WO2024251227A1 - 一种甲酰胺类化合物的制备方法 - Google Patents

一种甲酰胺类化合物的制备方法 Download PDF

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WO2024251227A1
WO2024251227A1 PCT/CN2024/097931 CN2024097931W WO2024251227A1 WO 2024251227 A1 WO2024251227 A1 WO 2024251227A1 CN 2024097931 W CN2024097931 W CN 2024097931W WO 2024251227 A1 WO2024251227 A1 WO 2024251227A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
acceptable salt
preparation
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English (en)
French (fr)
Inventor
姜威
彭应龙
李贝
俞强
黄建
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Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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Priority to AU2024286996A priority Critical patent/AU2024286996A1/en
Priority to EP24818758.5A priority patent/EP4725945A1/en
Priority to IL325177A priority patent/IL325177A/en
Priority to KR1020257043808A priority patent/KR20260021657A/ko
Priority to CN202480031427.XA priority patent/CN121175296A/zh
Priority to MX2025014625A priority patent/MX2025014625A/es
Publication of WO2024251227A1 publication Critical patent/WO2024251227A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicine and relates to a method for preparing a formamide compound.
  • PARP1 Poly(ADP-ribose) polymerase 1
  • PARP1 can catalyze the transfer of ADP-ribose residues from NAD+ to the target substrate to build a poly(ADP-ribose) (PAR) chain.
  • PAR chains occurs in almost all eukaryotic cells.
  • ADP-ribosylation is a post-translational modification of proteins that is widely present in various physiological and pathological processes. It refers to the binding of one or more ADP-ribose units to specific sites on proteins under the catalysis of enzymes.
  • PARP1 is the first member of the PARP superfamily, which consists of proteins with homology to PARP1. There are currently 17 members, of which 4 (PARP1, PARP2, PARP5A and PARP5B) can synthesize PAR chains. Most other enzymes in the family can only build a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs), i.e.
  • MARs mono(ADP-ribosyl)ases
  • WO2022247816A discloses the following synthetic route of formamide compounds, using compound 8a as the starting material, and obtaining compound 8 through six steps of reaction, with a total yield of 2.7%.
  • the present disclosure provides a method for preparing a compound as shown in Formula 7a or a pharmaceutically acceptable salt thereof, which has the advantages of low dosage of reaction catalyst, improved yield, controllable reaction temperature, etc.
  • the method comprises reacting a compound as shown in Formula 5a or a pharmaceutically acceptable salt thereof in the presence of carbon monoxide, a palladium catalyst and R 4 -NH 2 to obtain a compound as shown in Formula 7a or a pharmaceutically acceptable salt thereof,
  • R 1 is an amino protecting group
  • R2 is selected from halogen
  • R3 is selected from halogen
  • R4 is selected from hydrogen, C1-6 alkyl, hydroxy-substituted C1-6 alkyl, halogen-substituted C1-6 alkyl;
  • Each R 5 is independently selected from halogen, C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, hydroxy-substituted C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy, hydroxy, cyano, oxo;
  • Each R 6 is independently selected from halogen, C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, hydroxy-substituted C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy, hydroxyl, cyano;
  • n is an integer selected from 0 to 6;
  • n is selected from an integer of 0-2.
  • n is selected from 0, 1, 2, 3, 4, preferably n is selected from 0, 1, 2, and more preferably n is selected from 0, 1.
  • m is selected from 0 and 1.
  • R 2 is selected from fluorine, chlorine, bromine, and iodine, and preferably R 2 is bromine.
  • R 3 is selected from fluorine, chlorine, bromine, and iodine, and preferably R 3 is chlorine.
  • the palladium catalyst is selected from a divalent palladium catalyst.
  • the palladium catalyst is selected from palladium acetate, palladium dichloride, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, palladium trifluoroacetate, palladium pivalate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium chloride, bis(benzonitrile)palladium chloride, and bis(acetonitrile)palladium chloride.
  • the palladium catalyst is selected from palladium acetate.
  • the molar ratio of the compound represented by Formula 5a to the palladium catalyst is 1:0.1 to 1:0.0001; preferably 1:0.01 to 1:0.0005; more preferably 1:0.01 to 1:0.001; most preferably 1:0.005.
  • the compound represented by Formula 5a or a pharmaceutically acceptable salt thereof is reacted in the presence of a phosphine ligand to obtain the compound represented by Formula 7a or a pharmaceutically acceptable salt thereof.
  • the phosphine ligand is selected from triphenylphosphine, tri(o-methylphenyl)phosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2-(di-tert-butylphosphino)-2'-methylbiphenyl, 1,1'-bis(diphenylphosphino)ferrocene, ( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, bis(2-diphenylphosphinophen
  • the phosphine ligand is selected as 1,1'-bis(diphenylphosphino)ferrocene.
  • the molar ratio of the compound represented by Formula 5a to the phosphine ligand is 1:0.1 to 1:0.0001; preferably 1:0.01 to 1:0.0005; more preferably 1:0.01 to 1:0.001; most preferably 1:0.005.
  • the compound represented by Formula 5a or a pharmaceutically acceptable salt thereof is reacted in the presence of a base to obtain the compound represented by Formula 7a or a pharmaceutically acceptable salt thereof.
  • the base is selected from sodium hydroxide, sodium carbonate, cesium carbonate, triethylamine, sodium acetate or pyridine.
