WO2021175155A1 - 噻吩并嘧啶类衍生物及其制备方法 - Google Patents

噻吩并嘧啶类衍生物及其制备方法 Download PDF

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WO2021175155A1
WO2021175155A1 PCT/CN2021/078037 CN2021078037W WO2021175155A1 WO 2021175155 A1 WO2021175155 A1 WO 2021175155A1 CN 2021078037 W CN2021078037 W CN 2021078037W WO 2021175155 A1 WO2021175155 A1 WO 2021175155A1
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formula
compound represented
compound
solvent
palladium
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PCT/CN2021/078037
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English (en)
French (fr)
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王玉光
吴添智
张农
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广州再极医药科技有限公司
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Priority to EP21764740.3A priority Critical patent/EP4116305A1/en
Priority to US17/909,753 priority patent/US20230144170A1/en
Publication of WO2021175155A1 publication Critical patent/WO2021175155A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J21/00—Catalysts comprising the elements, oxides, or hydroxides of magnesium, boron, aluminium, carbon, silicon, titanium, zirconium, or hafnium
    • B01J21/18—Carbon
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/42—Platinum
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to a thienopyrimidine derivative and a preparation method thereof.
  • Pyrimidine-2-Ammonia is a strong JAK, FGFR, FLT3 kinase inhibitor, and has good application prospects in the treatment of tumors, immune system diseases, allergic diseases and cardiovascular diseases.
  • This compound is described in patent CN106366093A and has the following chemical structure:
  • CN106366093A discloses the preparation method of the compound:
  • NaBH 4 is sodium borohydride
  • MnO 2 is manganese dioxide
  • NIS is N-iodosuccinimide
  • TFA is trifluoroacetic acid
  • Pd(dppf)Cl 2 is [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride
  • DIAD is diisopropyl azodicarboxylate
  • PPh 3 triphenylphosphine
  • Pd/C palladium on carbon
  • Pd 2 (dba) 3 is Tris(dibenzylideneacetone)dipalladium
  • RuPhos is 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl.
  • the above method has the problems of a large number of reaction steps, low yield, and requires column chromatography for separation and purification, and is not suitable for industrial scale-up production. Therefore, it is necessary to improve its preparation method.
  • the technical problem to be solved by the present invention is to overcome the disadvantages of low yield and unsuitability for industrial production in the existing preparation methods of thienopyrimidine derivatives, and to provide a thienopyrimidine derivative and a preparation method thereof .
  • the present invention provides a new synthesis idea.
  • the preparation method of the present invention can increase the product yield and reduce the production cost; at the same time, the reaction conditions are simple, the process operability is strong, which is beneficial to industrial production and reduces the generation of three wastes.
  • the present invention provides a method for preparing a compound represented by formula B, which comprises the following steps: under a protective gas atmosphere, in a solvent, in the presence of a catalyst and a base, a compound represented by formula C is combined with a compound represented by formula K
  • the compound can be subjected to the coupling reaction shown below;
  • the catalyst includes a palladium compound and a phosphine ligand;
  • R is H or C 1 -C 3 alkyl.
  • X is preferably Br.
  • R is preferably a C 1 -C 3 alkyl group, more preferably a methyl group.
  • the solvent can be a conventional solvent in the art, preferably a mixed solvent of water and an organic solvent.
  • the organic solvent is preferably ether solvent, more preferably dioxane.
  • the volume ratio of water and organic solvent may be a conventional volume ratio in the art, preferably 1:1-1:10, more preferably 1:2-1:5 (for example, 1:3.3).
  • the base may be a conventional base in the art, preferably an inorganic base, and more preferably an alkali metal carbonate (such as sodium carbonate and/or potassium carbonate).
  • an alkali metal carbonate such as sodium carbonate and/or potassium carbonate.
  • the palladium compound may be a conventional palladium compound in the art, such as zero-valent palladium or a divalent palladium salt, and the divalent palladium salt is preferably PdCl 2 And/or Pd(OAc) 2 ;
  • the phosphine ligand may be a conventional phosphine ligand in the art, preferably 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos) and/or 1,1'-bis(diphenylphosphine)ferrocene, more preferably 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl.
  • the palladium compound and the phosphine ligand can be in the conventional form in the art, for example, the palladium compound and the phosphine ligand
  • the compound is added in the form of a complex, or the palladium compound and the phosphine ligand are added in the form of a mixture;
  • the complex is, for example, a complex of zero-valent palladium and a phosphine ligand, And/or, a complex form of a divalent palladium salt and a phosphine ligand.
  • the complex form of the divalent palladium salt and the phosphine ligand may be Pd(dppf)Cl 2 .
  • the molar concentration of the compound represented by formula C in the solvent can be a conventional molar concentration in the art, preferably 0.1-0.5 mol/L, more It is preferably 0.1-0.3 mol/L (for example, 0.19 mol/L).
  • the molar ratio of the compound represented by formula K to the compound represented by formula C may be a conventional molar ratio in the art, preferably 1:1. 3:1, more preferably 1:1-2:1 (e.g. 1.3:1).
  • the molar ratio of the base to the compound represented by formula C can be a conventional molar ratio in the art, preferably 1:1-3:1, more Preferably 1:1-2:1 (e.g. 1.6:1).
  • the molar ratio of the palladium compound to the compound represented by formula C can be a conventional molar ratio in the art, preferably 1:50-1:150 (E.g. 1:117), more preferably 1:100-1:120.
  • the molar ratio of the phosphine ligand to the palladium compound can be a conventional molar ratio in the art, preferably 1:1-5:1, more preferably 1:1-3:1 (e.g. 2.4:1).
  • the protective gas may be a conventional protective gas in the art, such as nitrogen and/or argon, preferably nitrogen.
  • the coupling reaction temperature can be a conventional reaction temperature in the art, preferably 50-100°C, more preferably 65-75°C (for example, 70°C).
  • the progress of the coupling reaction can be monitored by conventional means in the art (for example, TLC, LC-MS or HPLC, etc.).
  • the time is not particularly limited, and the content of the compound represented by formula C in the reaction system no longer changes.
  • the coupling reaction time is preferably 3-7h, more preferably 3-5h (for example, 4h) .
  • the post-treatment of the coupling reaction may also include the following steps: mixing the reaction solution with ammonia and water, extracting with an organic solvent, washing the resulting organic phase, removing palladium in the organic phase, filtering, concentrating the filtrate, and removing the concentrate. Just beating, filtering, and drying.
  • the volume ratio of the ammonia water to the solvent is preferably 1:5-1:8 (for example, 1:6.5). Before the ammonia water is mixed with the reaction liquid, the temperature is preferably lowered to 30-50°C (for example, 40°C). After the ammonia water is mixed with the reaction liquid, it is preferably stirred for 7-10 hours (for example, 8 hours).
  • the volume ratio of the water to the solvent is preferably 1:1-4:1 (for example, 2.2:1).
  • the temperature is preferably lowered to 10-30°C (for example, 20°C).
  • the organic solvent for extraction is preferably a halogenated hydrocarbon solvent (for example, dichloromethane).
