WO2021248763A1 - 一种辛酸拉尼米韦的制备方法 - Google Patents

一种辛酸拉尼米韦的制备方法 Download PDF

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WO2021248763A1
WO2021248763A1 PCT/CN2020/120750 CN2020120750W WO2021248763A1 WO 2021248763 A1 WO2021248763 A1 WO 2021248763A1 CN 2020120750 W CN2020120750 W CN 2020120750W WO 2021248763 A1 WO2021248763 A1 WO 2021248763A1
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compound
formula
compound represented
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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
    • 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
    • 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

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  • the present invention relates to the technical field of drug synthesis, in particular to a preparation method of lanimivir caprylate.
  • 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 and undergoes an 11-step reaction to synthesize lanimivir octoate.
  • the reaction steps in the production process of compound 4-6 are cumbersome and require column chromatography, and further optimization is required for industrialization.
  • 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 preparation method of lanimivir caprylate, which has simple process and high yield, and is suitable for industrial production.
  • a preparation method of lanimivir caprylate adopts a synthetic route including the following:
  • R 1 is benzyl, substituted benzyl or allyl
  • the aforementioned substituted benzyl group means that the benzene ring on the benzyl group is mono- or poly-substituted by groups such as chlorine, bromine, iodine, nitro, alkoxy, alkyl, and aromatic.
  • X is Cl -, Br -, I - , MeSO 4 -, TfO -.
  • Step 1 In the presence of a base, the compound represented by formula (1) is reacted 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 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.
  • Step 4 is to mix and stir the compound represented by formula (4) with organic solvent and R 1 OH, then under the protection of nitrogen, add NaH and stir for 30-60 min, then add (R 1 O) 2 CO and stir at 0-80°C After reacting for 30 minutes to 24 hours, and then separating, the compound represented by formula (5) is obtained.
  • 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 in step 4 above is 10-60°C. More preferably, the reaction temperature is 50-55°C.
  • the reaction time in step 4 above is 30 minutes to 5 hours.
  • the organic solvent described in step 4 is any one of toluene, N,N-dimethylformamide, benzyl alcohol, n-heptane, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or Several kinds.
  • the mass concentration of NaH in step 4 is 60%.
  • step 4 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.
  • 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 10 needs to adjust the pH to 6-8.
  • 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:
  • R1 is benzyl
  • the preparation method of lanimivir octoate of the present invention innovatively adopts a one-pot method to synthesize lanimivir octoate intermediate compound (5) from compound (4), and the yield is as high as 87%, and the two steps in CN101679339A are adopted.
  • the yield of the reaction is only 76.9%, the reaction of the present invention is mild and rapid, and the product does not require column chromatography, and the product can be subjected to the next step with simple post-treatment, saving energy consumption, reducing pollution, simple operation, low cost, and suitable for industrialized production.
  • the yield of lanimivir caprylate finally prepared by the invention is over 85%.
  • 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 preparation method of lanimivir caprylate of the present invention adopts a synthetic route including the following:
  • R 1 is benzyl, substituted benzyl or allyl
  • 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.
  • X is Cl -, Br -, I - , MeSO 4 -, TfO -.
  • Step 1 In the presence of a base, the compound represented by formula (1) is reacted with R1X 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 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.
  • Step 4 is to mix and stir the compound represented by formula (4) with organic solvent and R 1 OH, then under the protection of nitrogen, add NaH and stir for 30-60 min, then add (R 1 O) 2 CO and stir at 0-80°C After reacting for 30 minutes to 24 hours, and then separating, the compound represented by formula (5) is obtained.
  • 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 in step 4 above is 10-60°C. More preferably, the reaction temperature is 50-55°C.
  • the reaction time in step 4 above is 30 minutes to 5 hours.
  • the organic solvent described in step 4 is any one of toluene, N,N-dimethylformamide, benzyl alcohol, n-heptane, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or Several kinds.
  • the mass concentration of NaH in step 4 is 60%.
  • step 4 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.
  • 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:
  • R 1 is benzyl
  • 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 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.
  • R 1 is can also be chloro, bromo, iodo, nitro, alkoxy, alkyl or aryl-substituted benzyl; R1 may also be an allyl even.
  • 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.
  • 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 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:
  • 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.
  • the product has many impurities and requires column chromatography, and the final yield of compound (5) is only 25%.

