WO2021018112A1 - 一种1，6-二氢吡啶-3-甲酰胺衍生物的制备方法 - Google Patents

一种1，6-二氢吡啶-3-甲酰胺衍生物的制备方法 Download PDF

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WO2021018112A1
WO2021018112A1 PCT/CN2020/105036 CN2020105036W WO2021018112A1 WO 2021018112 A1 WO2021018112 A1 WO 2021018112A1 CN 2020105036 W CN2020105036 W CN 2020105036W WO 2021018112 A1 WO2021018112 A1 WO 2021018112A1
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formula
compound
pharmaceutically acceptable
acceptable salt
reaction
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PCT/CN2020/105036
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French (fr)
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黄建
姜威
王军政
贾君磊
王晓亮
韦艳丽
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江苏恒瑞医药股份有限公司
上海森辉医药有限公司
上海盛迪医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure belongs to the field of medicine, and specifically relates to a preparation method of 1,6-dihydropyridine-3-carboxamide derivatives.
  • MEKs also known as MAP kinases (MAPKK or Erk kinase)
  • MAPKK MAP kinases
  • Erk1 phosphorylation the serine/threonine residues and tyrosine residues (Erk1 phosphorylation) of MAPK
  • the sites are T202 and Y204, and the phosphorylation sites of Erk2 are T183 and Y185.
  • the MEK family contains five genes: MEK1, MEK2, MEK3, MEK4 and MEK5.
  • AZD8330 is an orally active, selective MEK inhibitor with IC50 of 7nM. It has potential anti-tumor activity, especially inhibits mitogen-activated protein kinase kinase 1 (MEK or MAP/ERK kinase 1), thereby inhibiting growth factor regulation Cell signal and tumor cell proliferation.
  • MEK or MAP/ERK kinase 1 mitogen-activated protein kinase kinase 1
  • Trametinib is an effective and selective allosteric inhibitor of MEK1 and MEK2 (MEK1/2) enzymes. It has shown anti-tumor activity in a phase I clinical trial (ASCO2010).
  • TAK-733 is a potent and selective ATP-noncompetitive MEK allosteric site inhibitor with IC50 of 3.2nM.
  • WO2015058589 discloses a new generation of high-efficiency and low-toxicity inhibitors against MAPKs signaling pathway, 4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodophenylamino)-1 -Methyl-6-carbonyl-1,6-dihydropyridine-3-carboxamide, the structural formula is as follows:
  • WO2016155473 reports the mesylate salt form of the aforementioned MEK kinase inhibitor, providing 4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodoanilino)-1-methyl- 6-carbonyl-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate, the drug salt has good crystal stability and chemical stability, and has low toxicity and low solvent residue, which is better for clinical use application.
  • 3-methyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-8-methylpyrido[2,3-d]pyrimidine-2,4,7(1H, 3H,8H)-trione is a key intermediate for the preparation of the aforementioned MEK kinase inhibitor.
  • WO2015058589 reports a conventional preparation method, that is, under high temperature conditions, a compound of formula a is reacted with diethyl malonate to form formula b Compound.
  • the reaction conditions of the process are harsh, and high temperature conditions are required to cause the condensation reaction.
  • the side reactions of the process are serious.
  • the present disclosure provides a new 4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodophenylamino)-1 -The preparation method of methyl-6-carbonyl-1,6-dihydropyridine-3-carboxamide, which has mild process conditions and is suitable for large-scale industrial production.
  • the disclosure provides a method for preparing a compound of formula b or a pharmaceutically acceptable salt thereof, which includes the step of reacting a compound of formula a with malonic acid to form a compound of formula b,
  • the molar ratio of the compound of formula a to malonic acid is 1:1 to 1:10, including but not limited to 1:2, 1:3, 1:4, 1:5, 1:6, 1: 7, 1:8, 1:9, 1:10 or any value between any two numbers, preferably 1:2 to 1:6.
  • the solvent used for the reaction of the compound of formula a with malonic acid is selected from aprotic solvents, including but not selected from acetonitrile, THF, dioxane, ethylene glycol dimethyl ether and toluene, preferably toluene.
