WO2023130334A1 - Method for preparing chromen-4-one compound and intermediate thereof - Google Patents

Method for preparing chromen-4-one compound and intermediate thereof Download PDF

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WO2023130334A1
WO2023130334A1 PCT/CN2022/070607 CN2022070607W WO2023130334A1 WO 2023130334 A1 WO2023130334 A1 WO 2023130334A1 CN 2022070607 W CN2022070607 W CN 2022070607W WO 2023130334 A1 WO2023130334 A1 WO 2023130334A1
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compound
reaction
combination
ethanol
preparation
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PCT/CN2022/070607
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French (fr)
Chinese (zh)
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郭振荣
唐恕一
李学飞
陈志宏
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同润生物医药(上海)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • the present invention relates to the field of drug synthesis, in particular to a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- Preparation methods of 4-ketones and intermediates thereof.
  • Phosphoinositide-3 kinases belong to a class of intracellular lipid kinases that phosphorylate the 3-hydroxyl of the inositol ring of phosphoinositide lipids (PI), thereby generating lipid second messengers. It has been reported in the art that targeted inhibitors of the phosphoinositide-3-kinase (PI3K) pathway can be used as immunomodulators.
  • Patent document WO2011055215A2 discloses a novel benzopyran kinase regulator.
  • patent document WO2014195888A1 further studies and discloses an inhibitor (S)-2-(1-( 9H-Purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one.
  • the present invention on the basis of the existing literature, to (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H -Chromene-4-ketone carries out further research, has obtained technical scheme of the present invention.
  • the present invention provides a novel preparation of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one Compared with the methods disclosed in existing documents, the present invention reduces the reaction steps, thereby improving the purity and yield of the reaction and reducing production costs.
  • the present invention provides the following technical solutions:
  • a compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one (formula (I))
  • the preparation method is characterized in that, comprises the following steps:
  • X represents halogen, preferably Cl, Br, more preferably Br;
  • Y represents a leaving group, preferably a halogen, more preferably Cl or Br.
  • the catalytic hydrogenation reaction of the step (I) is carried out under the condition of palladium as a catalyst and hydrogen.
  • the palladium catalyst is selected from any one of Pd/C, Pd(OH) 2 /C or a combination thereof.
  • reaction solvent of the step (I) is any one of methanol, ethanol, tetrahydrofuran, dioxane, DMSO, acetone, butanol or a combination thereof.
  • reaction condition of described step (II) is carried out under alkaline condition.
  • the alkaline condition is an inorganic base or an organic base, preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, N,N-di Any one or combination of isopropylethylamine (DIPEA), sodium tert-butyl, sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine, DMAP, morpholine, N-methylmorpholine, More preferred is triethylamine.
  • DIPEA isopropylethylamine
  • DIPEA isopropylethylamine
  • sodium tert-butyl sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine
  • DMAP morpholine
  • N-methylmorpholine More preferred is triethylamine.
  • reaction solvent in the described step (II) is any of water, methanol, ethanol, tetrahydrofuran, dioxane, DMSO, acetone, butanol, tert-butanol, ether one or a combination thereof.
  • the present invention also provides a preparation method of compound 2, which is characterized in that it comprises the following steps:
  • the reaction condition of the hydrogenation catalytic reaction is that in the presence of an organic solvent, palladium is used as a catalyst, and the catalytic hydrogenation reaction is carried out by hydrogen under high pressure;
  • X represents a halogen, preferably Cl or bromine, more preferably Br .
  • said palladium catalyst is selected from any one of Pd/C, Pd(OH) 2 /C or a combination thereof
  • the organic solvent is selected from any one of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO or a combination thereof.
  • the high pressure reaction is 0.5-1MPa.
  • the present invention also provides a preparation method of Compound 1, which is characterized in that it comprises the following steps:
  • Compound 4 and compound 5 are prepared by reacting in an organic solvent under alkaline/condensing agent conditions to obtain compound 1;
  • X represents halogen, preferably Cl or bromine, more preferably Br.
  • the alkaline condition is an inorganic base or an organic base, preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, N,N-di Any one of isopropylethylamine (DIPEA), tert-butyl sodium, sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine, DMAP, morpholine, N-methylmorpholine, or a combination thereof .
  • DIPEA isopropylethylamine
  • tert-butyl sodium sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine
  • DMAP morpholine
  • N-methylmorpholine or a combination thereof .
  • the organic solvent is selected from any of dichloromethane, carbon tetrachloride, chloroform, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, acetone one or a combination thereof.
  • the condensing agent is selected from any one of HATU, HBTU, TBTU, TATU, HOBt, DCC, EDCI, DMAP or a combination thereof.
  • X represents halogen, preferably Cl or bromine, more preferably Br.
  • the catalyst for the reaction is AlCl 3 .
  • organic solvent is preferably dichloromethane, carbon tetrachloride, chloroform, methyl alcohol, ethanol, isopropanol, tetrahydrofuran, Any one or combination of dioxane, DMF, acetone.
  • the preparation method of compound 5 comprises the following steps:
  • the base is selected from Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH any one or combination of them.
  • reaction solvent in step (i) is selected from any one of H 2 O, methanol, ethanol, tetrahydrofuran, dioxane or a combination thereof.
  • the base is selected from Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH Any one or combination thereof, preferably NaOH.
  • reaction solvent in step (ii) is selected from any one of H 2 O, methanol, ethanol, tetrahydrofuran, dioxane or a combination thereof.
  • X represents halogen, preferably Cl or bromine, more preferably Br.
  • Step 1) Add m-fluorophenylacetic acid (200g, 1.0eq.), DMF (2.4g, 0.012W), dichloromethane (750mL, 3.5V) into the reaction flask, replace with nitrogen 3 times; cool down and stir to -10 °C, SOCl2 (200.8 g, 1.3 eq.) was added dropwise at -10 °C. After the dropwise addition, the temperature was raised to 20° C., and kept stirring for 3 hours; the sample was controlled by HPLC (methanol quenching); after the reaction was completed, it was concentrated at 30° C. until no liquid flowed out. Add dichloromethane (600mL, 3V) and continue to concentrate until no liquid flows out to obtain m-fluorophenylacetyl chloride;
  • Step 2) Add m-fluorophenylacetyl chloride (1.0eq.), p-bromoanisole (315.6g, 1.3eq.), dichloromethane (750mL, 3.5V) into the reaction flask.
  • Step 1) Add m-fluorophenylacetic acid (200g, 1.0eq.), DMF (2.4g, 0.012W), dichloromethane (300mL, 1.5V) into the reaction flask, replace with nitrogen 3 times; cool down and stir to 20°C , add (COCl) 2 (181g, 1.1eq.) dropwise at 20°C; after the dropwise addition, keep stirring at 20-25°C for 12h; control HPLC during sampling (methanol quenching); step 2): m-fluorobenzene Add acetyl chloride (1.0eq.), p-bromoanisole (315.6g, 1.3eq.), dichloromethane (1250mL, 6.5V) into the reaction flask, cool and stir to 0°C; add AlCl 3 (225g , 1.3eq.), and control the reaction temperature at 0-10°C; after the addition, the temperature was raised to 40°C, and after 15 hours of heat preservation and stirring, the sample was controlled
  • Embodiment 2 N the preparation of N-dibenzyl aminobutyric acid (compound 5)
  • Step 1) Take KOH (108.9g, 1.94mol, 2.0eq.), K 2 CO 3 (268.05g, 1.94mol, 2.0eq.) and water (1L, 10V) into the reactor. At 25°C, 2-aminobutyric acid (100 g, 0.97 mol, 1.0 eq.) was added, and the temperature was raised to 90°C.
  • Step 2) Take the crude intermediate 1, heat up to 80°C, and add KOH aqueous solution (108.9g, 1.94mol, 2.0eq; 1080mL, 10.8V water) dropwise. After raising the temperature to 80°C, keep it warm for 12 hours, and take a sample to control it; precipitation at 75°C until there are basically no fractions, and the crude product of intermediate 2 is obtained as a yellow oily liquid;
  • KOH aqueous solution 108.9g, 1.94mol, 2.0eq; 1080mL, 10.8V water
  • Step 4) Take the crude compound 5 and add ethanol (1080mL, 3V), beat at room temperature (25°C) for 2h, filter, and wash with ethanol (50mL) to obtain 213.34g of compound 5 as a white solid with a purity of 96.17%. Take 213.34g of compound 5 product with a purity of 96.17%, add ethanol (600mL, 3V), beat at room temperature (25°C) for 2h, filter, and wash with ethanol (50mL) to obtain 193.01g of compound 5 product as a white solid, yield It is 70.24% and the purity is 98.58%.
  • Step 1) Take NaOH (77.57g, 1.94mol, 2.0eq.), K2CO3 (268.05g, 1.94mol, 2.0eq.) and water (1L, 10V) into the reactor. After cooling down to 25°C, 2-aminobutyric acid (100g, 0.97mol, 1.0eq.) was added, and the temperature was raised to 80°C. After that, benzyl bromide (855.8g, 5.09mol, 3.1eq.) was added dropwise, and after 10h of heat preservation at 80°C, the sample was taken for control; after cooling down to room temperature, it was allowed to stand still, and the upper organic layer was separated to obtain the crude intermediate 1, which was yellow oily liquid.
  • NaOH aqueous solution NaOH 154.21g, 3.86mol, 4.0eq; water 720mL, 7.2V
  • Step 4) Concentrate the above DCM layer solution to 336g, then add absolute ethanol (230mL, 2.3V) and n-heptane (230mL, 2.3V), heat up to 70°C to dissolve, and cool down to room temperature to precipitate fine granular compounds 5. Beat for 2 hours at room temperature, then lower to 0°C and stir for 1 hour. After filtration, the filter cake was washed with n-heptane (250 mL), and dried to obtain 189 g of compound 5 as a white solid with a yield of 65.50% and a purity of 99.4%.
  • the obtained yellow solid was added into (30 mL, 0.5V) tetrahydrofuran and (60 mL, 1V) MTBE and stirred at 50°C under reflux for 0.5h-1h. Cool down to room temperature, and add (240mL, 4V) n-heptane dropwise, and continue stirring for 1h-2h.
  • the yellow solid obtained by filtration was sampled for HPLC control, and the mother liquor was sampled; Compound 2 was obtained as 26.1 g of orange solid in a vacuum oven at 60° C. (16 h), with a yield of 81.3% and a purity of 99.34%.

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Abstract

A method for preparing an (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one PI3K δ/γ inhibitor and an intermediate thereof. Compared with a method in the prior art, this method reduces the reaction process, can increase the reaction yield and the product purity, and facilitates industrial production.

Description

一种色烯-4-酮化合物及其中间体的制备方法A kind of preparation method of chromene-4-one compound and its intermediate 技术领域technical field
本发明涉及药物合成领域，具体地涉及一种(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮及其中间体的制备方法。The present invention relates to the field of drug synthesis, in particular to a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- Preparation methods of 4-ketones and intermediates thereof.
背景技术Background technique
磷酸肌醇-3激酶(PI3K)属于一类细胞内脂质激酶，所述激酶磷酸化磷酸肌醇脂质(PI)的肌醇环的3位羟基，从而产生脂质第二信使。已有技术报道，磷酸肌醇-3-激酶(PI3K)途径的靶向抑制剂可以作为免疫调节剂。Phosphoinositide-3 kinases (PI3Ks) belong to a class of intracellular lipid kinases that phosphorylate the 3-hydroxyl of the inositol ring of phosphoinositide lipids (PI), thereby generating lipid second messengers. It has been reported in the art that targeted inhibitors of the phosphoinositide-3-kinase (PI3K) pathway can be used as immunomodulators.