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Abstract

涉及一种辛酸拉尼米韦的制备方法。采用一锅法由化合物（4）合成辛酸拉尼米韦中间体化合物（5），反应温和快速，简单后处理即可进行下一步反应，最终制得辛酸拉尼米韦。该方法节省能耗，减少污染，操作简单，成本低，适合工业化生产。辛酸拉尼米韦中间体化合物（5）的收率高达87％以上，最终制得的辛酸拉尼米韦的收率在85％以上。

Description

一种辛酸拉尼米韦的制备方法 技术领域
本发明涉及药物合成技术领域，具体涉及一种辛酸拉尼米韦的制备方法。
背景技术
辛酸拉尼米韦(Laninamivir)是Biota Pharmaceuticals和Daiichi Sankyo公司研发的一种神经氨酸酶抑制剂，可用于治疗对奥司他韦(达菲)具有抗药性的流感病毒感染。于2010年获得批准以Inavir名称在日本上市。
辛酸拉尼米韦化学结构式如下：
Figure PCTCN2020120750-appb-000001
辛酸拉尼米韦对H1N1、H5N1、N9和B型流感病毒以及对达菲耐药病毒均有较好的效果，截至目前，辛酸拉尼米韦在国内未上市，也没有注册申报厂家。为引导仿制药研发生产，提高公众用药可及性，国家食品药品监督管理总局药品审评中心组织对国内化合物专利权到期、终止、无效且尚无仿制申请的国外已上市药品进行筛选，其中辛酸拉尼米韦初步筛选并纳入《首批专利权到期、终止、无效尚且无仿制申请的药品清单》。
目前，辛酸拉尼米韦的制备方法归结为如下三种方法：
方法一，专利CN101679339A公开了以唾液酸为起始物料经11步反应合成辛酸拉尼米韦，合成路线如下所示：
Figure PCTCN2020120750-appb-000002
Figure PCTCN2020120750-appb-000003
该路线以商业化供应的唾液酸为起始物料，经11步反应合成辛酸拉尼米韦，化合物4-6生产过程中反应步骤繁琐且需要柱层析，若要工业化仍需要进一步的优化。
方法二，专利CN103435582A公开了以扎那米韦为起始物料经5步反应合成辛酸拉尼米韦，合成路线如下所示：
Figure PCTCN2020120750-appb-000004
该方法虽然步骤少，但是以扎纳米韦为起始原料，原料的价格过于昂贵，难以满足仿制药的需求；
方法三，马大伟课题组以D-异抗坏血酸为起始物料，经手性催化关环，再经一系列氧化、还原、保护、脱保护等反应合成辛酸拉尼米韦，合成路线如下所示：
Figure PCTCN2020120750-appb-000005
该合成路线比较新颖，单元反应收率适中，但起始物料及催化剂配体市场供应较少，价格昂贵，不适合放大生产，同时中间体S-3和中间体S-8手性纯度不高，导致后续异构体杂质较多，最终产品质量难以控制。
综上，上述三条路线均不适合工业化生产，开发一条适合工业化生产辛酸拉尼米韦的路线将具有非常好的应用前景。
发明内容
本发明的目的在于提供一种辛酸拉尼米韦的制备方法，该方法工艺简单且收率高，适合工业化生产。
为实现上述目的，本发明的技术方案是：
一种辛酸拉尼米韦的制备方法，采用包括如下的合成路线：
Figure PCTCN2020120750-appb-000006
其中，R 1为苄基、取代苄基或烯丙基；
化合物13和化合物14的结构式如下所示：
Figure PCTCN2020120750-appb-000007
上述取代苄基为苄基上的苯环被氯、溴、碘、硝基、烷氧基、烷基、芳香基等基团单取代或多取代。
上述式(4)所示化合物采用包括如下的合成路线得到：
Figure PCTCN2020120750-appb-000008
其中，X为Cl -、Br -、I -、MeSO 4 -、TfO -。