  • the base is sodium acetate.
  • the molar ratio of the compound represented by Formula 5a to the base is 1:5 to 1:0.5, preferably 1:5 to 1:1, more preferably and most preferably 1:2.
  • the preparation method as described in the first aspect is carried out in a solvent
  • the solvent includes but is not limited to one or more of a halogenated hydrocarbon solvent, a nitrile solvent, an amide solvent, and a sulfoxide solvent.
  • the preparation method as described in the first aspect is carried out in a solvent
  • the solvent includes but is not limited to one or more of dichloromethane, methanol, ethanol, N,N-dimethylformamide, and N,N-dimethylacetamide.
  • the preparation method as described in the first aspect is carried out in a solvent, and the solvent is methanol and N,N-dimethylformamide.
  • R 4 is selected from C 1-6 alkyl, hydroxylated C 1-6 alkyl, and halogenated C 1-6 alkyl.
  • R4 is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, halomethyl, haloethyl, halopropyl, and halobutyl.
  • R 4 is methyl
  • R1 is selected from C1 - C6 alkyl acyl, C6 - C10 aryl acyl , C1-C6 alkyl sulfonyl, C6 - C10 aryl sulfonyl, C1 - C6 alkoxycarbonyl, C6 - C10 aryloxycarbonyl, substituted or unsubstituted C7 - C12 benzyl.
  • the R 1 is selected from formyl, acetyl, benzoyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).
  • R 1 is tert-butyloxycarbonyl (Boc).
  • the preparation method as described in the first aspect can be reacting a compound as shown in Formula 5b or a pharmaceutically acceptable salt thereof to obtain a compound as shown in Formula 7b or a pharmaceutically acceptable salt thereof,
  • the preparation method according to the first aspect can be: 5 or a pharmaceutically acceptable salt thereof to obtain a compound as shown in Formula 7 or a pharmaceutically acceptable salt thereof,
  • the preparation method as described in the first aspect further comprises adding an organic acid after the reaction is completed, wherein the organic acid is selected from formic acid, acetic acid, and p-toluenesulfonic acid.
  • the preparation method as described in the first aspect further comprises adding an organic acid after the reaction is completed, wherein the organic acid is p-toluenesulfonic acid.
  • the organic acid is p-toluenesulfonic acid.
  • the conversion from the salt form to the free state can be carried out in a manner well known to those skilled in the art, such as using an appropriate base, including but not limited to sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate, potassium hydroxide, etc.
  • the present disclosure further provides a method for preparing a compound as shown in Formula 8a or a pharmaceutically acceptable salt thereof, comprising: reacting a compound as shown in Formula 7a or a pharmaceutically acceptable salt thereof to obtain a compound as shown in Formula 8a or a pharmaceutically acceptable salt thereof,
  • R 1 , R 3 , R 4 , R 5 , R 6 , n and m are as defined in the first aspect.
  • each R 5 is independently selected from C 1-6 alkyl, hydroxylated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, hydroxylated C 1-6 alkoxy, halogenated C 1-6 alkoxy.
  • each R 5 is independently selected from halogen, hydroxyl, cyano, and oxo.
  • each R 5 is independently selected from C 1-6 alkyl, hydroxylated C 1-6 alkyl, and halogenated C 1-6 alkyl.
  • each R 6 is independently selected from halogen, hydroxyl, and cyano.
  • each R 6 is independently is selected from C 1-6 alkyl, hydroxylated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, hydroxylated C 1-6 alkoxy, halogenated C 1-6 alkoxy.
  • each R 6 is independently selected from C 1-6 alkyl, hydroxylated C 1-6 alkyl, and halogenated C 1-6 alkyl.
  • the preparation method as described in the second aspect comprises reacting a compound as shown in Formula 7b or a pharmaceutically acceptable salt thereof to obtain a compound as shown in Formula 8b or a pharmaceutically acceptable salt thereof,
  • the preparation method as described in the second aspect comprises reacting the compound represented by Formula 7 or a pharmaceutically acceptable salt thereof to obtain the compound represented by Formula 8 or a pharmaceutically acceptable salt thereof,
  • the preparation method as described in the second aspect comprises the preparation method of the compound as shown in Formula 7a, 7b or 7 or a pharmaceutically acceptable salt thereof as described in the first aspect.
  • the preparation method as described in the second aspect wherein the preparation method is carried out in the presence of a palladium catalyst, a phosphine ligand, and a base.
  • the preparation method as described in the second aspect wherein:
  • the palladium catalyst can be selected from tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, palladium acetate, palladium chloride, bis(acetonitrile)palladium chloride, bis(benzonitrile)palladium chloride, chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) chloride methyl tert-butyl ether complex, methanesulfonic acid(2-dicyclohexylphosphino-2',6'-diiso
  • the phosphine ligand can be selected from 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, tri-tert-butylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2-(di-tert-butylphosphino)-2'-methylbiphenyl, 1,1'-bis(diphenylphosphino)ferrocene, ( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, bis(2-diphenylphosphinophenyl)ether, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-(dicyclohexylphos
  • the base can be selected from cesium carbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide, sodium tert-amylate, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and cesium hydroxide.