专利文献WO2011055215A2公开了一种新型苯并吡喃激酶调节剂，在此基础上，专利文献WO2014195888A1进一步研究，公开了一种能够同时抑制PI3Kδ/γ的抑制剂(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮。Patent document WO2011055215A2 discloses a novel benzopyran kinase regulator. On this basis, patent document WO2014195888A1 further studies and discloses an inhibitor (S)-2-(1-( 9H-Purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one.
在专利文献WO2014195888A1公开了(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮的合成工艺：The patent document WO2014195888A1 discloses the synthesis process of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one :
Figure PCTCN2022070607-appb-000001
Figure PCTCN2022070607-appb-000001
然而，该方法反应过程复杂，对产物的纯度和收率均有影响。However, the reaction process of this method is complicated, which affects the purity and yield of the product.
尽管，在专利文献WO2011055215A2公开了(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮类似物(R)-2-(1-(9H-嘌呤-6-基氨基)乙基)-3-(3-氟苯基)-4H-色烯-4-酮(说明书实施例56)：Although, (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one is disclosed in patent document WO2011055215A2 Compound (R)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one (Example 56 of the specification):
Figure PCTCN2022070607-appb-000002
Figure PCTCN2022070607-appb-000002
然而，仍需对上述反应过程中的各步骤进行优化，得到一种能够提高反应纯度和收率的工艺。However, each step in the above reaction process still needs to be optimized to obtain a process that can improve the reaction purity and yield.
出于上述目的，本发明在已有文献的基础上，对(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮进行进一步的研究，得到了本发明的技术方案。For the above-mentioned purpose, the present invention, on the basis of the existing literature, to (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H -Chromene-4-ketone carries out further research, has obtained technical scheme of the present invention.
发明内容Contents of the invention
本发明提供了一种新颖的制备(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮的方法，相比于已有文献所公开的方法，本发明减少了反应步骤，从而能够提高反应的纯度、收率，降低生产成本。The present invention provides a novel preparation of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one Compared with the methods disclosed in existing documents, the present invention reduces the reaction steps, thereby improving the purity and yield of the reaction and reducing production costs.
为了解决上述技术问题，本发明提供了以下技术方案：In order to solve the above technical problems, the present invention provides the following technical solutions:
一种化合物(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮(式(I))的制备方法，其特征在于，包括以下步骤：A compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one (formula (I)) The preparation method is characterized in that, comprises the following steps:
Figure PCTCN2022070607-appb-000003
Figure PCTCN2022070607-appb-000003
步骤(I)：化合物1发生催化氢化反应制备得到化合物2；Step (I): compound 1 is prepared by catalytic hydrogenation reaction to obtain compound 2;
步骤(II)：化合物2与取代的嘌呤衍生物(化合物3)发生反应制备得到所述的式(I)化合物；Step (II): Compound 2 reacts with a substituted purine derivative (compound 3) to prepare the compound of formula (I);
其中，X表示卤素，优选为Cl、Br，更优选为Br；Wherein, X represents halogen, preferably Cl, Br, more preferably Br;
其中，Y表示离去基团，优选为卤素，更优选为Cl或者Br。Wherein, Y represents a leaving group, preferably a halogen, more preferably Cl or Br.
在本发明的优选技术方案中，其中，所述步骤(I)的催化氢化反应是在钯作为催化剂、氢气条件下进行的。In the preferred technical solution of the present invention, wherein, the catalytic hydrogenation reaction of the step (I) is carried out under the condition of palladium as a catalyst and hydrogen.
在本发明的优选技术方案中，其中所述的钯催化剂选自Pd/C、Pd(OH) 2/C中的任意一种或其组合。 In the preferred technical solution of the present invention, the palladium catalyst is selected from any one of Pd/C, Pd(OH) 2 /C or a combination thereof.
在本发明的优选技术方案中，其中，所述步骤(I)的反应溶剂为甲醇、乙醇、四氢呋喃、二氧六环、DMSO、丙酮、丁醇中的任意一种或者其组合。In the preferred technical solution of the present invention, wherein, the reaction solvent of the step (I) is any one of methanol, ethanol, tetrahydrofuran, dioxane, DMSO, acetone, butanol or a combination thereof.
在本发明的优选技术方案中，其中，所述的步骤(II)的反应条件是在碱性 条件下进行的。In the preferred technical scheme of the present invention, wherein, the reaction condition of described step (II) is carried out under alkaline condition.
在本发明的优选技术方案中，其中，所述的碱性条件为无机碱或者有机碱，优选为Na 2CO 3、K 2CO 3、Cs 2CO 3、NaOH、KOH、N,N-二异丙基乙胺(DIPEA)、叔丁基钠、乙醇钠、甲醇钠、三乙胺、二乙胺、吡啶、DMAP、吗啉、N-甲基吗啉中的任意一种或者其组合，更优选为三乙胺。 In the preferred technical solution of the present invention, wherein, the alkaline condition is an inorganic base or an organic base, preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, N,N-di Any one or combination of isopropylethylamine (DIPEA), sodium tert-butyl, sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine, DMAP, morpholine, N-methylmorpholine, More preferred is triethylamine.
在本发明的优选技术方案中，其中，所述的步骤(II)中反应溶剂为水、甲醇、乙醇、四氢呋喃、二氧六环、DMSO、丙酮、丁醇、叔丁醇、乙醚中的任意一种或其组合。In the preferred technical scheme of the present invention, wherein, the reaction solvent in the described step (II) is any of water, methanol, ethanol, tetrahydrofuran, dioxane, DMSO, acetone, butanol, tert-butanol, ether one or a combination thereof.
除此之外，本发明还提供了一种化合物2的制备方法，其特征在于包括以下步骤：In addition, the present invention also provides a preparation method of compound 2, which is characterized in that it comprises the following steps:
Figure PCTCN2022070607-appb-000004
Figure PCTCN2022070607-appb-000004
其中，所述的氢化催化反应的反应条件为在有机溶剂的存在下，以钯作为催化剂，通过氢气在高压下进行催化氢化反应；其中，X表示卤素，优选为Cl或者溴，更优选为Br。Wherein, the reaction condition of the hydrogenation catalytic reaction is that in the presence of an organic solvent, palladium is used as a catalyst, and the catalytic hydrogenation reaction is carried out by hydrogen under high pressure; wherein, X represents a halogen, preferably Cl or bromine, more preferably Br .
在本发明的优选技术方案中，其中所述的钯催化剂选自Pd/C、Pd(OH) 2/C中的任意一种或其组合 In the preferred technical scheme of the present invention, wherein said palladium catalyst is selected from any one of Pd/C, Pd(OH) 2 /C or a combination thereof
在本发明的优选技术方案中，其中，所述的有机溶剂选自甲醇、乙醇、异丙醇、四氢呋喃，二氧六环、DMF、DMSO中的任意一种或其组合。In the preferred technical solution of the present invention, wherein, the organic solvent is selected from any one of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO or a combination thereof.
在本发明的优选技术方案中，其中，所述的高压反应为0.5-1MPa。In the preferred technical solution of the present invention, wherein, the high pressure reaction is 0.5-1MPa.
除此之外，本发明还提供了一种化合物1的制备方法，其特征在于，包括以下步骤：In addition, the present invention also provides a preparation method of Compound 1, which is characterized in that it comprises the following steps:
Figure PCTCN2022070607-appb-000005
Figure PCTCN2022070607-appb-000005
化合物4与化合物5在碱性/缩合剂条件下，有机溶剂中发生反应制备得 到化合物1；Compound 4 and compound 5 are prepared by reacting in an organic solvent under alkaline/condensing agent conditions to obtain compound 1;
其中，X表示卤素，优选为Cl或者溴，更优选为Br。Wherein, X represents halogen, preferably Cl or bromine, more preferably Br.
在本发明的优选技术方案中，其中，所述的碱性条件为无机碱或者有机碱，优选为Na 2CO 3、K 2CO 3、Cs 2CO 3、NaOH、KOH、N,N-二异丙基乙胺(DIPEA)、叔丁基钠、乙醇钠、甲醇钠、三乙胺、二乙胺、吡啶、DMAP、吗啉、N-甲基吗啉、中的任意一种或者其组合。 In the preferred technical solution of the present invention, wherein, the alkaline condition is an inorganic base or an organic base, preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, N,N-di Any one of isopropylethylamine (DIPEA), tert-butyl sodium, sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine, DMAP, morpholine, N-methylmorpholine, or a combination thereof .
在本发明的优选技术方案中，其中，所述的有机溶剂选自二氯甲烷、四氯化碳、氯仿、甲醇、乙醇、异丙醇、四氢呋喃、二氧六环、DMF、丙酮中的任意一种或其组合。In the preferred technical solution of the present invention, wherein, the organic solvent is selected from any of dichloromethane, carbon tetrachloride, chloroform, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, acetone one or a combination thereof.
在本发明的优选技术方案中，其中，所述的缩合剂选自HATU、HBTU、TBTU、TATU、HOBt、DCC、EDCI、DMAP中的任意一种或其组合。In the preferred technical solution of the present invention, wherein the condensing agent is selected from any one of HATU, HBTU, TBTU, TATU, HOBt, DCC, EDCI, DMAP or a combination thereof.
在本发明的优选技术方案中，其中，化合物4由以下方法制备所得：In the preferred technical scheme of the present invention, wherein, compound 4 is prepared by the following method:
Figure PCTCN2022070607-appb-000006
Figure PCTCN2022070607-appb-000006
由化合物6与化合物7发生Friedel—Crafts反应制备得到；Prepared by the Friedel-Crafts reaction of compound 6 and compound 7;
其中，X表示卤素，优选为Cl或者溴，更优选为Br。Wherein, X represents halogen, preferably Cl or bromine, more preferably Br.
在本发明的优选技术方案中，其中，所述的反应的催化剂为AlCl 3。 In the preferred technical solution of the present invention, wherein, the catalyst for the reaction is AlCl 3 .
在本发明的优选技术方案中，其中，所述的反应在有机溶剂中进行的，所述的有机溶剂优选为二氯甲烷、四氯化碳、氯仿、甲醇、乙醇、异丙醇、四氢呋喃、二氧六环、DMF、丙酮中的任意一种或其组合。In the preferred technical scheme of the present invention, wherein, described reaction is carried out in organic solvent, and described organic solvent is preferably dichloromethane, carbon tetrachloride, chloroform, methyl alcohol, ethanol, isopropanol, tetrahydrofuran, Any one or combination of dioxane, DMF, acetone.
在本发明的优选技术方案中，其中，化合物5的制备方法包括以下步骤：In the preferred technical scheme of the present invention, wherein, the preparation method of compound 5 comprises the following steps:
Figure PCTCN2022070607-appb-000007
Figure PCTCN2022070607-appb-000007
步骤(i)：化合物8在碱性条件下与苄基溴发生反应制备得到化合物9；Step (i): compound 8 is reacted with benzyl bromide under basic conditions to prepare compound 9;
步骤(ii)：化合物9在控制水解条件下得到化合物5。Step (ii): Compound 9 was hydrolyzed under controlled conditions to obtain Compound 5.
在本发明的优选技术方案中，其中，步骤(i)中的反应在碱性条件下进行，所述的碱选自Na 2CO 3、K 2CO 3、Cs 2CO 3、NaOH、KOH中的任意一种或其组合。 In the preferred technical solution of the present invention, wherein the reaction in step (i) is carried out under alkaline conditions, the base is selected from Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH any one or combination of them.
在本发明的优选技术方案中，其中，步骤(i)的反应溶剂选自H 2O、甲醇、乙醇、四氢呋喃、二氧六环中的任意一种或其组合。 In a preferred technical solution of the present invention, wherein the reaction solvent in step (i) is selected from any one of H 2 O, methanol, ethanol, tetrahydrofuran, dioxane or a combination thereof.