步骤1，在碱存在下，式(1)所示的化合物与R 1X反应生成式(2)表示的化合物。所述碱没有特别的限制，可以与羧酸中和即可，可以是有机碱或无机碱。优选的，所述有机碱诸如三乙胺、二异丙基乙胺、N,N-二甲基-4-氨基吡啶或吡啶；无机碱诸如碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾。优选无机碱，且进一步优选碳酸铯或碳酸钾。
步骤2，在有机碱存在下，式(2)表示的化合物与乙酸酐反应，生成式(3)表示的化合物。关于有机碱没有限制，可以与羧酸中和即可。
优选的，所述有机碱为三乙胺、二异丙基乙胺、N,N-二甲基-4-氨基吡啶、吡啶中的任 意一种或几种。
步骤2的反应温度为-30℃～100℃。优选为0～35℃。
步骤2的反应时间是30min～24h。优选为10～15h。
步骤3，式(3)表示的化合物在三氟甲磺酸三甲硅酯催化下，产生式(4)表示的化合物。
步骤3的反应温度0～70℃。优选为30℃～60℃。
步骤3的反应时间是1.0h～24h。优选为1.0～3.0h。
步骤3后处理滴加三乙胺淬灭反应。
步骤4为将式(4)所示化合物与有机溶剂、R 1OH混合搅拌，之后在氮气保护下，加入NaH搅拌30～60min，然后加入(R 1O) 2CO，于0～80℃搅拌反应30min～24h，之后分离，得式(5)所示化合物。式(5)化合物粗品经甲苯或甲醇结晶，可得式(5)表示化合物的晶体。
优选的，上述步骤4的反应温度为10～60℃。进一步优选的，所述反应温度为50～55℃。
优选的，上述步骤4的反应时间为30min～5h。
步骤4中所述有机溶剂为甲苯、N,N-二甲基甲酰胺、苯甲醇、正庚烷、甲基叔丁基醚、四氢呋喃、1,4-二氧六环中的任意一种或几种。
步骤4中NaH的质量浓度为60％。
步骤4中，式(4)所示化合物、R 1OH、NaH、(R 1O) 2CO的质量比为8-12：15-30：0.02-0.1：12-36。优选地，式(4)所示化合物、R 1OH、NaH、(R 1O) 2CO的质量比为9.8：20：0.04：24.22。
步骤5是在碱存在下，式(5)表示的化合物与硫酸二甲酯或碘甲烷反应，产生式(6)表示的化合物。
步骤5反应温度为0-70℃，优选0-30℃。
步骤5反应时间为30min～24h，优选1.0～15h。
步骤6是在异丙醇钛催化下使式(6)表示的化合物与叠氮三甲基硅烷反应，以产生式(7)表示的化合物。
步骤6反应温度为0～120℃，优选为0～40℃。
步骤6反应时间为3.0～48h，优选3.0～24h。
步骤7是式(7)表示的化合物与三苯基膦反应以产生式(8)表示的化合物。
步骤7反应温度为-10～80℃，优选0～60℃。
步骤7反应时间为10分钟～48h，优选10min～5h。
步骤8是式(8)表示的化合物与碱反应以产生式(9)表示的化合物。
关于碱，优选无机碱，且更优选氢氧化锂、氢氧化钠、氢氧化钾。
步骤8反应温度优选-10～100℃，进一步优选0～50℃。
步骤8反应时间优选10分钟～48h，进一步优选0.5h～6h。
步骤9是式(9)表示的化合物与式(10)表示的化合物反应以产生式(11)表示的化合物。
步骤9反应溶剂优选纯化水。
步骤9反应温度是0-100℃，且优选5～50℃。
步骤9反应时间是24h～72h，且优选24～60h。
步骤10是式(11)表示的化合物在三氟乙酸存在下反应，以产生式(12)表示的化合物。
步骤10反应温度是-20～100℃，且优选0～45℃。
步骤10反应时间是0.5h～24h，且优选0.5～8h。
步骤10需要调pH至6～8。
步骤11是在酸存在下使式(12)表示的化合物与化合物13或化合物14反应，之后再与水反应，以产生由式(Ⅰ)表示的化合物或其药理学可接受的盐。
步骤11中的酸优选无机酸，且更优选盐酸。
步骤11反应温度优选-10～70℃，且优选0～50℃。
步骤11反应时间优选10分钟至24小时，且更优选10分钟至5小时。
化合物13和化合物14可以通过现有技术中的制备方法制得；也可以通过如下路线制得：