  • the molar ratio of the compound of Formula 7a to the palladium catalyst is selected from 1:0.1 to 1:0.001, preferably the molar ratio is selected from 1:0.1 to 1:0.005, and more preferably the molar ratio is selected from 1:0.1 to 1:0.01;
  • the molar ratio of the palladium catalyst to the phosphine ligand is selected from 1:10 to 1:0.1, preferably the molar ratio is selected from 1:5 to 1:0.1, and more preferably the molar ratio is selected from 1:5 to 1:1.
  • the preparation method as described in the second aspect is carried out under an inert gas atmosphere, preferably under a nitrogen atmosphere or an argon atmosphere.
  • the preparation method as described in the second aspect comprises the step of reacting the compound represented by Formula 5a or a pharmaceutically acceptable salt thereof to obtain the compound represented by Formula 7a or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a method for preparing a compound as shown in Formula 11a or a pharmaceutically acceptable salt thereof, comprising:
  • R 1 , R 4 , R 5 , R 6 , n, and m are as defined in the first aspect
  • R7 is selected from halogen
  • R 8 is selected from hydrogen, C 1-6 alkyl, hydroxy C 1-6 alkyl, halogenated C 1-6 alkyl, preferably R 8 is selected from methyl, Ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, halomethyl, haloethyl, halopropyl, halobutyl.
  • the present disclosure also provides a method for preparing a compound as shown in Formula 11b or a pharmaceutically acceptable salt thereof, comprising:
  • the present disclosure also provides a method for preparing a compound as shown in Formula 11 or a pharmaceutically acceptable salt thereof, comprising:
  • the compound of formula 11 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is Malate.
  • the preparation method disclosed in the present invention 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 salt of the compound described in the present disclosure can be selected from inorganic salts or organic salts. Including “acid” addition salts and “base” addition salts.
  • the salt formed by the acid-base reaction with the basic group (amino group) the acid includes an organic acid or an inorganic acid.
  • the salt of the compound shown in Formula 7a is p-toluenesulfonate.
  • the salt of the compound shown in Formula 9 is hydrochloride, and the salt of the compound shown in Formula 11 is fumarate.
  • 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 or include both and 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.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • hydroxy refers to an -OH group.
  • mercapto refers to a -SH group.
  • the substituents are preferably one or more of the following groups, such as halogen, oxo, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 cycloalkyl.