在本发明的优选技术方案中，其中，步骤(ii)的反应在碱性条件下进行，所述的碱选自Na 2CO 3、K 2CO 3、Cs 2CO 3、NaOH、KOH中的任意一种或其组合，优选为NaOH。 In the preferred technical solution of the present invention, wherein the reaction in step (ii) is carried out under alkaline conditions, the base is selected from Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH Any one or combination thereof, preferably NaOH.
在本发明的优选技术方案中，其中，步骤(ii)的反应溶剂选自H 2O、甲醇、乙醇、四氢呋喃、二氧六环中的任意一种或其组合。 In a preferred technical solution of the present invention, wherein the reaction solvent in step (ii) is selected from any one of H 2 O, methanol, ethanol, tetrahydrofuran, dioxane or a combination thereof.
进一步地，本发明提供了一种化合物1：Further, the present invention provides a compound 1:
Figure PCTCN2022070607-appb-000008
Figure PCTCN2022070607-appb-000008
其中，X表示卤素，优选为Cl或者溴，更优选为Br。Wherein, X represents halogen, preferably Cl or bromine, more preferably Br.
更进一步地，本发明提供了一种化合物1Furthermore, the present invention provides a compound 1
Figure PCTCN2022070607-appb-000009
Figure PCTCN2022070607-appb-000009
在制备(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮(式(I))In the preparation of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one (formula (I))
中的应用application in
Figure PCTCN2022070607-appb-000010
Figure PCTCN2022070607-appb-000010
附图说明Description of drawings
图1中间体1-(5-溴-2羟基-苯基)-2-(3-氟-苯基)乙酮(化合物4)的核磁氢谱图Figure 1 H NMR spectrum of intermediate 1-(5-bromo-2-hydroxy-phenyl)-2-(3-fluoro-phenyl)ethanone (compound 4)
图2中间体N,N-二苄基氨基丁酸(化合物5)的核磁氢谱图Figure 2 The NMR spectrum of the intermediate N,N-dibenzylaminobutyric acid (compound 5)
图3中间体(S)-6-溴-2-(1-二苯基氨基丙基)-3-(3-氟苯基)-4H-色烯-4-酮(化合物1)的核磁氢谱图Figure 3 NMR hydrogen of intermediate (S)-6-bromo-2-(1-diphenylaminopropyl)-3-(3-fluorophenyl)-4H-chromen-4-one (compound 1) spectrogram
图4中间体(S)-6-溴-2-(1-二苯基氨基丙基)-3-(3-氟苯基)-4H-色烯-4-酮(化合物1)的核磁碳谱图Figure 4 NMR carbon of intermediate (S)-6-bromo-2-(1-diphenylaminopropyl)-3-(3-fluorophenyl)-4H-chromen-4-one (compound 1) spectrogram
图5中间体2-(氨基-丙基)-3-(3-氟苯基)--4H-色烯-4-酮(化合物2)的核磁氢谱图Figure 5 The NMR spectrum of intermediate 2-(amino-propyl)-3-(3-fluorophenyl)--4H-chromen-4-one (compound 2)
图6中间体2-(氨基-丙基)-3-(3-氟苯基)--4H-色烯-4-酮(化合物2)的核磁碳谱图Figure 6 C NMR spectrum of intermediate 2-(amino-propyl)-3-(3-fluorophenyl)--4H-chromen-4-one (compound 2)
图7(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮(式(I))的核磁氢谱图Figure 7 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one (formula (I)) H NMR spectrum
图8(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮(式(I))的核磁碳谱图Figure 8 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one (formula (I)) NMR spectrum
具体实施方式Detailed ways
实施例1 1-(5-溴-2羟基-苯基)-2-(3-氟-苯基)乙酮(化合物4)的制备Example 1 Preparation of 1-(5-bromo-2 hydroxy-phenyl)-2-(3-fluoro-phenyl)ethanone (compound 4)
实施例1.1Example 1.1
Figure PCTCN2022070607-appb-000011
Figure PCTCN2022070607-appb-000011
步骤1)：将间氟苯乙酸(200g,1.0eq.)，DMF(2.4g,0.012W)，二氯甲烷(750mL,3.5V)加至反应瓶，氮气置换3次；降温搅拌至-10℃，在-10℃滴加SOCl 2(200.8g,1.3eq.)。滴加完毕后升温至20℃，保温搅拌3h；取样中控HPLC(甲醇淬灭)；反应结束后，30℃下浓缩至无液体流出。加二氯甲烷(600mL,3V)继续浓缩至无液体流出，得间氟苯乙酰氯； Step 1): Add m-fluorophenylacetic acid (200g, 1.0eq.), DMF (2.4g, 0.012W), dichloromethane (750mL, 3.5V) into the reaction flask, replace with nitrogen 3 times; cool down and stir to -10 °C, SOCl2 (200.8 g, 1.3 eq.) was added dropwise at -10 °C. After the dropwise addition, the temperature was raised to 20° C., and kept stirring for 3 hours; the sample was controlled by HPLC (methanol quenching); after the reaction was completed, it was concentrated at 30° C. until no liquid flowed out. Add dichloromethane (600mL, 3V) and continue to concentrate until no liquid flows out to obtain m-fluorophenylacetyl chloride;
步骤2)：将间氟苯乙酰氯(1.0eq.)，对溴苯甲醚(315.6g,1.3eq.)，二氯甲烷(750mL,3.5V)加至反应瓶中。降温搅拌至-10℃，分批加AlCl 3(225g,1.3eq.)，并控制反应温度在-10-0℃；加料完毕后升温至25℃，保温搅拌15h后取样HPLC中控(甲醇淬灭)；待降温到-10℃后将6N盐酸(900mL,4.5V)滴加至反应液中，并控温-10-0℃；滴加完毕，将二氯甲烷(600mL,3.0V)，水(10.0V)加入到反应瓶中搅拌，静置分层；用二氯甲烷(600mL,3.0V)萃取两次水相，合并有机层；加无水硫酸钠(40g,0.2W)干燥，过滤；40℃下浓缩有机层至200mL(1.0V)；加入乙醇(2.0V)在室温下打浆0.5h，过滤得滤饼；50℃烘料4h，取样检测HPLC 纯度，得到化合物4 1-(5-溴-2羟基-苯基)-2-(3-氟-苯基)乙酮，得类白色固体242.7g,收率为60.5％。 Step 2): Add m-fluorophenylacetyl chloride (1.0eq.), p-bromoanisole (315.6g, 1.3eq.), dichloromethane (750mL, 3.5V) into the reaction flask. Lower the temperature and stir to -10°C, add AlCl 3 (225g, 1.3eq.) in batches, and control the reaction temperature at -10-0°C; after the addition is complete, raise the temperature to 25°C, keep stirring for 15h and then sample the HPLC control (methanol quenching After cooling down to -10°C, 6N hydrochloric acid (900mL, 4.5V) was added dropwise to the reaction solution, and the temperature was controlled at -10-0°C; after the dropwise addition, methylene chloride (600mL, 3.0V), Water (10.0V) was added to the reaction flask and stirred, and the layers were separated; the aqueous phase was extracted twice with dichloromethane (600mL, 3.0V), and the organic layers were combined; dried by adding anhydrous sodium sulfate (40g, 0.2W), Filtrate; concentrate the organic layer to 200mL (1.0V) at 40°C; add ethanol (2.0V) to make a slurry at room temperature for 0.5h, and filter to obtain a filter cake; bake at 50°C for 4h, take a sample to check the purity by HPLC, and obtain compound 4 1-( 5-Bromo-2-hydroxy-phenyl)-2-(3-fluoro-phenyl)ethanone gave 242.7 g of off-white solid with a yield of 60.5%.
1H NMR(400MHz，CDCl 3，ppm)δ：12.06(s，1H)，7.98(s，1H)，7.58-7.97(d，1H)，7.35-7.40(m，1H)，6.99-7.08(m，3H)，6.94-6.96(d，1H)，4.31(S，2H). 13C NMR(100MHz，CDCl 3，ppm)δ：202.20，164.18，161.76，139.45，135.53，135.45，132.40，130.40，130.32，125.29，125.26，120.86，120.17，116.74，116.53，114.61，114.40，110.66，44.67.HRMS(ESIMS)for C 14H 10BrFO 2(M-H) -Anal.calcd.307.98；found 307.98。 1 H NMR (400MHz, CDCl 3 , ppm) δ: 12.06(s, 1H), 7.98(s, 1H), 7.58-7.97(d, 1H), 7.35-7.40(m, 1H), 6.99-7.08(m , 3H), 6.94-6.96 (d, 1H), 4.31 (S, 2H). 13 C NMR (100MHz, CDCl 3 , ppm) δ: 202.20, 164.18, 161.76, 139.45, 135.53, 135.45, 132.40, 130.40, 130.32 , 125.29, 125.26, 120.86, 120.17, 116.74, 116.53, 114.61, 114.40, 110.66, 44.67. HRMS (ESIMS) for C 14 H 10 BrFO 2 (MH) - Anal.calcd.307.98; found 307.98.
实施例1.2Example 1.2
Figure PCTCN2022070607-appb-000012
Figure PCTCN2022070607-appb-000012
步骤1)：将间氟苯乙酸(200g,1.0eq.)，DMF(2.4g,0.012W)，二氯甲烷(300mL,1.5V)加至反应瓶，氮气置换3次；降温搅拌至20℃，在20℃滴加(COCl) 2(181g,1.1eq.)；滴加完毕后在20-25℃，保温搅拌12h；取样中控HPLC(甲醇淬灭)；步骤2)：将间氟苯乙酰氯(1.0eq.)，对溴苯甲醚(315.6g,1.3eq.)，二氯甲烷(1250mL,6.5V)加至反应瓶中，降温搅拌至0℃；分批加AlCl 3(225g,1.3eq.)，并控制反应温度在0-10℃；加料完毕后升温至40℃，保温搅拌15h后取样HPLC中控(甲醇淬灭)；控制内温40℃以下，把上述反应液滴加至将稀盐酸(6.7％,15.0V)中；静置分层，用二氯甲烷(600mL,3.0V)萃取两次水相；合并有机层，用水(5.0V)洗涤三次；取有机层，40℃下浓缩有机层至200mL(1.0V)；加入乙酸乙酯(1V)，正庚烷(8.0V),在20℃下搅拌1小时，过滤得滤饼，正庚烷(1.0V)洗涤；50℃烘料4h，取样检测HPLC纯度，得到类白色化合物4 1-(5-溴-2羟基-苯基)-2-(3-氟-苯基)乙酮150g，收率37.5％。 Step 1): Add m-fluorophenylacetic acid (200g, 1.0eq.), DMF (2.4g, 0.012W), dichloromethane (300mL, 1.5V) into the reaction flask, replace with nitrogen 3 times; cool down and stir to 20°C , add (COCl) 2 (181g, 1.1eq.) dropwise at 20°C; after the dropwise addition, keep stirring at 20-25°C for 12h; control HPLC during sampling (methanol quenching); step 2): m-fluorobenzene Add acetyl chloride (1.0eq.), p-bromoanisole (315.6g, 1.3eq.), dichloromethane (1250mL, 6.5V) into the reaction flask, cool and stir to 0°C; add AlCl 3 (225g , 1.3eq.), and control the reaction temperature at 0-10°C; after the addition, the temperature was raised to 40°C, and after 15 hours of heat preservation and stirring, the sample was controlled by HPLC (methanol quenching); the internal temperature was controlled below 40°C, and the above reaction liquid was Add to dilute hydrochloric acid (6.7%, 15.0V); stand to separate the layers, extract the aqueous phase twice with dichloromethane (600mL, 3.0V); combine the organic layers, wash with water (5.0V) three times; take the organic layer , concentrated the organic layer to 200mL (1.0V) at 40°C; added ethyl acetate (1V), n-heptane (8.0V), stirred at 20°C for 1 hour, and filtered to obtain a filter cake, n-heptane (1.0V) Washing; drying at 50°C for 4 hours, sampling for HPLC purity, and obtaining off-white compound 4 1-(5-bromo-2hydroxy-phenyl)-2-(3-fluoro-phenyl)ethanone 150g, yield 37.5% .