Figure PCTCN2020120750-appb-000009
优选的，R1为苄基。
本发明的有益效果：
本发明辛酸拉尼米韦的制备方法，创新性地采用一锅法由化合物(4)合成辛酸拉尼米韦中间体化合物(5)，收率高达87％以上，而采用CN101679339A中的两步反应的产率仅为76.9％，本发明反应温和快速，并且产物无需柱层析，简单后处理即可进行下一步反应，节 省能耗，减少污染，操作简单，成本低，适合工业化生产。本发明最终制得的辛酸拉尼米韦的收率在85％以上。
附图说明
图1为化合物(2)的氢谱图；
图2为化合物(3)的氢谱图；
图3为化合物(4)的氢谱图；
图4为化合物(5)的氢谱图；
图5为化合物(6)的氢谱图；
图6为化合物(12)的氢谱图；
图7为化合物(13)的氢谱图。
具体实施方式
本发明辛酸拉尼米韦的制备方法，采用包括如下的合成路线：
Figure PCTCN2020120750-appb-000010
其中，R 1为苄基、取代苄基或烯丙基；
化合物13和化合物14的结构式如下所示：
Figure PCTCN2020120750-appb-000011
上述取代苄基，指：苄基上的苯环被氯、溴、碘、硝基、烷氧基、烷基、芳香基等基团单取代或多取代。
上述式(4)所示化合物采用包括如下的合成路线得到：
Figure PCTCN2020120750-appb-000012
其中，X为Cl -、Br -、I -、MeSO 4 -、TfO -。
步骤1，在碱存在下，式(1)所示的化合物与R1X反应生成式(2)表示的化合物。所述碱没有特别的限制，可以与羧酸中和即可，可以是有机碱或无机碱。优选的，所述有机碱诸如三乙胺、二异丙基乙胺、N,N-二甲基-4-氨基吡啶或吡啶；无机碱诸如碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾。优选无机碱，且进一步优选碳酸铯或碳酸钾。
步骤2，在有机碱存在下，式(2)表示的化合物与乙酸酐反应，生成式(3)表示的化合物。关于有机碱没有限制，可以与羧酸中和即可。
优选的，所述有机碱为三乙胺、二异丙基乙胺、N,N-二甲基-4-氨基吡啶、吡啶中的任意一种或几种。
步骤2的反应温度为-30℃～100℃。优选为0～35℃。
步骤2的反应时间是30min～24h。优选为10～15h。
步骤3，式(3)表示的化合物在三氟甲磺酸三甲硅酯催化下，产生式(4)表示的化合物。
步骤3的反应温度0～70℃。优选为30℃～60℃。
步骤3的反应时间是1.0h～24h。优选为1.0～3.0h。
步骤3后处理滴加三乙胺淬灭反应。
步骤4为将式(4)所示化合物与有机溶剂、R 1OH混合搅拌，之后在氮气保护下，加入NaH搅拌30～60min，然后加入(R 1O) 2CO，于0～80℃搅拌反应30min～24h，之后分离，得式(5)所示化合物。式(5)化合物粗品经甲苯或甲醇结晶，可得式(5)表示化合物的晶体。
优选的，上述步骤4的反应温度为10～60℃。进一步优选的，所述反应温度为50～55℃。
优选的，上述步骤4的反应时间为30min～5h。
步骤4中所述有机溶剂为甲苯、N,N-二甲基甲酰胺、苯甲醇、正庚烷、甲基叔丁基醚、四氢呋喃、1,4-二氧六环中的任意一种或几种。
步骤4中NaH的质量浓度为60％。
步骤4中，式(4)所示化合物、R 1OH、NaH、(R 1O) 2CO的质量比为8-12：15-30：0.02-0.1：12-36。优选地，式(4)所示化合物、R 1OH、NaH、(R 1O) 2CO的质量比为9.8：20：0.04： 24.22。
步骤5是在碱存在下，式(5)表示的化合物与硫酸二甲酯或碘甲烷反应，产生式(6)表示的化合物。
步骤5反应温度为0-70℃，优选0-30℃。
步骤5反应时间为30min～24h，优选1.0～15h。