  • the washing is preferably washed with water and saturated brine in sequence.
  • the reagent used for removing the palladium in the organic phase can be a conventional reagent in the art, preferably 3-mercaptopropyl ethyl sulfide-based silica.
  • the beating is performed sequentially with an ether solvent (for example, methyl tert-butyl ether) and an alcohol solvent (for example, ethanol).
  • the drying is preferably vacuum drying.
  • the method for preparing the compound represented by formula B may further include the following steps: in an organic solvent, in the presence of a base, the compound represented by formula E and the compound represented by formula D are subjected to the substitution reaction shown below, To obtain the compound represented by formula C;
  • the organic solvent may be a conventional solvent in the art, preferably an alcohol solvent, and more preferably n-butanol.
  • the base can be a conventional base in the art, preferably an organic base, more preferably an organic amine, and further preferably N,N-diisopropylethylamine (DIPEA ).
  • DIPEA N,N-diisopropylethylamine
  • the molar concentration of the compound represented by formula E in the organic solvent can be a conventional molar concentration in the art, preferably 0.3-1.0 mol/L, More preferably, it is 0.5-0.7 mol/L (e.g., 0.65 mol/L).
  • the molar ratio of the compound represented by formula D and the compound represented by formula E may be a conventional molar ratio in the art, preferably 1:1. 2:1, more preferably 1:1-1.5:1 (e.g., 1.3:1).
  • the temperature of the substitution reaction can be a conventional reaction temperature in the art, preferably 80°C to the boiling point temperature of the organic solvent, more preferably 95-105°C (for example, 100°C). ).
  • the progress of the substitution reaction can be monitored by conventional means in the art (for example, TLC, LC-MS or HPLC, etc.), and the time of the substitution reaction
  • the time of the substitution reaction is preferably 30-60h, more preferably 40-50h (for example, 42h).
  • the post-treatment of the substitution reaction may also include the following steps: concentrating, beating the obtained concentrate, filtering, and drying.
  • concentration can be conventional concentration in the field, preferably concentration under reduced pressure.
  • the solvent used for beating is preferably an alcohol solvent (for example, methanol).
  • the filtration can be conventional filtration in the field.
  • the drying can be conventional drying in the field, preferably vacuum drying.
  • the present invention provides a method for preparing a compound represented by formula C, which comprises the following steps: in an organic solvent, in the presence of a base, a compound represented by formula E and a compound represented by formula D are subjected to the following steps: Substitution reaction is enough;
  • X is Br or I, preferably Br;
  • R is H or C 1 -C 3 alkyl, preferably C 1 -C 3 alkyl, more preferably methyl.
  • the present invention also provides a compound represented by formula C,
  • X is Br or I, preferably Br;
  • R is H or C 1 -C 3 alkyl, preferably C 1 -C 3 alkyl, more preferably methyl.
  • the compound represented by formula C may have the following structure,
  • the present invention also provides a method for preparing a compound represented by formula I, which comprises the following steps: in an organic solvent, in the presence of a base and a catalyst, the compound represented by formula J and hydrogen are subjected to a reduction reaction as shown below , That is; the organic solvent is an ether solvent;
  • R is H or C 1 -C 3 alkyl, preferably C 1 -C 3 alkyl, more preferably methyl.
  • the ether solvent is preferably tetrahydrofuran (THF).
  • the base can be a conventional base in the art, preferably an organic base, more preferably an organic amine, and still more preferably N,N-diisopropylethylamine.
  • the catalyst may be a conventional catalyst in the art, preferably a palladium compound, more preferably palladium on carbon (for example, palladium on carbon with a mass fraction of 10%).
  • the pressure of the hydrogen may be a conventional pressure in the art, preferably 0.3-0.8 MPa, more preferably 0.4-0.6 MPa (for example, 0.5 MPa).
  • the molar ratio of the base to the compound represented by formula J is preferably 1:1-2:1, more preferably 1:1-1.5:1 ( For example 1.2:1).
  • the mass molar ratio of the catalyst to the compound represented by formula J can be a conventional mass molar ratio in the art, preferably 10-50 g/mol, more It is preferably 40-50 g/mol (for example 42 g/mol).
  • the molar concentration of the compound represented by formula J in the organic solvent can be a conventional molar concentration in the art, preferably 0.2-1.0 mol/L, More preferably, it is 0.5-0.7 mol/L (e.g., 0.65 mol/L).
  • the temperature of the reduction reaction can be a conventional reaction temperature in the art, preferably 10-40°C, more preferably 20-30°C (for example, 25°C).
  • the progress of the reduction reaction can be monitored by conventional means in the art (for example, TLC, LC-MS or HPLC, etc.), and the time of the substitution reaction
  • the reduction reaction time is preferably 90-150h, more preferably 110-130h (for example, 120h).
  • the post-treatment of the reduction reaction may also include the following steps: filtering, concentrating the filtrate to obtain a concentrate, dissolving the concentrate with a solvent, adding water to precipitate the solid, separating the solid, and drying.
  • the filtering conditions and operations can be conventional conditions and operations in the field.
  • the conditions and operations of the concentration can be conventional conditions and operations in the art, and concentration under reduced pressure is preferred.
  • a solvent is preferably an alcohol solvent (for example, ethanol).
  • the solvent used for dissolving the concentrate is preferably an alcohol solvent (for example, ethanol).
  • the temperature for dissolving the concentrate is preferably 65-75°C (for example, 70°C).
  • the water is preferably added dropwise.
  • the temperature is preferably 20-30°C (for example, 25°C).
  • the method for separating solids can be a conventional method in the field, preferably centrifugation.
  • the drying conditions and methods can be conventional conditions and methods in the art, and vacuum drying is preferred.
  • the present invention also provides a method for preparing the compound represented by formula E, which comprises the following steps:
  • X is Br or I, preferably Br;
  • R is H or C 1 -C 3 alkyl, preferably C 1 -C 3 alkyl, more preferably methyl.
  • step (2) the conditions and operations of the substitution reaction are the same as those conventionally used in this type of reaction in the art.
  • the present invention also provides a method for preparing the compound represented by formula C, which comprises the following steps:
  • X is Br or I, preferably Br;
  • R is H or C 1 -C 3 alkyl, preferably C 1 -C 3 alkyl, more preferably methyl.
  • step (2) the conditions and operation of the substitution reaction are the same as those of the aforementioned type of reaction.
  • the present invention provides a method for preparing a compound represented by formula F, which comprises the following steps: in an organic solvent, in the presence of a base, a compound represented by formula G and a compound represented by formula L are subjected to the following steps: Reaction, that's it;
  • the organic solvent may be a conventional organic solvent in the art, preferably an amide solvent (for example, N,N-dimethylformamide).
  • the base may be a conventional base in the art, preferably an inorganic base, and more preferably an alkali metal carbonate (for example, potassium carbonate).
  • an alkali metal carbonate for example, potassium carbonate
  • the molar ratio of the compound represented by formula L to the compound represented by formula G may be a conventional molar ratio in the art, preferably 1:1. 4:1, more preferably 1:1-2:1 (e.g., 1.1:1).
