrui Medicine Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to CN201780020531.9A priority Critical patent/CN108884048B/zh
Publication of WO2018099424A1 publication Critical patent/WO2018099424A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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).

Landscapes

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

Abstract

本发明涉及一种吡啶酮类衍生物的制备方法及其中间体。具体地，本发明涉及一种由式（6）所示化合物制备得到式（II）所示吡啶酮类衍生物、其可药用盐的制备方法和制备过程中的中间体及其制备方法。

Description

一种吡啶酮类衍生物的制备方法及其中间体 技术领域
本发明涉及一种吡啶酮类衍生物、其可药用盐的制备方法和制备过程中的中间体及其制备方法，该吡啶酮类衍生物、其可药用盐及含有该衍生物的药物组合物作为MEK抑制剂用于制备治疗癌症药物中的用途。
背景技术
丝/苏氨酸促分裂原活化蛋白激酶(MAPKs，也称胞外信号调节激酶，ERKs)由酪氨酸激酶受体(如EGF受体)和/或G蛋白异源三聚体相关的细胞因子受体激活，可与多种由不同第二信使激起的胞内信号相互作用，磷酸化和调节各种酶及转录因子的活性(如NF-κB，Rsk 90，磷脂酶A2，c-Myc，CREB，Ets-1，AP-1及c-jun等)。MEKs也称MAP激酶(MAPKK或Erk激酶)，属于双特异性激酶，可磷酸化MAPK(p44MAPK(Erk1)及p42MAPK(Erk2)的丝/苏氨酸残基和酪氨酸残基(Erk1磷酸化位点为T202和Y204，Erk2磷酸化位点为T183和Y185)，MEK家族包含五种基因：MEK1，MEK2，MEK3，MEK4和MEK5。MEKs的N-端为负调控区，C-端的催化区具有与Erks结合并激活Erks的功能，实验发现，敲除MEK1的调控区会导致MEK1和Erk固有活性的抑制。
针对MAPK信号通路，目前已有多个特异性抑制Raf和MEK活性的化合物处于临床和上市阶段。其中sorafenib(Bay 43-9006)于2006年上市，属非特异性的丝/苏氨酸和酪氨酸激酶抑制剂，其作用靶点包含Raf，MEK，VEGFR2/3，Flt-3，PDGFR，c-Kit等。B-Raf特异性抑制剂如dabrafenib(GSK2118436)和vemurafenib(PLX4032)显示良好的临床效果，但持续时间并不长久，同时，临床研究发现，接受PLX4032有效治疗的患者，其症状大部分复发，提示B-Raf抑制剂的长期治疗会导致患者产生获得性耐药性，对B-Raf抑制剂不再敏感。为克服患者的耐药性，临床上常将MEK抑制剂与B-Raf抑制剂联用。特异性抑制MEK1/2抑制剂Trametinib(GSK-1120212)由GSK公司开发，现已进入预注册阶段，其它MEK1/2抑制剂Selumetinib(AZD-6422)，Pimasertib hydrochloride(AS-703026)，TAK-733等已进入临床试验阶段，但这些MEK抑制剂并无公布其与Erk1或Erk2的相互作用数据。
目前公开了一系列的MEK抑制剂的专利申请，其中包括WO2007096259、WO2010003022和WO2012162293等。
专利申请WO2015058589A1(公开日2015.04.30)中公开了一种结构新型的高效低毒的针对MAPKs信号通路的抑制剂，特别是CYP450抑制作用小、活性高、优异的抗肿瘤细胞增殖作用的MEK靶点抑制剂，结构如下式(II)所示：
Figure PCTCN2017113902-appb-000001
WO2015058589A1(公开日2015.04.30)的实施例1和实施例31公开了化合物31的制备方法，总计十一步反应，具体反应如下所示：
Figure PCTCN2017113902-appb-000002
该方法最终通过制备分离法纯化得到目标产物，产率为30.3％，该方法存在反应步数较多、反应时间较长、存在高温反应(第七步反应温度为230℃)、产率低等问题，不利于工业扩大生产。
发明内容
本发明要解决的技术问题是提供一种与现有技术完全不相同的制备式(II)所示化合物的方法，改变起始原料和中间体制备目标产物，通过缩短反应步骤、起始原料等反应物简单易购买、反应条件简单可控、避免高温反应、反应后处理方法简单等途径优化制备方法，提高产率、利于工业扩大生产。
本发明的技术方案如下：
本发明提供一种制备通式(II)所示化合物的方法，其特征在于，所述方法为由式(6)化合物制备式(II)所示化合物，
Figure PCTCN2017113902-appb-000003
其中，
Ra、Rb选自氢原子、卤素、C1-6烷基或卤代C1-6烷基；
R1选自任选取代的苯基或吡啶基，所述取代基选自C1-6烷基、卤素、卤代C1-6烷基、C1-6烷氧基、C1-6烷基氨基羰基、C1-6烷基羰基氨基、3-14元杂环基氧基、3-14元环烷基氨基羰基、3-14元环烷基羰基氨基或C1-6烷基磺酰氨基，3-14元杂环基优选为3-8元杂环基，3-14元环烷基优选为3-8元环烷基；
R2选自氢原子、卤素或任选取代的C1-6烷基，所述取代基选自卤素、羟基、氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基，3-14元环烷基优选为3-8元环烷基，3-14元杂环基优选为3-8元杂环基，6-14元芳基优选为6-8元芳基，5-15元杂芳基优选为5-8元杂芳基。
