WO2021248764A1 - Procédé de préparation d'un intermédiaire d'octanoate de laninamivir au moyen d'une synthèse monotope - Google Patents

Procédé de préparation d'un intermédiaire d'octanoate de laninamivir au moyen d'une synthèse monotope Download PDF

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WO2021248764A1
WO2021248764A1 PCT/CN2020/120751 CN2020120751W WO2021248764A1 WO 2021248764 A1 WO2021248764 A1 WO 2021248764A1 CN 2020120751 W CN2020120751 W CN 2020120751W WO 2021248764 A1 WO2021248764 A1 WO 2021248764A1
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formula
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袁建栋
黄仰青
池建文
顾家宁
杭文明
林祥义
孙鹏
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博瑞生物医药（苏州）股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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

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  • the invention relates to the technical field of drug synthesis, in particular to a one-pot method for preparing an intermediate of lanimivir octoate.
  • Laninamivir caprylate is a neuraminidase inhibitor developed by Biota Pharmaceuticals and Daiichi Sankyo. It can be used to treat influenza virus infections that are resistant to oseltamivir (Tamiflu). In 2010, it was approved to be marketed in Japan under the name Inavir.
  • Lanimivir caprylate has good effects on H1N1, H5N1, N9 and influenza B viruses and Tamiflu-resistant viruses. Up to now, lanimivir caprylate has not been listed in the country, and there is no registered manufacturer. In order to guide the R&D and production of generic drugs and improve the availability of drugs to the public, the Center for Drug Evaluation of the State Food and Drug Administration organized a screening of foreign drugs that have expired, terminated, or become invalid and have no generic applications. Lanimivir caprylate was initially screened and included in the "List of the First Batch of Drugs with Expiration, Termination, and Invalidation without Generic Application".
  • Patent CN101679339A discloses the synthesis of lanimivir octoate by 11-step reaction with sialic acid as the starting material.
  • the synthesis route is as follows:
  • This route uses commercially supplied sialic acid as the starting material to synthesize lanimivir octoate through an 11-step reaction.
  • the unit reaction effect is good and the overall yield is high.
  • Patent CN103435582A discloses the synthesis of lanimivir octoate via a 5-step reaction with zanamivir as the starting material.
  • the synthesis route is as follows:
  • Method 3 Ma Dawei's research group used D-isoascorbic acid as the starting material, followed by a series of oxidation, reduction, protection, deprotection and other reactions to synthesize lanimivir octoate.
  • the synthetic route is as follows:
  • the synthesis route is relatively novel, the unit reaction yield is moderate, but the market supply of starting materials and catalyst ligands is small, the price is expensive, and it is not suitable for scale-up production.
  • the chiral purity of intermediate S-3 and intermediate S-8 is not high. , Resulting in more impurities in subsequent isomers, and the quality of the final product is difficult to control.
  • the purpose of the present invention is to provide a one-pot method for preparing lanimivir octoate intermediates.
  • a one-pot method for preparing lanimivir octoate intermediates adopts a synthetic method including the following:
  • R 1 is a benzyl group, a substituted benzyl group, or an allyl group.
  • the aforementioned substituted benzyl group means that the benzene ring on the benzyl group is mono- or multiple-substituted by groups such as chlorine, bromine, iodine, nitro, alkoxy, alkyl, and aromatic.
  • the above-mentioned one-pot method for preparing lanimivir octoate intermediate includes the following steps: mixing and stirring the compound represented by formula (4) with an organic solvent and R 1 OH, and then adding NaH and stirring for 30-60 min under the protection of nitrogen. Then (R 1 O) 2 CO is added, and the reaction is stirred at 0-80° C. for 30 min-24 h, and then separated to obtain the compound represented by formula (5).
  • the crude compound of formula (5) is crystallized by toluene or methanol to obtain crystals of the compound represented by formula (5).
  • the reaction temperature is 10-60°C.
  • reaction temperature is 50-55°C.
  • the reaction time is 30 minutes to 5 hours.
  • the organic solvent is any one or more of toluene, N,N-dimethylformamide, benzyl alcohol, n-heptane, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane.
  • the mass concentration of the NaH is 60%.
