WO2022151615A1 - 一种泰格列净中间体的合成方法 - Google Patents

一种泰格列净中间体的合成方法 Download PDF

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WO2022151615A1
WO2022151615A1 PCT/CN2021/090968 CN2021090968W WO2022151615A1 WO 2022151615 A1 WO2022151615 A1 WO 2022151615A1 CN 2021090968 W CN2021090968 W CN 2021090968W WO 2022151615 A1 WO2022151615 A1 WO 2022151615A1
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compound
reaction
ethyl acetate
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高悦译
卢江
刘恩桂
张倩
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广州市力鑫药业有限公司
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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
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the application belongs to the field of medicinal chemistry, and in particular relates to a method for synthesizing a tagagliflozin intermediate.
  • Diabetes is a metabolic disease characterized by hyperglycemia due to insulin secretion defect or insulin action disorder.
  • the prior art also shows that the kidney plays an important role in the regulation of blood sugar, and is responsible for the reabsorption of sugar in the renal tubules.
  • the substance is "sodium-glucose co-transporter 2" (SGLT-2), and SGLT-2 inhibitors can selectively inhibit SGLT-2, thereby reducing body weight, rarely causing hypoglycemia, and the therapeutic effect is independent of insulin secretion hypoglycemic pathway and other effects.
  • SGLT-2 inhibitors include taipagliflozin, dapagliflozin, repagliflozin, etc. Among them, taipagliflozin is the strongest SGLT-2 inhibitor discovered so far, providing a new option for clinical treatment.
  • the synthetic method has a long route and requires seven-step reactions, and a large amount of benzyl ether will be produced during the synthetic process, and the qualified target product must be obtained by column chromatography;
  • the synthetic method uses NaH and DMF system, resulting in A large amount of hydrogen is generated.
  • the present application provides a method for synthesizing a tagagliflozin intermediate, which simplifies the reaction steps, and can obtain a high-yield final product through crystallization without column chromatography.
  • the total yield can reach 56%, which is significantly improved synthesis efficiency.
  • the danger of explosion easily occurs when only NaH can be used when benzyl groups are used to protect three secondary alcohols due to the use of selective silicon groups to protect primary alcohols in the prior art is avoided.
  • the method provided by the application has simple steps, no high and low temperature reactions and dangerous reagents, and the raw materials used are easy to obtain, which effectively reduces the production cost.
  • the application provides a method for synthesizing the taipagliflozin intermediate having the structure shown in formula F, the method for synthesizing comprises the following steps:
  • step S6 adding the crude product of compound F obtained in step S5 into ethanol, heating to reflux for dissolution, cooling for crystallization, and suction filtration to obtain purified compound F,
  • reaction formula is as follows:
  • the raw materials used in the step S1 to prepare compound B from compound A include compound A, triphenylphosphine, imidazole, tetrahydrofuran and iodine, and the mass ratio of compound A, triphenylphosphine and imidazole is 1.8- 2.3:3:1, the mass of the iodine is 1.2-1.6 times the mass of compound A.
  • the post-processing described in the step S1 is as follows: the product after the acetylation reaction of primary hydroxyl iodide and acetic anhydride/triethylamine is cooled to 25-30° C., and ethyl acetate and 10% ethyl acetate are added. The aqueous sodium chloride solution was stirred for 10 min, and the liquid was separated. The organic phase was washed once with an aqueous sodium chloride solution with a mass fraction of 10%. The aqueous sodium chloride solution contained 30%-50% of concentrated hydrochloric acid by volume.
  • the step of preparing the compound C through the reduction reaction of the compound B is as follows, the compound B prepared in the step S1, the palladium-carbon catalyst, the diisopropylethylamine and the methanol are added to the reaction flask, and the mixture is passed through.
  • the H replacement reaction was carried out 3 times;
  • step S1 compound B, water and zinc powder obtained in step S1 can be added to the reaction flask, acetic acid is added dropwise to react to completion, suction filtration, the filter cake is washed with ethyl acetate, and the filtrate is extracted with ethyl acetate.
  • the ethyl acetate phase was washed once with water, once with saturated sodium bicarbonate, once with saturated brine, concentrated and dried, the solid was slurried with methanol, filtered with suction, and the filter cake was dried to obtain a white solid C, which was compound C.
  • the mass ratio of the sodium methoxide and the compound C used for the deacetylation protection of the compound C by the catalytic amount of sodium methoxide in the step S3 is 1:50-55.