在本发明的一个优选实施例方案中，本发明提供一种制备通式(Ⅱ)所示化合物的方法，其特征在于，所述方法还包括由式(5)化合物制备式(6)化合物，
Figure PCTCN2017113902-appb-000004
在本发明的一个优选实施例方案中，本发明提供一种制备通式(Ⅱ)所示化合物的方法，其特征在于，所述方法还包括由式(4)化合物制备式(5)化合物，
Figure PCTCN2017113902-appb-000005
在本发明的一个优选实施例方案中，本发明提供一种制备通式(Ⅱ)所示化合物的方法，其特征在于，所述方法还包括由式(3)化合物制备式(4)化合物，
Figure PCTCN2017113902-appb-000006
在本发明的一个优选实施例方案中，本发明提供一种制备通式(Ⅱ)所示化合物的方法，其特征在于，所述方法还包括由式(2)化合物制备式(3)化合物，
Figure PCTCN2017113902-appb-000007
在本发明的一个优选实施例方案中，本发明提供一种制备通式(Ⅱ)所示化合物的方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
Figure PCTCN2017113902-appb-000008
本发明进一步涉及一种化合物如式(6)所示，
Figure PCTCN2017113902-appb-000009
其中，Ra、R1、R2如式(II)中所定义。
本发明的另一方面涉及一种制备通式(6)所示化合物的方法，其特征在于，所述方法包括由式(5)化合物制备式(6)化合物，
Figure PCTCN2017113902-appb-000010
本发明的另一方面涉及一种制备通式(6)所示化合物的方法，其特征在于，所述方法还包括由式(4)化合物制备式(5)化合物，
Figure PCTCN2017113902-appb-000011
本发明的另一方面涉及一种制备通式(6)所示化合物的方法，其特征在于，所述方法还包括由式(3)化合物制备式(4)化合物，
Figure PCTCN2017113902-appb-000012
本发明的另一方面涉及一种制备通式(6)所示化合物的方法，其特征在于，所述方法还包括由式(2)化合物制备式(3)化合物，
Figure PCTCN2017113902-appb-000013
本发明的另一方面涉及一种制备通式(6)所示化合物的方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
Figure PCTCN2017113902-appb-000014
本发明进一步涉及一种化合物如式(5)所示，
Figure PCTCN2017113902-appb-000015
其中，Ra、R1、R2如式(II)中所定义。
本发明的另一方面涉及一种制备通式(5)所示化合物的方法，其特征在于，所述方法包括由式(4)化合物制备式(5)化合物，
Figure PCTCN2017113902-appb-000016
本发明的另一方面涉及一种制备通式(5)所示化合物的方法，其特征在于，所述方法还包括由式(3)化合物制备式(4)化合物，
Figure PCTCN2017113902-appb-000017
本发明的另一方面涉及一种制备通式(5)所示化合物的方法，其特征在于，所述方法还包括由式(2)化合物制备式(3)化合物，
Figure PCTCN2017113902-appb-000018
本发明的另一方面涉及一种制备通式(5)所示化合物的方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
Figure PCTCN2017113902-appb-000019
本发明进一步涉及一种化合物如式(4)所示，
Figure PCTCN2017113902-appb-000020
其中，Ra、R1、R2如式(II)中所定义。
本发明的另一方面涉及一种制备通式(4)所示化合物的方法，其特征在于，所述方法包括由式(3)化合物制备式(4)化合物，
Figure PCTCN2017113902-appb-000021
本发明的另一方面涉及一种制备通式(4)所示化合物的方法，其特征在于，所述方法还包括由式(2)化合物制备式(3)化合物，
Figure PCTCN2017113902-appb-000022
本发明的另一方面涉及一种制备通式(4)所示化合物的方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
Figure PCTCN2017113902-appb-000023
本发明进一步涉及一种化合物如式(3)所示，
Figure PCTCN2017113902-appb-000024
其中，R1、R2如式(II)中所定义。
本发明的另一方面涉及一种制备通式(3)所示化合物的方法，其特征在于，所述方法包括由式(2)化合物制备式(3)化合物，
Figure PCTCN2017113902-appb-000025
本发明的另一方面涉及一种制备通式(3)所示化合物的方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
Figure PCTCN2017113902-appb-000026
优选的，本发明提供一种式(3-1)所示化合物，
Figure PCTCN2017113902-appb-000027
本发明还提供式(3-1)所示化合物的制备方法，其方法与式(3)所示化合物的制备方法相同。
本发明的另一方面涉及一种制备通式(6)所示化合物的方法，其特征在于，所述化合物具有下述式(6-1)所示的结构，
Figure PCTCN2017113902-appb-000028
其中，
Ra、R1、R2、如式(6)中的定义；
Ra优选为F原子；
