WO2024153159A1 - 一种四氢-1-萘胺及其衍生物的制备方法 - Google Patents

一种四氢-1-萘胺及其衍生物的制备方法 Download PDF

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WO2024153159A1
WO2024153159A1 PCT/CN2024/072912 CN2024072912W WO2024153159A1 WO 2024153159 A1 WO2024153159 A1 WO 2024153159A1 CN 2024072912 W CN2024072912 W CN 2024072912W WO 2024153159 A1 WO2024153159 A1 WO 2024153159A1
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formula
compound
compound represented
alkyl
alkoxy
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姜威
黄庆
高军峰
黄建
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上海森辉医药有限公司
江苏恒瑞医药股份有限公司
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Publication of WO2024153159A1 publication Critical patent/WO2024153159A1/zh

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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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/16—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring
    • C07C13/18—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring with a cyclohexane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention belongs to the field of medicine and relates to a method for preparing tetrahydro-1-naphthylamine and its derivatives.
  • Chiral amines are components or fragments of many important biologically active compounds.
  • (1S,4S)-4-methoxy-1,2,3,4-tetrahydronaphthalene-1-amine is a key intermediate in the synthesis of the MOR agonist (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine.
  • WO2017063509 discloses that (S)-4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester is used as a starting material, (1S,4S)-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester is obtained under chiral reducing agent conditions, and then etherification and deprotection are performed to obtain the target product.
  • the present disclosure provides a method for preparing a compound represented by formula I or a salt thereof.
  • the method comprises the steps of reacting the compound represented by formula C under (R)-2-methyl-CBS-oxazaborolidine conditions to form a compound represented by formula D,
  • R1 is selected from halogen, nitro, cyano, C1-6 alkyl or C1-6 alkoxy, the alkyl or alkoxy is optionally substituted by one or more selected from halogen, oxo, nitro, cyano, C1-6 alkyl or C1-6 alkoxy, n is 0, 1, 2 or 3,
  • R2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, the alkyl or cycloalkyl is optionally substituted by one or more selected from halogen, oxo, nitro, cyano, C1-6 alkyl or C1-6 alkoxy
  • One or more groups selected from halogen, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl are substituted.
  • the molar ratio of (R)-2-methyl-CBS-oxazaborolidine to the compound of formula C in the method is 1:10 to 1:1, including but not limited to 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1 or any value between two numbers. In some embodiments, the molar ratio of (R)-2-methyl-CBS-oxazaborolidine to the compound of formula C in the method is 1:10.
  • the process of the compound shown in formula C reacting to form the compound shown in formula D also contains a reducing agent, and the reducing agent is selected from but not limited to borane.
  • the amount of borane used in the method is 0.5 to 1 equivalent (eq.) of the molar amount of the compound shown in formula C, including but not limited to 0.5 equivalent, 0.6 equivalent, 0.7 equivalent, 0.8 equivalent, 0.9 equivalent, 1.0 equivalent or any value between two numbers.
  • the amount of borane used in the method is 0.8 to 1 equivalent (eq.) of the molar amount of the compound shown in formula C.
  • the solvent used in the reaction of the compound shown in formula C is selected from but not limited to toluene or tetrahydrofuran. In some embodiments, the solvent used in the reaction of the compound shown in formula C is tetrahydrofuran.
  • reaction temperature of the compound represented by formula C is -10 to 10°C, including but not limited to -10°C, -8°C, -6°C, -4°C, -2°C, 0°C, 2°C, 4°C, 6°C, 8°C, 10°C or any value between two numbers.
  • some embodiments provide a method for preparing a compound of formula I or a salt thereof, further comprising reacting a compound of formula B under oxidizing conditions to form a compound of formula C,
  • R1 and n are as defined above.
  • the oxidant is selected from, but not limited to, potassium permanganate or sodium hypochlorite.
  • the compound of formula B in the method reacts under potassium permanganate conditions to form a compound of formula C.
  • the reaction temperature of the compound of formula B is 0 to 30°C, including but not limited to 0°C, 6°C, 10°C, 16°C, 20°C, 26°C, 30°C, or any value between two numbers.
  • the solvent used in the reaction of the compound of formula B is acetone.