1H NMR(400MHz，CDCl 3，ppm)δ：12.06(s，1H)，7.98(s，1H)，7.58-7.97(d，1H)，7.35-7.40(m，1H)，6.99-7.08(m，3H)，6.94-6.96(d，1H)，4.31(S，2H). 13C NMR(100MHz，CDCl 3，ppm)δ：202.20，164.18，161.76，139.45，135.53，135.45，132.40，130.40，130.32，125.29，125.26，120.86，120.17，116.74，116.53，114.61，114.40，110.66，44.67.HRMS(ESIMS)for C 14H 10BrFO 2(M-H) -Anal.calcd.307.98；found 307.98。 1 H NMR (400MHz, CDCl 3 , ppm) δ: 12.06(s, 1H), 7.98(s, 1H), 7.58-7.97(d, 1H), 7.35-7.40(m, 1H), 6.99-7.08(m , 3H), 6.94-6.96 (d, 1H), 4.31 (S, 2H). 13 C NMR (100MHz, CDCl 3 , ppm) δ: 202.20, 164.18, 161.76, 139.45, 135.53, 135.45, 132.40, 130.40, 130.32 , 125.29, 125.26, 120.86, 120.17, 116.74, 116.53, 114.61, 114.40, 110.66, 44.67. HRMS (ESIMS) for C 14 H 10 BrFO 2 (MH) - Anal.calcd.307.98; found 307.98.
实施例2 N,N-二苄基氨基丁酸(化合物5)的制备Embodiment 2 N, the preparation of N-dibenzyl aminobutyric acid (compound 5)
实施例2.1Example 2.1
Figure PCTCN2022070607-appb-000013
Figure PCTCN2022070607-appb-000013
步骤1)：取KOH(108.9g,1.94mol,2.0eq.)，K 2CO 3(268.05g,1.94mol,2.0eq.)和水(1L,10V)加入反应器中。在25℃，加入2-氨基丁酸(100g,0.97mol,1.0eq.)，升温至90℃。后滴加苄氯(381.0g,3.01mol,3.1eq.)，90℃保温反应5h后，取样中控；降至室温，用二氯甲烷(1L,10V)萃取，分层，上层有机层浓缩至干，得黄色油状液体，为中间体1粗品； Step 1): Take KOH (108.9g, 1.94mol, 2.0eq.), K 2 CO 3 (268.05g, 1.94mol, 2.0eq.) and water (1L, 10V) into the reactor. At 25°C, 2-aminobutyric acid (100 g, 0.97 mol, 1.0 eq.) was added, and the temperature was raised to 90°C. Afterwards, benzyl chloride (381.0g, 3.01mol, 3.1eq.) was added dropwise, and after 5 hours of heat preservation at 90°C, the sample was controlled in the central control; the temperature was lowered to room temperature, extracted with dichloromethane (1L, 10V), the layers were separated, and the upper organic layer was concentrated To dryness, a yellow oily liquid was obtained, which was the crude product of Intermediate 1;
步骤2)：取中间体1粗品，升温至80℃，滴加的KOH水溶液(108.9g,1.94mol,2.0eq；1080mL,10.8V水)。升温至80℃后保温反应12h，取样中控；75℃脱溶至基本无馏分，得中间体2粗品为黄色油状液体；Step 2): Take the crude intermediate 1, heat up to 80°C, and add KOH aqueous solution (108.9g, 1.94mol, 2.0eq; 1080mL, 10.8V water) dropwise. After raising the temperature to 80°C, keep it warm for 12 hours, and take a sample to control it; precipitation at 75°C until there are basically no fractions, and the crude product of intermediate 2 is obtained as a yellow oily liquid;
步骤3)：再加入水(1080mL,10.8V)稀释，于室温(25℃)下加入6M盐酸调节pH＝2，固体逐渐析出。室温(25℃)下析晶1h，随后低温析晶2h，趁冷过滤，3M盐酸(50mL)洗涤，得化合物5粗品，为浅黄色固体；Step 3): add water (1080mL, 10.8V) to dilute, add 6M hydrochloric acid at room temperature (25°C) to adjust pH = 2, solids gradually precipitate out. Crystallize at room temperature (25°C) for 1 h, then crystallize at low temperature for 2 h, filter while cold, and wash with 3M hydrochloric acid (50 mL) to obtain crude compound 5 as a light yellow solid;
步骤4)：取化合物5粗品加入乙醇(1080mL,3V)，室温(25℃)下打浆2h，过滤，乙醇(50mL)洗涤，得到化合物5产品213.34g，为白色固体，纯度96.17％。取纯度为96.17％的化合物5产品213.34g，加入乙醇(600mL,3V)，室温(25℃)下打浆2h，过滤，乙醇(50mL)洗涤，得到化合物5产品193.01g，为白色固体，收率为70.24％，纯度为98.58％。Step 4): Take the crude compound 5 and add ethanol (1080mL, 3V), beat at room temperature (25°C) for 2h, filter, and wash with ethanol (50mL) to obtain 213.34g of compound 5 as a white solid with a purity of 96.17%. Take 213.34g of compound 5 product with a purity of 96.17%, add ethanol (600mL, 3V), beat at room temperature (25°C) for 2h, filter, and wash with ethanol (50mL) to obtain 193.01g of compound 5 product as a white solid, yield It is 70.24% and the purity is 98.58%.
1H NMR(400MHz,DMSO,ppm)δ:12.48(s,1H),7.23-7.34(m,10H),3.81(d,2H)，3.57(d,2H)，3.025(t,1H),1.67(d,2H),0.84(t,3H). 13C NMR(100MHz,CDCl 3,ppm):δ174.1,140.2,128.9,128.7,127.3,62.7,54.4,22.53,11.53.HRMS(ESIMS)for C 18H 21NO 2H(M+H) +Anal.calcd.284.16；found 284.1642. 1 H NMR (400MHz,DMSO,ppm)δ:12.48(s,1H),7.23-7.34(m,10H),3.81(d,2H),3.57(d,2H),3.025(t,1H),1.67 (d,2H),0.84(t,3H) .13 C NMR(100MHz,CDCl 3 ,ppm):δ174.1,140.2,128.9,128.7,127.3,62.7,54.4,22.53,11.53.HRMS(ESIMS)for C 18 H 21 NO 2 H(M+H) + Anal.calcd.284.16; found 284.1642.
实施例2.2 N,N-二苄基氨基丁酸(化合物5)的制备Example 2.2 Preparation of N,N-dibenzylaminobutyric acid (compound 5)
Figure PCTCN2022070607-appb-000014
Figure PCTCN2022070607-appb-000014
步骤1)：取NaOH(77.57g,1.94mol,2.0eq.)，K2CO3(268.05g,1.94mol,2.0eq.)和水(1L,10V)加入反应器中。降至25℃下，加入2-氨基丁酸(100g,0.97mol,1.0eq.)，升温至80℃。后滴加苄溴(855.8g,5.09mol,3.1eq.)，80℃保温反应10h后，取样中控；降至室温后，静置，分出上层有机层，得中间体1粗品，为黄色油状液体。Step 1): Take NaOH (77.57g, 1.94mol, 2.0eq.), K2CO3 (268.05g, 1.94mol, 2.0eq.) and water (1L, 10V) into the reactor. After cooling down to 25°C, 2-aminobutyric acid (100g, 0.97mol, 1.0eq.) was added, and the temperature was raised to 80°C. After that, benzyl bromide (855.8g, 5.09mol, 3.1eq.) was added dropwise, and after 10h of heat preservation at 80°C, the sample was taken for control; after cooling down to room temperature, it was allowed to stand still, and the upper organic layer was separated to obtain the crude intermediate 1, which was yellow oily liquid.
步骤2)：向中间体1粗品滴加入NaOH的水溶液(NaOH 154.21g,3.86mol,4.0eq；水720mL,7.2V)。升温至90℃后保温反应12h，取样中控；将反应液降温至30℃，加入DCM(1500mL,15V),振荡、摇匀、静置，在30℃下分层、保留下层有机层。向上述有机层中加入水(1080mL,15V)萃取，在30℃下分液、保留上层水层。向水层中加入DCM(1500mL,15V)除去大部分苄醇，静置，在30℃下分液、保留上层水层。Step 2): Add NaOH aqueous solution (NaOH 154.21g, 3.86mol, 4.0eq; water 720mL, 7.2V) to the crude intermediate 1 dropwise. After raising the temperature to 90°C, keep the reaction for 12 hours, take a sample and control it; cool the reaction solution to 30°C, add DCM (1500mL, 15V), oscillate, shake well, stand still, separate layers at 30°C, and keep the lower organic layer. Water (1080 mL, 15 V) was added to the above organic layer for extraction, and the liquid was separated at 30° C., and the upper aqueous layer was retained. DCM (1500 mL, 15V) was added to the water layer to remove most of the benzyl alcohol, left to stand, separated at 30°C, and the upper water layer was retained.
步骤3)：加入DCM(1000mL,10V)稀释，于30℃下加入6M盐酸(210mL)调节pH＝3。搅拌10min后静置，分液、保留下层DCM层。DCM层加入水(1000mL,10V)洗，分液、保留下层DCM层。Step 3): DCM (1000 mL, 10V) was added for dilution, and 6M hydrochloric acid (210 mL) was added at 30° C. to adjust the pH=3. After stirring for 10 min, let it stand, separate the liquid, and keep the lower DCM layer. The DCM layer was washed with water (1000 mL, 10 V), separated, and the lower DCM layer was retained.
步骤4)：将上述DCM层溶液浓缩至336g，再加入无水乙醇(230mL,2.3V)、正庚烷(230mL,2.3V)，升温至70℃溶清，降至室温析出细小颗粒状化合物5，室温打浆2h，降至0℃搅拌1h。过滤，用正庚烷(250mL)洗涤滤饼，烘干得到化合物5产品189g，为白色固体，收率为65.50％，纯度为99.4％。Step 4): Concentrate the above DCM layer solution to 336g, then add absolute ethanol (230mL, 2.3V) and n-heptane (230mL, 2.3V), heat up to 70°C to dissolve, and cool down to room temperature to precipitate fine granular compounds 5. Beat for 2 hours at room temperature, then lower to 0°C and stir for 1 hour. After filtration, the filter cake was washed with n-heptane (250 mL), and dried to obtain 189 g of compound 5 as a white solid with a yield of 65.50% and a purity of 99.4%.
1H NMR(400MHz,DMSO,ppm)δ:12.48(s,1H),7.23-7.34(m,10H),3.81(d,2H)，3.57(d,2H)，3.025(t,1H),1.67(d,2H),0.84(t,3H). 13C NMR(100MHz,CDCl 3,ppm):δ174.1,140.2,128.9,128.7,127.3,62.7,54.4,22.53,11.53.HRMS(ESIMS)for C 18H 21NO 2H(M+H) +Anal.calcd.284.16；found 284.1642. 1 H NMR (400MHz,DMSO,ppm)δ:12.48(s,1H),7.23-7.34(m,10H),3.81(d,2H),3.57(d,2H),3.025(t,1H),1.67 (d,2H),0.84(t,3H) .13 C NMR(100MHz,CDCl 3 ,ppm):δ174.1,140.2,128.9,128.7,127.3,62.7,54.4,22.53,11.53.HRMS(ESIMS)for C 18 H 21 NO 2 H(M+H) + Anal.calcd.284.16; found 284.1642.