  • the method for preparing the compound of formula b or its pharmaceutically acceptable salt further contains C 1 -C 6 alkyl acid anhydride or C 1 -C 6 alkyl acid chloride, including but not limited to trifluoroacetic anhydride, trifluoro Acetyl chloride, acetic anhydride, acetyl chloride, preferably acetyl chloride or acetic anhydride.
  • acetic anhydride or acetyl chloride is selected to promote the condensation reaction.
  • C 1 -C 6 alkyl acid anhydride or C 1 -C 6 alkyl acid chloride can effectively reduce the reaction temperature, making the condensation reaction conditions more mild, suitable for industrial scale-up production, and at the same time, the mild reaction also reduces the side effects caused by temperature. The reaction rate can effectively improve the product yield and quality.
  • the aforementioned condensation reaction temperature is 40 to 150°C, including 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C °C or any value between any two numbers, preferably 60-90°C.
  • the molar ratio of acetic anhydride or acetyl chloride to the compound of formula a is 2:1-20:1, including but not limited to 2:1, 3:1, 4:1, 5:1 , 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18 :1, 19:1, 20:1 or any value between any two numbers, preferably 4:1-12:1.
  • the method for preparing a compound of formula b or a pharmaceutically acceptable salt thereof includes the step of reacting a compound of formula a with malonic acid to form a compound of formula b, wherein the molar ratio of the compound of formula a to malonic acid is 1:2 ⁇ 1 :6, the molar ratio of the compound of formula a to acetyl chloride or acetic anhydride is 1:4 ⁇ 1:12, the solvent used in the reaction is an aprotic solvent, and the reaction temperature is 40 ⁇ 150°C, including but not limited to 40°C, 50°C, 60 °C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C or any value between any two numbers.
  • the method for preparing the compound of formula b or a pharmaceutically acceptable salt thereof in the present disclosure further includes the steps of filtration, washing or drying.
  • the present disclosure also provides a method for preparing a compound of formula I or a usable salt thereof, which includes the aforementioned method steps for preparing a compound of formula b or a pharmaceutically acceptable salt thereof, and the conversion of a compound of formula b into a compound of formula I or its usable salt. Salt steps,
  • the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof includes the step of reacting a compound of formula c with 6-methyl-3-hydroxypyridine under alkaline conditions to form a compound of formula d,
  • the agent that provides alkalinity is selected from lithium (trimethylsilyl)amide, n-butyl lithium, or tert-butyl lithium.
  • the ratio of the used amount of the alkaline reagent to the molar amount of the compound of formula c is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1. :1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2 or any value between any two numbers.
  • the molar ratio of the compound of formula c to 6-methyl-3-hydroxypyridine is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1: 1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2 or any value between any two numbers.
  • the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof further comprises the step of converting a compound of formula e into a compound of formula I,
  • the compound of formula e is subjected to trifluoroacetic acid conditions to form the compound of formula I.
  • the method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof includes:
  • Step 1) A compound of formula a reacts with malonic acid to form a compound of formula b; Step 2) A compound of formula b is converted to a compound of formula c; Step 3) A compound of formula c and 6-methyl-3-hydroxypyridine under basic conditions React to form a compound of formula d; step 4) convert a compound of formula d into a compound of formula e; step 5) convert a compound of formula e into a compound of formula I,
  • reaction of the compound of formula b with trifluoromethanesulfonic anhydride to form the compound of formula c can be carried out with reference to the reaction conditions in WO2015058589, and related content is incorporated into the present disclosure for illustration.
  • the compound of formula d is converted into the compound of formula e under the condition of lithium hydroxide, which can be carried out with reference to the reaction conditions in WO2015058589, and the relevant content is incorporated into the present disclosure for illustration.
  • the method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof in the present disclosure further includes the steps of filtration, washing or drying.
  • the present disclosure also provides another method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the step of converting a compound of formula e into a compound of formula I,
  • the compound of formula e is subjected to trifluoroacetic acid conditions to form the compound of formula I.