R1优选为任选取代的苯基或吡啶基，所述取代基选自甲基；
R2优选为氢原子。
本发明还提供式(6-1)所示化合物的制备方法，其方法与式(6)所示化合物的制备方法相同。
优选的，本发明提供一种式(6-2)所示化合物，
Figure PCTCN2017113902-appb-000029
本发明还提供式(6-2)所示化合物的制备方法，其方法与式(6)或(6-1)所示化合物的制备方法相同。
本发明的另一方面涉及一种制备通式(5)所示化合物的方法，其特征在于，所述化合物具有下述式(5-1)所示的结构，
Figure PCTCN2017113902-appb-000030
其中，
Ra、R1、R2、如式(5)中的定义；
Ra优选为F原子；
R1优选为任选取代的苯基或吡啶基，所述取代基选自甲基；
R2优选为氢原子。
本发明还提供式(5-1)所示化合物的制备方法，其方法与式(5)所示化合物的制备方法相同。
优选的，本发明提供一种式(5-2)所示化合物，
Figure PCTCN2017113902-appb-000031
本发明还提供式(5-2)所示化合物的制备方法，其方法与式(5)或(5-1)所示化合物的制备方法相同。
本发明的另一方面涉及一种制备通式(4)所示化合物的方法，其特征在于，所述化合物具有下述式(4-1)所示的结构，
Figure PCTCN2017113902-appb-000032
其中，
Ra、R1、R2、如式(4)中的定义；
Ra优选为F原子；
R1优选为任选取代的苯基或吡啶基，所述取代基选自甲基；
R2优选为氢原子。
本发明还提供式(4-1)所示化合物的制备方法，其方法与式(4)所示化合物的制 备方法相同。
优选的，本发明提供一种式(4-2)所示化合物，
Figure PCTCN2017113902-appb-000033
本发明还提供式(4-2)所示化合物的制备方法，其方法与式(4)或(4-1)所示化合物的制备方法相同。
本发明进一步涉及一种化合物如式(2)所示，
Figure PCTCN2017113902-appb-000034
其中，
R2选自氢原子、卤素或任选取代的C1-6烷基，所述取代基选自卤素、羟基、氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基，3-14元环烷基优选为3-8元环烷基，3-14元杂环基优选为3-8元杂环基，6-14元芳基优选为6-8元芳基，5-15元杂芳基优选为5-8元杂芳基；R2优选为氢原子；
X选自卤素，优选为氯原子。
优选的，本发明提供一种式(2-1)所示化合物，
Figure PCTCN2017113902-appb-000035
本发明进一步涉及一种化合物如式(1)所示，
Figure PCTCN2017113902-appb-000036
其中，
R2选自氢原子、卤素或任选取代的C1-6烷基，所述取代基选自卤素、羟基、 氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基，3-14元环烷基优选为3-8元环烷基，3-14元杂环基优选为3-8元杂环基，6-14元芳基优选为6-8元芳基，5-15元杂芳基优选为5-8元杂芳基；R2优选为氢原子。
优选的，本发明提供一种式(1-1)所示化合物，
Figure PCTCN2017113902-appb-000037
本发明的另一方面涉及一种制备通式(IIA)所示化合物的方法，其特征在于，所述方法为
Figure PCTCN2017113902-appb-000038
第一步，中间体(1-1)的制备
将丙二酸二甲酯与丙二腈加入到醚类有机溶剂中中，在碱的作用下与甲胺水溶液反应，滴加氢氧化钠溶液，过滤、干燥后得到中间体(1-1)，所述醚类有机溶剂包括但不限于甲基叔丁基醚、乙二醇二甲醚、乙二醇单甲醚或四氢呋喃，优选四氢呋喃，所述碱选自1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)或液氨。
第二步，中间体(2-1)的制备
将中间体(1-1)与卤化试剂进行卤代反应后，加水，固体析出，过滤，干燥后得到中间体(2-1)，所述卤化试剂选自三氯氧磷、N-氯代丁二酰亚胺、三氯化磷或五氯化磷，优选三氯氧磷。
第三步，中间体(3-1)的制备
中间体(2-1)与3-羟基-6-甲基吡啶加入到极性非质子性有机溶剂中，在惰性气体保护下，在碱的作用下进行取代反应后，加水，固体析出，过滤、洗涤、干燥后得到中间体(3-1)，所述惰性气体选自氮气或氩气，所述极性非质子性有机溶剂包括但不限于二甲基亚砜、1,4-二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺， 优选N,N-二甲基乙酰胺；所述碱选自有机碱或无机碱，优选无机碱，所述的无机碱包括但不限于碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、叔丁醇钾、叔丁醇钠、氢氧化钠或氢氧化钾，优选碳酸铯。
第四步，中间体(4-2)的制备
中间体(3-1)与1,2-二氟-4-硝基苯加入到极性非质子性有机溶剂中，在惰性气体保护下，在碱的作用下进行取代反应后，加水，用有机溶剂萃取，有机相减压浓缩后得到中间体(4-2)，所述惰性气体选自氮气或氩气，所述极性非质子性有机溶剂包括但不限于二甲基亚砜、1,4-二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，所述萃取有机溶剂包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、二氯甲烷、三氯甲烷或甲基叔丁基醚，所述碱选自有机碱或无机碱，优选无机碱，所述的无机碱包括但不限于碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、叔丁醇钾、叔丁醇钠、氢氧化钠或氢氧化钾，优选碳酸铯。