实施例3(S)-6-溴-2-(1-二苯基氨基丙基)-3-(3-氟苯基)-4H-色烯-4-酮(化合物1)的制备Example 3 Preparation of (S)-6-bromo-2-(1-diphenylaminopropyl)-3-(3-fluorophenyl)-4H-chromen-4-one (compound 1)
实施例3.1Example 3.1
Figure PCTCN2022070607-appb-000015
Figure PCTCN2022070607-appb-000015
将实施例1制备得到的化合物4(10g,32.35mmol,1.0eq.)，实施例2制备得到的化合物5(13.75g,48.52mmol,1.5eq.)，HATU(18.45g,48.52mmol,1.5eq.)溶于DCM(100mL)中,于25℃下搅拌5min；向混合液中滴加Et 3N(35.42g,10.8eq.)，(体系放热，温度升高5-6℃)；将反应液于42℃下搅拌48h，取样中控；加入30mL DCM稀释反应液，用水(3×100mL)淬灭，合并有机相；加入Na 2SO 4(2g)干燥有机相、过滤、浓缩(-0.1MPa,55℃)，得到黄色固体粗品化合物1(39.46g)。向上述粗产品中加入无水EtOH(135mL),70℃下搅拌回流至粗产品溶解；部分不溶杂质趁热过滤。于25℃下冷却至产品逐渐析出，过滤，用无水冰EtOH(15mL)淋洗滤饼；真空干燥4h(-0.1MPa,55℃)得到白色固体化合物1 10.5g,收率58.3％)，纯度99.32％。 Compound 4 (10g, 32.35mmol, 1.0eq.) prepared in Example 1, Compound 5 (13.75g, 48.52mmol, 1.5eq.) prepared in Example 2, HATU (18.45g, 48.52mmol, 1.5eq .) was dissolved in DCM (100mL), and stirred at 25°C for 5min; Et 3 N (35.42g, 10.8eq.) was added dropwise to the mixture, (the system released heat, and the temperature increased by 5-6°C); The reaction solution was stirred at 42°C for 48h, and the sample was controlled; 30mL DCM was added to dilute the reaction solution, quenched with water (3×100mL), and the organic phase was combined; Na 2 SO 4 (2g) was added to dry the organic phase, filtered, and concentrated (- 0.1MPa, 55°C), the crude compound 1 (39.46g) was obtained as a yellow solid. Add anhydrous EtOH (135mL) to the above crude product, stir and reflux at 70°C until the crude product dissolves; filter some insoluble impurities while hot. Cool at 25°C until the product gradually precipitates, filter, rinse the filter cake with anhydrous ice EtOH (15mL); vacuum dry for 4h (-0.1MPa, 55°C) to obtain 10.5g of white solid compound 1, yield 58.3%), 99.32% pure.
1HNMR(400MHz,CDCl 3,ppm)δ:8.41(d,1H),7.82(dd,1H),7.45(s,1H),7.43(s,1H),7.17-7.25(m,11H),6.87-7.00(m,3H),4.09(d,2H)，3.962(t，1H),3.58(d,2H),2.02-2.21(m,2H)，1.06(t，1H). 13C NMR(100MHz,CDCl 3,ppm):δ175.4，166.1，163.6，161.1,154.2，139.3，136.6，133.6，133.5，129.7，128.8，128.07，128.0，126.8，124.7，124.3，119.9，118.5，115.0，114.8，59.9，54.4，23.4，11.2.HRMS(ESIMS)for C 32H 27BrFNO 2H(M+H) +Anal.calcd.556.12；found 556.1285. 1 H NMR (400MHz, CDCl 3 , ppm) δ: 8.41 (d, 1H), 7.82 (dd, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 7.17-7.25 (m, 11H), 6.87 -7.00(m, 3H), 4.09(d, 2H), 3.962(t, 1H), 3.58(d, 2H), 2.02-2.21(m, 2H), 1.06(t, 1H). 13 C NMR (100MHz , CDCl 3 , ppm): δ175.4, 166.1, 163.6, 161.1, 154.2, 139.3, 136.6, 133.6, 133.5, 129.7, 128.8, 128.07, 128.0, 126.8, 124.7, 124.3, 119.9, 118.5, 115.0, 114.8, 59.9 , 54.4, 23.4, 11.2. HRMS (ESIMS) for C 32 H 27 BrFNO 2 H (M+H) + Anal.calcd.556.12; found 556.1285.
实施例3.2Example 3.2
Figure PCTCN2022070607-appb-000016
Figure PCTCN2022070607-appb-000016
将实施例1制备得到的化合物4(10g,32.35mmol,1.0eq.)，加入乙腈(90g,10V),搅拌溶解。加入N-甲基咪唑(18.6g,7.0eq)，TCFH(28.1g,3.1eq)。加入实施例2制备得到的化合物5(13.75g,48.52mmol,1.5eq.)，将反应液于25℃下搅拌12h，取样中控；加入水(120g,12V),再加入二氯甲烷，降至0℃保温1h,过滤，二氯甲烷(1V)洗涤，取滤液。用水(100mL)洗涤3次。取二氯甲烷层，40℃浓缩至无液体流出。加入乙醇(2V),50-55℃浓缩至无液体流出。加入乙醇(650mL，6.5V)，升温至78℃回流30分钟，滴加水(162g,1.6V)。搅拌下降至室温，并保温1小时，过滤，用(乙醇：水＝6：4，1V)洗涤。真空干燥 4h(-0.1MPa,55℃)得到白色固体化合物1为5.85g,纯度为99.15％，收率为32.5％。Compound 4 (10g, 32.35mmol, 1.0eq.) prepared in Example 1 was added into acetonitrile (90g, 10V) and stirred to dissolve. N-Methylimidazole (18.6 g, 7.0 eq), TCFH (28.1 g, 3.1 eq) were added. Compound 5 (13.75g, 48.52mmol, 1.5eq.) prepared in Example 2 was added, the reaction solution was stirred at 25°C for 12h, and the sample was controlled in the center; water (120g, 12V) was added, and then dichloromethane was added to reduce Keep warm at 0°C for 1h, filter, wash with dichloromethane (1V), and take the filtrate. Wash with water (100 mL) 3 times. The dichloromethane layer was taken and concentrated at 40°C until no liquid flowed out. Add ethanol (2V), concentrate at 50-55°C until no liquid flows out. Add ethanol (650mL, 6.5V), heat up to 78°C and reflux for 30 minutes, then add water (162g, 1.6V) dropwise. Stir down to room temperature and keep warm for 1 hour, filter and wash with (ethanol:water=6:4, 1V). Vacuum drying for 4h (-0.1MPa, 55°C) gave 5.85g of white solid compound 1 with a purity of 99.15% and a yield of 32.5%.
1HNMR(400MHz,CDCl 3,ppm)δ:8.41(d,1H),7.82(dd,1H),7.45(s,1H),7.43(s,1H),7.17-7.25(m,11H),6.87-7.00(m,3H),4.09(d,2H)，3.962(t，1H),3.58(d,2H),2.02-2.21(m,2H)，1.06(t，1H). 13C NMR(100MHz,CDCl 3,ppm):δ175.4，166.1，163.6，161.1,154.2，139.3，136.6，133.6，133.5，129.7，128.8，128.07，128.0，126.8，124.7，124.3，119.9，118.5，115.0，114.8，59.9，54.4，23.4，11.2.HRMS(ESIMS)for C 32H 27BrFNO 2H(M+H) +Anal.calcd.556.12；found 556.1285. 1 H NMR (400MHz, CDCl 3 , ppm) δ: 8.41 (d, 1H), 7.82 (dd, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 7.17-7.25 (m, 11H), 6.87 -7.00(m, 3H), 4.09(d, 2H), 3.962(t, 1H), 3.58(d, 2H), 2.02-2.21(m, 2H), 1.06(t, 1H). 13 C NMR (100MHz , CDCl 3 , ppm): δ175.4, 166.1, 163.6, 161.1, 154.2, 139.3, 136.6, 133.6, 133.5, 129.7, 128.8, 128.07, 128.0, 126.8, 124.7, 124.3, 119.9, 118.5, 115.0, 114.8, 59.9 , 54.4, 23.4, 11.2. HRMS (ESIMS) for C 32 H 27 BrFNO 2 H (M+H) + Anal.calcd.556.12; found 556.1285.
实施例3.3Example 3.3
Figure PCTCN2022070607-appb-000017
Figure PCTCN2022070607-appb-000017
将实施例1制备得到的化合物4(100g,323.5mmol,1.0eq.)，加入二氯甲烷(665g,5V),搅拌溶解。加入三乙胺(354.2g,10.82eq)。将实施例2制备得到的化合物5(137.5g,485.2mmol,1.5eq.)，HBTU(184.0g,485.2mmol,1.5eq.)溶解在DCM(665g,5V)中，滴加上述溶液。继续滴加三乙胺(98.2g,3eq)，将反应液于47℃下回流24h，取样中控；降至0℃保温1h,过滤，二氯甲烷(1V)洗涤，取滤液。用水(1000mL)洗涤3次。取二氯甲烷层，40℃浓缩至无液体流出。加入乙醇(2V),50-55℃浓缩至无液体流出。加入乙醇(650mL，6.5V)，升温至78℃回流30分钟，滴加水(72g,0.7V)。搅拌下降至室温，并保温1小时，过滤，用(乙醇：水＝6：4，1V)洗涤。真空干燥4h(-0.1MPa,55℃)得到白色固体化合物1为111.6g,纯度为99.25％，收率为62％。Compound 4 (100g, 323.5mmol, 1.0eq.) prepared in Example 1 was added to dichloromethane (665g, 5V), and stirred to dissolve. Triethylamine (354.2g, 10.82eq) was added. Compound 5 (137.5g, 485.2mmol, 1.5eq.) and HBTU (184.0g, 485.2mmol, 1.5eq.) prepared in Example 2 were dissolved in DCM (665g, 5V), and the above solution was added dropwise. Continue to add triethylamine (98.2g, 3eq) dropwise, reflux the reaction solution at 47°C for 24h, take a sample and control it; lower it to 0°C for 1h, filter, wash with dichloromethane (1V), and take the filtrate. Washed 3 times with water (1000 mL). The dichloromethane layer was taken and concentrated at 40°C until no liquid flowed out. Add ethanol (2V), concentrate at 50-55°C until no liquid flows out. Ethanol (650 mL, 6.5 V) was added, the temperature was raised to 78° C. and refluxed for 30 minutes, and water (72 g, 0.7 V) was added dropwise. Stir down to room temperature and keep warm for 1 hour, filter and wash with (ethanol:water=6:4, 1V). Vacuum drying for 4h (-0.1MPa, 55°C) yielded 111.6g of white solid compound 1 with a purity of 99.25% and a yield of 62%.
1HNMR(400MHz,CDCl 3,ppm)δ:8.41(d,1H),7.82(dd,1H),7.45(s,1H),7.43(s,1H),7.17-7.25(m,11H),6.87-7.00(m,3H),4.09(d,2H)，3.962(t，1H),3.58(d,2H),2.02-2.21(m,2H)，1.06(t，1H). 13C NMR(100MHz,CDCl 3,ppm):δ175.4，166.1，163.6，161.1,154.2，139.3，136.6，133.6，133.5，129.7，128.8，128.07，128.0，126.8，124.7，124.3，119.9，118.5，115.0，114.8，59.9，54.4，23.4，11.2.HRMS(ESIMS)for C 32H 27BrFNO 2H(M+H) +Anal.calcd.556.12；found 556.1285. 1 H NMR (400MHz, CDCl 3 , ppm) δ: 8.41 (d, 1H), 7.82 (dd, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 7.17-7.25 (m, 11H), 6.87 -7.00(m, 3H), 4.09(d, 2H), 3.962(t, 1H), 3.58(d, 2H), 2.02-2.21(m, 2H), 1.06(t, 1H). 13 C NMR (100MHz , CDCl 3 , ppm): δ175.4, 166.1, 163.6, 161.1, 154.2, 139.3, 136.6, 133.6, 133.5, 129.7, 128.8, 128.07, 128.0, 126.8, 124.7, 124.3, 119.9, 118.5, 115.0, 114.8, 59.9 , 54.4, 23.4, 11.2. HRMS (ESIMS) for C 32 H 27 BrFNO 2 H (M+H) + Anal.calcd.556.12; found 556.1285.