  • the post-processing step of the step S3 is as follows: cooling the product after the pre-treatment in step S3 to 25-30°C, adding ethyl acetate and water at 10-15°C, separating liquids, and using ethyl acetate for the water phase. Ester extraction was performed once, the organic phases were combined, washed once with hydrochloric acid, and once with saturated brine, concentrated to dryness, the obtained concentrate was added to 1,4-dioxane, and concentrated to dryness again to obtain compound D.
  • the compound D in the step S4 is heated and hydrolyzed by a sulfuric acid solution, an acetic acid solution and 1,4-dioxane, which needs to be heated to 100° C. for a reflux reaction for 10-12 hours.
  • the steps of the post-processing in the step S4 are: cooling the product after the pre-processing in the step S4 to 20-25 ° C, adding water and ethyl acetate, separating the liquids, and extracting the aqueous phase twice with ethyl acetate, The ethyl acetate phases were combined, washed once with water, once with saturated sodium bicarbonate, once with saturated brine, concentrated to dryness, the obtained concentrate was added to ethanol, concentrated to dryness to obtain compound E.
  • the step of the Swern oxidation reaction in the step S5 includes: adding DMSO into the reaction flask, and adding acid anhydride dropwise at a temperature of 20-25° C., and then dissolving the compound E obtained in the step S4 in DMSO and dropping it into the reaction flask. , the reaction was carried out at 20-25 °C.
  • the method provided by the application has simple steps, no high and low temperature reactions and dangerous reagents, the raw materials used are easy to obtain, suitable for large-scale production, and the cost is only 1/2-1/3 of the currently reported route, with significant Advantages, wide application prospects.
  • FIG. 1 is a chromatogram showing the purity of the tagagliflozin intermediate obtained by the synthetic method of Example 3.
  • FIG. 2 is the nuclear magnetic resonance spectrum of the tagagliflozin intermediate obtained by the synthesis method of Example 3.
  • FIG. 2 is the nuclear magnetic resonance spectrum of the tagagliflozin intermediate obtained by the synthesis method of Example 3.
  • Embodiment 1 a kind of synthetic method of Taipagliflozin intermediate
  • a kind of synthetic method of taipagliflozin intermediate, described synthetic method comprises:
  • step S1 Post-treatment: the pre-treated product obtained in step S1 was cooled to 25° C., 720 mL of ethyl acetate and 480 mL of an aqueous sodium chloride solution with a mass fraction of 10% were added, stirred for 10 min, and the liquids were separated, and the obtained organic phase used 360 mL of mass fraction Wash once with a 10% aqueous sodium chloride solution, the aqueous sodium chloride solution contains 108 mL of concentrated hydrochloric acid, and the organic phase is then washed with 480 mL of a 10% aqueous sodium chloride solution (containing 24 g of sodium thiosulfate pentahydrate) in mass fraction for 1 time, concentrated to remove the organic solvent, added 400 mL of isopropanol, suction filtered, the filter cake was washed with isopropanol, dried, and the obtained white solid was compound B 85.5g;
  • step S1 Add 85.5 g of compound B prepared in step S1, 4.8 g of palladium-carbon catalyst, 33.6 g of diisopropylethylamine and 1 L of methanol into the reaction flask, pass H 2 for replacement reaction 3 times, and react at room temperature until it passes through a thin layer.
  • step S3 Post-treatment: the pre-treated product obtained in step S3 was cooled to 25°C, 200mL of ethyl acetate and 300mL of 10°C water were added, the liquids were separated, the aqueous phase was extracted once with 100mL of ethyl acetate, the organic phases were combined, and 150mL of 1mol/L hydrochloric acid was washed once, then washed once with saturated brine, concentrated and dried, the obtained concentrate was added with 50mL of 1,4-dioxane, concentrated and dried again, and the obtained light yellow oily matter was Compound D 100.5 g;
  • step S4 Post-treatment: the pre-treated product obtained in step S4 is cooled to 20° C., 1 L of water and 200 mL of ethyl acetate are added, the liquids are separated, the aqueous phase is extracted twice with 200 mL of ethyl acetate, the ethyl acetate phases are combined, and the Wash with 100 mL of water once, once with 300 mL of saturated sodium bicarbonate, once with 200 mL of saturated brine, concentrate and dry, add ethanol solution to the obtained concentrate, concentrate and dry, and the obtained off-white solid is compound E 51.1 g;
  • step S4 400mL DMSO was added to the reaction flask, and 200mL acid anhydride was added dropwise under temperature control at 20°C, and then 51.1 g of compound E obtained in step S4 was dissolved in 160mL DMSO and dropped into the reaction flask, reacted at 20°C, and passed through thin layer chromatography.