  • amino protecting group is a suitable group for amino protection known in the art, see the amino protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th. Ed. TW Greene & P. GMWuts), preferably, the amino protecting group can be (C 1 ⁇ C 10 alkyl or aromatic) acyl, such as formyl, acetyl, benzoyl, etc.; can be (C 1 ⁇ C 6 alkyl or C 1 ⁇ C 10 aromatic) sulfonyl; It may also be (C 1 ⁇ C 6 alkoxy or C 1 ⁇ C 10 aryloxy)carbonyl, such as Boc or Cbz; or it may be substituted or unsubstituted alkyl, such as trityl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).
  • Tr trityl
  • DMB 2,4-dimethoxybenzyl
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using Agilent 1200/1290DAD-6110/6120 Quadrupole MS LC-MS (Manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (Manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.
  • the known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Clear Blue QL-500 hydrogen generator or a HC2-SS hydrogenator.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound and the developing solvent system of the thin layer chromatography include: A: dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • compound 5 38.8 g, 92.22 mmol, 1.0 eq. was dissolved in N, N-dimethylacetamide (194 mL, 5 V) and methanol (194 mL, 5 V), palladium acetate (104 mg, 0.461 mmol, 0.005 eq.), 1,1'-bis(diphenylphosphino)ferrocene (256 mg, 0.461 mmol, 0.005 eq.), sodium acetate (15.13 g, 184.4 mmol, 2.0 eq.) and 30% methylamine ethanol solution were added, and stirred at 90-100°C under carbon monoxide conditions until the reaction was completed.

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Abstract

本公开涉及一种甲酰胺类化合物的制备方法。具体而言，本公开涉及一种如式7a所示化合物或其可药用盐的制备方法。该制备方法收率高，适合于工业化生产。

Description

一种甲酰胺类化合物的制备方法 技术领域
本公开属于医药领域，涉及制备一种甲酰胺类化合物的制备方法。
背景技术
多聚ADP核糖聚合酶1(poly(ADP-ribose)polymerase 1，PARP1)，首次被报道是在50多年前，之后逐渐被发现在DNA修复、维持基因组完整性以及调控多种代谢和信号转导过程等方面扮演着重要角色。PARP1能够催化ADP核糖残基从NAD+转移到目标底物上，构建一个多聚ADP核糖(poly(ADP-ribose)，PAR)链。PAR链的形成和清除发生在几乎所有的真核细胞中。
ADP-核糖化(ADP-ribosylation)是一种广泛存在于各种生理和病理过程的蛋白质翻译后修饰，指在酶的催化下将一个或多个ADP-核糖单元结合到蛋白质特定位点。PARP1是PARP超家族的第一个成员，该超家族由与PARP1具有同源性的蛋白质组成，现有17个成员，其中4个(PARP1、PARP2、PARP5A和PARP5B)能够合成PAR链。家族中的大多数其他酶只能构建单个ADP核糖(ADP-ribose)单元，因此被归类为单ADP核糖化酶(mono(ADP-ribosyl)ases，MARs)，即。
WO2022247816A公开了如下甲酰胺类化合物的合成路线，以化合物8a作为起始原料，经六步反应制得化合物8，总收率为2.7％。
发明内容
第一方面，本公开提供一种如式7a所示化合物或其可药用盐的制备方法，具有反应催化剂的用量低，收率提高、反应温度可控等优势。其包括如式5a所示化合物或其可药用盐在一氧化碳、钯催化剂和R4-NH2存在条件下反应得到如式7a所示化合物或其可药用盐，
其中，R1为氨基保护基；
R2选自卤素；
R3选自卤素；
R4选自氢、C1-6烷基、羟代C1-6烷基、卤代C1-6烷基；
每个R5独立地选自卤素、C1-6烷基、羟代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、羟代C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基、氧代基；
每个R6独立地选自卤素、C1-6烷基、羟代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、羟代C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基；
n选自0-6的整数；