  • the amount of the oxidant used in the method is 1 to 6 equivalents (eq.) of the molar amount of the compound of formula B, including but not limited to 1 equivalent, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents or any value between two numbers.
  • Some other embodiments provide a method for preparing a compound of formula I or a salt thereof, further comprising the step of reacting a compound of formula A with phthalic anhydride to form a compound of formula B,
  • R1 and n are as defined above.
  • the molar ratio of the compound represented by Formula A to phthalic anhydride in the method is 1:1 to 1:3, including but not limited to 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8 or any value between two numbers. In some embodiments, the molar ratio of the compound represented by Formula A to phthalic anhydride in the method is 1:1.
  • the solvent used in the reaction of the compound represented by formula A is toluene.
  • the method comprises the following steps:
  • R1 and n are as defined above.
  • the compound of formula I in the method is a compound of formula I-1,
  • the method comprises the steps of reacting compound C-1 under (R)-2-methyl-CBS-oxazaborolidine conditions to form compound D-1
  • the method for preparing the compound of formula I-1 comprises the step of forming compound C-1 by reacting compound B-1 with an oxidizing agent such as potassium permanganate.
  • the method for preparing the compound of formula I-1 comprises the step of forming compound B-1 by reacting compound A-1 with phthalic anhydride.
  • the method for preparing the compound of formula I-1 comprises the following steps:
  • step a) compound A-1 is reacted with phthalic anhydride under heating conditions to form compound B-1.
  • step a) compound A-1 is reacted with phthalic anhydride under triethylamine conditions to form compound B-1.
  • step b) Compound B-1 is reacted under potassium permanganate conditions to form Compound C-1.
  • step c) Compound C-1 is reduced under (R)-2-methyl-CBS-oxazaborolidine conditions to form Compound D-1.
  • the reducing agent used for the reduction of Compound C-1 is borane.
  • the method for preparing the compound of formula I-1 also includes the steps of reacting compound D-1 with ethane halides to form a compound of formula E-1, followed by deprotection of compound E-1 to form a compound of formula I-1 or a salt thereof.
  • the ethyl halide in the method is selected from ethyl iodide or ethyl bromide.
  • compound D-1 reacts with an ethyl halide such as ethyl iodide under silver oxide conditions to form compound E-1.
  • compound E-1 is reacted under methylamine conditions to form a compound of formula I-1.
  • the relevant experimental procedures can be found in Protective Groups in Organic Synthesis, 5 Th Ed. TW Greene & P. GM Wuts, and the relevant contents are introduced into this text for illustration.
  • the present disclosure also provides a compound represented by formula D or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from halogen, nitro, cyano, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by one or more selected from halogen, oxo, nitro, cyano, C 1-6 alkyl or C 1-6 alkoxy, and n is 0, 1, 2 or 3.
  • the compound represented by formula D is compound D-1,
  • the present disclosure also provides a compound represented by formula C or a pharmaceutically acceptable salt thereof,
  • R1 is selected from halogen, nitro, cyano, C1-6 alkyl or C1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more selected from halogen, oxo, nitro, cyano, C1-6 alkyl or The moiety is substituted by a C 1-6 alkoxy group, and n is 0, 1, 2 or 3.
  • the compound represented by formula C is compound C-1,
  • the present disclosure also provides a method for preparing compound AA, the method comprising the aforementioned steps of preparing the compound represented by formula I,
  • the method for preparing compound AA further comprises the step of reacting a compound of formula I-1 with compound F to form compound AA,
  • the preparation method disclosed in the present disclosure further comprises one or more steps of filtration, concentration, purification by column chromatography and drying.
  • the "formation” and “conversion” of the present disclosure do not specifically mean that the conversion reaction between two substrates is a single step, and can be a single step or multi-step reaction between two substrates. If the intermediate contains a protecting group, the intermediate is subjected to a step of removing the protecting agent, and then reacts with the corresponding substrate to obtain the corresponding target product.
  • the numerical values in this disclosure are instrumental measurements, which have a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used needs to be considered.
  • the particle size of the active ingredient the numerical value is the error change after measurement does not exceed plus or minus 10%, which can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.
  • the pharmaceutically acceptable salts or salts thereof of the compounds described in the present disclosure may be selected from inorganic salts or organic salts. Including “acid” addition salts and “base” addition salts. For example, salts formed by acid-base reaction with a basic group (amino group), the acid including organic acid or inorganic acid.