  • trifluoroacetic acid is more conducive to the removal of amino protective groups, and at the same time, avoid side reactions in the process.
  • the compound of formula e can be prepared according to the aforementioned scheme.
  • the present disclosure also provides a pharmaceutical composition containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof prepared by the foregoing method, and one or more pharmaceutically acceptable carriers and diluents Or excipients.
  • the present disclosure also provides a use of the compound of formula I prepared by the foregoing method or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating diseases related to MEK kinase inhibitors, the diseases are preferably tumors, more preferably melanoma.
  • salts of the compounds of the present disclosure refer to the salts of the compounds of the present disclosure.
  • Such salts are safe and effective when used in the body of mammals, and have due biological activities, specifically the compounds of the present disclosure and inorganic Compounds formed by acids or organic acids, including but not limited to: hydrohalide, carbonate, sulfate, hydrogen sulfate, phosphate, acetate, oxalate, tartrate, maleate, fumarate Acid salt, sulfonate, amino acid salt, etc., preferably p-toluenesulfonate.
  • alkyl refers to a saturated aliphatic hydrocarbon group, preferably an alkyl group containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers Wait.
  • Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from aryl and heteroaryl , Substituted by halogen.
  • the "pharmaceutical composition” in the present disclosure means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmacological Medicinal carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • the purity or content of the present disclosure is determined by HPLC detection, and the compound characterization data is obtained by analyzing the nuclear magnetic resonance spectrum; the reagents used in the present disclosure can be purchased through commercial channels.
  • step 1

Abstract

一种制备4-（6-甲基吡啶-3-基氧基）-2-（2-氟-4-碘苯氨基）-1-甲基-6-羰基-1，6-二氢吡啶-3-甲酰胺的方法。

Description

一种1,6-二氢吡啶-3-甲酰胺衍生物的制备方法 技术领域
本公开属于医药领域，具体涉及一种1,6-二氢吡啶-3-甲酰胺衍生物的制备方法。