  • the molar ratio of the base to the compound represented by formula G can be a conventional molar ratio in the art, preferably 1:1-5:1, more Preferably 1:1-2:1 (e.g. 1.5:1).
  • the molar concentration of the compound represented by formula G in the solvent can be a conventional molar concentration in the art, preferably 0.3-0.9 mol/L, more It is preferably 0.5-0.7 mol/L (for example, 0.6 mol/L).
  • the reaction temperature can be a conventional reaction temperature in the art, preferably 50-100°C, more preferably 75-85°C (for example, 80°C).
  • the progress of the reaction can be monitored by conventional means in the art (for example, TLC, LC-MS or HPLC, etc.), and the reaction time is not particularly specified.
  • the coupling reaction time is preferably 10-30h, more preferably 16-20h (for example, 18h).
  • the post-treatment of the reaction may also include the following steps: mixing the reaction liquid with water, filtering, washing the solid, and drying. Said water is preferably added. The temperature during the mixing is preferably 10-40°C (10-20°C). After the mixing, it is preferably stirred for 1-5 hours. The washing solvent is preferably water. The drying is preferably vacuum drying.
  • the method for preparing the compound represented by formula F may further include the following steps: in the presence of pyridine, the compound represented by formula H and p-toluenesulfonyl chloride are subjected to the substitution reaction shown below to obtain the compound represented by formula G Show compound;
  • the molar ratio of the p-toluenesulfonyl chloride to the compound represented by formula H can be a conventional molar ratio in the art, preferably 1:1-4:1, more preferably 1:1-2:1 ( For example 1.5:1).
  • the mass molar ratio of the pyridine to the compound represented by formula H can be a conventional mass molar ratio in the art, preferably 0.5:1-3:1, more preferably 1:1-2:1 (e.g. 1: 1).
  • the temperature of the substitution reaction may be a conventional reaction temperature in the art, preferably 10-40°C, more preferably 20-30°C.
  • the progress of the substitution reaction can be monitored by conventional means in the art (for example, TLC, LC-MS or HPLC, etc.), and the time of the substitution reaction is not particularly limited, and the compound represented by formula H
  • the content in the reaction system does not change any more, and the time of the substitution reaction is preferably 10-30h, more preferably 15-20h (for example, 18h).
  • the post-treatment of the reaction may also include the following steps: mixing the reaction liquid with water, filtering, washing the solid, and drying. Said water is preferably added. The temperature during the mixing is preferably 10-40°C (10-20°C). After the mixing, it is preferably stirred for 1-5 hours. The washing solvent is preferably water. The drying is preferably vacuum drying.
  • the present invention provides a method for preparing a compound represented by formula D, which comprises the following steps:
  • step (2) the conditions and operations of the reduction reaction are the same as those of this type of reaction in the art.
  • the present invention provides a method for preparing a compound represented by formula C, which comprises the following steps:
  • X is Br or I, preferably Br;
  • R is H or C 1 -C 3 alkyl, preferably C 1 -C 3 alkyl, more preferably methyl.
  • step (2) the conditions and operation of the substitution reaction are the same as those of the aforementioned type of reaction.
  • the present invention provides a method for preparing a compound represented by formula B, which comprises the following steps:
  • the compound represented by formula C and the compound represented by formula K are subjected to the following coupling reaction;
  • the catalyst includes Palladium compounds and phosphine ligands;
  • X is Br or I, preferably Br;
  • R is H or C 1 -C 3 alkyl, preferably C 1 -C 3 alkyl, more preferably methyl.
  • step (2) the conditions and operation of the coupling reaction are the same as those of the aforementioned type of reaction.
  • the present invention also provides a method for preparing the compound shown in G, which includes the following steps: in the presence of pyridine, the compound shown in formula H and p-toluenesulfonyl chloride are subjected to the substitution reaction shown below;
  • the reagents and raw materials used in the present invention are all commercially available.
  • the present invention provides a new synthetic idea
  • the preparation method of the present invention can increase the yield of the product and reduce the production cost; at the same time, the reaction conditions are simple, the process operability is strong, and it is beneficial to industrial production. The generation of three wastes.
  • Example 8 4-(4-((7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1 Hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound B)
  • the temperature is controlled at 70 ⁇ 5°C to react for 4 hours. Cool down to 40 ⁇ 5°C, add ammonia water (68Kg), and stir for 8 hours. Cool down to 20 ⁇ 5°C and dilute with water (1110Kg). Dichloromethane was extracted twice (244Kg, 170Kg). Combine the organic phases, wash sequentially with water and then with saturated brine. Add 3-mercaptopropyl ethyl sulfide-based silica (4.0Kg, used to remove heavy metal palladium) into the organic phase, control the temperature at 40 ⁇ 5°C and stir for 20 hours. After filtration, the filtrate was concentrated under reduced pressure.
  • Triethylamine 25mL
  • N-BOC-4-hydroxypiperidine 5g
  • P-toluenesulfonyl chloride 7.1g was added in batches while controlling the temperature at 10 ⁇ 10°C. After the addition, the temperature is controlled at 25 ⁇ 5°C to react for 25 hours.
  • Monitoring by LC-MS showed a large amount of unreacted raw materials and the reaction liquid was black and red.