m选自0-2的整数。
在一些实施方案中，如第一方面所述的制备方法，n选自0、1、2、3、4，优选n选自0、1、2，更优选你选自0、1。
在一些实施方案中，如第一方面所述的制备方法，m选自0、1。
在一些实施方案中，如第一方面所述的制备方法，R2选自氟、氯、溴、碘，优选R2为溴。
在一些实施方案中，如第一方面所述的制备方法，R3选自氟、氯、溴、碘，优选R3为氯。
在一些实施方案中，如第一方面所述的制备方法，所述钯催化剂选自二价钯催化剂。
在一些实施方案中，如第一方面所述的制备方法，所述钯催化剂选自醋酸钯、二氯化钯、三(二亚苄基丙酮)二钯、双(二亚芐基丙酮)钯、三氟乙酸钯、新戊酸钯、四(三苯基膦)钯、双(三苯基膦)氯化钯、双(苯腈)氯化钯、双(乙腈)氯化钯。
在一些实施方案中，如第一方面所述的制备方法，所述所述钯催化剂选自醋酸钯。
在一些实施方案中，如第一方面所述的制备方法，所述如式5a所示化合物与钯催化剂的摩尔比为1:0.1～1:0.0001；优选1:0.01～1:0.0005；更优选1:0.01～1:0.001；最优选为1:0.005。
在一些实施方案中，如第一方面所述的制备方法，如式5a所示化合物或其可药用盐在膦配体的存在下反应得到如式7a所示化合物或其可药用盐。
在一些实施方案中，如第一方面所述的制备方法，所述膦配体选自三苯基膦、三(邻甲基苯基)磷、三叔丁基膦、三环己基膦、2-(二环己基膦基)联苯、2-(二叔丁基膦)联苯、2-双环己基膦-2'-甲基联苯、2-(二-叔丁膦)-2'-甲基联苯、1,1'-双(二苯基膦)二茂铁、(±)-2,2'-双-(二苯膦基)-1,1'-联萘、4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(2-二苯基磷苯基)醚、2-双环已基膦-2',6'-二异丙氧基联、2-二环己基磷-2',4',6'-三异丙基联苯、2-(二环己基膦基)联苯、2-(二叔丁基膦)联苯、2-二环己膦基-2'-(N,N-二甲胺)联苯、2-双环己基膦-2',6'-二甲氧基联苯、2-(二叔丁基膦)-3,6-二甲氧基-2'-4'-6'三异丙基-1,1'-双苯基、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦、[(4-(N,N-二甲氨基)苯基]二叔丁基膦、2-二叔丁基磷-3,4,5,6-四甲基-2',4',6'-三异丙基联苯、1,2-双(二苯膦)乙烷、1,3-双(二苯膦)丙烷、1,4-双(二苯膦)丁烷。
在一些实施方案中，如第一方面所述的制备方法，所述膦配体选为1,1'-双(二苯基膦)二茂铁。
在一些实施方案中，如第一方面所述的制备方法，所述如式5a所示化合物与膦配体的摩尔比为1:0.1～1:0.0001；优选1:0.01～1:0.0005；更优选1:0.01～1:0.001；最优选为1:0.005。
在一些实施方案中，如第一方面所述的制备方法，如式5a所示化合物或其可药用盐在碱的存在下反应得到如式7a所示化合物或其可药用盐。
在一些实施方案中，如第一方面所述的制备方法，所述碱选自氢氧化钠、碳酸钠、碳酸铯、三乙胺、醋酸钠或吡啶。
在一些实施方案中，如第一方面所述的制备方法，所述碱为醋酸钠。
在一些实施方案中，如第一方面所述的制备方法，所述如式5a所示化合物与碱的摩尔比为1:5～1:0.5，优选为1:5～1:1，更优选为最优选为1:2。
在一些实施方案中，如第一方面所述的制备方法，所述制备方法在溶剂中进行，所述溶剂包括但不限于卤代烃类溶剂、腈类溶剂、酰胺类溶剂、亚砜类溶剂中的一种或几种。
在一些实施方案中，如第一方面所述的制备方法，所述制备方法在溶剂中进行，所述溶剂包括但不限于二氯甲烷、甲醇、乙醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中一种或几种。
在一些实施方案中，如第一方面所述的制备方法，所述制备方法在溶剂中进行，所述溶剂为甲醇和N,N-二甲基甲酰胺。
在一些实施方案中，如第一方面所述的制备方法，所述R4选自C1-6烷基、羟代C1-6烷基、卤代C1-6烷基。
在一些实施方案中，如第一方面所述的制备方法，所述R4选自甲基、乙基、丙基、丁基、羟代甲基、羟代乙基、羟代丙基、羟代丁基、卤代甲基、卤代乙基、卤代丙基、卤代丁基。
在一些实施方案中，如第一方面所述的制备方法，所述R4为甲基。
在一些实施方案中，如第一方面所述的制备方法，所述R1选自C1～C6烷基酰基、C6～C10芳基酰基、C1～C6烷基磺酰基、C6～C10芳基磺酰基、C1～C6烷氧基羰基、C6～C10芳基氧基羰基、取代或未取代的C7～C12苄基。
在一些实施方案中，如第一方面所述的制备方法，所述R1选自甲酰基、乙酰基、苯甲酰基、叔丁氧羰基(Boc)、苄氧基羰基(Cbz)、2,4-二甲氧基苄基(DMB)、对甲氧基苄基(PMB)或苄基(Bn)。
在一些实施方案中，如第一方面所述的制备方法，所述R1为叔丁氧羰基(Boc)。
在一些实施方案中，如第一方面所述的制备方法，所述制备方法可以是将如式5b所示化合物或其可药用盐反应得到如式7b所示化合物或其可药用盐，
在一些实施方案中，如第一方面所述的制备方法，所述制备方法可以是将如式 5所示化合物或其可药用盐反应得到如式7所示化合物或其可药用盐，
在一些实施方案中，如第一方面所述的制备方法，所述制备方法还包括在反应结束后，加入有机酸，其中所述有机酸选自甲酸、醋酸、对甲基苯磺酸。
在一些实施方案中，如第一方面所述的制备方法，所述制备方法还包括在反应结束后，加入有机酸，其中所述有机酸为对甲基苯磺酸。通过加入有机酸，形成相应的盐，可以增加产物的结晶性，除掉反应中生成的杂质和催化剂配体等，便于后处理和纯化。从盐型转化为游离态可通过本领域技术人员熟知的方式进行，例如使用适当的碱，包括但不限于碳酸氢钠、碳酸钠、氢氧化钠、碳酸氢钾、碳酸钾、氢氧化钾等。
第二方面，本公开还提供一种如式8a所示化合物或其可药用盐的制备方法，其包括：将如式7a所示化合物或其可药用盐反应得到如8a所示化合物或其可药用盐，
其中，R1、R3、R4、R5、R6、n、m如第一方面中所定义。
在一些实施方案中，如第一或第二方面所述的制备方法，其中，每个R5独立地选自C1-6烷基、羟代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、羟代C1-6烷氧基、卤代C1-6烷氧基。
在一些实施方案中，如第一或第二方面所述的制备方法，其中，每个R5独立地选自卤素、羟基、氰基、氧代基。
在一些实施方案中，如第一或第二方面所述的制备方法，其中，每个R5独立地选自C1-6烷基、羟代C1-6烷基、卤代C1-6烷基。