  • the salt of the compound shown in Formula I is oxalate.
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or both Two configurations.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl. Alkyl groups may be optionally substituted or unsubstituted.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy groups may be optionally substituted or unsubstituted.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 6 carbon atoms.
  • Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.
  • Cycloalkyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable point of attachment.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • amino refers to -NH2 .
  • nitro refers to -NO2 .
  • the substituents are preferably one or more of the following groups, such as halogen, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive/negative ion mode with a mass scan range of 120-1300.
  • the thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate.
  • the specification of silica gel plate used in thin layer chromatography (TLC) was 0.2mm ⁇ 0.03mm, and the specification of thin layer chromatography separation and purification product was 0.4mm-0.5mm.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Step 2 Preparation of (S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione
  • the reaction was completed by HPLC detection; EA (1000 mL, 16.7 V) and water (1000 mL, 16.7V), quench the reaction with saturated sodium thiosulfate aqueous solution under ice bath; filter, rinse the filter cake with EA; separate the filtrate, wash the organic phase with 1000mL water once; dry the organic phase over anhydrous sodium sulfate; filter, concentrate to obtain a crude product; add EA (180mL, 3.0V) and petroleum ether (540mL, 9.0V) to the crude product, slurry, filter, and dry in vacuo to obtain product 4 as an off-white solid (48.5g). The yield is 77.0% and the purity is 98.4%.

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Abstract

本公开涉及一种四氢-1-萘胺及其衍生物的制备方法。具体而言，本公开涉及一种(1S,4S)-4-甲氧基-1,2,3,4-四氢萘-1-胺的制备方法，所述方法包括化合物C-1在(R)-2-甲基-CBS-恶唑硼烷条件下反应形成化合物D-1的步骤。该方法操作简单，适合于工业化生产。