Abstract

本发明公开了一种噻吩并嘧啶类衍生物及其制备方法。本发明提供了一种如式B所示化合物的制备方法，其特征在于，其包括以下步骤：保护气体氛围下，溶剂中，在催化剂和碱的存在下，将如式C所示化合物与如式K所示化合物进行如下所示的偶联反应，即可；所述的催化剂包括钯类化合物和膦配体。本发明的制备方法可提高产物收率，降低生产成本；同时反应条件简单，工艺可操作性强，利于工业生产，减少三废的生成。

Description

噻吩并嘧啶类衍生物及其制备方法
本申请要求申请日为2020年3月6日的中国专利申请CN2020101527756的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种噻吩并嘧啶类衍生物及其制备方法。
背景技术
7-(4-氟-2-甲氧基苯基)-6-甲基-N-(1-哌啶-4-基)-1氢-吡唑-4-基)噻吩并[3,2-D]嘧啶-2-氨是一种强的JAK，FGFR，FLT3激酶抑制剂，在肿瘤、免疫系统疾病、过敏性疾病以及心血管疾病的治疗方面具有良好的应用前景。该化合物描述在专利CN106366093A并具有如下化学结构：
Figure PCTCN2021078037-appb-000001
CN106366093A公开了该化合物的制备方法：
Figure PCTCN2021078037-appb-000002
上述合成路线中，NaBH 4为硼氢化钠，MnO 2为二氧化锰，NIS为N-碘代丁二酰亚胺，TFA为三氟乙酸，Pd(dppf)Cl 2为[1,1'-双(二苯基膦基)二茂铁]二氯化钯，DIAD为偶氮二甲酸二异丙酯，PPh 3为三苯基膦，Pd/C为钯炭，Pd 2(dba) 3为三(二亚苄基丙酮)二钯，RuPhos为2-双环已基膦-2',6'-二异丙氧基联苯。
但上述方法存在反应步数较多，产率低，需要柱层析分离纯化等问题，不适合工业放大生产，所以有必要改进其制备方法。
发明内容
本发明所要解决的技术问题在于克服现有的噻吩并嘧啶类衍生物的制备方法中存在的收率低、不适合工业化生产等缺陷，而提供了一种噻吩并嘧啶类衍生物及其制备方法。本发明提供了一种新的合成思路，本发明的制备方法可提高产物收率，降低生产成本；同时反应条件简单，工艺可操作性强，利于工业生产，减少三废的生成。
本发明提供了一种如式B所示化合物的制备方法，其包括以下步骤：保护气体氛围下，溶剂中，在催化剂和碱的存在下，将如式C所示化合物与如式K所示化合物进行如下所示的偶联反应，即可；所述的催化剂包括钯类化合物和膦配体；
Figure PCTCN2021078037-appb-000003
其中，X为Br或I；
R为H或C 1-C 3烷基。
所述的如式B所示化合物的制备方法中，X优选Br。
所述的如式B所示化合物的制备方法中，R优选C 1-C 3烷基，更优选甲基。
所述的如式B所示化合物的制备方法中，所述的溶剂可为本领域常规的溶剂，优选水和有机溶剂的混合溶剂。所述的有机溶剂优选醚类溶剂，更优选二氧六环。所述的水和有机溶剂的体积比可为本领域常规的体积比，优选1:1-1:10，更优选1:2-1:5(例如1:3.3)。
所述的如式B所示化合物的制备方法中，所述的碱可为本领域常规的碱，优选无机碱，更优选碱金属碳酸盐(例如碳酸钠和/或碳酸钾)。
所述的如式B所示化合物的制备方法中，所述的钯类化合物可为本领域常规的钯类化合物，例如零价钯或二价钯盐，所述的二价钯盐优选PdCl 2和/或Pd(OAc) 2；
所述的如式B所示化合物的制备方法中，所述的膦配体可为本领域常规的膦配体，优选2-二环己基膦-2,4,6-三异丙基联苯(X-Phos)和/或1,1'-双(二苯基膦)二茂铁，更优选2-二环己基膦-2,4,6-三异丙基联苯。
所述的如式B所示化合物的制备方法中，所述的钯类化合物和所述的膦配体可为本领域常规的存在形式，例如，所述的钯类化合物和所述的膦配体以络合物的形式加入，或者，所述的钯类化合物和所述的膦配体以混合物的形式加入；所述的络合物例如零价钯和膦配体的络合物形式、和/或、二价钯盐和膦配体的络合物形式。所述的二价钯盐和膦配体的络合物形式可为Pd(dppf)Cl 2。
所述的如式B所示化合物的制备方法中，所述的如式C所示化合物在所述的溶剂中的摩尔浓度可为本领域常规的摩尔浓度，优选0.1-0.5mol/L，更优选0.1-0.3mol/L(例如0.19mol/L)。
所述的如式B所示化合物的制备方法中，所述的如式K所示化合物与所述的如式C所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-3:1，更优选1:1-2:1(例如1.3:1)。
所述的如式B所示化合物的制备方法中，所述的碱与所述的如式C所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-3:1，更优选1:1-2:1(例如1.6:1)。
所述的如式B所示化合物的制备方法中，所述的钯类化合物与所述的如式C所示化合物的摩尔比可为本领域常规的摩尔比，优选1:50-1:150(例如1:117)，更优选1:100-1:120。
所述的如式B所示化合物的制备方法中，所述的膦配体与所述的钯类化合物的摩尔比可为本领域常规的摩尔比，优选1:1-5:1，更优选1:1-3:1(例如2.4:1)。
所述的如式B所示化合物的制备方法中，所述的保护气体可为本领域常规的保护气体，例如氮气和/或氩气，优选氮气。
所述的如式B所示化合物的制备方法中，所述的偶联反应的温度可为本领域常规的反应温度，优选50-100℃，更优选65-75℃(例如70℃)。
所述的如式B所示化合物的制备方法中，所述的偶联反应的进程可通过本领域常规的手段进行监控(例如TLC、LC-MS或HPLC等)，对所述的偶联反应的时间不作特别限定，以所述的如式C所示化合物在反应体系中的含量不再变化为准，所述的偶联反应的时间优选3-7h，更优选3-5h(例如4h)。
所述的偶联反应的后处理还可包括以下步骤：将反应液与氨水、水混合，用有机溶剂萃取，洗涤所得的有机相，除去有机相中的钯，过滤，浓缩滤液，将浓缩物进行打浆，过滤，干燥即可。所述的氨水与所述的溶剂的体积比优选1:5-1:8(例如1:6.5)。所述的氨水与反应液混合前，优选降温至30-50℃(例如40℃)。所述的氨水与反应液混合后，优选搅拌7-10h(例如8h)。所述的水与所述的溶剂的体积比优选1:1-4:1(例如2.2:1)。所述的水加入前，优选降温至10-30℃(例如20℃)。所述的萃取用的有机溶剂优选卤代烃类溶剂(例如二氯甲烷)。所述的洗涤优选依次经水、饱和食盐水洗涤。所述的除 去有机相中的钯所用的试剂可为本领域常规的试剂，优选3-巯丙基乙硫醚基氧化硅。所述的打浆优选依次经醚类溶剂(例如甲基叔丁基醚)、醇类溶剂(例如乙醇)打浆。所述的干燥优选真空干燥。
所述的如式B所示化合物的制备方法可进一步包括以下步骤：有机溶剂中，在碱的存在下，将如式E所示化合物和如式D所示化合物进行如下所示的取代反应，得到所述的如式C所示化合物；
Figure PCTCN2021078037-appb-000004
其中，X和R的定义同前任一方案所述。
所述的如式B所示化合物的制备方法中，所述的有机溶剂可为本领域常规的溶剂，优选醇类溶剂，更优选正丁醇。