步骤6是在异丙醇钛催化下使式(6)表示的化合物与叠氮三甲基硅烷反应，以产生式(7)表示的化合物。
步骤6反应温度为0～120℃，优选为0～40℃。
步骤6反应时间为3.0～48h，优选3.0～24h。
步骤7是式(7)表示的化合物与三苯基膦反应以产生式(8)表示的化合物。
步骤7反应温度为-10～80℃，优选0～60℃。
步骤7反应时间为10分钟～48h，优选10min～5h。
步骤8是式(8)表示的化合物与碱反应以产生式(9)表示的化合物。
关于碱，优选无机碱，且更优选氢氧化锂、氢氧化钠、氢氧化钾。
步骤8反应温度优选-10～100℃，进一步优选0～50℃。
步骤8反应时间优选10分钟～48h，进一步优选0.5h～6h。
步骤9是式(9)表示的化合物与式(10)表示的化合物反应以产生式(11)表示的化合物。
步骤9反应溶剂优选纯化水。
步骤9反应温度是0-100℃，且优选5～50℃。
步骤9反应时间是24h～72h，且优选24～60h。
步骤10是式(11)表示的化合物在三氟乙酸存在下反应，以产生式(12)表示的化合物。
步骤10反应温度是-20～100℃，且优选0～45℃。
步骤10反应时间是0.5h～24h，且优选0.5～8h。
步骤11是在酸存在下使式(12)表示的化合物与化合物13或化合物14反应，之后再与水反应，以产生由式(Ⅰ)表示的化合物或其药理学可接受的盐。
步骤11中的酸优选无机酸，且更优选盐酸。
步骤11反应温度优选-10～70℃，且优选0～50℃。
步骤11反应时间优选10分钟至24小时，且更优选10分钟至5小时。
化合物13和化合物14可以通过现有技术中的制备方法制得；也可以通过如下路线制得：
Figure PCTCN2020120750-appb-000013
优选的，R 1为苄基。
实施例1
化合物(2)的制备包括以下步骤：
常温，于500ml反应瓶中依次加入N-乙酰神经氨酸(化合物1)30.93g、Cs 2CO 3 16.30g、125ml DMF、BrBn 26.70g，磁力搅拌反应24h，待反应结束后，过滤，母液浓缩至干，加入300ml异丙醇，升温至70℃，热滤出去不溶物，滤液常温搅拌3-4h，过滤，滤饼用异丙醇淋洗，滤饼减压干燥恒重得化合物(2)白色粉末18.50g，收率46.25％。化合物(2)的氢谱图如图1所示。
在其它实施例中，化合物(2)的制备过程中，加入300ml异丙醇后，还可以升温至80℃或75℃，然后再热滤出去不溶物。
实施例2
化合物(3)的制备包括以下步骤：
常温，于250ml反应瓶中，依次加入吡啶约70ml、化合物(2)18.50g，加毕控温20～25℃范围内，滴加醋酸酐37.50g，之后，加入4-二甲氨基吡啶(DMAP)约0.2g，维持20～25℃，搅拌反应过夜，反应液倒入350ml纯化水与1850ml乙酸乙酯混合液中，加毕，静置分层，有机层依次用200ml*2 5.0％HCl水溶液萃洗、200ml*2饱和碳酸氢钠水溶液萃洗，之后有机层无水硫酸钠干燥，过滤，淋洗，减压浓缩至干得无色油状物30.02g，收率106.4％。经柱层析(正庚烷～正庚烷/乙酸乙酯＝1/2)纯化，收集目标组分(展开剂：乙酸乙酯)，减压浓缩干，得化合物(3)白色粉末14.50g。化合物(3)的氢谱图如图2所示。
实施例3
化合物(4)的制备包括以下步骤：
常温，N 2保护下，于1000ml反应瓶中，依次加入化合物(3)13.20g、乙酸乙酯265ml，搅拌溶解澄清，控温15～25℃，滴加TMSOTf 14.46g，滴加结束，控温50～55℃范围内，搅拌反应2h，然后控温0～5℃，滴加三乙胺11.0g，之后加入冰水100ml，搅拌10min，静置 分层，有机层再用100ml+50ml纯化水萃洗两次，有机层无水硫酸钠干燥，过滤，淋洗，减压浓缩至干，得无色油状物。柱层析纯化(正庚烷～正庚烷/乙酸乙酯＝1/1～乙酸乙酯)收集目标组分，减压浓缩至干得化合物(4)无色油状物9.14g。化合物(4)的氢谱图如图3所示。