Description

一种四氢-1-萘胺及其衍生物的制备方法 技术领域
本公开属于医药领域，涉及制备一种四氢-1-萘胺及其衍生物的制备方法。
背景技术
手性胺是众多具有重要生物活性化合物结构的组成部分或片段。例如(1S,4S)-4-甲氧基-1,2,3,4-四氢萘-1-胺是合成MOR激动剂(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺关键中间体。
WO2017063509公开了以(S)-4-羰基-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯为起始物，经手性还原剂条件下获得(1S,4S)-4-羟基-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯，随后醚化、脱保护获得目标产物，
发明内容
本公开提供了一种制备式I所示化合物或其盐的方法，
所述方法包括式C所示化合物在(R)-2-甲基-CBS-恶唑硼烷条件下反应形成式D所示化合物的步骤，
其中，R1选自卤素、硝基、氰基、C1-6烷基或C1-6烷氧基，所述烷基或烷氧基任选被一个或多个选自卤素、氧代、硝基、氰基、C1-6烷基或C1-6烷氧基所取代，n为0、1、2或3，R2选自氢、C1-6烷基、C3-6环烷基，所述烷基或环烷基任选被 一个或多个选自卤素、氧代、硝基、氰基、C1-6烷基、C1-6烷氧基或C3-6环烷基所取代。
在一些实施方案中，所述方法中(R)-2-甲基-CBS-恶唑硼烷与式C所示化合物的摩尔量比1:10～1:1，包括但不限于1:10、1:9、1:8、1:7、1:6、1:5、1:4、1:3、1:2、1:1或任意两数之间值。在一些实施方案中，所述方法中(R)-2-甲基-CBS-恶唑硼烷与式C所示化合物的摩尔量比1:10。
在一些实施方案中，式C所示化合物反应形成式D所示化合物过程中还含有还原剂，所述还原剂选自但不限于硼烷。在一些实施方案中，所述方法中硼烷用量为式C所示化合物的摩尔量的0.5～1当量(eq.)，包括但不限于0.5当量、0.6当量、0.7当量、0.8当量、0.9当量、1.0当量或任意两数之间值。在一些实施方案中，所述方法中硼烷用量为式C所示化合物的摩尔量的0.8～1当量(eq.)。
在另一些实施方案中，式C所示化合物反应所用溶剂选自但不限于甲苯或四氢呋喃。在一些实施方案中，式C所示化合物反应所用溶剂为四氢呋喃。
另一方面，式C所示化合物反应温度为-10～10℃，包括但不限于-10℃、-8℃、-6℃、-4℃、-2℃、0℃、2℃、4℃、6℃、8℃、10℃或任意两数之间值。
进一步地，一些实施方案提供制备式I所示化合物或其盐的方法还包括式B所示化合物在氧化剂条件下反应形成式C所示化合物，
其中R1和n如前述定义。
在一些实施方案中，所述氧化剂选自但不限于高锰酸钾或次氯酸钠。在一些实施方案中，所述方法中式B所示化合物在高锰酸钾条件下反应形成式C所示化合物。在一些实施方案中，式B所示化合物反应温度为0～30℃，包括但不限于0℃、6℃、10℃、16℃、20℃、26℃、30℃或任意两数之间值。
在一些实施方案中，式B所示化合物反应所用溶剂为丙酮。在另一些实施方案中，所述方法中氧化剂用量为式B所示化合物的摩尔量的1～6当量(eq.)，包括但不限于1当量、2当量、3当量、4当量、5当量、6当量或任意两数之间值。
另一些实施方案提供制备式I所示化合物或其盐的方法还包括式A所示化合物与邻苯二甲酸酐反应形成式B所示化合物的步骤，
其中R1和n如前述定义。
在一些实施方案中，所述方法中式A所示化合物与邻苯二甲酸酐的摩尔量比1:1～1:3，包括但不限于1:1、1:1.2、1:1.4、1:1.6、1:1.8、1:2、1:2.2、1:2.4、1:2.6、1:2.8或任意两数之间值。在一些实施方案中，所述方法中式A所示化合物与邻苯二甲酸酐的摩尔量比1:1。
在另一些实施方案中，式A所示化合物反应所用溶剂为甲苯。
在一些实施方案中，所述方法包括以下步骤：
a)式A所示化合物与邻苯二甲酸酐反应形成式B所示化合物，
b)式B所示化合物在氧化剂条件下反应形成式C所示化合物，
c)式C所示化合物在(R)-2-甲基-CBS-恶唑硼烷条件下反应形成式D所示化合物，
其中R1和n如前述定义。
在另一些实施方案中，所述方法中式I所示化合物为式I-1所示化合物，
所述方法包括化合物C-1在(R)-2-甲基-CBS-恶唑硼烷条件下反应形成化合物D-1的步骤
在一些实施方案中，制备式I-1所示化合物的方法包括化合物B-1在氧化剂如高锰酸钾条件下形成化合物C-1的步骤，