在一些实施方案中，如第一或第二方面所述的制备方法，其中，每个R6独立地选自卤素、羟基、氰基。
在一些实施方案中，如第一或第二方面所述的制备方法，其中，每个R6独立 地选自C1-6烷基、羟代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、羟代C1-6烷氧基、卤代C1-6烷氧基。
在一些实施方案中，如第一或第二方面所述的制备方法，其中，每个R6独立地选自C1-6烷基、羟代C1-6烷基、卤代C1-6烷基。
在一些实施方案中，如第二方面所述的制备方法，其包括，将如式7b所示化合物或其可药用盐反应得到如式8b所示化合物或其可药用盐，
在一些实施方案中，如第二方面所述的制备方法，其包括将式7所示化合物或其可药用盐反应得到如式8所示化合物或其可药用盐，
在一些实施方案中，如第二方面所述的制备方法，其中，包含第一方面所述的制备如式7a、7b或7所示化合物或其可药用盐的制备方法。
在一些实施方案中，如第二方面所述的制备方法，其中，所述制备方法在钯催化剂、膦配体、碱存在的条件下反应。
在一些实施方案中，如第二方面所述的制备方法，其中，
所述钯催化剂可选自三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、醋酸钯、氯化钯、双(乙腈)氯化钯、双(苯腈)氯化钯、氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)、(2-二环己膦-2',6'-二异丙氧基-1,1'-联苯)[2-(2-氨基乙基苯基)]氯化钯(II)甲基叔丁基醚络合物、甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)，
所述膦配体可选自2-双环已基膦-2',6'-二异丙氧基联苯、三叔丁基膦、三环己基膦、2-双环己基膦-2'-甲基联苯、2-(二-叔丁膦)-2'-甲基联苯、1,1'-双(二苯基膦)二茂铁、(±)-2,2'-双-(二苯膦基)-1,1'-联萘、4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(2-二苯基磷苯基)醚、2-二环己基磷-2',4',6'-三异丙基联苯、2-(二环己基膦基)联苯、2-(二叔丁基膦)联苯、2-二环己膦基-2'-(N,N-二甲胺)联苯、2-双环己基膦-2',6'-二甲氧基 联苯、2-(二叔丁基膦)-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-双苯基、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦、[(4-(N,N-二甲氨基)苯基]二叔丁基膦、2-二叔丁基磷-3,4,5,6-四甲基-2',4',6'-三异丙基联苯，
所述碱可选自碳酸铯、碳酸钾、磷酸钾、叔丁醇钠、叔戊醇钠、叔丁醇钾、六甲基二硅基胺基锂、六甲基二硅基胺基钠、六甲基二硅基胺基钾、氢氧化铯。
在一些实施方案中，如第二方面所述的制备方法，所述如式7a所述的化合物与钯催化剂的摩尔比选自1:0.1～1:0.001，优选摩尔比选自1:0.1～1:0.005，更优选摩尔比选自1:0.1～1:0.01；
所述钯催化剂与膦配体的摩尔比选自1:10～1:0.1，优选摩尔比选自1:5～1:0.1，更优选摩尔比选自1:5～1:1。
在一些实施方案中，如第二方面所述的制备方法，所述制备方法在惰性气体气氛下进行，优选在氮气氛或氩气氛下进行。
在一些实施方案中，如第二方面所述的制备方法，其包括将式5a所示化合物或其可药用盐反应得到如式7a所示化合物或其可要盐的步骤。
第三方面，本公开还提供了一种如式11a所示化合物或其可药用盐的制备方法，其包括
(1)根据第二方面所述的制备方法制得如8a所示的化合物或其可药用盐；
(2)使用如式8a所示化合物或其可药用盐制备如式11a所示化合物或其可药用盐；
其中，R1、R4、R5、R6、n、m如第一方面中所定义；
R7选自卤素；
R8选自氢、C1-6烷基、羟代C1-6烷基、卤代C1-6烷基，优选所述R8选自甲基、 乙基、丙基、丁基、羟代甲基、羟代乙基、羟代丙基、羟代丁基、卤代甲基、卤代乙基、卤代丙基、卤代丁基。
第四方面，本公开还提供了一种如式11b所示化合物或其可药用盐的制备方法，其包括
(1)根据第二方面所述的制备方法制得如8b所示的化合物或其可药用盐；
(2)使用如式8b所示化合物或其可药用盐制备如式11b所示化合物或其可药用盐；
第五方面，本公开还提供了一种如式11所示化合物或其可药用盐的制备方法，其包括
(1)根据第二方面所述的制备方法制得如8所示的化合物或其可药用盐；
(2)使用如式8所示化合物或其可药用盐制备如式11所示化合物或其可药用盐；
在一些实施方案中，所述式11所述化合物或其可药用盐，其中可药用盐为富 马酸盐。
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的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7a所示化合物的盐为对甲苯磺酸盐。在一些实施方案中，式9所示化合物的盐为盐酸盐，式11所示化合物的盐为富马酸盐。
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，键可以为或或者同时包含和两种构型。
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“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“羟基”指-OH基团。
术语“巯基”指-SH基团。
术语“羧基”指-C(O)OH。
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～C6烷基、C1～C6烷氧基或C1～C6环烷基。
“氨基保护基”是本领域已知的适当的用于氨基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5Th.Ed.T.W.Greene&P.G.M.Wuts)中的氨基保护基团，优选地，所述的氨基保护基可以是(C1～C10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基等；可以是(C1～C6烷基或C1～C10芳基)磺酰基； 也可以是(C1～C6烷氧基或C1～C10芳基氧基)羰基，例如：Boc或Cbz；还可以是取代或非取代的烷基，例如：三苯甲基(Tr)、2,4-二甲氧基苄基(DMB)、对甲氧基苄基(PMB)或苄基(Bn)。