所述的如式B所示化合物的制备方法中，所述的碱可为本领域常规的碱，优选有机碱，更优选有机胺，进一步优选N,N-二异丙基乙基胺(DIPEA)。
所述的如式B所示化合物的制备方法中，所述的如式E所示化合物在所述的有机溶剂中的摩尔浓度可为本领域常规的摩尔浓度，优选0.3-1.0mol/L，更优选0.5-0.7mol/L(例如0.65mol/L)。
所述的如式B所示化合物的制备方法中，所述的如式D所示化合物和所述的如式E所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-2:1，更优选1:1-1.5:1(例如1.3:1)。
所述的如式B所示化合物的制备方法中，所述的取代反应的温度可为本领域常规的反应温度，优选80℃至有机溶剂的沸点温度，更优选95-105℃(例如100℃)。
所述的如式B所示化合物的制备方法中，所述的取代反应的进程可通过本领域常规的手段进行监控(例如TLC、LC-MS或HPLC等)，对所述的取代反应的时间不作特别限定，以所述的如式E所示化合物在反应体系中的含量不再变化为准，所述的取代反应的时间优选30-60h，更优选40-50h(例如42h)。
所述的取代反应的后处理还可包括以下步骤：浓缩，将所得的浓缩物打浆，过滤，干燥，即可。所述的浓缩可为本领域常规的浓缩，优选减压浓缩。所述的打浆所用的溶剂优选醇类溶剂(例如甲醇)。所述的过滤可为本领域常规的过滤。所述的干燥可为本领域常规的干燥，优选真空干燥。
本发明提供了一种如式C所示化合物的制备方法，其包括以下步骤：有机溶剂中，在碱的存在下，将如式E所示化合物和如式D所示化合物进行如下所示的取代反应，即可；
Figure PCTCN2021078037-appb-000005
其中，X为Br或I，优选Br；
R为H或C 1-C 3烷基，优选C 1-C 3烷基，更优选甲基。
所述的如式C所示化合物的制备方法中，所述的取代反应的条件和操作与前述该类反应的条件和操作相同。
本发明还提供了一种如式C所示的化合物，
Figure PCTCN2021078037-appb-000006
其中，X为Br或I，优选Br；
R为H或C 1-C 3烷基，优选C 1-C 3烷基，更优选甲基。
所述的如式C所示的化合物可为以下结构，
Figure PCTCN2021078037-appb-000007
本发明还提供了一种如式I所示化合物的制备方法，其包括以下步骤：有机溶剂中，在碱和催化剂的存在下，将如式J所示化合物与氢气进行如下所示的还原反应，即可；所述的有机溶剂为醚类溶剂；
Figure PCTCN2021078037-appb-000008
其中，R为H或C 1-C 3烷基，优选C 1-C 3烷基，更优选甲基。
所述的如式I所示化合物的制备方法中，所述的醚类溶剂优选四氢呋喃(THF)。
所述的如式I所示化合物的制备方法中，所述的碱可为本领域常规的碱，优选有机碱，更优选有机胺，进一步优选N,N-二异丙基乙基胺。
所述的如式I所示化合物的制备方法中，所述的催化剂可为本领域常规 的催化剂，优选钯类化合物，更优选钯炭(例如质量分数为10％的钯炭)。
所述的如式I所示化合物的制备方法中，所述的氢气的压力可为本领域常规的压力，优选0.3-0.8MPa，更优选0.4-0.6MPa(例如0.5MPa)。
所述的如式I所示化合物的制备方法中，所述的碱与所述的如式J所示化合物的摩尔比优选1:1-2:1，更优选1:1-1.5:1(例如1.2:1)。
所述的如式I所示化合物的制备方法中，所述的催化剂与所述的如式J所示化合物的质量摩尔比可为本领域常规的质量摩尔比，优选10-50g/mol，更优选40-50g/mol(例如42g/mol)。
所述的如式I所示化合物的制备方法中，所述的如式J所示化合物在所述的有机溶剂中的摩尔浓度可为本领域常规的摩尔浓度，优选0.2-1.0mol/L，更优选0.5-0.7mol/L(例如0.65mol/L)。
所述的如式I所示化合物的制备方法中，所述的还原反应的温度可为本领域常规的反应温度，优选10-40℃，更优选20-30℃(例如25℃)。
所述的如式I所示化合物的制备方法中，所述的还原反应的进程可通过本领域常规的手段进行监控(例如TLC、LC-MS或HPLC等)，对所述的取代反应的时间不作特别限定，以所述的如式J所示化合物在反应体系中的含量不再变化为准，所述的还原反应的时间优选90-150h，更优选110-130h(例如120h)。
所述的还原反应的后处理还可包括以下步骤：过滤，将滤液浓缩得浓缩物，用溶剂溶解浓缩物，加入水，析出固体，分离固体，干燥，即可。所述的过滤的条件和操作可为本领域常规的条件和操作。所述的浓缩的条件和操作可为本领域常规的条件和操作，优选减压浓缩。所述的用溶剂溶解浓缩物之前，优选加入溶剂后进一步浓缩，所述的溶剂优选醇类溶剂(例如乙醇)。所述的溶解浓缩物所用的溶剂优选醇类溶剂(例如乙醇)。所述的溶解浓缩物的温度优选65-75℃(例如70℃)。所述的水的加入方式优选滴加。所述的水加入时，温度优选20-30℃(例如25℃)。所述的分离固体的方式可为本领 域常规的方式，优选离心。所述的干燥的条件和方法可为本领域常规的条件和方法，优选真空干燥。
本发明还提供了一种如式E所示化合物的制备方法，其包括以下步骤：
(1)根据上述任一种制备方法制得如式I所示化合物；
(2)在酸的存在下，将如式I所示化合物和卤代试剂进行如下所示的取代反应，即可；
Figure PCTCN2021078037-appb-000009
其中，X为Br或I，优选Br；
R为H或C 1-C 3烷基，优选C 1-C 3烷基，更优选甲基。
如式E所示化合物的制备方法中，步骤(2)中，所述的取代反应的条件和操作与本领域该类反应常规的条件和操作相同。
本发明还提供了一种如式C所示化合物的制备方法，其包括以下步骤：
(1)根据上述任一制备方法制得如式E所示化合物；
(2)有机溶剂中，在碱的存在下，将如式E所示化合物和如式D所示化合物进行如下所示的取代反应，即可；
Figure PCTCN2021078037-appb-000010
其中，X为Br或I，优选Br；
R为H或C 1-C 3烷基，优选C 1-C 3烷基，更优选甲基。
所述的如式C所示化合物的制备方法中，步骤(2)中，所述的取代反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式F所示化合物的制备方法，其包括以下步骤：有机溶剂中，在碱的存在下，将如式G所示化合物和如式L所示化合物进行如下所示的反应，即可；
Figure PCTCN2021078037-appb-000011
所述的如式F所示化合物的制备方法中，所述的有机溶剂可为本领域常规的有机溶剂，优选酰胺类溶剂(例如N,N-二甲基甲酰胺)。
所述的如式F所示化合物的制备方法中，所述的碱可为本领域常规的碱，优选无机碱，更优选碱金属碳酸盐(例如碳酸钾)。
所述的如式F所示化合物的制备方法中，所述的如式L所示化合物与所述的如式G所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-4:1，更优选1:1-2:1(例如1.1:1)。
所述的如式F所示化合物的制备方法中，所述的碱与所述的如式G所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-5:1，更优选1:1-2:1(例如1.5:1)。