  • R 1 is benzyl
  • the mass ratio of the compound represented by formula (4), R 1 OH, NaH, and (R 1 O) 2 CO is 8-12:15-30:0.02-0.1:12-36.
  • the mass ratio of the compound represented by formula (4), R 1 OH, NaH, and (R 1 O) 2 CO is 9.8:20:0.04:24.22.
  • R 1 is benzyl, substituted benzyl or allyl
  • X is Cl -, Br -, I - , MeSO 4 -, TfO -.
  • Step 1 In the presence of a base, the compound represented by formula (1) reacts with R 1 X to produce the compound represented by formula (2).
  • the base is not particularly limited, as long as it can be neutralized with a carboxylic acid, and it may be an organic base or an inorganic base.
  • the organic base such as triethylamine, diisopropylethylamine, N,N-dimethyl-4-aminopyridine or pyridine
  • inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide or Potassium hydroxide.
  • An inorganic base is preferable, and cesium carbonate or potassium carbonate is more preferable.
  • Step 2 In the presence of an organic base, the compound represented by formula (2) reacts with acetic anhydride to produce the compound represented by formula (3). There is no restriction on the organic base, as long as it can be neutralized with carboxylic acid.
  • the organic base is any one or more of triethylamine, diisopropylethylamine, N,N-dimethyl-4-aminopyridine, and pyridine.
  • the reaction temperature in step 2 is -30°C to 100°C. Preferably it is 0-35 degreeC.
  • the reaction time of step 2 is 30min-24h. Preferably it is 10-15h.
  • Step 3 The compound represented by the formula (3) is catalyzed by trimethylsilyl trifluoromethanesulfonate to produce the compound represented by the formula (4).
  • the reaction temperature in step 3 is 0 to 70°C. Preferably it is 30 degreeC-60 degreeC.
  • the reaction time of step 3 is 1.0h-24h. Preferably it is 1.0-3.0h.
  • a preparation method of lanimivir octoate (compound of formula I) adopts a synthetic method including the following:
  • Step 5 is to react the compound represented by formula (5) with dimethyl sulfate or methyl iodide in the presence of a base to produce the compound represented by formula (6).
  • the reaction temperature in step 5 is 0-70°C, preferably 0-30°C.
  • Step 5 The reaction time is 30 minutes to 24 hours, preferably 1.0 to 15 hours.
  • Step 6 is to react the compound represented by formula (6) with azide trimethylsilane under the catalysis of titanium isopropoxide to produce the compound represented by formula (7).
  • Step 6 The reaction temperature is 0 to 120°C, preferably 0 to 40°C.
  • Step 6 The reaction time is 3.0 to 48 hours, preferably 3.0 to 24 hours.
  • Step 7 is the reaction of the compound represented by formula (7) with triphenylphosphine to produce the compound represented by formula (8).
  • the reaction temperature in step 7 is -10 to 80°C, preferably 0 to 60°C.
  • Step 7 The reaction time is 10 minutes to 48 hours, preferably 10 minutes to 5 hours.
  • Step 8 is the reaction of the compound represented by formula (8) with a base to produce the compound represented by formula (9).
  • inorganic bases are preferred, and lithium hydroxide, sodium hydroxide, and potassium hydroxide are more preferred.
  • the reaction temperature in step 8 is preferably -10 to 100°C, more preferably 0 to 50°C.
  • Step 8 The reaction time is preferably 10 minutes to 48 hours, more preferably 0.5 hours to 6 hours.
  • Step 9 is the reaction of the compound represented by formula (9) with the compound represented by formula (10) to produce the compound represented by formula (11).
  • the step 9 reaction solvent is preferably purified water.
  • the reaction temperature in Step 9 is 0-100°C, and preferably 5-50°C.
  • Step 9 The reaction time is 24h to 72h, and preferably 24 to 60h.
  • Step 10 is the reaction of the compound represented by formula (11) in the presence of trifluoroacetic acid to produce the compound represented by formula (12).
  • the reaction temperature in step 10 is -20 to 100°C, and preferably 0 to 45°C.
  • the reaction time of step 10 is 0.5 to 24 hours, and preferably 0.5 to 8 hours.