背景技术
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。
目前公开了一系列的MEK抑制剂，如通过Raf激酶抑制Mek活性的PD98059、PD184352、AZD8330(司美替尼)、TAK-733、Trametinib、Vemurafenib等。AZD8330是一种口服活性、选择性MEK抑制剂，IC50为7nM，其具有潜在的抗肿瘤活性，特别抑制丝裂原活化蛋白激酶激酶1(MEK或MAP/ERK激酶1)，从而抑制生长因子调节的细胞信号以及肿瘤细胞增殖。Trametinib是一种有效的、具有选择性的MEK1和MEK2(MEK1/2)酶的变构抑制剂，在一期临床试验(ASCO2010)中已表现出抗肿瘤活性。TAK-733是一种有效的、具有选择性的ATP-非竞争性MEK变构部位抑制剂，IC50为3.2nM。
WO2015058589公开了新一代的高效而低毒的针对MAPKs信号通路的抑制剂，4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺，结构式如下所示：
Figure PCTCN2020105036-appb-000001
WO2016155473报道前述MEK激酶抑制剂的甲磺酸盐形式，提供4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐，该药物盐具备良好的晶型稳定性和化学稳定性，并且低毒低溶剂残留，更好地适用于临床应用。
另一方面，3-甲基-1-(2-氟-4-碘苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮是制备前述MEK激酶抑制剂的关键中间体，WO2015058589报道一种常规的制备方法，即，在高温条件下，式a化合物与丙二酸二乙酯反应以形成式b化合物。该工艺反应条件苛刻，需要高温条件方能发生缩合反应，工艺的副反应现象严重，
Figure PCTCN2020105036-appb-000002
鉴于简化制备工艺、降低生产成本的考虑，本公开提供了一种新的4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺的制备方法，该工艺条件温和，适合工业化大生产。
发明内容
本公开(the disclosure)提供了一种制备式b化合物或其可药用盐的方法，包括：式a化合物与丙二酸反应以形成式b化合物的步骤，
Figure PCTCN2020105036-appb-000003
在一些实施方案中，式a化合物与丙二酸的摩尔比1:1～1:10，包括但不限于1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10或任意两数之间任意值，优选1:2～1:6。
另一些实施方案中，式a化合物与丙二酸反应所用溶剂选自非质子性溶剂，包括但不选与乙腈、THF、二氧六环、乙二醇二甲醚和甲苯，优选甲苯。
在一些优选实施方案中，制备式b化合物或其可药用盐的方法还含有C 1-C 6烷基酸酐或C 1-C 6烷基酰氯，包括但不限于三氟乙酸酐、三氟乙酰氯、乙酸酐、乙酰氯，优选乙酰氯或乙酸酐。
在实施方案中，选用乙酸酐或乙酰氯促进缩合反应的进行。另一方面，C 1-C 6烷基酸酐或C 1-C 6烷基酰氯能有效降低反应温度，使得缩合反应条件更为温和，适合工业放大生产，同时，反应温和也降低由温度引起副反应发生率，有效提高产品收率和质量。在一些实施方案中，前述缩合反应温度40～150℃，包括40℃、50℃、60℃、70℃、80℃、90℃、100℃、110℃、120℃、130℃、140℃、150℃或任意两数之间任意值，优选60～90℃。
在另一些实施方案中，乙酸酐或乙酰氯的使用量与式a化合物的摩尔比为2:1～20:1，包括但不限于2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、11:1、12:1、13:1、14:1、15:1、16:1、17:1、18:1、19:1、20:1或任意两数之间任意值，优选4:1～12:1。
进一步地，制备式b化合物或其可药用盐的方法包括：式a化合物与丙二酸反应以形成式b化合物的步骤，其中，式a化合物与丙二酸的摩尔比1:2～1:6，式a化合物与乙酰氯或乙酸酐的摩尔比1:4～1:12，反应所用溶剂为非质子性溶剂，反应温度40～150℃，包括但不限于40℃、50℃、60℃、70℃、80℃、90℃、100℃、110℃、120℃、130℃、140℃、150℃或任 意两数之间任意值。
进一步地，本公开中制备式b化合物或其可药用盐的方法还包括过滤、洗涤或干燥的步骤。
另一方面，本公开还提供了一种制备式I化合物或其可用盐的方法，包括前述制备式b化合物或其可药用盐的方法步骤，以及式b化合物转化为式I化合物或其可用盐的步骤，
Figure PCTCN2020105036-appb-000004
进一步地，制备式I化合物或其可药用盐的方法包括碱性条件下，式c化合物与6-甲基-3-羟基吡啶反应以形成式d化合物的步骤，