第五步，中间体(5-2)的制备
中间体(4-2)在强氧化剂作用下进行氧化反应，去除过量的氧化剂，析晶、过滤、干燥后得到中间体(5-2)，所述强氧化剂包括但不限于硫酸、过氧化氢、高锰酸钾、二氧化锰，优选硫酸。
第六步，中间体(6-2)的制备
中间体(5-2)发生还原反应后，过滤、滤液浓缩后得到中间体(6-2)，所述还原反应可以选自铁粉还原(铁粉与盐酸、乙酸或氯化铵配合)、锌粉还原(锌粉与盐酸、乙酸或氯化铵配合)、金属催化剂催化氢化(兰尼镍，钯炭等为催化剂，通入氢气作为还原剂)、无机盐类还原剂还原法(硫化钠、连二亚硫酸钠或硼氢化钠等作为还原剂)、水合肼还原法(水合肼作为还原剂)等，优选钯碳/乙酸条件下进行还原。
第七步，中间体IIA的制备
式(6-2)化合物在低温条件、酸水溶液中和亚硝酸钠作用下生成重氮化合物，再与碘化钾发生碘代反应，反应结束后，过滤，滤饼加入弱还原性水溶液中打浆，过滤、干燥后得到目标产物IIA，所述的酸水溶液选自盐酸或硫酸，优选盐酸，所述盐酸包含稀盐酸和浓盐酸，优选浓盐酸，所述低温选自0-5℃，所述弱还原性水溶液选自亚硫酸钠水溶液、亚硫酸氢钠水溶液、硫代硫酸钠水溶液等。
本发明的另一方面涉及一种制备如通式(II)所示化合物或上述方案所述IIA所示化合物的药学上可接受的盐方法，包括上述方案所述的制备式(II)所示化合物的步骤，还包括与酸反应制备得到式(II)所示化合物或IIA所式化合物的药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选有机酸；所述有机酸选自对甲苯磺酸、苯磺酸或甲磺酸，优选对甲苯磺酸；所述无机酸选自盐酸、硫酸或磷酸。
发明详述
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除显而易见 在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
本发明所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本发明所述“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C1-4烷基”、“C1-3烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述的“3-14元环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至14个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至8个碳原子，最优选环烷基环包含5至6个碳原子，最佳为环丙基。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。多环环烷基包括螺环、稠环和桥环的环烷基。
本发明所述的“3-14元杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至14个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1-4个是杂原子，更优选杂环基环包含3至8个环原子，更优选杂环基环包含5至6个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
本发明所述的“6-14元芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至8元的芳基，更优选苯基和萘基，最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2017113902-appb-000039
本发明所述的“5-15元杂芳基”指具有共轭的π电子体系的5至15元全碳单环或稠合多环基团，进一步包含1至4个杂原子的，其中杂原子选自一个或多个氧、硫或氮。优选为5至8元的杂芳基，更优选为5元至6元的杂芳基，甚至更优选呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、 四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含：
Figure PCTCN2017113902-appb-000040
本发明所述的“C1-6烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中C1-6烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。
本发明所述的“卤代C1-6烷基”指烷基上的氢原子被一个或多个卤素取代，其中烷基的定义如上所述。
本发明所述的“C1-6烷基氨基羰基、C1-6烷基羰基氨基”分别指C1-6烷基-NH-CO-、C1-6烷基-CO-NH-，其中C1-6烷基的定义如上所述。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：甲基叔丁基醚、乙二醇二甲醚、乙二醇单甲醚或四氢呋喃。
本发明所述的“极性非质子性有机溶剂”是指是由不对称结构的极性分子构成的不含有活泼氢原子的液体化合物；具体实例包括但不限于：二甲基亚砜、1,4-二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
本发明所述的“卤化试剂”指在单质或化合物分子中引入卤素原子以生产卤化物的反应过程中提供卤素的化合物简称卤化试剂，具体实例包括但不限于：氯气、液溴、三溴化磷、三氯氧磷、三氯化磷、五氯化磷、次氯酸叔丁酯、N-溴(氯)代丁二酰亚胺等。本发明所述的“金属催化剂”指一种在化学反应里能改变反应物化学反应速率(提高或降低)而不改变化学平衡，且本身的质量和化学性质在化学反应前后都没有发生改变的金属材料，一般为过渡金属，具体实例包括但不限于：兰尼镍(Raney-Ni)、钯炭(Pd/C)、铂(Pt)、钌(Ru)等。