在另一些实施方案中，制备式I-1所示化合物的方法包括化合物A-1在邻苯二甲酸酐条件下形成化合物B-1的步骤，
在一些实施方案中，制备式I-1所示化合物的方法包括以下步骤：
a)化合物A-1与邻苯二甲酸酐反应形成化合物B-1，
b)化合物B-1在氧化剂条件下反应形成化合物C-1，
c)化合物C-1在(R)-2-甲基-CBS-恶唑硼烷条件下反应形成化合物D-1，
在一些实施方案中，步骤a)化合物A-1与邻苯二甲酸酐在加热条件下反应形成化合物B-1。
在一些实施方案中，步骤a)化合物A-1与邻苯二甲酸酐在三乙胺条件下反应形成化合物B-1。
在一些实施方案中，步骤b)化合物B-1在高锰酸钾条件下反应形成化合物C-1。
在一些实施方案中，步骤c)化合物C-1在(R)-2-甲基-CBS-恶唑硼烷条件下还原形成化合物D-1。在一些实施方案中，化合物C-1还原所用还原剂为硼烷。
进一步地，制备式I-1所示化合物的方法还包括化合物D-1与卤代乙烷反应形成式E-1所示化合物，随后化合物E-1脱保护基形成式I-1化合物或其盐的步骤，
在一些实施方案中，所述方法中卤代乙烷选自碘乙烷或溴乙烷。在另一些实施方案中，化合物D-1在氧化银条件下与卤代乙烷如碘乙烷反应形成化合物E-1。
在一些实施方案中，化合物E-1在甲胺条件下反应形成式I-1化合物。相关实验操作可参见《Protective Groups in Organic Synthesis》，5Th Ed.T.W.Greene&P.G.M.Wuts中所述，并将相关内容引入本文本以示说明。
本公开还提供式D所示化合物或其可药用盐，
其中，R1选自卤素、硝基、氰基、C1-6烷基或C1-6烷氧基，所述烷基或烷氧基任选被一个或多个选自卤素、氧代、硝基、氰基、C1-6烷基或C1-6烷氧基所取代，n为0、1、2或3。
在一些实施方案中，式D所示化合物为化合物D-1，
本公开还提供式C所示化合物或其可药用盐，
其中，R1选自卤素、硝基、氰基、C1-6烷基或C1-6烷氧基，所述烷基或烷氧基任选被一个或多个选自卤素、氧代、硝基、氰基、C1-6烷基或 C1-6烷氧基所取代，n为0、1、2或3。
在一些实施方案中，式C所示化合物为化合物C-1，
本公开还提供制备化合物AA的方法，所述方法包括前述制备式I所示化合物的步骤，
在一些实施方案中，制备化合物AA的方法还包括式I-1化合物与化合物F反应形成化合物AA的步骤，
相关实验操作可参见WO2019062804中所述，并将相关内容引入本文本以示说明。
另一方面，本公开所述制备方法还包括过滤、浓缩、经柱层析纯化和干燥中一步或多步操作。
本公开“形成”和“转化为”并不特指两个底物间的转化反应为单步骤的，可为两个底物间的单步骤或多步骤的反应。如中间体含有保护基，所述中间体经过一步脱除保护剂，随后再与相应底物反应以获得相应目标产物。
本公开中数值为仪器测量值，存在一定程度的误差，一般而言，正负10％均属于合理误差范围内。当然需要考虑该数值所用之处的上下文，例如，活性成分的粒径，该数值为测量后误差变化不超过正负10％，可以为正负9％、正负8％、正负7％、正负6％、正负5％、正负4％、正负3％、正负2％或正负1％，优选正负5％。
本公开中所述化合物可药用盐或其盐可选自无机盐或有机盐。包括“酸”加成盐和“碱”加成盐。例如，通过与碱性基团(氨基)的酸-碱反应形成的盐，所述酸包括有机酸或无机酸。在一些实施方案中，式I所示化合物的盐为草酸盐。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含 两种构型。
术语“烷基”指饱和的脂族烃基团，包括有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。烷基可以是任选取代的或非取代的。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至6个碳原子。非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等。环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。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-CN。
术语“氨基”指-NH2。
术语“硝基”指-NO2。
术语“氧代”指＝O取代基。
本公开官能团当被取代时，取代基优选为一个或多个以下基团，如卤素、氧代、硝基、氰基、C1-6烷基、C1-6烷氧基或C3-6环烷基。
具体实施方式
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。
本公开中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。