  • step S6 The crude product of compound F obtained in step S5 was added to 200 mL of ethanol, heated to reflux to dissolve, cooled for crystallization, and suction filtered to obtain 38.1 g of purified compound F.
  • Embodiment 2 a kind of synthetic method of Taipagliflozin intermediate
  • a kind of synthetic method of Taipagliflozin intermediate, described synthetic method comprises:
  • step S1 Post-treatment: the pre-treated product obtained in step S1 was cooled to 30° C., 720 mL of ethyl acetate and 480 mL of an aqueous sodium chloride solution with a mass fraction of 10% were added, stirred for 10 min, and the liquid was separated, and the obtained organic phase used 360 mL of mass fraction Wash once with a 10% aqueous sodium chloride solution, the aqueous sodium chloride solution contains 180 mL of concentrated hydrochloric acid, and the organic phase is then washed with 480 mL of a 10% aqueous sodium chloride solution (containing 24 g of sodium thiosulfate pentahydrate) in mass fraction for 1 time, concentrated to remove the organic solvent, added 400mL isopropanol, suction filtered, the filter cake was washed with isopropanol, dried, and the obtained white solid was compound B 115g;
  • step S3 Post-treatment: the pre-treated product obtained in step S3 was cooled to 30°C, 200mL of ethyl acetate and 300mL of 15°C water were added, the liquid was separated, the aqueous phase was extracted once with 100mL of ethyl acetate, the organic phases were combined, and 150mL of 1mol/L hydrochloric acid was washed once, then washed once with saturated brine, concentrated and dried, the obtained concentrate was added with 50mL of 1,4-dioxane, concentrated and dried again, and the obtained pale yellow oil was compound D 139g ;
  • step S4 Post-treatment: the pre-treated product obtained in step S4 was cooled to 25° C., 1 L of water and 200 mL of ethyl acetate were added, the liquids were separated, the aqueous phase was extracted twice with 200 mL of ethyl acetate, the ethyl acetate phases were combined, and the 100 mL of water was washed once, 300 mL of saturated sodium bicarbonate was washed once, 200 mL of saturated brine was washed once, concentrated to dryness, ethanol solution was added to the obtained concentrate, concentrated to dryness, and the obtained off-white solid was Compound E 76.2g;
  • step S6 The crude product of compound F obtained in step S5 was added to 200 mL of ethanol, heated to reflux to dissolve, cooled for crystallization, and suction filtered to obtain 58.3 g of purified compound F.
  • Embodiment 3 a kind of synthetic method of Taipagliflozin intermediate
  • a kind of synthetic method of taipagliflozin intermediate, described synthetic method comprises:
  • step S1 Post-treatment: the pre-treated product obtained in step S1 was cooled to 28° C., 720 mL of ethyl acetate and 480 mL of an aqueous sodium chloride solution with a mass fraction of 10% were added, stirred for 10 min, and the liquid was separated, and the obtained organic phase used 360 mL of mass fraction Wash once with 10% aqueous sodium chloride solution, the aqueous sodium chloride solution contains 150 mL of concentrated hydrochloric acid, and the organic phase is then washed with 480 mL of 10% aqueous sodium chloride solution (containing 24 g of sodium thiosulfate pentahydrate) in mass fraction for 1 time, concentrated to remove the organic solvent, added 400mL isopropanol, suction filtered, the filter cake was washed with isopropanol, dried, and the obtained white solid was compound B 106g;
  • step S2 Pretreatment: 79 g of compound C, 1.3 g of sodium methoxide and 400 mL of anhydrous methanol obtained in step S2 were added to the reaction flask, stirred for 0.5 h at 28° C., and subjected to thin-layer chromatography (developing solvent: DCM/MEOH).
  • step S3 Post-treatment: the pre-treated product obtained in step S3 was cooled to 25°C, 200mL of ethyl acetate and 300mL of water at 12°C were added, the liquids were separated, the aqueous phase was extracted once with 100mL of ethyl acetate, the organic phases were combined, and 150mL of 1mol/L hydrochloric acid was washed once, then washed once with saturated brine, concentrated and dried, the obtained concentrate was added with 50mL of 1,4-dioxane, concentrated and dried again, and the obtained pale yellow oil was compound D 140g ;
  • sulfuric acid solution 102 g of concentrated sulfuric acid is diluted into 350 mL with water
  • acetic acid solution 279 g of acetic acid is diluted with water into 350 mL of 80% acetic acid aqueous solution by volume
  • 460 mL of 1,4 -Dioxane 460 mL of 1,4 -Di
  • step S4 Post-treatment: the pre-treated product obtained in step S4 is cooled to 22° C., 1 L of water and 200 mL of ethyl acetate are added, the liquids are separated, the aqueous phase is extracted twice with 200 mL of ethyl acetate, the ethyl acetate phases are combined, and the 100 mL of water was washed once, 300 mL of saturated sodium bicarbonate was washed once, 200 mL of saturated brine was washed once, concentrated and dried, ethanol solution was added to the obtained concentrate, concentrated and dried, and the obtained off-white solid was compound E 79g;
  • step S4 400mL DMSO was added into the reaction flask, and 200mL acid anhydride was added dropwise under temperature control at 23°C, and then 79g of compound E obtained in step S4 was dissolved in 160mL DMSO and dropped into the reaction flask, reacted at 25°C, and passed through thin-layer chromatography.