所述的如式F所示化合物的制备方法中，所述的如式G所示化合物在所述的溶剂中的摩尔浓度可为本领域常规的摩尔浓度，优选0.3-0.9mol/L，更优选0.5-0.7mol/L(例如0.6mol/L)。
所述的如式F所示化合物的制备方法中，所述的反应的的温度可为本领域常规的反应温度，优选50-100℃，更优选75-85℃(例如80℃)。
所述的如式F所示化合物的制备方法中，所述的反应的进程可通过本领域常规的手段进行监控(例如TLC、LC-MS或HPLC等)，对所述的反应的 时间不作特别限定，以所述的如式G所示化合物在反应体系中的含量不再变化为准，所述的偶联反应的时间优选10-30h，更优选16-20h(例如18h)。
所述的反应的后处理还可包括以下步骤：将反应液与水混合，过滤，洗涤固体，干燥，即可。所述的水优选加入。所述的混合时的温度优选10-40℃(10-20℃)。所述的混合后，优选搅拌1-5h。所述的洗涤的溶剂优选水。所述的干燥优选真空干燥。
所述的如式F所示化合物的制备方法可进一步包括以下步骤：在吡啶的存在下，将如式H所示化合物和对甲苯磺酰氯进行如下所示的取代反应，即得如式G所示化合物；
Figure PCTCN2021078037-appb-000012
其中，所述的对甲苯磺酰氯与所述的如式H所示化合物的摩尔比可为本领域常规的摩尔比，优选1:1-4:1，更优选1:1-2:1(例如1.5:1)。
所述的吡啶与所述的如式H所示化合物的质量摩尔比可为本领域常规的质量摩尔比，优选0.5:1-3:1，更优选1:1-2:1(例如1:1)。
所述的取代反应的温度可为本领域常规的反应温度，优选10-40℃，更优选20-30℃。
所述的取代反应的进程可通过本领域常规的手段进行监控(例如TLC、LC-MS或HPLC等)，对所述的取代反应的时间不作特别限定，以所述的如式H所示化合物在反应体系中的含量不再变化为准，所述的取代反应的时间优选10-30h，更优选15-20h(例如18h)。
所述的反应的后处理还可包括以下步骤：将反应液与水混合，过滤，洗 涤固体，干燥，即可。所述的水优选加入。所述的混合时的温度优选10-40℃(10-20℃)。所述的混合后，优选搅拌1-5h。所述的洗涤的溶剂优选水。所述的干燥优选真空干燥。
本发明提供了一种如式D所示化合物的制备方法，其包括以下步骤：
(1)按照上述任一中制备方法制得如式F所示化合物；
(2)有机溶剂中，在催化剂的存在下，将如式F所示化合物和氢气进行如下所示的还原反应，即可；
Figure PCTCN2021078037-appb-000013
步骤(2)中，所述的还原反应的条件和操作与本领域该类反应的条件和操作相同。
本发明提供了一种如式C所示化合物的制备方法，其包括以下步骤：
(1)按照上述任一中制备方法制得如式D所示化合物；
(2)有机溶剂中，在碱的存在下，将如式E所示化合物和如式D所示化合物进行如下所示的取代反应，即可；
Figure PCTCN2021078037-appb-000014
其中，X为Br或I，优选Br；
R为H或C 1-C 3烷基，优选C 1-C 3烷基，更优选甲基。
步骤(2)中，所述的取代反应的条件和操作与前述该类反应的条件和操作相同。
本发明提供了一种如式B所示化合物的制备方法，其包括以下步骤：
(1)根据上述任一制备方法制得如式C所示化合物；
(2)保护气体氛围下，溶剂中，在催化剂和碱的存在下，将如式C所示化合物与如式K所示化合物进行如下所示的偶联反应，即可；所述的催化剂包括钯类化合物和膦配体；
Figure PCTCN2021078037-appb-000015
其中，X为Br或I，优选Br；
R为H或C 1-C 3烷基，优选C 1-C 3烷基，更优选甲基。
步骤(2)中，所述的偶联反应的条件和操作与前述该类反应的条件和操作相同。
本发明还提供了一种如G所示化合物的制备方法，其包括以下步骤：在吡啶的存在下，将如式H所示化合物和对甲苯磺酰氯进行如下所示的取代反应，即可；
Figure PCTCN2021078037-appb-000016
所述的取代反应的条件和操作与前述该类反应的条件和操作相同。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供了一种新的合成思路，本发明的制备方法可提高产物收率，降低生产成本；同时反应条件简单，工艺可操作性强，利于工业生产，减少三废的生成。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1：2-氯-6-甲基噻吩并[3,2-D]嘧啶(化合物I)
向500L反应釜中，依次加入10％钯碳(4.6Kg)，2,4-二氯-6-甲基噻吩并[3,2-D]嘧啶(24.2Kg，109.5mol)，四氢呋喃(150Kg)以及N,N-二异丙基乙基胺(17.0Kg,131.5mol)。向釜内充入氢气，控制氢气压力在0.5MPa。开启搅拌，保持温度在25±5℃下反应120小时。过滤，收集滤液，滤液减压浓缩，向浓缩物加入乙醇(58Kg)，再次浓缩以带出残留的四氢呋喃。加入乙醇(60Kg)，于70±5℃下搅拌至固体全部溶解。降温，控制温度在25±5℃，向釜内滴加360Kg纯化水，控制滴加速度，保持温度在25±5℃。固体产物析出，离心，滤饼经真空干燥，得到产物2-氯-6-甲基噻吩并[3,2-D]嘧啶18.94Kg，产率：93.2％。LC-MS(ESI):m/z＝185.1[M+H] +.
1H NMR(400MHz,d 6-DMSO):δ9.30(s,1H),7.34(s,1H),2.73(s,3H).
实施例2：2-氯-6-甲基噻吩并[3,2-D]嘧啶(化合物I)
向100mL反应瓶中，依次加入10％钯碳(0.17g)，2,4-二氯-6-甲基噻吩并[3,2-D]嘧啶(2g，9.2mmol)，四氢呋喃(40mL)以及N,N-二异丙基乙基胺(1.412g,10.9mmol)。向瓶内充入氢气，控制氢气压力在0.5MPa。开 启搅拌，保持温度在25±5℃下反应20小时。过滤，收集滤液，滤液减压浓缩，向浓缩物加入乙醇(2.1g)，再次浓缩以带出残留的四氢呋喃。加入乙醇(2.2g)，于70±5℃下搅拌至固体全部溶解。降温，控制温度在25±5℃，向釜内滴加13.3g纯化水，控制滴加速度，保持温度在25±5℃。固体产物析出，离心，滤饼经真空干燥，得到产物2-氯-6-甲基噻吩并[3,2-D]嘧啶2.4g，产率：82％。其LC-MS和 1H NMR同实施例1。
实施例3：7-溴2-氯-6-甲基噻吩并[3,2-D]嘧啶(化合物E)
向500L搪瓷反应釜中加入三氟乙酸(150Kg)，2-氯-6-甲基噻吩并[3,2-D]嘧啶(18.90Kg,102.4mol)。控温于15±5℃下加入N-溴代丁二酰亚胺(18.33Kg,103.0mol)。加毕，控温于25±5℃下反应2小时。取样监测反应，尚有少量原料剩余。补加N-溴代丁二酰亚胺(1.0Kg,5.6mol)，继续搅拌1小时，取样监测，显示反应完全。控温于10±5℃下，滴加274Kg水。加毕，于10±5℃下搅拌2小时。离心，固体经真空干燥，得产物7-溴2-氯-6-甲基噻吩并[3,2-D]嘧啶，24.68Kg，产率：91.4％。LC-MS(ESI):m/z＝265.0[M+H] +.