本发明所述的“酸”是指有机酸或无机酸，“有机酸”指按照广义的酸碱理论，能接受电子对的化合物。有机酸包括羧酸、卤代酸、羟基酸、酮酸、氨基酸、磺酸、亚磺酸、硫羧酸、酚酸等，优选磺酸，磺酸的具体实例包括但不限于：甲磺酸、十二烷基苯磺酸、苯磺酸、对甲苯磺酸、三氟甲磺酸等；“无机酸”指能解离出氢离子的无机化合物，按照组成成分，无机酸可分成含氧酸、无氧酸、络合酸、混酸、超酸等，优选含氧酸或无氧酸，含氧酸的具体实例包括但不限于：碳酸、硝酸、亚硝酸、次氯酸、硫酸或磷酸等；无氧酸的具体实例包括但不限于：氢氟酸、盐酸、溴酸或氢硫酸等，优选硫酸。
本发明所述的“碱”是指有机碱或无机碱，“有机碱”指按照广义的酸碱理论，碱就是能给出电子对的化合物，有机碱分为胺类、酰胺类、醇的碱金属盐类、烷基金属锂化合物、氨基锂化合物、氨基钠化合物、含氮的杂环化合物、提供氢氧根的有机碱、氨基酸等，具体实例包括但不限于：二甲胺、三乙胺、乙二胺、秋水仙碱、甲醇钠、乙醇钾、叔丁醇锂、叔丁醇钠、叔丁醇钾、正丁基锂、二异丙基氨基锂(LDA)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、氨基钠、吡咯烷、吡啶、四甲基氢氧化铵、赖氨酸(Lys)等。“无机碱”指能解离出氢氧根离子的无机化合物，按照组成成分，无机碱可分成金属氢氧化物、氨水或一水合氨、能够解离出氢氧根离子的盐等，具体实例包括但不限于：氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、碳酸钠(纯碱)、碳酸钾、碳酸氢钠(小苏打)、碳酸氢钾、碳酸铯等。
本发明所述的“强氧化剂”是指在氧化还原反应中，有较强的获得电子能力的物质，具体实例包括但不限于：硫酸、过氧化氢、高锰酸钾、二氧化锰等。
本发明所述的“药学上可接受的盐或可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性，具体为本发明化合物与无机酸或有机酸形成的化合物，具体实例包括但不限于：氢卤酸盐、碳酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、草酸盐、酒石酸盐、马来酸盐、富马酸盐、磺酸盐、氨基酸盐等。
发明的有益效果
与现有技术相比，本发明制备式(II)所示化合物的技术方案具有以下优点：
(1)反应步骤减少，现有技术公开的反应步骤为11步，本发明的反应步骤为7步。
(2)与现有技术比较，本发明的起始原料和中间体不相同，提供了一种完全不同思路的合成方法，并且起始原料和反应物均简单、易购买。
(3)现有技术方法中的每一步反应所得的中间体基本均未进行纯化直接进行下一步反应，本发明方法中的每一个中间体均在反应后处理过程中进行纯化后再投入下一步反应，利于提高产物纯度，避免复杂杂质的出现。
(4)避免高温反应，降低反应危险；反应的后处理简单，易于工业扩大生产。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo,型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Agilent Plus C18 150×4.6mm色谱柱)。
实施例1、2-(2-氟-4-碘苯氨基)-1-甲基-4-(6-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(化合物31或IIA)的制备
Figure PCTCN2017113902-appb-000041
第一步
2-氨基-4-羟基-1-甲基-6-羰基-1,6-二氢吡啶-3-甲腈(1-1)
将丙二酸二甲酯(39.6g，0.3mol)、丙二腈(19.8g，0.3mol)和四氢呋喃(200ml)加入反应瓶中，氩气保护条件下，-25℃滴加1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU，91.34g，0.6mol)，1小时滴加完毕，室温搅拌反应18h，滴加30％甲胺水溶液(200ml)，室温搅拌24h。滴加氢氧化钠溶液(10N，45ml)后室温搅拌，反应5h，冰浴下，加丙酮搅拌30min过滤，收集滤饼，减压干燥，得到标题产物(40g，浅黄色固体)，产率80.8％。
MS m/z(ESI):166.2[M+1]
第二步
2-氨基-4-氯-1-甲基-6-羰基-1,6-二氢吡啶-3-甲腈(2-1)
将2-氨基-4-羟基-1-甲基-6-羰基-1,6-二氢吡啶-3-甲腈(25g，151.51mmol)和乙腈(250ml)加入反应瓶中，冰浴下滴加三氯氧磷(92.9g，605.88mmol)，40min滴加完毕，搅拌20分钟，升温至70℃，反应12h，将反应液滴加到冰水(500ml)中，析出大量固体，过滤，滤饼用水(100ml×2)洗涤，母液用饱和KOH调节pH到7，过滤，滤饼合并用丙酮打浆，减压干燥，得到标题产物(15g，浅黄色固体)，产率54.0％。
MS m/z(ESI):184.2[M+1]
第三步
2-氨基-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲腈(3-1)
将2-氨基-4-氯-1-甲基-6-羰基-1,6-二氢吡啶-3-甲腈(4.5g，24.59mmol)和3-羟基-6-甲基吡啶(2.95g，27.0mmol)溶于二甲基乙酰胺(67.5ml)中，加入碳酸铯(15.98g，49.18mmol)，氩气保护下，150℃反应18小时，冷却至室温，倒入冰水(300ml)中，析出固体，继续搅拌30min，过滤，滤饼用水(200ml×1)洗涤，减压干燥，得到标题产物(4.5g，类白色固体)，产率71.6％。
MS m/z(ESI):257.2[M+1]
第四步