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。
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核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)。waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489液相色谱仪。
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1 (3,6-二氯吡啶-2-基)甲醇(化合物2)的制备
在烧瓶中，加入化合物1(57.6g，0.3mol，1.0eq.)和乙二醇二甲醚(400mL，7V)，冰水冷却，滴入N-甲基吗啉(38.23g，0.378mol，1.26eq.)和氯甲酸异丁酯(51.22g，0.375mol，1.25eq.)，搅拌，过滤，滤液记为溶液A；在另一烧瓶中，加入水(375mL，6.5V)、乙二醇二甲醚(375mL，6.5V)和硼氢化钠(25.31g，0.669mol，2.23eq.)，滴入溶液A，搅拌至反应结束。加入水和乙酸乙酯，分出有机相，干燥，浓缩，得到53.5g化合物2，为黄色油状物，收率100％，纯度96.4％。
实施例2 6-溴-2-(溴甲基)-3-氯吡啶(化合物3)的制备
在烧瓶中，加入化合物2(52.0g，0.292mol，1.0eq.)和33％氢溴酸醋酸溶液(501.4g，2.05mol，7eq.)，升至105～110℃，HPLC跟踪至原料转化完全。降至室温，加入水，过滤，干燥，得到75.6g化合物3，收率90.7％，纯度98.02％。
实施例3 (R)-3-(((6-溴-3-氯吡啶-2-基)甲氧基)甲基)哌嗪-1-甲酸叔丁酯(化合物5)的制备
在烧瓶中，化合物3(31.83g,147.18mmol,1.2eq.)溶于四氢呋喃(350mL,10V)，冰水冷却，加入60％氢化钠(7.36g,183.98mmol,1.5eq.)，搅拌均匀，滴入化合物4(35.00g,122.65mmol,1.0eq.)的四氢呋喃(175mL,5V)溶液，搅拌至反应结束。加入饱和氯化铵水溶液，乙酸乙酯萃取，浓缩，得到44.04g化合物5，收率85.3％。
实施例4 (R)-3-(((3-氯-6-(甲胺甲酰基)吡啶-2-基)甲氧基)甲基)哌嗪-1-甲酸叔丁酯4-甲基苯磺酸盐(化合物6)的制备
在压力瓶中，化合物5(38.8g,92.22mmol,1.0eq.)溶于N,N-二甲基乙酰胺(194mL,5V)和甲醇(194mL,5V)，加入醋酸钯(104mg,0.461mmol,0.005eq.)、1,1'-双(二苯基膦)二茂铁(256mg,0.461mmol，0.005eq.)、醋酸钠(15.13g,184.4mmol,2.0eq.)和30％甲胺乙醇溶液，一氧化碳条件下于90～100℃搅拌至反应结束。加入饱和碳酸氢钠溶液，乙酸乙酯萃取，有机相中加入4-甲基苯磺酸一水合物，搅拌过滤，干燥，得44.80g化合物6，收率85％，纯度98.3％。
实施例5 (R)-3-(((3-氯-6-(甲胺甲酰基)吡啶-2-基)甲氧基)甲基)哌嗪-1-甲酸叔丁酯(化合物7)的制备
在烧瓶中，加入化合物6(26.0g，45.53mmol，1.0eq.)和乙酸乙酯(130mL，5V)，搅拌均匀，分批加入饱和碳酸氢钠(78mL，3V)，溶解澄清，分出 有机相，浓缩，得到17.6g化合物7，收率96.92％，纯度96.7％。
实施例6 (R)-9-(甲胺甲酰基)-1,2,4a,5-四氢-7H-吡嗪并[2,1-c]吡啶并[3,2-e][1,4]氧氮杂卓-3(4H)-甲酸叔丁酯(化合物8)的制备
在三口烧瓶中，加入化合物7(17.6g，44.12mmol，1.0eq.)、三(二亚苄基丙酮)二钯(1.21g，1.32mmol，0.03eq.)、2-双环已基膦-2',6'-二异丙氧基联苯(1.24g，2.66mol，0.06q.)、碳酸铯(17.25g，52.94mmol，1.2eq.)和二氧六环(141mL，8V)，置换氮气三次，100～110℃搅拌至反应结束。加入乙酸乙酯和水，分出有机相有机相中加入硅基金属消除剂MS001，搅拌过滤，浓缩，得到19.74g化合物8，纯度95.65％，直接用于下一步反应。
实施例7 (R)-N-甲基-1,2,3,4,4a,5-六氢-7H-吡嗪并[2,1-c]吡啶并[3,2-e][1,4]氧氮杂卓-9-甲酰胺二盐酸盐(化合物9c)的制备
在烧瓶中，加入化合物8粗品(19.74g)和甲醇(127mL，6.5V)，搅拌溶解，滴入4N HCl/二氧六环室温搅拌至反应结束。浓缩得到13.85g化合物9c，两步收率93.6％，纯度98.48％。
实施例8 (R)-3-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-N-甲基-1,2,3,4,4a,5-六氢-7H-吡嗪并[2,1-c]吡啶并[3,2-e][1,4]氧氮杂卓-9-甲酰胺(化合物11)的制备
在烧瓶中，加入化合物9c(13.0g，38.78mmol，1.0eq.)、化合物10(8.63g，38.76mmol，1.0eq.)、碘化钠(581mg，3.88mmol，0.1eq.)、N,N-二甲基甲酰胺(43mL，5V)和N,N-二异丙基乙胺(27.55g，213.16mmol，5.5eq.)，50～60℃搅拌，至反应结束。加入水，，过滤，干燥，得到16.08g化合物11，收率92.4％，纯度97.75％。
实施例9 (R)-3-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-N-甲基-1,2,3,4,4a,5-六氢-7H-吡嗪并[2,1-c]吡啶并[3,2-e][1,4]氧氮杂卓-9-甲酰胺富马酸盐(化合物12)的制备
在烧瓶中，加入化合物11(15.48g，34.51mmol，1.0eq.)、富马酸(4.4g，37.91mmol，1.1eq.)、乙醇(464mL，30V)和水(46mL，3V)，85～95℃搅拌至溶解澄清，趁热过滤，滤液室温搅拌析出固体过滤，干燥，得到16.60g化合物12收率85.2％，纯度99.22％，手性纯度100％。

Claims (18)