实施例4(S)-2-(氨基-丙基)-3-(3-氟苯基)--4H-色烯-4-酮(化合物2)的制备Example 4 Preparation of (S)-2-(amino-propyl)-3-(3-fluorophenyl)--4H-chromen-4-one (compound 2)
实施例4.1Example 4.1
Figure PCTCN2022070607-appb-000018
Figure PCTCN2022070607-appb-000018
分别称取60.0g由实施例3制备得到的化合物1(108.2mmol,1.0eq),12.0g Pd(OH) 2/C(5％wt,0.2W),300mL四氢呋喃(5V)加入500mL的高压釜。高压反应釜抽真空，再氢气置换，重复三次，最后加入氢气至0.8MPa后关闭反应釜，在室温(20℃)搅拌2.5h后，反应釜氢气压力降为0.4MPa，向反应釜补加氢气至0.6MPa后，继续室温(20℃)下搅拌反应22.5h，反应结束后，放掉过量氢气，打开高压釜，反应液取样做HPLC中控；过滤反应液(20℃)，往反应液里加5％NaHCO 3(300mL，5V)，搅拌15min，静置分层。过滤出的水层往里加入MTBE(300mL，5V)，搅拌15min，静置分层。合并有机层再用10％NaCl(300mL，5V)，搅拌15min，静置分层。将有机层在40℃下浓缩干。将得到的黄色固体加入(30mL，0.5V)四氢呋喃与(60mL，1V)MTBE在50℃回流条件下搅拌0.5h-1h。降至室温，并往里滴加(240mL，4V)正庚烷，继续搅拌1h-2h。过滤得到黄色固体取样做HPLC控，母液取样；在60℃真空烘箱(16h)得到化合物2为26.1g橘黄色固体,收率为81.3％，纯度为99.34％。 Weigh 60.0g of compound 1 (108.2mmol, 1.0eq) prepared in Example 3, 12.0g of Pd(OH) 2 /C (5%wt, 0.2W), and 300mL of tetrahydrofuran (5V) into a 500mL autoclave . Vacuum the autoclave, then replace it with hydrogen, repeat three times, finally add hydrogen to 0.8MPa, close the autoclave, stir at room temperature (20°C) for 2.5h, the hydrogen pressure in the autoclave drops to 0.4MPa, and add hydrogen to the autoclave After reaching 0.6MPa, continue to stir and react at room temperature (20°C) for 22.5h. After the reaction is over, let off excess hydrogen, open the autoclave, and sample the reaction solution for HPLC control; filter the reaction solution (20°C), and add 5% NaHCO 3 (300mL, 5V), stirred for 15min, and allowed to stand to separate layers. MTBE (300mL, 5V) was added to the filtered water layer, stirred for 15min, and allowed to stand to separate into layers. Combine the organic layers and then add 10% NaCl (300mL, 5V), stir for 15min, and let stand to separate the layers. The organic layer was concentrated to dryness at 40°C. The obtained yellow solid was added into (30 mL, 0.5V) tetrahydrofuran and (60 mL, 1V) MTBE and stirred at 50°C under reflux for 0.5h-1h. Cool down to room temperature, and add (240mL, 4V) n-heptane dropwise, and continue stirring for 1h-2h. The yellow solid obtained by filtration was sampled for HPLC control, and the mother liquor was sampled; Compound 2 was obtained as 26.1 g of orange solid in a vacuum oven at 60° C. (16 h), with a yield of 81.3% and a purity of 99.34%.
实施例4.2Example 4.2
Figure PCTCN2022070607-appb-000019
Figure PCTCN2022070607-appb-000019
分别称取58.5g由实施例3制备得到的化合物1(105.4mmol，1.0eq),11.7g Pd/C(5％wt,0.2W),292.5mL甲醇(5V)加入500mL的高压釜。高压反应釜抽真空，再氢气置换，重复三次，最后加入氢气至1.0MPa后关闭反应釜。在室温(20℃)搅拌2.5h后，反应釜氢气压力降为0.4MPa，向反应釜补加氢气至1.0MPa后，继续室温(20℃)下搅拌反应24h。反应结束后，放掉过量氢气， 打开高压釜，反应液取样做HPLC中控。过滤反应液(20℃)，往反应液里加5％NaOH(292.5mL，5V)，搅拌15min，静置分层。过滤出的水层往里加入DCM(292.5mL，5V)，搅拌15min，静置分层。合并有机层再用10％NaCl(292.5mL，5V)，搅拌15min，静置分层。将有机层在40℃下浓缩干。将得到的黄色固体加入(175.5mL，3V)MTBE在室温条件下搅拌1h。过滤得到黄色固体取样做HPLC中控。在60℃真空烘箱(16h)得到化合物2为19.34g橘黄色固体,收率为61.8％，纯度为99.58％。Weighed 58.5g of compound 1 (105.4mmol, 1.0eq) prepared in Example 3, 11.7g of Pd/C (5%wt, 0.2W), and 292.5mL of methanol (5V) into a 500mL autoclave. The autoclave was evacuated, replaced with hydrogen, and repeated three times, and finally the autoclave was closed after adding hydrogen to 1.0 MPa. After stirring at room temperature (20° C.) for 2.5 h, the hydrogen pressure in the reactor dropped to 0.4 MPa. After adding hydrogen to the reactor to 1.0 MPa, the stirring reaction was continued at room temperature (20° C.) for 24 h. After the reaction, the excess hydrogen gas was let off, the autoclave was opened, and the reaction solution was sampled for HPLC control. Filter the reaction solution (20°C), add 5% NaOH (292.5 mL, 5V) to the reaction solution, stir for 15 min, and let stand to separate layers. DCM (292.5 mL, 5V) was added to the filtered water layer, stirred for 15 min, and the layers were separated. Combine the organic layers and add 10% NaCl (292.5 mL, 5V), stir for 15 min, and let stand to separate the layers. The organic layer was concentrated to dryness at 40°C. The obtained yellow solid was added into (175.5 mL, 3V) MTBE and stirred at room temperature for 1 h. The yellow solid obtained by filtration was sampled for HPLC central control. Compound 2 was obtained in a vacuum oven at 60° C. (16 h) as 19.34 g of an orange solid, with a yield of 61.8% and a purity of 99.58%.
实施例4.3Example 4.3
Figure PCTCN2022070607-appb-000020
Figure PCTCN2022070607-appb-000020
分别称取50.0g由实施例3制备得到的化合物1(90.1mmol，1.0eq),5.0g Pd/C(10％wt,0.1W),350mL四氢呋喃(7V)加入500mL的高压釜。高压反应釜抽真空，再氢气置换，重复三次，最后加入氢气至0.8MPa后关闭反应釜。在室温(20℃)搅拌2.5h后，反应釜氢气压力降为0.4MPa，向反应釜补加氢气至0.8MPa后，继续室温(20℃)下搅拌反应24h，反应结束后，放掉过量氢气，打开高压釜，反应液取样做HPLC中控，过滤反应液(20℃)，往反应液里加5％NaHCO 3(250mL，5V)，搅拌15min，静置分层。过滤出的水层往里加入MTBE(250mL，5V)，搅拌15min，静置分层。合并有机层再用10％NaCl(250mL，5V)，搅拌15min，静置分层。将有机层在40℃下浓缩干。将得到的黄色固体加入(100mL，2V)四氢呋喃与(500mL，10V)正庚烷在50℃回流条件下搅拌0.5h-1h。降至室温，继续搅拌1h-2h。过滤得到黄色固体取样做HPLC中控，母液取样。在60℃真空烘箱(16h)得到化合物2为19.1g橘黄色固体,收率为71.5％，纯度为98.57％。 Weighed 50.0g of compound 1 (90.1mmol, 1.0eq) prepared in Example 3, 5.0g of Pd/C (10%wt, 0.1W), and 350mL of tetrahydrofuran (7V) into a 500mL autoclave. The autoclave was evacuated, replaced with hydrogen, and repeated three times, and finally the autoclave was closed after adding hydrogen to 0.8MPa. After stirring at room temperature (20°C) for 2.5h, the hydrogen pressure in the reactor dropped to 0.4MPa. After adding hydrogen to the reactor to 0.8MPa, continue to stir and react at room temperature (20°C) for 24h. After the reaction, let off excess hydrogen. , open the autoclave, sample the reaction solution for HPLC control, filter the reaction solution (20°C), add 5% NaHCO 3 (250mL, 5V) to the reaction solution, stir for 15min, and let stand to separate layers. MTBE (250mL, 5V) was added to the filtered water layer, stirred for 15min, and allowed to stand to separate into layers. Combine the organic layers and then add 10% NaCl (250mL, 5V), stir for 15min, and let stand to separate the layers. The organic layer was concentrated to dryness at 40°C. Add (100 mL, 2V) tetrahydrofuran and (500 mL, 10V) n-heptane to the obtained yellow solid and stir under reflux at 50°C for 0.5h-1h. Cool down to room temperature and continue stirring for 1h-2h. The yellow solid obtained by filtration was sampled for HPLC control, and the mother liquor was sampled. Compound 2 was obtained in a vacuum oven at 60° C. (16 h) as 19.1 g of an orange solid, with a yield of 71.5% and a purity of 98.57%.
1H NMR(400MHz，CDCl 3，ppm)δ：0.896(t，3H)，1.556(m，2H)，1.777(t，2H)，3.697(s，1H)，7.058(t，3H)，7.395(m，2H)，7.477(s，1H)，7.679(s，1H)，8.219(s，1H)， 13C NMR(100MHz，CDCl 3，ppm)δ：176.05，164.14，161.69，156.30，155.41，134.38，132.54，132.46，130.71，126.43，124.68，122.87，117.95，116.18，115.98,52.91,25.80,9.97.HRMS(ESIMS)for  C 18H 16FNO 2(M+H) +Anal.calcd:298.12,found 298.13. 1 H NMR (400MHz, CDCl 3 , ppm) δ: 0.896(t, 3H), 1.556(m, 2H), 1.777(t, 2H), 3.697(s, 1H), 7.058(t, 3H), 7.395( m, 2H), 7.477(s, 1H), 7.679(s, 1H), 8.219(s, 1H), 13 C NMR (100MHz, CDCl 3 , ppm) δ: 176.05, 164.14, 161.69, 156.30, 155.41, 134.38 , 132.54, 132.46, 130.71, 126.43, 124.68, 122.87, 117.95, 116.18, 115.98, 52.91, 25.80, 9.97. HRMS (ESIMS) for C 18 H 16 FNO 2 (M+H) + Anal.calcd: 298.12, found 298.13 .