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，测定溶剂为氘代氯仿(CDCl3)。
MS的测定用Waters Micromass Quattro micro API三重四级杆质谱仪，以正/负离子模式扫描，质量扫描范围为120～1300。
HPLC色谱柱：YMC-Pack ODS-A(3μm,4.6mmx 150mm)
薄层层析硅胶板使用烟台黄海HSGF254硅胶板，薄层色谱法(TLC)使用硅胶板采用规格是0.2mm±0.03mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
实施例1:
步骤1)(S)-2-(1,2,3,4-四氢萘-1-基)异二氢吲哚-1,3-二酮的制备
向1L烧瓶中加入原料1(100.0g,1.0eq.)、邻苯二甲酸酐(100.0g,1.0eq.)，升温至140℃左右，保温反应，HPLC检测反应结束，缓慢降温；异丙醇(600mL,6.0V)结晶，过滤干燥得类白色固体166.0g，收率88.3％，纯度98.8％。
1HNMR(400MHz,DMSO-d6):δ7.84-7.89(t.,4H),7.12-7.19(m,2H),7.01–7.06(m,1H),6.93-6.94(d,1H),5.36-5.40(m,1H),2.80-2.87(m,2H),2.24-2.30(m,1H),2.02-2.05(m,2H),1.79-1.83(m,1H)。
LCMS(ESI):m/z 278[M+1]+
步骤2)(S)-2-(4-氧代-1,2,3,4-四氢萘-1-基)异二氢吲哚-1,3-二酮的制备
向5L烧瓶中加入化合物3(60.0g,1.0eq.)、水(600mL,10.0V)、丙酮(1200mL,20.0V)、硫酸镁(52.1g,2.0eq.)；0～10℃加入高锰酸钾(170.6g,5.0eq.)；加毕，自然升至室温，反应过夜，HPLC检测反应结束；加入EA(1000mL,16.7V)，加入水(1000mL,16.7V)，冰浴下，饱和硫代硫酸钠水溶液淬灭反应；过滤，EA淋洗滤饼；所得滤液分液，有机相用1000mL水洗1次；有机相无水硫酸钠干燥；过滤，浓缩得到粗品；向粗品中加入EA(180mL，3.0V)，石油醚(540mL，9.0V)，打浆，过滤，真空干燥，得到产物4，类白色固体48.5g，收率77.0％，纯度98.4％。
1HNMR(400MHz,DMSO-d6):δ7.87-7.95(t.,5H),7.51-7.55(m,1H),7.41–7.45(m,1H),7.24-7.26(d,1H),5.71-5.75(m,1H),2.91-2.95(m,1H),2.71-2.76(m,2H),2.28-2.30(m,1H)。
LCMS(ESI):m/z 292[M+1]+。
步骤3)2-((1S,4S)-4-羟基-1,2,3,4-四氢萘-1-基)异二氢吲哚-1,3-二酮的制备
向1L反应瓶中加入化合物4(95.0g,1.0eq.)、(R)-2-甲基-CBS-恶唑硼烷(9.0g,0.1eq.)、THF(475.0mL,5.0V)，搅拌溶清；冰浴下，滴加1M的硼烷/四氢呋喃(176mL,0.54eq.)；滴加完毕，0℃左右保温反应，HPLC检测反应结束；缓慢滴乙酸20mL淬灭反应；加入EA(500mL)，水(500mL)，萃取分液；水相用EA(300mL)反萃；合并有机相，300mL水洗1次，再用5％碳酸氢钠300mL洗1次，分液，有机相用无水硫酸钠干燥；过滤，浓缩得到产物5，类白色固体93.7g，收率97.9％，HPLC检测产物93.6％(非对映异构体为2.6％)。
1HNMR(400MHz,DMSO-d6):δ7.86-7.89(m,4H),7.54-7.56(d,1H),7.20–7.24(t,1H),7.08-7.11(t,1H),6.91-6.93(d,1H),5.38-5.42(m,2H),4.70-4.73(m,1H),2.31-2.35(m,1H),2.19-2.23(m,1H),2.06-2.19(m,1H),1.71-1.75(m,1H)。
LCMS(ESI):m/z 276[M-17]+(EM＝293)。
步骤4)2-((1S,4S)-4-乙氧基-1,2,3,4-四氢萘-1-基)异二氢吲哚-1,3-二酮的制备
向反应瓶中依次加入化合物5(83.27g,1.0eq.)、氧化银(131.6g,2.0eq.)、4A粉状分子筛(249.8g,3.0wt)、四丁基碘化铵(209.7g,2.0eq.)、二氯甲烷(832mL,10.0V)，最后加入碘乙烷(398.5g,9.0eq.)，外温升至40℃反应；HPLC中控原料小于1.0％；降温至室温，垫硅藻土过滤，滤饼用二氯甲烷(249mL，3V)淋洗，将滤液浓缩至干；加入乙酸乙酯(832mL，10V)室温打浆，过滤，滤饼用乙酸乙酯(249mL,3V)淋洗；滤液用纯化水(416mL*2，5V*2)洗2次，有机相用无水硫酸钠干燥，过滤，浓缩干得到92.8g粗品，纯度93.6％，粗品直接用于下一步。