实施例4
化合物(5)的制备包括以下步骤：
常温，于反应瓶中依次加入化合物(4)9.80g、甲苯40ml、苯甲醇(即R 1取苄基)20.0ml，加毕，室温搅拌，氮气保护，之后，加入60％NaH 0.04g，搅拌30min，加入碳酸二苄酯(即R 1取苄基)24.22g，于50℃搅拌反应1h，加入0.032mol冰乙酸淬灭反应，湿法上柱，二氯甲烷冲洗小极性杂质，二氯甲烷/甲醇＝40/1，洗刷目标组分，减压浓缩干得化合物(5)类白色固体，6.85g，收率87.96％。该收率远远高于CN101679339A中两步法得化合物(5)的收率(76.9％)。化合物(5)的氢谱图如图4所示。
在其它化合物(5)的制备实施例中，加入碳酸二苄酯后于55℃搅拌反应2h。在其他的实施例中，搅拌反应温度还可以为10℃、52℃、60℃或80℃。搅拌反应时间可以在30min～24h内调整。改变上述反应温度或时间，化合物(5)的收率与实施例4基本相同。
在其他实施例中，R 1还可以为被氯、溴、碘、硝基、烷氧基、烷基或芳香基取代的苄基；甚至R1还可以为烯丙基。
在其他的化合物(5)的制备实施例中，式(4)所示化合物、R 1OH、NaH、(R 1O) 2CO的质量比为8：30：0.02：36。
在其他的化合物(5)的制备实施例中，式(4)所示化合物、R 1OH、NaH、(R 1O) 2CO的质量比为12：15：0.1：12。
在其它化合物(5)的制备实施例中，甲苯溶剂还可以被替换为N,N-二甲基甲酰胺、苯甲醇、正庚烷、甲基叔丁基醚、四氢呋喃、1,4-二氧六环中的任意一种或几种。
实施例5
化合物(6)的制备包括以下步骤：
N 2保护下，于250ml反应瓶中，依次加入化合物(5)6.85g、THF 28ml、DMF 7ml，加毕，搅拌至溶解澄清，控温0-5℃范围内，分批次加入60％NaH 0.91g，加毕维持温度0-5℃，搅拌30min，加入硫酸二甲酯2.88g，维持温度搅拌反应过夜，之后加入甲苯100ml、冰乙酸1.06g淬灭反应，反应液用40ml*2 5.0％NaHCO 3水溶液萃洗2次，水层用70ml*2甲苯萃洗2次，合并所有甲苯层无水硫酸钠干燥，过滤，淋洗，浓缩至近干，柱层析纯化(二氯甲 烷→二氯甲烷/甲醇20/1)，得化合物(6)无色油状物8.0g。化合物(6)的氢谱图如图5所示。
实施例6
化合物(7)的制备包括以下步骤：
N 2保护下，室温，于100ml反应瓶中，依次加入化合物(6)7.10g、甲苯21ml、叔丁醇7ml，加毕，搅拌至溶解澄清，加入TMSN 3 4.10g、异丙醇钛1.55g，维持20～25℃搅拌反应24h，之后过滤，滤液抽干，10ml甲醇淋洗，油泵带干滤饼，得化合物(7)米白色固体5.76g，收率：72.6％。
实施例7
化合物(8)的制备包括以下步骤：
常温，于100ml反应瓶，依次加入化合物(7)5.00g、四氢呋喃20ml，搅拌至溶清，加入三苯基膦3.24g，加毕升温至40～50℃，搅拌反应10min，TLC(DCM/ME＝10/1)，原料消失，降至室温，得化合物(8)反应液。
实施例8
化合物(9)的制备包括以下步骤：
于实施例7得到的化合物(8)的反应液中，加入纯化水12.5g、25％NaOH水溶液5.40g，控温40～45℃，搅拌反应2h，TLC(DCM/ME＝10/1)，原料消失，降至室温，静置分液，水层加入6ml THF萃洗一次，水层滴加约4ml浓盐酸，调PH＝2～3,再用25％NaOH水溶液调pH＝9～10，得化合物(9)反应液。
实施例9
化合物(11)的制备包括以下步骤：
室温，于实施例8的化合物(9)反应液中，加入甲醇30ml、N,N’-双(叔丁氧羰基)-1H-吡唑-1-甲脒3.82g，维持20～25℃搅拌反应48h，调pH＝8.5～8.8，反应液浓缩至尽干，加入100ml乙酸乙酯减压浓缩带除甲醇，浓缩液用50ml*3乙酸乙酯萃洗3次，水层用约1.3g浓盐酸调PH＝2～3，水层用50ml*3乙酸乙酯萃取，合并有机层浓缩干，得白色固体5.20g，收率85.1％。