实施例5(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮(式(I))的制备Example 5 (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one (formula (I)) preparation of
实施例5.1Example 5.1
Figure PCTCN2022070607-appb-000021
Figure PCTCN2022070607-appb-000021
分别称取由实施例4制备得到的化合物2：5g(16.84mmol，1.0eq.)、化合物6-溴代嘌呤6.50g(6.50mmol，2.0eq.)、醋酸钠2.68g(32.68mmol，2.0eq.)和乙酸(3.0g,3.0eq)至反应器1中,异丙醇(50mL,10V)；搅拌均匀后，搅拌下将反应器缓慢升温至回流反应；反应48h后，反应液取样做HPLC中控；停止加热反应，反应液降至室温(25℃),并将反应液转至反应器2中，在45℃下减压蒸馏，浓缩滤液至无液体流出；向反应器2中加水(30V)，在100℃油浴中搅拌1h，趁热过滤，得到黑色油状粗产物。向粗产物中加入乙腈(7V)，在60℃油浴下加热搅拌溶解后，室温冷却结晶12h得到白色粉末状固体产物，过滤，真空干燥(65℃)2h，得到式(I)化合物粗品4.10g，纯度为98.06％；Weigh respectively the compound 2 prepared by Example 4: 5g (16.84mmol, 1.0eq.), compound 6-bromopurine 6.50g (6.50mmol, 2.0eq.), sodium acetate 2.68g (32.68mmol, 2.0eq. .) and acetic acid (3.0g, 3.0eq) into reactor 1, isopropanol (50mL, 10V); after stirring evenly, the reactor was slowly heated to reflux reaction under stirring; after reacting for 48h, the reaction solution was sampled for HPLC Central control; stop the heating reaction, drop the reaction solution to room temperature (25°C), and transfer the reaction solution to reactor 2, distill under reduced pressure at 45°C, concentrate the filtrate until no liquid flows out; add water to reactor 2 ( 30V), stirred in an oil bath at 100°C for 1 h, and filtered while hot to obtain a black oily crude product. Add acetonitrile (7V) to the crude product, heat and stir in an oil bath at 60°C to dissolve, then cool and crystallize at room temperature for 12 hours to obtain a white powdery solid product, filter, and vacuum dry (65°C) for 2 hours to obtain the crude compound of formula (I) 4.10 g, with a purity of 98.06%;
1H NMR(400MHz，CDCl 3，ppm)δ：13.93(s，1H)，8.45(s，1H)，8.23(d，1H)，8.01(s，1H)，7.61(t，1H)，7.31-7.45(m，3H)，7.11-7.33(m，3H)，6.52(s，1H)，5.51(s，1H)，2.01(t，2H)，0.96(t，3H)， 13C NMR(100MHz，CDCl3，ppm)δ：176.98，167.04，164.01，155.92，134.63，134.55，133.81，130.17，130.19，126.28，125.19，123.42，121.88，117.84，117.78，117.57，115.17，114.96，53.64，28.65，10.83.HRMS(ESIMS)for C 23H 18FN 5O 2(M+H) +Anal.calcd.415.144；found 416.14 1 H NMR (400MHz, CDCl 3 , ppm) δ: 13.93(s, 1H), 8.45(s, 1H), 8.23(d, 1H), 8.01(s, 1H), 7.61(t, 1H), 7.31- 7.45(m, 3H), 7.11-7.33(m, 3H), 6.52(s, 1H), 5.51(s, 1H), 2.01(t, 2H), 0.96(t, 3H), 13 C NMR (100MHz, CDCl3, ppm) δ: 176.98, 167.04, 164.01, 155.92, 134.63, 134.55, 133.81, 130.17, 130.19, 126.28, 125.19, 123.42, 121.88, 117.84, 117.78, 117.57, 115.17, 114.96, 53.64, 28.65, 10.83.HRMS( ESIMS) for C 23 H 18 FN 5 O 2 (M+H) + Anal.calcd.415.144; found 416.14
实施例5.2Example 5.2
Figure PCTCN2022070607-appb-000022
Figure PCTCN2022070607-appb-000022
分别称取由实施例4制备得到的化合物2：5g(16.84mmol,1.0eq.)、化合物6-溴代嘌呤6.5g(32.68mmol，2.0eq.)、DIPEA:4.34g(32.68mmol,2.0eq.)和t-BuOH:100mL(20V)至反应器1中；搅拌均匀后,将反应器缓慢升温至90℃(外温)搅拌回流反应；反应36h后，反应液取样做HPLC中控；将反应液用二氯甲烷(200mL,40V)稀释，过滤。取滤液，用10％AcOH水溶液(50mL，5V洗涤)，后水洗涤，碳酸钠水溶液洗涤。有机相浓缩至干，向粗产物中加入乙酸乙酯(4V)，在60℃油浴下加热搅拌溶解后，室温冷却结晶12h得到白色粉末状固体产物，再经过滤，真空干燥(65℃)2h，得到式(I)化合物4.30g，纯度为97.75％；Weigh respectively the compound 2 prepared by Example 4: 5g (16.84mmol, 1.0eq.), compound 6-bromopurine 6.5g (32.68mmol, 2.0eq.), DIPEA: 4.34g (32.68mmol, 2.0eq. .) and t-BuOH: 100mL (20V) into Reactor 1; after stirring evenly, slowly raise the temperature of the reactor to 90°C (external temperature) and stir and reflux for reaction; after reacting for 36h, sample the reaction solution for HPLC control; The reaction solution was diluted with dichloromethane (200 mL, 40V) and filtered. The filtrate was taken and washed with 10% AcOH aqueous solution (50 mL, 5 V), followed by water and sodium carbonate aqueous solution. Concentrate the organic phase to dryness, add ethyl acetate (4V) to the crude product, heat and stir in an oil bath at 60°C to dissolve, then cool and crystallize at room temperature for 12 hours to obtain a white powdery solid product, which is then filtered and vacuum-dried (65°C) After 2h, 4.30 g of the compound of formula (I) was obtained with a purity of 97.75%;
1H NMR(400MHz,CDCl 3，ppm)δ：13.93(s，1H)，8.45(s，1H)，8.23(d，1H)，8.01(s，1H)，7.61(t，1H)，7.31-7.45(m，3H)，7.11-7.33(m，3H)，6.52(s，1H)，5.51(s，1H)，2.01(t，2H)，0.96(t，3H)， 13C NMR(100MHz，CDCl 3，ppm)δ：176.98，167.04，164.01，155.92，134.63，134.55，133.81，130.17，130.19，126.28，125.19，123.42，121.88，117.84，117.78，117.57，115.17，114.96，53.64，28.65，10.83.HRMS(ESIMS)for C 23H 18FN 5O 2(M+H) +Anal.calcd.415.144；found 416.149. 1 H NMR (400MHz, CDCl 3 , ppm) δ: 13.93(s, 1H), 8.45(s, 1H), 8.23(d, 1H), 8.01(s, 1H), 7.61(t, 1H), 7.31- 7.45(m, 3H), 7.11-7.33(m, 3H), 6.52(s, 1H), 5.51(s, 1H), 2.01(t, 2H), 0.96(t, 3H), 13 C NMR (100MHz, CDCl 3 , ppm) δ: 176.98, 167.04, 164.01, 155.92, 134.63, 134.55, 133.81, 130.17, 130.19, 126.28, 125.19, 123.42, 121.88, 117.84, 117.78, 117.5 7, 115.17, 114.96, 53.64, 28.65, 10.83.HRMS (ESIMS) for C 23 H 18 FN 5 O 2 (M+H) + Anal. calcd. 415.144; found 416.149.
实施例5.3Example 5.3
Figure PCTCN2022070607-appb-000023
Figure PCTCN2022070607-appb-000023
分别称取由实施例4制备得到的化合物2：20g(67.34mmol，1.0eq.)、6-氯代嘌呤20.7g(134.68mmol，2.0eq.)、DIPEA：17.4g(134.68mmol，2.0eq.)和t-BuOH： 400mL(20V)至反应器1中；搅拌均匀后，将反应器缓慢升温至90℃(外温)搅拌回流反应；反应66h后，反应液取样做HPLC中控；停止加热反应，反应液降至室温(25℃),并将反应液转至反应器2中，在45℃下减压蒸馏，浓缩滤液至叔丁醇为1V；向反应器2中加水(30V)，在100℃油浴中搅拌2h，趁热过滤，得到黑色油状粗产物。向粗产物中加入乙腈(4V)，在60℃油浴下加热搅拌溶解后，室温冷却结晶12h得到白色粉末状固体产物，再经过滤，真空干燥(65℃)2h，得到式(I)化合物为15.8g，纯度为98.46％。Weigh the compound 2 prepared by Example 4: 20g (67.34mmol, 1.0eq.), 6-chloropurine 20.7g (134.68mmol, 2.0eq.), DIPEA: 17.4g (134.68mmol, 2.0eq. ) and t-BuOH: 400mL (20V) into Reactor 1; after stirring evenly, slowly raise the temperature of the reactor to 90°C (external temperature) and stir and reflux for reaction; after reacting for 66h, sample the reaction solution for HPLC control; stop heating Reaction, the reaction solution was lowered to room temperature (25°C), and the reaction solution was transferred to Reactor 2, distilled under reduced pressure at 45°C, and the filtrate was concentrated until tert-butanol was 1V; water (30V) was added to Reactor 2, Stir in an oil bath at 100°C for 2h, and filter while hot to obtain a black oily crude product. Add acetonitrile (4V) to the crude product, heat and stir in an oil bath at 60°C to dissolve, then cool and crystallize at room temperature for 12 hours to obtain a white powdery solid product, then filter and dry in vacuum (65°C) for 2 hours to obtain the compound of formula (I) It is 15.8g, and the purity is 98.46%.
1H NMR(400MHz，CDCl 3，ppm)δ：13.93(s，1H)，8.45(s，1H)，8.23(d，1H)，8.01(s，1H)，7.61(t，1H)，7.31-7.45(m，3H)，7.11-7.33(m，3H)，6.52(s，1H)，5.51(s，1H)，2.01(t，2H)，0.96(t，3H)， 13C NMR(100MHz，CDCl 3，ppm)δ：176.98，167.04，164.01，155.92，134.63，134.55，133.81，130.17，130.19，126.28，125.19，123.42，121.88，117.84，117.78，117.57，115.17，114.96，53.64，28.65，10.83.HRMS(ESIMS)for C 23H 18FN 5O 2(M+H) +Anal.calcd.415.144；found 416.149. 1 H NMR (400MHz, CDCl 3 , ppm) δ: 13.93(s, 1H), 8.45(s, 1H), 8.23(d, 1H), 8.01(s, 1H), 7.61(t, 1H), 7.31- 7.45(m, 3H), 7.11-7.33(m, 3H), 6.52(s, 1H), 5.51(s, 1H), 2.01(t, 2H), 0.96(t, 3H), 13 C NMR (100MHz, CDCl 3 , ppm) δ: 176.98, 167.04, 164.01, 155.92, 134.63, 134.55, 133.81, 130.17, 130.19, 126.28, 125.19, 123.42, 121.88, 117.84, 117.78, 117.5 7, 115.17, 114.96, 53.64, 28.65, 10.83.HRMS (ESIMS) for C 23 H 18 FN 5 O 2 (M+H) + Anal. calcd. 415.144; found 416.149.

Claims (25)

  1. 一种化合物(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮(式(I))的制备方法，其特征在于，包括以下步骤：A compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one (formula (I)) The preparation method is characterized in that, comprises the following steps:
    Figure PCTCN2022070607-appb-100001
    Figure PCTCN2022070607-appb-100001
    步骤(I)：化合物1发生催化氢化反应制备得到中间体化合物2；Step (I): compound 1 undergoes catalytic hydrogenation reaction to prepare intermediate compound 2;
    步骤(II)：化合物2与取代的嘌呤衍生物(化合物3)发生反应制备得到所述的式(I)化合物；Step (II): Compound 2 reacts with a substituted purine derivative (compound 3) to prepare the compound of formula (I);
    其中，X表示卤素，优选为Cl、Br，更优选为Br；Wherein, X represents halogen, preferably Cl, Br, more preferably Br;
    其中，Y表示离去基团，优选为卤素，更优选为Cl或者Br。Wherein, Y represents a leaving group, preferably a halogen, more preferably Cl or Br.