  • Step 11 is to react the compound represented by formula (12) with compound 13 or compound 14 in the presence of an acid, and then react with water to produce the compound represented by formula (I) or a pharmacologically acceptable salt thereof.
  • the acid in step 11 is preferably an inorganic acid, and more preferably hydrochloric acid.
  • the reaction temperature in step 11 is preferably -10 to 70°C, and preferably 0 to 50°C.
  • the step 11 reaction time is preferably 10 minutes to 24 hours, and more preferably 10 minutes to 5 hours.
  • Compound 13 and compound 14 can be prepared by the preparation methods in the prior art; they can also be prepared by the following route:
  • the present invention innovatively adopts a one-pot method to synthesize lanimivir octoate intermediate compound (5) from compound (4).
  • the reaction is mild and fast, and the product does not require column chromatography, and simple post-treatment can proceed to the next reaction, saving energy Consumption, pollution reduction, simple operation, low cost, suitable for industrial production.
  • the lanimivir octoate intermediate compound (5) prepared by the one-pot method in the present invention has a yield of more than 87%, and the yield of lanimivir octoate prepared by using the intermediate is more than 85%.
  • the product of the CN101679339A method has many impurities and requires column chromatography, and the yield of the two-step method is only 76.9%.
  • Figure 1 is a hydrogen spectrum of compound (2)
  • Figure 2 is a hydrogen spectrum of compound (3)
  • Figure 3 is a hydrogen spectrum of compound (4)
  • Figure 4 is a hydrogen spectrum of compound (5)
  • Figure 5 is a hydrogen spectrum of compound (6)
  • Figure 6 is a hydrogen spectrum of compound (12).
  • Figure 7 is a hydrogen spectrum of compound (13).
  • the one-pot method for preparing the lanimivir caprylate intermediate of the present invention adopts the following synthetic methods:
  • R 1 is a benzyl group, a substituted benzyl group, or an allyl group.
  • the aforementioned substituted benzyl group means that the benzene ring on the benzyl group is mono- or multiple-substituted by groups such as chlorine, bromine, iodine, nitro, alkoxy, alkyl, and aromatic.
  • the above-mentioned one-pot method for preparing lanimivir octoate intermediate includes the following steps: mixing and stirring the compound represented by formula (4) with an organic solvent and R 1 OH, and then adding NaH and stirring for 30-60 min under the protection of nitrogen. Then (R 1 O) 2 CO is added, and the reaction is stirred at 0-80° C. for 30 min-24 h, and then separated to obtain the compound represented by formula (5).
  • the crude compound of formula (5) is crystallized by toluene or methanol to obtain crystals of the compound represented by formula (5).
  • the reaction temperature is 10-60°C.
  • reaction temperature is 50-55°C.
  • the reaction time is 30 minutes to 5 hours.
  • the organic solvent is any one or more of toluene, N,N-dimethylformamide, benzyl alcohol, n-heptane, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane.
  • the mass concentration of the NaH is 60%.
  • R 1 is benzyl
  • the mass ratio of the compound represented by formula (4), R 1 OH, NaH, and (R 1 O) 2 CO is 8-12:15-30:0.02-0.1:12-36.
  • the mass ratio of the compound represented by formula (4), R 1 OH, NaH, and (R 1 O) 2 CO is 9.8:20:0.04:24.22.
  • R 1 is benzyl, substituted benzyl or allyl
  • X is Cl -, Br -, I - , MeSO 4 -, TfO -.
  • Step 1 In the presence of a base, the compound represented by formula (1) reacts with R 1 X to produce the compound represented by formula (2).
  • the base is not particularly limited, as long as it can be neutralized with a carboxylic acid, and it may be an organic base or an inorganic base.
  • the organic base such as triethylamine, diisopropylethylamine, N,N-dimethyl-4-aminopyridine or pyridine
  • inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, Potassium hydroxide.
  • An inorganic base is preferable, and cesium carbonate or potassium carbonate is more preferable.
  • Step 2 In the presence of an organic base, the compound represented by formula (2) reacts with acetic anhydride to produce the compound represented by formula (3). There is no restriction on the organic base, as long as it can be neutralized with a carboxylic acid.
  • the organic base is any one or more of triethylamine, diisopropylethylamine, N,N-dimethyl-4-aminopyridine, and pyridine.