1HNMR(400MHz,CDCl3):δ7.81-7.85(m,2H),7.71-7.75(m,2H),7.55–7.57(d,1H),7.23-7.26(t,1H),7.11-7.15(t,1H),6.92-6.94(d,1H),5.56-5.60(m,1H),4.69-4.72(m,1H),3.71-3.80(m,2H),2.36-2.46(m,2H),2.21-2.26(m,1H)，1.85-1.88(m,1H),1.30-1.33(t,3H)。
LCMS(ESI):m/z 276[M-45]+(EM＝321)。
步骤5)(1S,4S)-4-乙氧基-1,2,3,4-四氢-1-萘胺的制备
在1L三口瓶中加入化合物6(80.0g)和甲醇(640mL,8V)，加热至50℃，搅拌使其溶解。向其中加入30％甲胺水溶液(411.5g)，保持内温45-55℃搅拌反应20-24h，反应结束。冷却至室温，垫硅藻土过滤，减压浓缩滤液得粗品，柱层析纯化得化合物7(37.7g，类白色固体)，HPLC纯度98.6％，手性纯度99.7％，两步收率：80.6％。
1H NMR(400MHz,DMSO-d6):δ7.46(d,J＝7.34Hz,1H),7.29(d,J＝7.34Hz,1H),7.12-7.26(m,2H),4.37(s,1H),3.83(s,1H),3.60(d,J＝6.85Hz,1H),3.48(d,J＝6.85Hz,1H),2.01-2.19(m,2H),1.87(br,2H),1.65-1.75(m,1H),1.39-1.52(m,1H),1.14(d,J＝6.97Hz,3H)。
LCMS(ESI):m/z 192[M+H]+。

Claims (11)

  1. 制备式I所示化合物或其盐的方法，
    所述方法包括式C所示化合物在(R)-2-甲基-CBS-恶唑硼烷条件下反应形成式D所示化合物的步骤，
    其中，R1选自卤素、硝基、氰基、C1-6烷基或C1-6烷氧基，所述烷基或烷氧基任选被一个或多个选自卤素、氧代、硝基、氰基、C1-6烷基或C1-6烷氧基所取代，n为0、1、2或3，R2选自氢、C1-6烷基、C3-6环烷基，所述烷基或环烷基任选被一个或多个选自卤素、氧代、硝基、氰基、C1-6烷基、C1-6烷氧基或C3-6环烷基所取代。
  2. 如权利要求1所述的方法，其中(R)-2-甲基-CBS-恶唑硼烷与式C所示化合物的摩尔量比1:10～1:1，优选1:10。
  3. 如权利要求1或2所述的方法，其还包括式B所示化合物在氧化剂条件下反应形成式C所示化合物，
    其中R1和n如权利要求1中定义。
  4. 如权利要求3所述的方法，其中所述氧化剂选自高锰酸钾或次氯酸钠。
  5. 如权利要求1-4任一项所述的方法，其还包括式A所示化合物与邻苯二甲 酸酐反应形成式B所示化合物的步骤，
    其中R1和n如权利要求1中定义。
  6. 如权利要求1-5任一项所述的方法，其包括以下步骤：
    a)式A所示化合物与邻苯二甲酸酐反应形成式B所示化合物，
    b)式B所示化合物在氧化剂条件下反应形成式C所示化合物，
    c)式C所示化合物在(R)-2-甲基-CBS-恶唑硼烷条件下反应形成式D所示化合物，
    其中R1和n如权利要求1中定义。
  7. 如权利要求1-6任一项所述的方法，其中式I所示化合物为式I-1所示化合物，
    所述方法包括化合物C-1在(R)-2-甲基-CBS-恶唑硼烷条件下反应形成化合物D-1的步骤
  8. 如权利要求7所述的方法，还包括化合物D-1与卤代乙烷反应形成化合物E-1，随后化合物E-1脱保护基形成式I-1化合物的步骤，
  9. 式D所示化合物或其可药用盐，
    其中，R1选自卤素、硝基、氰基、C1-6烷基或C1-6烷氧基，所述烷基或烷氧基任选被一个或多个选自卤素、氧代、硝基、氰基、C1-6烷基或C1-6烷氧基所取代，n为0、1、2或3。
  10. 式C所示化合物或其可药用盐，
    其中，R1选自卤素、硝基、氰基、C1-6烷基或C1-6烷氧基，所述烷基或烷氧基任选被一个或多个选自卤素、氧代、硝基、氰基、C1-6烷基或C1-6烷氧基所取代，n为0、1、2或3。
  11. 制备化合物AA的方法，所述方法包括权利要求1-8任一项所述的方法步骤，
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