2-((2-氟-4-硝基苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲腈(4-2)
将2-氨基-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲腈(12g，43.68mmol)、1,2-二氟-4-硝基苯(7.29g，45.9mmol)和碳酸铯(21.3g，65.5mmol)加入反应瓶中，加入二甲基乙酰胺(120ml)，氩气保护下，120℃反应6小时，将反应液倒入冰水(500ml)中，搅拌10分钟，用乙酸乙酯(200ml×3)萃取，合并有机相，用饱和氯化钠溶液(300ml×1)洗涤，用无水硫酸镁干燥，过滤，滤液减压浓缩，得到红色固体，用正己烷(150ml)打浆，得到标题产物(17.2g，红色固体)，产率100％。
MS m/z(ESI):396.1[M+1]
第五步
2-((2-氟-4-硝基苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(5-2)
将硫酸(90％，170ml)加入反应瓶中，2-((2-氟-4-硝基苯基)氨基)-1-甲基-4-((6- 甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲腈(17.2g，43.5mmol)分批加入，缓慢加热，100℃反应40min，将反应液缓慢倒入碎冰(170ml)中，冰浴条件下，滴加氨水调节pH至8，过滤，滤饼用丙酮(80ml)打浆，得到标题产物(11.4g，浅黄色固体)，产率60％。
MS m/z(ESI):414.1[M+1]
第六步
2-((4-氨基-2-氟苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(6-2)
反应瓶中依次加入2-((2-氟-4-硝基苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(320g，0.77mol)、乙酸(6kg)和10％Pd/C(35g)，搅拌均匀，氮气置换3次，氢气置换3次，40-45℃常压加氢反应4-5h，趁热将反应液过滤，滤液减压浓缩后加入乙酸乙酯(4kg)室温打浆2-3h，过滤，滤饼抽干，加入乙酸乙酯(2kg)打浆2-3h，过滤，滤饼用乙酸乙酯洗涤，减压干燥，得产物(207.7g，收率70.0％，HPLC检测纯度不低于96％)。
MS m/z(ESI):384.1[M+1]
第七步
2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(31or IIA)
反应瓶中投入2-((4-氨基-2-氟苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(180g，0.47mol)和盐酸(1.4kg)，搅拌均匀，在0-5℃下缓慢滴加535.7g亚硝酸钠溶液中(配置方式：35.7g亚硝酸钠溶解在500g水中)，0-5℃下，将上述溶液滴加到1234g碘化钾溶液中(配置方式：234g碘化钾溶于1kg纯化水)，室温搅拌反应18-20h，过滤，滤饼用纯化水(200g)洗涤，将滤饼加入(6kg)硫代硫酸钠的水溶液中(配置方式：3kg硫代硫酸钠溶解在3kg纯化水中)室温打浆0.5-1h，过滤，滤饼用水(500g)洗，干燥后中性氧化铝柱层析纯化(二氯甲烷:乙酸乙酯＝4:1～1:4)，收集正组分，减压浓缩后，加入丙酮(500g)室温打浆1-2h，过滤，减压干燥得产物(60.3g，收率26.0％，HPLC检测纯度不低于96％)。
MS m/z(ESI):494.1[M+1]
1H-NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.38-8.44(m,1H),7.57-7.75(m,4H),7.35-7.49(m,2H),6.65(t,1H),5.09(s,1H),3.15(s,3H),2.51(s,3H).
实施例2、2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐的制备
Figure PCTCN2017113902-appb-000042
(1)粗品的制备
反应瓶中投入2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺(43g，0.09mol)、对甲苯磺酸(19.0g，0.10mol)和异丙醇(1.0kg)，回流反应2-2.5h。停止加热，继续搅拌12-14h，停止反应，过滤，滤饼用异丙醇洗涤，减压干燥，得产物(56.2g，收率97.0％，HPLC检测纯度不低于97％)。
(2)产品的纯化
反应瓶中投入2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐粗品(52.9g，0.08mol)，丙酮(715g)，纯化水(120g)，加热回流，搅拌溶解，趁热过滤，滤液加入丙酮(1.6kg)，室温搅拌16-18h，冰浴搅拌2-3h，过滤，滤饼用丙酮洗涤，40-45℃减压干燥4-5h，得目标产物(42.3g，收率80.0％，HPLC检测纯度不低于98％)。
MS m/z(ESI):494.1[M+1]
1H-NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.82-8.83(d,1H),8.25-8.28(dd,1H),7.85-7.88(d,1H),7.70(br,1H),7.65(br,1H),7.63-7.66(dd,1H)，7.48-7.50(d,2H),7.42-7.44(dd,1H),7.11-7.13(d,2H),6.66-6.70(t,1H)，5.42(s,1H),3.19(s,3H)，2.67(s,3H),2.29(s,3H).