实施例10
化合物(12)的制备包括以下步骤：
将实施例9中化合物(11)加入50ml二氯甲烷，加入5g三氟乙酸室温反应3h，减压浓缩至干，加入25ml纯化水，用10％氢氧化钠水溶液调至pH＝6～8，加入50ml甲醇，常温搅 拌析晶，过滤，滤饼甲醇淋洗，40℃减压干燥得化合物(12)白色粉末2.74g，收率70.62％。
实施例11
常温，N 2保护下，与100ml反应瓶中，依次加入化合物(12)2.00g、甲醇10ml、3.54g化合物13，最后加入10.5ml HCl甲醇溶液(1N氯化氢甲醇溶液)，加毕，体系澄清，维持20-25℃，搅拌反应1h，减压浓缩近干，加入20ml纯化水，用20ml*3乙酸乙酯萃洗三次，水层用饱和碳酸钠调pH＝7,搅拌1h，之后，用饱和碳酸钠调pH＝8.5～9.0，搅拌3h，用6N盐酸调pH＝5～6，搅拌30min，过滤，滤饼纯化水淋洗，滤饼35℃，减压干燥至恒重，得化合物(I)白色粉末2.34g，收率85.6％，HPLC 99.84％。
本实施例中的化合物13可以替换为化合物14，其它条件不变。
对比例1
该对比例与实施例4的区别仅在于，将碳酸二苄酯替换为羰基二咪唑。产物杂质较多，需要柱层析，最终得到的化合物(5)的收率仅为20％。
对比例2
该对比例与实施例4的区别仅在于，将碳酸二苄酯替换为氯甲酸苄酯。产物杂质较多，需要柱层析，最终得到的化合物(5)的收率仅为25％。
对本领域的技术人员来说，可根据以上描述的技术方案以及构思，做出其它各种相应的改变以及形变，而所有的这些改变以及形变都应该属于本发明权利要求的保护范围之内。

Claims (10)

  1. 一种辛酸拉尼米韦的制备方法，其特征在于，采用包括如下的合成路线：
    Figure PCTCN2020120750-appb-100001
    其中，R 1为苄基、取代苄基或烯丙基；
    化合物13和化合物14的结构式如下所示：
    Figure PCTCN2020120750-appb-100002
  2. 根据权利要求1所述的制备方法，其特征在于，式(4)所示化合物采用包括如下的合成路线得到：
    Figure PCTCN2020120750-appb-100003
    其中，X为Cl -、Br -、I -、MeSO 4 -、TfO -。
  3. 根据权利要求1所述的制备方法，其特征在于，步骤4为将式(4)所示化合物与有机溶剂、R 1OH混合搅拌，之后在氮气保护下，加入NaH搅拌30～60min，然后加入(R 1O) 2CO，于0～80℃搅拌反应30min～24h，之后分离，得式(5)所示化合物。
  4. 根据权利要求3所述的制备方法，其特征在于，所述反应温度为10～60℃。
  5. 根据权利要求3所述的制备方法，其特征在于，所述反应时间为30min～5h。
  6. 根据权利要求3所述的制备方法，其特征在于，所述有机溶剂为甲苯、N,N-二甲基甲酰胺、苯甲醇、正庚烷、甲基叔丁基醚、四氢呋喃、1,4-二氧六环中的任意一种或几种。
  7. 根据权利要求1所述的制备方法，其特征在于，所述NaH的质量浓度为60％。
  8. 根据权利要求1所述的制备方法，其特征在于，式(4)所示化合物、R 1OH、NaH、(R 1O) 2CO的质量比为8-12：15-30：0.02-0.1：12-36。
  9. 根据权利要求1所述的制备方法，其特征在于，式(4)所示化合物、R 1OH、NaH、(R 1O) 2CO的质量比为9.8：20：0.04：24.22。
  10. 根据权利要求1-9任一项所述的制备方法，其特征在于，R 1为苄基。
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