  • the reaction temperature in step 2 is -30°C to 100°C. Preferably it is 0-35 degreeC.
  • the reaction time of step 2 is 30min-24h. Preferably it is 10-15h.
  • Step 3 The compound represented by formula (3) is catalyzed by trimethylsilyl trifluoromethanesulfonate to produce the compound represented by formula (4).
  • the reaction temperature in step 3 is 0 to 70°C. Preferably it is 30 degreeC-60 degreeC.
  • the reaction time of step 3 is 1.0h-24h. Preferably it is 1.0-3.0h.
  • the preparation method of lanimivir octoate (compound of formula I) of the present invention adopts a synthetic method including the following:
  • Step 5 is to react the compound represented by formula (5) with dimethyl sulfate or methyl iodide in the presence of a base to produce the compound represented by formula (6).
  • the reaction temperature in step 5 is 0-70°C, preferably 0-30°C.
  • Step 5 The reaction time is 30 minutes to 24 hours, preferably 1.0 to 15 hours.
  • Step 6 is to react the compound represented by formula (6) with azidotrimethylsilane under the catalysis of titanium isopropoxide to produce the compound represented by formula (7).
  • Step 6 The reaction temperature is 0 to 120°C, preferably 0 to 40°C.
  • Step 6 The reaction time is 3.0 to 48 hours, preferably 3.0 to 24 hours.
  • Step 7 is the reaction of the compound represented by formula (7) with triphenylphosphine to produce the compound represented by formula (8).
  • the reaction temperature in step 7 is -10 to 80°C, preferably 0 to 60°C.
  • Step 7 The reaction time is 10 minutes to 48 hours, preferably 10 minutes to 5 hours.
  • Step 8 is the reaction of the compound represented by formula (8) with a base to produce the compound represented by formula (9).
  • inorganic bases are preferred, and lithium hydroxide, sodium hydroxide, and potassium hydroxide are more preferred.
  • the reaction temperature in step 8 is preferably -10 to 100°C, more preferably 0 to 50°C.
  • Step 8 The reaction time is preferably 10 minutes to 48 hours, more preferably 0.5 hours to 6 hours.
  • Step 9 is the reaction of the compound represented by formula (9) with the compound represented by formula (10) to produce the compound represented by formula (11).
  • the step 9 reaction solvent is preferably purified water.
  • the reaction temperature in Step 9 is 0-100°C, and preferably 5-50°C.
  • Step 9 The reaction time is 24h to 72h, and preferably 24 to 60h.
  • Step 10 is the reaction of the compound represented by formula (11) in the presence of trifluoroacetic acid to produce the compound represented by formula (12).
  • the reaction temperature in step 10 is -20 to 100°C, and preferably 0 to 45°C.
  • the reaction time of step 10 is 0.5 to 24 hours, and preferably 0.5 to 8 hours.
  • Step 11 is to react the compound represented by formula (12) with compound 13 or compound 14 in the presence of an acid, and then react with water to produce the compound represented by formula (I) or a pharmacologically acceptable salt thereof.
  • the acid in step 11 is preferably an inorganic acid, and more preferably hydrochloric acid.
  • the reaction temperature in step 11 is preferably -10 to 70°C, and preferably 0 to 50°C.
  • the step 11 reaction time is preferably 10 minutes to 24 hours, and more preferably 10 minutes to 5 hours.
  • Compound 13 and compound 14 can be prepared by the preparation methods in the prior art; they can also be prepared by the following route:
  • the preparation of compound (2) includes the following steps:
  • N-acetylneuraminic acid compound 1
  • Cs 2 CO 3 16.30g, 125ml DMF compound 2
  • BrBn 26.70g compound 2
  • 500ml reaction flask 500ml reaction flask
  • To dryness add 300ml isopropanol, heat to 70°C, heat to filter out the insoluble matter, stir the filtrate at room temperature for 3-4h, filter, rinse the filter cake with isopropanol, dry the filter cake under reduced pressure to obtain compound (2) White powder 18.50g, yield 46.25%.
  • the hydrogen spectrum of compound (2) is shown in Figure 1.
  • the temperature in the preparation process of compound (2), after adding 300 ml of isopropanol, the temperature can be increased to 80°C or 75°C, and then the insoluble matter can be filtered out by hot filtration.