  • step S6 The crude product of compound F obtained in step S5 was added to 200 mL of ethanol, heated to reflux to dissolve, cooled for crystallization, and suction filtered to obtain 62 g of purified compound F.
  • Example 3 is the best technical solution provided by the application, and the total yield can reach 56%, which is a significant improvement.
  • the purity and impurity content of the tagagliflozin intermediate obtained by the synthetic method of Example 3 are shown in Table 2.
  • the chromatogram of the purity of the tagagliflozin intermediate obtained by the synthetic method of Example 3 is shown in FIG. 1
  • the nuclear magnetic resonance spectrum diagram is shown in FIG. 2 .
  • Test items Example 3 purity 99.7% Impurity content Single impurity ⁇ 0.22%

Abstract

本申请属于药物化学领域，具体涉及一种泰格列净中间体的合成方法，所述泰格列净中间体的合成方法为：以化合物A为原料经伯羟基碘代，乙酰化反应制得碘代醋酸酯，将碘化物还原成甲基化合物，再制备成苄基保护产物，然后脱去甲基保护，swern氧化羟基共计五步反应制得泰格列净中间体，即化合物F。本申请避免了现有技术由于采用选择性硅基保护伯醇，导致苄基保护三个仲醇时采用NaH而带来的易爆炸的危险，并进一步简化了反应步骤，不需要柱层析就能得到高产率的最终产品，总产率可达56％。本申请提供的方法没有高低温反应及危险试剂，所用原材料易于获得，并极大的节省了成本，成本仅为目前报道过的路线的1/2-1/3，具有显著的优势。

Description

一种泰格列净中间体的合成方法 技术领域
本申请属于药物化学领域，具体涉及一种泰格列净中间体的合成方法。
背景技术
糖尿病是一种由于胰岛素分泌缺陷或胰岛素作用障碍所致的以高血糖为特征的代谢性疾病，现有技术也说明了肾脏对血糖的调节起到了重要的作用，在肾小管负责糖回吸收的物质为“钠-葡萄糖协同转运蛋白2”(SGLT-2)，而SGLT-2抑制剂能够选择性抑制SGLT-2，从而起到降低体重、很少引起低血糖、治疗作用不依赖于胰岛素分泌的降糖途径等功效。SGLT-2抑制剂包括泰格列净、达格列净、瑞格列净等，其中泰格列净是目前发现的最强的SGLT-2抑制剂，为临床治疗提供了新的选择。
在泰格列净的合成过程中，不可避免的需要大量的泰格列净中间体进行药物的合成，该中间体的中文名为(3R,4S,5R,6R)-3,4,5-三(苄氧基)-四氢-6-甲基吡喃-2-酮，英文名为(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one，结构为
Figure PCTCN2021090968-appb-000001
作为泰格列净进入GMP生产的原料，该中间体的需求量非常大，要求其纯度高，单杂低，并且快速，低廉，高效得到大量的泰格列净中间体是控制泰格列净纯度，降低成本的关键。
现有技术中已有了对该泰格列净中间体的合成路径，如下所示，但存在诸多缺陷。
Figure PCTCN2021090968-appb-000002