Claims (37)

  1. 一种制备通式(II)所示化合物的方法，其特征在于，所述方法为由式(6)化合物制备式(II)所示化合物，
    Figure PCTCN2017113902-appb-100001
    其中，
    Ra、Rb选自氢原子、卤素、C1-6烷基或卤代C1-6烷基；
    R1选自任选取代的苯基或吡啶基，所述取代基选自C1-6烷基、卤素、卤代C1-6烷基、C1-6烷氧基、C1-6烷基氨基羰基、C1-6烷基羰基氨基、3-14元杂环基氧基、3-14元环烷基氨基羰基、3-14元环烷基羰基氨基或C1-6烷基磺酰氨基，3-14元杂环基优选为3-8元杂环基，3-14元环烷基优选为3-8元环烷基；
    R2选自氢原子、卤素或任选取代的C1-6烷基，所述取代基选自卤素、羟基、氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基，3-14元环烷基优选为3-8元环烷基，3-14元杂环基优选为3-8元杂环基，6-14元芳基优选为6-8元芳基，5-15元杂芳基优选为5-8元杂芳基。
  2. 如权利要求1所述的制备方法，其特征在于，所述方法还包括由式(5)化合物制备式(6)化合物，
    Figure PCTCN2017113902-appb-100002
  3. 如权利要求2所述的制备方法，其特征在于，所述方法还包括由式(4)化合物制备式(5)化合物，
    Figure PCTCN2017113902-appb-100003
  4. 如权利要求3所述的制备方法，其特征在于，所述方法还包括由式(3)化合物制备式(4)化合物，
    Figure PCTCN2017113902-appb-100004
  5. 如权利要求4所述的制备方法，其特征在于，所述方法还包括由式(2)化合物制备式(3)化合物，
    Figure PCTCN2017113902-appb-100005
  6. 如权利要求5所述的制备方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
    Figure PCTCN2017113902-appb-100006
  7. 一种化合物如式(6)所示，
    Figure PCTCN2017113902-appb-100007
    其中，Ra、R1、R2如权利要求1中定义。
  8. 一种制备如权利要求7所述式(6)化合物的方法，其特征在于，所述方法包括由式(5)化合物制备式(6)化合物，
    Figure PCTCN2017113902-appb-100008
  9. 如权利要求8所述的制备方法，其特征在于，所述方法还包括由式(4)化合物制备式(5)化合物，
    Figure PCTCN2017113902-appb-100009
  10. 如权利要求9所述的制备方法，其特征在于，所述方法还包括由式(3)化合物制备式(4)化合物，
    Figure PCTCN2017113902-appb-100010
  11. 如权利要求10所述的制备方法，其特征在于，所述方法还包括由式(2)化合物制备式(3)化合物，
    Figure PCTCN2017113902-appb-100011
  12. 如权利要求11所述的制备方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
    Figure PCTCN2017113902-appb-100012
  13. 一种化合物如式(5)所示，
    Figure PCTCN2017113902-appb-100013
    其中，Ra、R1、R2如权利要求1中定义。
  14. 一种制备如权利要求13所述的式(5)化合物的方法，其特征在于，所述方法包括由式(4)化合物制备式(5)化合物，
    Figure PCTCN2017113902-appb-100014
  15. 如权利要求14所述的制备方法，其特征在于，所述方法还包括由式(3)化合物制备式(4)化合物，
    Figure PCTCN2017113902-appb-100015
  16. 如权利要求15所述的制备方法，其特征在于，所述方法还包括由式(2)化合物制备式(3)化合物，
    Figure PCTCN2017113902-appb-100016
  17. 如权利要求16所述的制备方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
    Figure PCTCN2017113902-appb-100017
  18. 一种化合物如式(4)所示，
    Figure PCTCN2017113902-appb-100018
    其中，Ra、R1、R2如权利要求1中定义。
  19. 一种制备如权利要求18所述式(4)化合物的方法，其特征在于，所述方法包括由式(3)化合物制备式(4)化合物，
    Figure PCTCN2017113902-appb-100019
  20. 如权利要求19所述的制备方法，其特征在于，所述方法还包括由式(2)化合物制备式(3)化合物，
    Figure PCTCN2017113902-appb-100020
  21. 如权利要求20所述的制备方法，其特征在于，所述方法还包括由式(1)化合物制备式(2)化合物，
    Figure PCTCN2017113902-appb-100021
  22. 一种化合物如式(3)所示，
    Figure PCTCN2017113902-appb-100022
    其中，R1、R2如权利要求1中定义。
  23. 一种制备如权利要求22所述式(3)化合物的方法，其特征在于，所述方法包括由式(2)化合物制备式(3)化合物，
    Figure PCTCN2017113902-appb-100023
  24. 如权利要求23所述的制备方法，其特征在于，所述方法还包括由式(1) 化合物制备式(2)化合物，
    Figure PCTCN2017113902-appb-100024
  25. 如权利要求22所述化合物，其特征在于，所述化合物具有下述式(3-1)所示的结构，
    Figure PCTCN2017113902-appb-100025
  26. 如权利要求7所述化合物，其特征在于，所述化合物具有下述式(6-1)所示的结构，
    Figure PCTCN2017113902-appb-100026
    其中，
    Ra、R1、R2如权利要求7中所定义。
  27. 如权利要求26所述化合物，其特征在于，所述化合物具有下述式(6-2)所示的结构，
    Figure PCTCN2017113902-appb-100027
  28. 如权利要求13所述化合物，其特征在于，所述化合物具有下述式(5-1) 所示的结构，
    Figure PCTCN2017113902-appb-100028
    其中，
    Ra、R1、R2如权利要求13中所定义。
  29. 如权利要求28所述化合物，其特征在于，所述化合物具有下述式(5-2)所示的结构，
    Figure PCTCN2017113902-appb-100029
  30. 如权利要求18所述化合物，其特征在于，所述化合物具有下述式(4-1)所示的结构，
    Figure PCTCN2017113902-appb-100030
    其中，
    Ra、R1、R2如权利要求18中所定义。
  31. 如权利要求30所述化合物，其特征在于，所述化合物具有下述式(4-2)所示的结构，
    Figure PCTCN2017113902-appb-100031
  32. 一种化合物如式(2)所示，
    Figure PCTCN2017113902-appb-100032
    其中，
    R2选自氢原子、卤素或任选取代的C1-6烷基，所述取代基选自卤素、羟基、氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基，3-14元环烷基优选为3-8元环烷基，3-14元杂环基优选为3-8元杂环基，6-14元芳基优选为6-8元芳基，5-15元杂芳基优选为5-8元杂芳基；R2优选为氢原子；
    X选自卤素，优选为氯原子。
  33. 如权利要求32所述化合物，其特征在于，所述化合物具有下述式(2-1)所示的结构，
    Figure PCTCN2017113902-appb-100033
  34. 一种化合物如式(1)所示，
    Figure PCTCN2017113902-appb-100034
    其中，
    R2选自氢原子、卤素或任选取代的C1-6烷基，所述取代基选自卤素、羟基、 氰基、硝基、C1-6烷氧基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-15元杂芳基，3-14元环烷基优选为3-8元环烷基，3-14元杂环基优选为3-8元杂环基，6-14元芳基优选为6-8元芳基，5-15元杂芳基优选为5-8元杂芳基；R2优选为氢原子。
  35. 如权利要求34所述化合物，其特征在于，所述化合物具有下述式(1-1)所示的结构，
    Figure PCTCN2017113902-appb-100035
  36. 一种式IIA所式化合物的制备方法，其包括如下步骤，
    Figure PCTCN2017113902-appb-100036
  37. 一种制备如权利要求1所述通式(II)所示化合物或权利要求36所述IIA所示化合物的药学上可接受的盐方法，包括权利要求1-6中任一项所述的制备式(II)所示化合物的步骤或权利要求36中制备式IIA所式化合物的步骤，还包括与酸反应制备得到式(II)所示化合物或IIA所式化合物的药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选有机酸；所述有机酸选自对甲苯磺酸、苯磺酸或甲磺酸，优选对甲苯磺酸；所述无机酸选自盐酸、硫酸或磷酸。
PCT/CN2017/113902 2016-12-01 2017-11-30 一种吡啶酮类衍生物的制备方法及其中间体 Ceased WO2018099424A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780020531.9A CN108884048B (zh) 2016-12-01 2017-11-30 一种吡啶酮类衍生物的制备方法及其中间体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201611089452.7 2016-12-01
CN201611089452 2016-12-01