  • the preparation of compound (3) includes the following steps:
  • the preparation of compound (4) includes the following steps:
  • the reaction was stirred at 55° C. for 2 h.
  • the stirring reaction temperature can also be 10°C, 52°C, 60°C, or 80°C.
  • the stirring reaction time can be adjusted within 30min-24h. Changing the above reaction temperature or time, the yield of compound (5) is basically the same as that of Example 4.
  • the toluene solvent can also be replaced with N,N-dimethylformamide, benzyl alcohol, n-heptane, methyl tert-butyl ether, tetrahydrofuran, 1,4-di Any one or more of oxane.
  • the mass ratio of the compound represented by formula (4), R 1 OH, NaH, and (R 1 O) 2 CO is 12:15:0.1:12.
  • R1 can also be benzyl substituted by chlorine, bromine, iodine, nitro, alkoxy, alkyl or aromatic; even R1 can also be allyl.
  • the preparation of compound (9) includes the following steps:
  • the preparation of compound (11) includes the following steps:
  • the preparation of compound (12) includes the following steps:
  • the hydrogen spectrum of compound (12) is shown in Fig. 7.
  • Compound 13 in this example can be replaced with compound 14, and other conditions remain unchanged.
  • This comparative example is different from Example 4 only in that dibenzyl carbonate is replaced with carbonyl diimidazole.
  • the product has many impurities and requires column chromatography, and the final yield of compound (5) is only 20%.
  • This comparative example is different from Example 4 only in that dibenzyl carbonate is replaced with benzyl chloroformate. There are many impurities and column chromatography is required. The final yield of compound (5) is only 25%.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention relève du domaine technique de la synthèse des médicaments, et concerne en particulier un procédé de préparation d'un intermédiaire d'octanoate de laninamivir au moyen d'une synthèse monotope. Le procédé de préparation d'un intermédiaire d'octanoate de laninamivir au moyen d'une synthèse monotope comprend les étapes consistant à : soumettre un composé tel que représenté par la formule (4) à une réaction en présence de R1OH, NaH et (R1O)2CO pour obtenir un composé tel que représenté par la formule (5), R1 étant du benzyle, benzyle substitué ou allyle. L'invention concerne un composé (5) intermédiaire d'octanoate de laninamivir qui est synthétisé de manière innovante à partir d'un composé (4) au moyen d'une synthèse monotope; la réaction est douce et rapide, et la réaction en étape suivante peut être effectuée après un post-traitement simple; le procédé est économique en matière de consommation d'énergie, la pollution est réduite, le fonctionnement est simple et le coût est faible, de telle sorte que le procédé est approprié pour une production industrielle. Le composé (5) intermédiaire d'octanoate de laninamivir préparé au moyen d'une synthèse monotope a un rendement d'au moins 87 %.
PCT/CN2020/120751 2020-06-12 2020-10-14 Procédé de préparation d'un intermédiaire d'octanoate de laninamivir au moyen d'une synthèse monotope WO2021248764A1 (fr)

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CN101679339A (zh) * 2007-04-11 2010-03-24 第一三共株式会社 制备神经氨酸衍生物的方法
CN102532080A (zh) * 2010-12-29 2012-07-04 中国科学院上海药物研究所 新型唾液酸衍生物及其制备方法,包含该衍生物的药物组合物,以及其用途
CN103435582A (zh) * 2013-06-28 2013-12-11 深圳海王药业有限公司 一种拉尼那米韦辛酯的制备方法
CN103974945A (zh) * 2011-12-16 2014-08-06 第一三共株式会社 用于制备神经氨酸衍生物的方法
CN105085455A (zh) * 2014-05-13 2015-11-25 中国科学院广州生物医药与健康研究院 唾液酸类似物或其药学上可接受的盐及其应用
WO2020051498A1 (fr) * 2018-09-06 2020-03-12 Cidara Therapeutics, Inc. Compositions et procédés pour le traitement d'infections virales

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CN102532080A (zh) * 2010-12-29 2012-07-04 中国科学院上海药物研究所 新型唾液酸衍生物及其制备方法,包含该衍生物的药物组合物,以及其用途
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