Figure PCTCN2020105036-appb-000005
在一些实施方案中，提供碱性的试剂选自(三甲基硅基)氨基锂、正丁基锂或叔丁基锂。
在另一些实施方案中，碱性试剂的使用量与式c化合物摩尔量比为1:1～1:2，包括但不限于1:1、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2或任意两数之间任意值。
在一些实施方案中，式c化合物与6-甲基-3-羟基吡啶的摩尔量比为1:1～1:2，包括但不限于1:1、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2或任意两数之间任意值。
更进一步地，制备式I化合物或其可药用盐的方法还包括式e化合物转化为式I化合物的步骤，
Figure PCTCN2020105036-appb-000006
在一些实施方案中，式e化合物在三氟乙酸条件下以形成式I化合物。
在一些实施方案中，制备式I化合物或其可药用盐的方法包括：
步骤1)式a化合物与丙二酸反应以形成式b化合物；步骤2)式b化合物转化为式c化 合物；步骤3)碱性条件下，式c化合物与6-甲基-3-羟基吡啶反应以形成式d化合物；步骤4)式d化合物转化为式e化合物；步骤5)式e化合物转化为式I化合物，
Figure PCTCN2020105036-appb-000007
在一些实施方案中，式b化合物与三氟甲磺酸酐反应以形成式c化合物，可参照WO2015058589中反应条件进行，并将相关内容引入本公开中以示说明。
在另一些实施方案中，式d化合物在氢氧化锂的条件下转化为式e化合物，可参照WO2015058589中反应条件进行，并将相关内容引入本公开中以示说明。
本公开式I化合物与无机酸或有机酸形成的化合物制备获得式I化合物可药用盐，可参照WO2016155473中反应条件进行，并将相关内容引入本公开中以示说明。
进一步地，本公开中制备式I化合物或其可药用盐的方法还包括过滤、洗涤或干燥的步骤。
本公开还提供另一种制备式I化合物或其可药用盐的方法包括式e化合物转化为式I化合物的步骤，
Figure PCTCN2020105036-appb-000008
在一些实施方案中，式e化合物在三氟乙酸条件下以形成式I化合物。相比于三氯化铝，三氟乙酸更利于氨基保护基脱除，同时，避免工艺中副反应的发生。
进一步地，式e化合物可以按照前述方案制备获得。
本公开还提供一种药物组合物，所述药物组合物含有治疗有效量的由前述方法制备获得式I化合物或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开还提供一种由前述方法制备获得式I化合物或其可药用盐在制备治疗与MEK激酶抑制剂有关的疾病的药物中用途，所述疾病优选肿瘤，更优选黑色素瘤。
本公开所述的“可药用盐”是指本公开化合物的盐，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，具体为本公开化合物与无机酸或有机酸形成的化合物，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，优选对甲苯磺酸盐。
本公开所述“烷基”指饱和的脂族烃基团，优选含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基，及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自芳基、杂芳基、卤素所取代。
本公开所述“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本公开所述纯度或含量通过HPLC检测确定的，化合物表征数据是通过对核磁共振图谱的解析获得；本公开所用试剂可以通过商业途径购得。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，本公开的实质和范围并不局限于此。
实施例1：
Figure PCTCN2020105036-appb-000009
依次将甲苯(160ml)，丙二酸(8.65g，4.0eq)和乙酰氯(9.79g，6.0eq)加入到250ml的三颈瓶中，加热至70～80℃搅拌反应，加入式a化合物(10.0g，1.0eq)，继续搅拌反应，冷却，加水淬灭反应，二氯甲烷萃取，干燥，浓缩得12.3g黄色固体。
取9.1g黄色固体加入18.4ml四氢呋喃和92ml叔丁基甲醚，加热回流搅拌反应2h，降至室温过滤得6.12g固体，HPLC：98.23％，收率：72.58％。
实施例2：
Figure PCTCN2020105036-appb-000010
依次将丙二酸二乙酯(4.99g，3.0eq)、式a化合物(5g)以及二苯甲醚(50ml)，加入到100ml的反应瓶中，加热240℃搅拌反应，冷却，浓缩反应液得粗品，HPLC：75.88％。
实施例3
Figure PCTCN2020105036-appb-000011