  1. 一种如式7a所示化合物或其可药用盐的制备方法，其包括如式5a所示化合物或其可药用盐在一氧化碳、钯催化剂和R4-NH2存在条件下反应得到如式7a所示化合物或其可药用盐，
    其中，R1为氨基保护基；
    R2选自卤素；
    R3选自卤素；
    R4选自氢、C1-6烷基、羟代C1-6烷基、卤代C1-6烷基；
    每个R5独立地选自卤素、C1-6烷基、羟代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、羟代C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基、氧代基；
    每个R6独立地选自卤素、C1-6烷基、羟代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、羟代C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基；
    n选自0-6的整数；
    m选自0-2的整数。
  2. 根据权利要求1所述的制备方法，其中，所述钯催化剂选自二价钯催化剂，优选钯催化剂选自醋酸钯、二氯化钯、三(二亚苄基丙酮)二钯、双(二亚芐基丙酮)钯、三氟乙酸钯、新戊酸钯、四(三苯基膦)钯、双(三苯基膦)氯化钯、双(苯腈)氯化钯、双(乙腈)氯化钯。
  3. 根据权利要求1所述的制备方法，其中所述如式5a所示化合物与钯催化剂的摩尔比为1:0.1～1:0.0001；优选1:0.01～1:0.0005；更优选1:0.01～1:0.001，最优选为1:0.005。
  4. 根据权利要求1所述的制备方法，其中，如式5a所示化合物或其可药用盐 在膦配体的存在下反应得到如式7a所示化合物或其可药用盐。
  5. 根据权利要求4所述的制备方法，其中，所述膦配体选自三苯基膦、三(邻甲基苯基)磷、三叔丁基膦、三环己基膦、2-(二环己基膦基)联苯、2-(二叔丁基膦)联苯、2-双环己基膦-2'-甲基联苯、2-(二-叔丁膦)-2'-甲基联苯、1,1'-双(二苯基膦)二茂铁、(±)-2,2'-双-(二苯膦基)-1,1'-联萘、4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(2-二苯基磷苯基)醚、2-双环已基膦-2',6'-二异丙氧基联、2-二环己基磷-2',4',6'-三异丙基联苯、2-(二环己基膦基)联苯、2-(二叔丁基膦)联苯、2-二环己膦基-2'-(N,N-二甲胺)联苯、2-双环己基膦-2',6'-二甲氧基联苯、2-(二叔丁基膦)-3,6-二甲氧基-2'-4'-6'三异丙基-1,1'-双苯基、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦、[(4-(N,N-二甲氨基)苯基]二叔丁基膦、2-二叔丁基磷-3,4,5,6-四甲基-2',4',6'-三异丙基联苯、1,2-双(二苯膦)乙烷、1,3-双(二苯膦)丙烷、1,4-双(二苯膦)丁烷，优选膦配体选为1,1'-双(二苯基膦)二茂铁。
  6. 根据权利要求4所述的制备方法，其中，所述如式5a所示化合物与膦配体的摩尔比为1:0.1～1:0.0001；优选1:0.01～1:0.0005；更优选1:0.01～1:0.001；最优选为1:0.005。
  7. 根据权利要求1所述的制备方法，其中，如式5a所示化合物或其可药用盐在碱的存在下反应得到如式7a所示化合物或其可药用盐。
  8. 根据权利要求7所述的制备方法，其中，所述碱选自氢氧化钠、碳酸钠、碳酸铯、三乙胺、醋酸钠或吡啶。
  9. 根据权利要求7所述的制备方法，其中，所述如式5a所示化合物与碱的摩尔比为1:5～1:0.5，优选为1:5～1:1，更优选为最优选为1:2。
  10. 根据权利要求1所述的制备方法，其中，所述R4选自C1-6烷基、羟代C1- 6烷基、卤代C1-6烷基，优选所述R4选自甲基、乙基、丙基、丁基、羟代甲基、羟代乙基、羟代丙基、羟代丁基、卤代甲基、卤代乙基、卤代丙基、卤代丁基。
  11. 根据权利要求1所述的制备方法，其中，R1选自C1～C6烷基酰基、C6～C10芳基酰基、C1～C6烷基磺酰基、C6～C10芳基磺酰基、C1～C6烷氧基羰基、C6～C10芳基氧基羰基、取代或未取代的C7～C12苄基，优选R1选自甲酰基、乙酰基、苯甲酰基、叔丁氧羰基(Boc)、苄氧基羰基(Cbz)、2,4-二甲氧基苄基(DMB)、对甲氧基苄基(PMB)或苄基(Bn)，更优选R1为叔丁氧羰基(Boc)。
  12. 根据权利要求1所述的制备方法，其包括将如式5b所示化合物或其可药用盐反应得到如式7b所示化合物或其可药用盐，
  13. 根据权利要求1所述的制备方法，其包括将如式5所示化合物或其可药用盐反应得到如式7所示化合物或其可药用盐，
  14. 一种如式8a所示化合物或其可药用盐的制备方法，其中，包含权利要求1所述的制备如式7a所示化合物或其可药用盐的制备方法，
    其中，R1、R3、R4、R5、R6、n、m如权1中所定义。
  15. 根据权利要求14所述的制备方法，其包括：将如式7b所示化合物或其可药用盐反应得到如式8b所示化合物或其可药用盐，
  16. 根据权利要求14所述的制备方法，其包括将式7所示化合物或其可药用盐反应得到如式8所示化合物或其可药用盐，
  17. 一种如式11a所示化合物或其可药用盐的制备方法，其包括
    (1)根据权利要求14所述的制备方法制得如8a所示的化合物或其可药用盐；
    (2)使用如式8a所示化合物或其可药用盐制备如式11a所示化合物或其可药用盐；
    其中，R1、R4、R5、R6、n、m如权1中所定义；
    R7选自卤素；
    R8选自氢、C1-6烷基、羟代C1-6烷基、卤代C1-6烷基，优选所述R8选自甲基、乙基、丙基、丁基、羟代甲基、羟代乙基、羟代丙基、羟代丁基、卤代甲基、卤代乙基、卤代丙基、卤代丁基。
  18. 一种如式11所示化合物或其可药用盐的制备方法，其包括
    (1)根据权利要求16所述的制备方法制得如8所示的化合物或其可药用盐；
    (2)使用如式8所示化合物或其可药用盐制备如式11所示化合物或其可药用盐；
PCT/CN2024/097931 2023-06-08 2024-06-07 一种甲酰胺类化合物的制备方法 Ceased WO2024251227A1 (zh)

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