  2. 如权利要求1所述的制备方法，其特征在于，所述步骤(I)的催化氢化反应是在钯作为催化剂、氢气条件下进行的。preparation method as claimed in claim 1, is characterized in that, the catalytic hydrogenation reaction of described step (1) is carried out under palladium as catalyst, hydrogen condition.
  3. 如权利要求1或2所述的制备方法，其中，所述的钯催化剂选自Pd/C、Pd(OH) 2/C中的任意一种或其组合。 The preparation method according to claim 1 or 2, wherein the palladium catalyst is selected from any one of Pd/C, Pd(OH) 2 /C or a combination thereof.
  4. 如权利要求1至3任一项所述的制备方法，其特征在于，所述步骤(I)的反应溶剂为甲醇、乙醇、四氢呋喃、二氧六环、DMSO、丙酮、丁醇中的任意一种或者其组合。The preparation method according to any one of claims 1 to 3, wherein the reaction solvent of the step (1) is any one of methanol, ethanol, THF, dioxane, DMSO, acetone, butanol species or a combination thereof.
  5. 如权利要求1至4任一项所述的制备方法，其特征在于，所述的步骤(II)的反应条件是在碱性条件下进行的。The preparation method according to any one of claims 1 to 4, characterized in that, the reaction conditions of the step (II) are carried out under alkaline conditions.
  6. 如权利要求5所述的方法其中，其特征在于，所述的碱性条件为无机碱或者有机碱，优选为Na 2CO 3、K 2CO 3、Cs 2CO 3、NaOH、KOH、N,N-二异丙基乙胺(DIPEA)、叔丁基钠、乙醇钠、甲醇钠、三乙胺、二乙胺、吡啶、DMAP、吗啉、N-甲基吗啉中的任意一种或者其组合，更优选为三乙胺。 The method according to claim 5, wherein, it is characterized in that the alkaline condition is an inorganic base or an organic base, preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, N, Any one of N-diisopropylethylamine (DIPEA), sodium tert-butyl, sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine, DMAP, morpholine, N-methylmorpholine or Its combination is more preferably triethylamine.
  7. 如权利要求5或6所述的方法，其特征在于，所述的步骤(II)的反应溶剂为水、甲醇、乙醇、四氢呋喃、二氧六环、DMSO、丙酮、丁醇、叔丁醇、乙醚中 的任意一种或其组合。method as claimed in claim 5 or 6, is characterized in that, the reaction solvent of described step (II) is water, methanol, ethanol, THF, dioxane, DMSO, acetone, butanol, tert-butanol, Any one or combination of diethyl ethers.
  8. 一种化合物2的制备方法，其特征在于包括以下步骤：A preparation method of compound 2, characterized in that it comprises the following steps:
    Figure PCTCN2022070607-appb-100002
    Figure PCTCN2022070607-appb-100002
    其中，所述的氢化催化反应的反应条件为在有机溶剂的存在下，以钯作为催化剂，通过氢气在高压下进行催化氢化反应；Wherein, the reaction condition of the hydrogenation catalytic reaction is that in the presence of an organic solvent, palladium is used as a catalyst, and the catalytic hydrogenation reaction is carried out by hydrogen at high pressure;
    其中，X表示卤素，优选为Cl或者溴，更优选为Br。Wherein, X represents halogen, preferably Cl or bromine, more preferably Br.
  9. 如权利要求8所述的方法，其中，所述的钯催化剂选自Pd/C、Pd(OH) 2/C中的任意一种或其组合。 The method according to claim 8, wherein the palladium catalyst is selected from any one of Pd/C, Pd(OH) 2 /C or a combination thereof.
  10. 如权利要求8所述的方法，其中，所述的有机溶剂选自甲醇、乙醇、异丙醇、四氢呋喃，二氧六环、DMF、DMSO中的任意一种或其组合。The method according to claim 8, wherein the organic solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, any one of dioxane, DMF, DMSO or a combination thereof.
  11. 如权利要求8至10任一项所述的方法，其中，所述的高压反应为0.5-1MPa。The method according to any one of claims 8 to 10, wherein the high pressure reaction is 0.5-1MPa.
  12. 一种制备如权利要求8所述的化合物1的方法，其特征在于，包括以下步骤：A method for preparing compound 1 as claimed in claim 8, characterized in that it comprises the following steps:
    Figure PCTCN2022070607-appb-100003
    Figure PCTCN2022070607-appb-100003
    化合物4化合物5在碱性/缩合剂条件下，有机溶剂中发生反应制备得到化合物1；Compound 4 and Compound 5 were reacted in an organic solvent under alkaline/condensing agent conditions to obtain Compound 1;
    其中，X表示卤素，优选为Cl或者溴，更优选为Br。Wherein, X represents halogen, preferably Cl or bromine, more preferably Br.
  13. 如权利要求12所述的方法，其中，所述的碱性条件为无机碱或者有机碱，优选为Na 2CO 3、K 2CO 3、Cs 2CO 3、NaOH、KOH、N,N-二异丙基乙胺(DIPEA)、叔丁基钠、乙醇钠、甲醇钠、三乙胺、二乙胺、吡啶、DMAP、吗啉、N-甲基吗啉、中的任意一种或者其组合。 The method according to claim 12, wherein the alkaline condition is an inorganic base or an organic base, preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, N,N-di Any one of isopropylethylamine (DIPEA), tert-butyl sodium, sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine, DMAP, morpholine, N-methylmorpholine, or a combination thereof .
  14. 如权利要求12或13所述的方法，其中，所述的有机溶剂选自二氯甲烷、四氯化碳、氯仿、甲醇、乙醇、异丙醇、四氢呋喃、二氧六环、DMF、丙酮中的任意一种或其组合。The method according to claim 12 or 13, wherein, the organic solvent is selected from methylene chloride, carbon tetrachloride, chloroform, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, acetone any one or combination of them.
  15. 如权利要求12-13任一项所述的方法，其中所述的缩合剂选自HATU、HBTU、TBTU、TATU、HOBt、DCC、EDCI、DMAP中的任意一种或其组合。The method according to any one of claims 12-13, wherein the condensing agent is selected from any one of HATU, HBTU, TBTU, TATU, HOBt, DCC, EDCI, DMAP or a combination thereof.
  16. 如权利要求12所述的方法，其中，化合物4由以下方法制备所得：The method of claim 12, wherein compound 4 is prepared by the following method:
    Figure PCTCN2022070607-appb-100004
    Figure PCTCN2022070607-appb-100004
    由化合物6与化合物7发生Friedel—Crafts反应制备得到；Prepared by the Friedel-Crafts reaction of compound 6 and compound 7;
    其中，X表示卤素，优选为Cl或者溴，更优选为Br。Wherein, X represents halogen, preferably Cl or bromine, more preferably Br.
  17. 如权利要求16所述的方法，其中，所述的反应的催化剂为AlCl 3。 The method of claim 16, wherein the catalyst for the reaction is AlCl 3 .
  18. 如权利要求16或17所述的方法，其中，所述的反应在有机溶剂中进行的，所述的有机溶剂优选为二氯甲烷、四氯化碳、氯仿、甲醇、乙醇、异丙醇、四氢呋喃、二氧六环、DMF、丙酮中的任意一种或其组合。The method according to claim 16 or 17, wherein said reaction is carried out in an organic solvent, and said organic solvent is preferably dichloromethane, carbon tetrachloride, chloroform, methyl alcohol, ethanol, Virahol, Any one or combination of tetrahydrofuran, dioxane, DMF, acetone.
  19. 如权利要求12所述的化合物5的制备方法，其特征在于，包括以下步骤：The preparation method of compound 5 as claimed in claim 12, is characterized in that, comprises the following steps:
    Figure PCTCN2022070607-appb-100005
    Figure PCTCN2022070607-appb-100005
    步骤(i)：化合物8在碱性条件下与苄基溴发生反应制备得到化合物9；Step (i): compound 8 is reacted with benzyl bromide under basic conditions to prepare compound 9;
    步骤(ii)：化合物9在控制水解条件下得到化合物5。Step (ii): Compound 9 was hydrolyzed under controlled conditions to obtain Compound 5.
  20. 如权利要求19所述的方法，其中，步骤(i)中的反应在碱性条件下进行，所述的碱选自Na 2CO 3、K 2CO 3、Cs 2CO 3、NaOH、KOH中的任意一种或其组合。 The method according to claim 19, wherein the reaction in step (i) is carried out under alkaline conditions, and the base is selected from Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH any one or combination of them.
  21. 如权利要求19所述的方法，其中，步骤(i)的反应溶剂选自H 2O、甲醇、乙醇、四氢呋喃、二氧六环中的任意一种或其组合。 The method according to claim 19, wherein the reaction solvent in step (i) is selected from any one of H 2 O, methanol, ethanol, tetrahydrofuran, dioxane or a combination thereof.
  22. 如权利要求19-21任一项所述的方法，其中，步骤(ii)的反应在碱性条件下进行，所述的碱选自Na 2CO 3、K 2CO 3、Cs 2CO 3、NaOH、KOH中的任意一种或其组合，优选为NaOH。 The method according to any one of claims 19-21, wherein the reaction in step (ii) is carried out under alkaline conditions, and the base is selected from Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , Any one of NaOH, KOH or a combination thereof, preferably NaOH.
  23. 如权利要求19-22任一项所述的方法，其中，步骤(ii)的反应溶剂选自H 2O、甲醇、乙醇、四氢呋喃、二氧六环中的任意一种或其组合。 The method according to any one of claims 19-22, wherein the reaction solvent in step (ii) is selected from any one of H 2 O, methanol, ethanol, tetrahydrofuran, dioxane or a combination thereof.
  24. 化合物1：Compound 1:
    Figure PCTCN2022070607-appb-100006
    Figure PCTCN2022070607-appb-100006
    其中，X表示卤素，优选为Cl或者溴，更优选为Br。Wherein, X represents halogen, preferably Cl or bromine, more preferably Br.
  25. 化合物1Compound 1
    Figure PCTCN2022070607-appb-100007
    Figure PCTCN2022070607-appb-100007
    在制备(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-3-(3-氟苯基)-4H-色烯-4-酮(式(I))中的应用In the preparation of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one (formula (I)) Applications
    Figure PCTCN2022070607-appb-100008
    Figure PCTCN2022070607-appb-100008
PCT/CN2022/070607 2022-01-07 2022-01-07 Method for preparing chromen-4-one compound and intermediate thereof WO2023130334A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102812013A (en) * 2009-11-05 2012-12-05 理森制药股份公司 Novel Kinase Modulators
CN103946213A (en) * 2011-11-25 2014-07-23 霍夫曼-拉罗奇有限公司 Novel pyrrolidine derivatives as inhibitors of cathepsin
CN104507922A (en) * 2012-05-04 2015-04-08 理森制药股份公司 Process for preparation of optically pure and optionally substituted 2- (1 -hydroxy- alkyl) - chromen - 4 - one derivatives and their use in preparing pharmaceuticals
CN105358560A (en) * 2013-06-07 2016-02-24 理森制药股份公司 Dual selective PI3 delta and gamma kinase inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102812013A (en) * 2009-11-05 2012-12-05 理森制药股份公司 Novel Kinase Modulators
CN103946213A (en) * 2011-11-25 2014-07-23 霍夫曼-拉罗奇有限公司 Novel pyrrolidine derivatives as inhibitors of cathepsin
CN104507922A (en) * 2012-05-04 2015-04-08 理森制药股份公司 Process for preparation of optically pure and optionally substituted 2- (1 -hydroxy- alkyl) - chromen - 4 - one derivatives and their use in preparing pharmaceuticals
CN105358560A (en) * 2013-06-07 2016-02-24 理森制药股份公司 Dual selective PI3 delta and gamma kinase inhibitors

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