1H NMR(400MHz,d 6-DMSO):δ9.33(s,1H),2.64(s,3H).
实施例4：4-(对甲基苯磺酰基)-哌啶-1-碳酸叔丁酯(化合物G)
向500L搪瓷反应釜中加入吡啶(176Kg)，N-BOC-4-羟基哌啶(36.00Kg,178.9mol)。控温于10±10℃下分批加入对甲苯磺酰氯(50.5Kg,264.9mol)。加毕，控温于25±5℃下反应18小时。将反应液转移至1000L反应釜中，控温于15±5℃下，滴加710Kg水。加毕，于15±5℃下搅拌2小时。过滤，固体经水洗，真空干燥，得产物4-(对甲基苯磺酰基)-哌啶-1-碳酸叔丁酯，59.3Kg，产率：93.3％。LC-MS(ESI):m/z＝378.0[M+Na] +.
实施例5：4-(4-硝基-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯(化合物F)
向反应釜中加入N,N-二甲基甲酰胺(252Kg)，4-(对甲基苯磺酰基)-哌啶-1-碳酸叔丁酯(59.3Kg,166.8mol)，4-硝基吡唑(21.5Kg,190.1mol)，以及无水碳酸钾(34.3Kg,248.2mol)。控温于80±5℃搅拌反应18小时。降 温至15±5℃，滴加水900Kg，控制滴加速度，保持温度在15±5℃。加毕，于5±5℃下搅拌2小时。过滤，固体经水洗两次，真空干燥，得产物4-(4-硝基-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯39.92Kg，产率：80.8％。LC-MS(ESI):m/z＝319.1[M+Na] +。
1H NMR(400MHz,d 6-DMSO):δ8.96(s,1H),8.27(s,1H),4.44-4.51(m,1H),4.06-4.08(m,2H),2.75-2.91(m,2H),2.04-2.07(m,2H),1.80-1.89(m,2H),1.41(s,9H).
实施例6：4-(4-氨基-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯(化合物D)
向反应釜中加入10％钯碳(2.00Kg)，4-(4-硝基-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯(39.94Kg,134.09mol)，无水乙醇(314Kg)以及氨水(20.0Kg,134.09mol)。向釜内充入氢气，控制氢气压力在0.2MPa。开启搅拌，保持温度在45±5℃下反应4小时。过滤，收集滤液，滤液减压浓缩。向浓缩物加入乙酸乙酯(40Kg)与正庚烷(142Kg)，于25±5℃下搅拌1小时，再降温至5±5℃下搅拌2小时。过滤，固体经真空干燥，得到产物4-(4-氨基-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯31.85Kg，产率：88.6％。LC-MS(ESI):m/z＝267.2[M+H] +.
1H NMR(400MHz,d 6-DMSO):δ7.06(s,1H),6.91(s,1H),4.08-4.15(m,1H),3.98-4.01(m,2H),3.81(brs,2H),2.83-2.87(m,2H),1.88-1.91(m,2H),1.63-1.72(m,2H),1.41(s,9H).
实施例7：4-(4-(7-溴-6-甲基噻吩并[3,2-D]嘧啶-2-基)氨基)-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯(化合物C)
向反应釜中加入正丁醇(117Kg)，N,N-二异丙基乙基胺(15.00Kg,116.06mol)，4-(4-氨基-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯(32.02Kg,120.22mol)以及7-溴2-氯-6-甲基噻吩并[3,2-D]嘧啶(24.68Kg,93.65mol)。开启搅拌，保持温度在100±5℃下反应42小时。减压浓缩。向浓缩物加入甲醇打浆。过滤，固体经真空干燥，得到产物4-(4-(7-溴-6-甲基噻吩并[3,2-D]嘧啶-2-基) 氨基)-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯37.26Kg，产率：80.6％。LC-MS(ESI):m/z＝493.1[M+H] +.
1H NMR(400MHz,d 6-DMSO):δ9.73(s,1H),8.97(s,1H),8.18(s,1H),7.68(s,1H),4.30-4.36(m,1H),4.01-4.04(m,2H),2.87-2.93(m,2H),2.53(s,3H),2.00-2.03(m,2H),1.70-1.80(m,2H),1.41(s,9H).
实施例8：4-(4-((7-(4-氟-2-甲氧基苯基)-6-甲基噻吩并[3,2-D]嘧啶-2-基)氨基)-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯(化合物B)
向反应釜中加入纯化水(113Kg)，二氧六环(390Kg)，4-(4-(7-溴-6-甲基噻吩并[3,2-D]嘧啶-2-基)氨基)-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯(37.26Kg,93.65mol)，2-甲氧基-4-氟苯硼酸频哪醇酯(23.05Kg,120.22mol)，无水碳酸钾(20.95Kg,151.8mol)，醋酸钯(0.18Kg,0.80mol)和2-二环己基膦-2,4,6-三异丙基联苯(0.90Kg,1.89mol)。氮气保护下，控温于70±5℃反应4小时。降温至40±5℃，加入氨水(68Kg)，搅拌8小时。降温至20±5℃，加水(1110Kg)稀释。二氯甲烷萃取两次(244Kg,170Kg)。合并有机相，依次经水洗，饱和食盐水洗。向有机相中加入3-巯丙基乙硫醚基氧化硅(4.0Kg，用于除重金属钯)，控温于40±5℃搅拌20小时。过滤，滤液减压浓缩。剩余物依次经甲基叔丁基醚和乙醇打浆。过滤，真空干燥，得4-(4-((7-(4-氟-2-甲氧基苯基)-6-甲基噻吩并[3,2-D]嘧啶-2-基)氨基)-1氢-吡唑-1-基)哌啶-1-碳酸叔丁酯34.6Kg，产率：68.6％。LC-MS(ESI):m/z＝539.3[M+H] +.
1H NMR(400MHz,d 6-DMSO):δ9.46(s,1H),8.94(s,1H),7.76(s,1H),7.38(s,1H),7.33-7.35(m,1H),7.08-7.11(m,1H),6.91-6.95(m,1H),4.03-4.12(m,3H),3.73(s,3H),2.85-2.89(m,2H),2.39(s,3H),1.90-1.93(m,2H),1.55-1.60(m,2H),1.41(s,9H).