Publications (1)

Publication Number Publication Date
WO2018099424A1 true WO2018099424A1 (zh) 2018-06-07

Family

ID=62242061

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/113902 Ceased WO2018099424A1 (zh) 2016-12-01 2017-11-30 一种吡啶酮类衍生物的制备方法及其中间体

Country Status (3)

Country Link
CN (1) CN108884048B (zh)
TW (1) TW201821408A (zh)
WO (1) WO2018099424A1 (zh)

Cited By (1)

* 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

Citations (4)

* Cited by examiner, † Cited by third party
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
WO2015058589A1 (zh) * 2013-10-25 2015-04-30 上海恒瑞医药有限公司 吡啶酮类衍生物、其制备方法及其在医药上的应用
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 (zh) * 2015-03-27 2016-10-06 江苏恒瑞医药股份有限公司 一种mek激酶抑制剂的对甲苯磺酸盐、其结晶形式及制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
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
WO2015058589A1 (zh) * 2013-10-25 2015-04-30 上海恒瑞医药有限公司 吡啶酮类衍生物、其制备方法及其在医药上的应用
WO2016155473A1 (zh) * 2015-03-27 2016-10-06 江苏恒瑞医药股份有限公司 一种mek激酶抑制剂的对甲苯磺酸盐、其结晶形式及制备方法

Cited By (1)

* 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

Also Published As

Publication number Publication date
CN108884048A (zh) 2018-11-23
TW201821408A (zh) 2018-06-16
CN108884048B (zh) 2021-07-27

Similar Documents

Publication Publication Date Title
CN108699063B (zh) 一种芦可替尼的合成工艺
JP6392436B2 (ja) 置換された５−フルオロ−１ｈ−ピラゾロピリジン類を製造するための方法
CN116987112B (zh) 制备氨基嘧啶衍生物的改善方法
TWI697494B (zh) 科帕利普（ｃｏｐａｎｌｉｓｉｂ）及其二鹽酸鹽之合成
JP6811717B2 (ja) トピロキソスタット及びその中間体の調製のための方法
CN108884100B (zh) 吡咯并六元杂芳环类衍生物的制备方法及中间体
CN111032650A (zh) 可用于合成氨基嘧啶衍生物的新型中间体、其制备方法以及使用其制备氨基嘧啶衍生物的方法
CN107176955A (zh) 一种巴瑞替尼的制备方法
CN118401528A (zh) 一种glp-1激动剂中间体及其制备方法及在医药中的用途
CN106831792B (zh) 一种PARP抑制剂Rucaparib中间体的制备方法
WO2022198904A1 (zh) 一种kras抑制剂关键中间体及其制备方法
JP2018522871A (ja) ブロモドメイン阻害剤としての二環式複素環誘導体
CN108884048B (zh) 一种吡啶酮类衍生物的制备方法及其中间体
WO2022107755A1 (ja) 新規アクリジニウム塩およびその製造方法
BR112015015880B1 (pt) Processos de produção de um composto e compostos
WO2017004964A1 (zh) 一种3-[5-(2-氟苯基)-1，2，4-噁二唑-3-基]苯甲酸的制备方法
CN108689904B (zh) 手性杂环叔醇中间体的制备方法及其应用
CN110770231B (zh) 一种酪氨酸激酶抑制剂及其中间体的制备方法
CN114560862A (zh) 一种吡咯并[1,2-a]喹喔啉-4(5h)-酮及其衍生物的合成方法
CN102491985B (zh) 6-氨基-2，2-二甲基-2H-吡啶[3，2-b][1，4]恶嗪-3(4H)-酮的合成方法
CN115819412B (zh) 一种n-杂环bet溴结构域抑制剂的合成方法及其中间体
KR102204267B1 (ko) 대체된 (r)-3-(4-메틸카바모일-3-플루오로페닐아미노)테트라하이드로퓨란-3-엔카르복실산(변이체) 및 이의 에스테르, 제조 방법 및 용도
RU2846415C2 (ru) Способ получения ингибитора нуклеокапсида вируса гепатита в
CN113354650B (zh) 一种4-氯-7H-吡咯并[2,3-d]嘧啶-5-甲腈的制备方法
HK40103024A (zh) 制备氨基嘧啶衍生物的改善方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17877171

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17877171

Country of ref document: EP

Kind code of ref document: A1