将式e(6.15g，10.01mmol)和三氟乙酸(56.8g)加入100mL反应瓶中，搅拌。加热至回流反应，TLC(DCM:MeOH＝20:1)跟踪至原料消失，停止反应。减压浓缩除去三氟乙酸，残余物加入丙酮(25mL)，0.5M氢氧化钠溶液调节pH至8～9，过滤，滤饼用纯化水洗涤，干燥得固体4.61g，收率93.2％，纯度98.14％。
实施例4：
Figure PCTCN2020105036-appb-000012
步骤1：
将原料3-羟基-6-甲基吡啶(51.6g，472.59mmol)和四氢呋喃(1.5kg)加入5L三口反应瓶中，滴加双(三甲基硅基)氨基锂(LiHMDS)1M四氢呋喃溶液(452mL，452.04mmol)，滴加式c化合物的四氢呋喃溶液(280.0g，1.5kg四氢呋喃)，50～55℃搅拌反应，TLC(DCM:MeOH＝20:1)跟踪至原料消失，停止反应。浓缩，残余物加入丙酮(440g)，搅拌，过滤，干燥得固体184.1g，收率69.9％，纯度98.77％。
步骤2：
将式d化合物(195.7g，305.59mmol)投于3L反应瓶中，加入四氢呋喃(1100g)，将一水合氢氧化锂(29.5g，916.76mmol)加入纯化水(400g)中，搅拌溶解，加入上述反应液中，50～55℃搅拌反应，TLC(MeOH:DCM＝20:1)跟踪至原料消失，停止反应。过滤除去不溶物，浓缩，残余物用二氯甲烷溶剂，盐水洗涤，干燥，浓缩，残余物加入丙酮(630g)室温搅拌，过滤，干燥，得固体151.5g，收率86.8％，纯度99.28％。
步骤3：
将式e(154.5g，251.46mmol)和三氟乙酸(1500g)加入2L三口反应瓶中，开启搅拌。加热至回流反应，TLC(DCM:MeOH＝20:1)跟踪至原料消失，停止反应。减压浓缩除去三氟乙酸，残余物加入丙酮(440g)，0.5M氢氧化钠溶液调节pH至8～9，过滤，滤饼用纯化水洗涤，干燥得固体110.3g，收率91.7％，纯度98.78％。

Claims (15)

  1. 制备式b化合物或其可药用盐的方法，包括：式a化合物与丙二酸反应以形成式b化合物的步骤，
    Figure PCTCN2020105036-appb-100001
  2. 如权利要求1所述的方法，其中还含有C 1-C 6烷基酸酐或C 1-C 6烷基酰氯，优选三氟乙酸酐、三氟乙酰氯、乙酸酐、乙酰氯，更优选乙酰氯或乙酸酐。
  3. 如权利要求1或2所述的方法，其中所述式a化合物与丙二酸的摩尔比1:1～1:10，优选1:2～1:6。
  4. 如权利要求2所述的方法，其中乙酸酐或乙酰氯与式a化合物的摩尔比为2:1～20:1，优选4:1～12:1。
  5. 如权利要求1-4任一项所述的方法，其中反应所用溶剂选自非质子性溶剂，优选乙腈、THF、二氧六环、乙二醇二甲醚和甲苯，更优选甲苯。
  6. 如权利要求1-5任一项所述的方法，其中反应温度40～150℃，优选60～90℃。
  7. 制备式I化合物或其可用盐的方法，包括如权利要求1-6任一项所述的方法步骤，以及式b化合物转化为式I化合物或其可药用盐的步骤，
    Figure PCTCN2020105036-appb-100002
  8. 如权利要求7任一项所述的方法，其中包括碱性条件下，式c化合物与6-甲基-3-羟基吡啶反应以形成式d化合物的步骤，
    Figure PCTCN2020105036-appb-100003
  9. 如权利要求8所述的方法，其中提供碱性的试剂选自(三甲基硅基)氨基锂、正丁基锂或叔丁基锂。
  10. 如权利要求8或9所述的方法，其中还包括式e化合物转化为式I化合物的步骤，
    Figure PCTCN2020105036-appb-100004
  11. 如权利要求10所述的方法，其中式e化合物在三氟乙酸条件下以形成式I化合物。
  12. 如权利要求7-11任一项所述的方法，包括：步骤1)式a化合物与丙二酸反应以形成式b化合物；步骤2)式b化合物转化为式c化合物；步骤3)碱性条件下，式c化合物与6-甲基-3-羟基吡啶反应以形成式d化合物；步骤4)式d化合物转化为式e化合物；步骤5)式e化合物转化为式I化合物，
    Figure PCTCN2020105036-appb-100005
  13. 如权利要求7-12任一项所述的方法，其中式I化合物可药用盐选自对甲苯磺酸盐。
  14. 一种药物组合物，所述药物组合物含有治疗有效量的由权利要求7-13任一项所述方法制备获得式I化合物或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  15. 由权利要求1-13任一项所述方法制备获得式I化合物或其可药用盐在制备治疗与MEK激酶抑制剂有关的疾病的药物中用途，所述疾病优选肿瘤，更优选黑色素瘤。
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WO2023230205A1 (en) * 2022-05-25 2023-11-30 Ikena Oncology, Inc. Mek inhibitors and uses thereof
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