对比例1：2-氯-6-甲基噻吩并[3,2-D]嘧啶(化合物I)
向100mL反应瓶中，依次加入10％钯碳(0.1g)，2,4-二氯-6-甲基噻吩并[3,2-D]嘧啶(2g，9.2mmol)，甲醇(40mL)以及N,N-二异丙基乙基胺 (1.412g,10.9mmol)。向瓶内充入氢气，控制氢气压力在0.5MPa。开启搅拌，保持温度在25±5℃下反应21小时。过滤，收集滤液，滤液减压浓缩，向浓缩物加入乙醇(2.1g)，再次浓缩以带出残留的四氢呋喃。加入乙醇(2.2g)，于70±5℃下搅拌至固体全部溶解。降温，控制温度在25±5℃，向釜内滴加13.3g纯化水，控制滴加速度，保持温度在25±5℃。固体产物析出，离心，滤饼经真空干燥，得到产物2-氯-6-甲基噻吩并[3,2-D]嘧啶1.6g，产率：54％。甲氧基取代的杂质
Figure PCTCN2021078037-appb-000017
的收率为20％。
对比例2：2-氯-6-甲基噻吩并[3,2-D]嘧啶(化合物I)
将实施例2中的溶剂四氢呋喃替换为乙酸乙酯后，2-氯-6-甲基噻吩并[3,2-D]嘧啶在乙酸乙酯中的溶解性差，仅有少量产物生成，未计算具体收率。
对比例3：4-(对甲基苯磺酰基)-哌啶-1-碳酸叔丁酯(化合物G)
向100mL反应瓶中加入三乙胺(25mL)，N-BOC-4-羟基哌啶(5g)。控温于10±10℃下分批加入对甲苯磺酰氯(7.1g)。加毕，控温于25±5℃下反应25小时。通过LC-MS监测显示有大量的原料未反应且反应液为黑红色。

Claims (10)

  1. 一种如式B所示化合物的制备方法，其特征在于，其包括以下步骤：保护气体氛围下，溶剂中，在催化剂和碱的存在下，将如式C所示化合物与如式K所示化合物进行如下所示的偶联反应，即可；所述的催化剂包括钯类化合物和膦配体；
    Figure PCTCN2021078037-appb-100001
    其中，X为Br或I；
    R为H或C 1-C 3烷基。
  2. 如权利要求1所述的如式B所示化合物的制备方法，其特征在于，
    X为Br；
    和/或，R为C 1-C 3烷基，优选甲基；
    和/或，所述的溶剂为水和有机溶剂的混合溶剂；
    和/或，所述的碱为无机碱；
    和/或，所述的钯类化合物为零价钯或二价钯盐；
    和/或，所述的膦配体为2-二环己基膦-2,4,6-三异丙基联苯和/或1,1'-双(二苯基膦)二茂铁；
    和/或，所述的钯类化合物和所述的膦配体以络合物的形式加入，或者，所述的钯类化合物和所述的膦配体以混合物的形式加入；
    和/或，所述的如式C所示化合物在所述的溶剂中的摩尔浓度为0.1-0.5mol/L；
    和/或，所述的如式K所示化合物与所述的如式C所示化合物的摩尔比 为1:1-3:1；
    和/或，所述的碱与所述的如式C所示化合物的摩尔比为1:1-3:1；
    和/或，所述的钯类化合物与所述的如式C所示化合物的摩尔比为1:50-1:150；
    和/或，所述的膦配体与所述的钯类化合物的摩尔比为1:1-5:1；
    和/或，所述的保护气体为氮气和/或氩气；
    和/或，所述的偶联反应的温度为50-100℃；
    和/或，所述的偶联反应的时间为3-7h。
  3. 如权利要求2所述的如式B所示化合物的制备方法，其特征在于，
    当所述的溶剂为水和有机溶剂的混合溶剂时，所述的有机溶剂为醚类溶剂，优选二氧六环；
    当所述的溶剂为水和有机溶剂的混合溶剂时，所述的水和有机溶剂的体积比为1:1-1:10，优选1:2-1:5；
    和/或，所述的碱为碱金属碳酸盐，优选碳酸钠和/或碳酸钾；
    和/或，当所述的钯类化合物为二价钯盐时，所述的二价钯盐为PdCl 2和/或Pd(OAc) 2；
    和/或，所述的膦配体为2-二环己基膦-2,4,6-三异丙基联苯；
    和/或，当所述的钯类化合物和所述的膦配体以络合物的形式加入时，所述的络合物为零价钯和膦配体的络合物形式、和/或、二价钯盐和膦配体的络合物形式；所述的二价钯盐和膦配体的络合物形式可为Pd(dppf)Cl 2；
    和/或，所述的如式C所示化合物在所述的溶剂中的摩尔浓度为0.1-0.3mol/L；
    和/或，所述的如式K所示化合物与所述的如式C所示化合物的摩尔比为1:1-2:1；
    和/或，所述的碱与所述的如式C所示化合物的摩尔比为1:1-2:1；
    和/或，所述的钯类化合物与所述的如式C所示化合物的摩尔比为1:100- 1:120；
    和/或，所述的膦配体与所述的钯类化合物的摩尔比为1:1-3:1；
    和/或，所述的偶联反应的温度为65-75℃；
    和/或，所述的偶联反应的时间为3-5h。
  4. 如权利要求1-3中任一项所述的如式B所示化合物的制备方法，其特征在于，其进一步包括以下步骤：有机溶剂中，在碱的存在下，将如式E所示化合物和如式D所示化合物进行如下所示的取代反应，得到所述的如式C所示化合物；
    Figure PCTCN2021078037-appb-100002
  5. 如权利要求4所述的如式B所示化合物的制备方法，其特征在于，
    所述的有机溶剂为醇类溶剂，优选正丁醇；
    和/或，所述的碱为有机碱，优选有机胺，进一步优选N,N-二异丙基乙基胺；
    和/或，所述的如式E所示化合物在所述的有机溶剂中的摩尔浓度为0.3-1.0mol/L，优选0.5-0.7mol/L；
    和/或，所述的如式D所示化合物和所述的如式E所示化合物的摩尔比为1:1-2:1，优选1:1-1.5:1；
    和/或，所述的取代反应的温度为80℃至有机溶剂的沸点温度，优选95-105℃；
    和/或，所述的取代反应的时间为30-60h，优选40-50h。
  6. 一种如式C所示化合物的制备方法，其特征在于，其包括以下步骤： 有机溶剂中，在碱的存在下，将如式E所示化合物和如式D所示化合物进行如下所示的取代反应，即可；
    Figure PCTCN2021078037-appb-100003
    其中，X为Br或I；
    R为H或C 1-C 3烷基；
    所述的取代反应的条件和操作如权利要求4或5所述。
  7. 一种如式C所示的化合物，
    Figure PCTCN2021078037-appb-100004
    其中，X为Br或I；
    R为H或C 1-C 3烷基；
    所述的如式C所示的化合物可为以下结构，
    Figure PCTCN2021078037-appb-100005
  8. 一种如式I所示化合物的制备方法，其特征在于，其包括以下步骤：有机溶剂中，在碱和催化剂的存在下，将如式J所示化合物与氢气进行如下所示的还原反应，即可；所述的有机溶剂为醚类溶剂；
    Figure PCTCN2021078037-appb-100006
    其中，R为H或C 1-C 3烷基。
  9. 一种如式F所示化合物的制备方法，其特征在于，其包括以下步骤：有机溶剂中，在碱的存在下，将如式G所示化合物和如式L所示化合物进行如下所示的反应，即可；
    Figure PCTCN2021078037-appb-100007
  10. 一种如式G所示化合物的制备方法，其特征在于，其包括以下步骤：在吡啶的存在下，将如式H所示化合物和对甲苯磺酰氯进行如下所示的取代反应，即可；
    Figure PCTCN2021078037-appb-100008
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