首先，该合成方法路径过长，需要七步反应，在合成过程中会产生大量的苄醚，必须通过柱层析才能得到合格的目标产物；其次，该合成方法使用了NaH和DMF体系，致使大量氢气产生，以1kg起始原料来计算，需要用1kg NaH，产生12.6mol、合计283L的H 2，极易爆炸，给反应的顺利进行带来了巨大的风险，因此难以大量生产；此外，该方法在合成过程中使用氢化铝锂，需要严格控制反应含水量，处理困难，不适合大量生产；最后，合成步骤的增多使得最终产率明显较低，较为昂贵的试剂和严苛的反应条件进一步限制了其大规模应用。
发明内容
本申请提供了一种泰格列净中间体的合成方法，该方法简化了反应步骤，并且不需要柱层析就能通过结晶得到高产率的最终产品，总产率可达56％，显著提高了合成效率。同时避免了现有技术由于采用选择性硅基保护伯醇，导致苄基保护三个仲醇时，只能采用NaH而易发生爆炸的危险。本申请提供的方法步骤简单、没有高低温反应及危险试剂，所用原材料易于获得，有效降低了生产成本，新路线成本约为现有路线的1/2-1/3，应用前景广泛。
本申请提供了一种具有式F所示结构的泰格列净中间体的合成方法，所述合成方法包括以下步骤：
S1：以化合物A为原料，通过伯羟基碘代后，用乙酸酐/三乙胺乙酰化反应得到前处理后的产物，并经过后处理制得化合物B；
S2：将化合物B通过还原反应制得化合物C；
S3：将化合物C通过催化量甲醇钠脱去乙酰基保护，然后采用NaOH/BnBr体系上苄基保护得到前处理后的产物，并经过后处理制得化合物D；
S4：将化合物D通过硫酸溶液、醋酸溶液和1,4-二氧六环加热水解得到前处理后的产物，并经过后处理制得化合物E；
S5：将化合物E通过Swern氧化反应后制得化合物F的粗品；和
S6：将步骤S5所得化合物F的粗品加入到乙醇中，加热至回流溶解，降温结晶，抽滤，得到纯化的化合物F，
其中，反应式如下所示：
Figure PCTCN2021090968-appb-000003
进一步地，所述步骤S1以化合物A制得化合物B用到的原料包括化合物A、三苯基膦、咪唑、四氢呋喃和碘，所述化合物A、三苯基膦和咪唑的质量比为1.8-2.3:3:1，所述碘的质量为1.2-1.6倍化合物A的质量。
进一步地，所述步骤S1所述后处理为：将经过伯羟基碘代和乙酸酐/三乙胺乙酰化反应后的产物降温至25-30℃，加入乙酸乙酯和质量分数为10％的氯化钠水溶液，搅拌10min，分液，有机相用质量分数为10％的氯化钠水溶液洗涤1次，所述氯化钠水溶液含有30％-50％体积的浓盐酸，有机相再用含有五水合硫代硫酸钠和氯化钠的水溶液洗涤1次，浓缩除去有机溶剂，加入异丙醇，抽滤，滤饼用异丙醇洗涤，干燥，得到化合物B。
进一步地，所述步骤S2将化合物B通过还原反应制得化合物C的步骤为中，将步骤S1制得的化合物B、钯碳催化剂、二异丙基乙基胺和甲醇加入反应瓶中，通入H 2置换反应进行3次；
或者还原反应还可以是将步骤S1制得的化合物B、水、锌粉加入到反应瓶中，滴加醋酸反应至完全，抽滤，滤饼用乙酸乙酯洗涤，滤液用乙酸乙酯萃取1次，乙酸乙酯相用水洗1次，饱和碳酸氢钠洗涤1次，饱和食盐水洗涤1次，浓缩干燥，固体用甲醇打浆，抽滤，滤饼干燥得白色固体C，制得化合物C。
进一步地，所述步骤S3所述化合物C通过催化量甲醇钠脱去乙酰基保护用到的甲醇钠和化合物C的质量比为1：50-55。
进一步地，所述步骤S3所述后处理的步骤为：将步骤S3前处理后的产物降温至25-30℃，加入乙酸乙酯和10-15℃的水，分液，水相用乙酸乙酯萃取1次，合并有机相，用盐酸洗涤1次，再用饱和食盐水洗涤1次，浓缩干燥，所得浓缩物加入1,4-二氧六环，再次浓缩干燥，制得化合物D。
进一步地，所述步骤S4所述化合物D通过硫酸溶液、醋酸溶液和1,4-二氧六环加热水解的反应需要加热至100℃，回流反应10-12h。
进一步地，所述步骤S4所述后处理的步骤为：将步骤S4前处理后的产物降温至20-25℃，加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并乙酸乙酯相，用水洗涤1次，饱和碳酸氢钠洗涤1次，饱和食盐水洗涤1次，浓缩干燥，所得浓缩物加入乙醇，浓缩干燥，制得化合物E。
进一步地，所述步骤S5所述Swern氧化反应的步骤包括：将DMSO加入反应瓶中，并控温20-25℃滴加酸酐，再将步骤S4所得化合物E溶于DMSO后滴入反应瓶中，在20-25℃的条件下进行反应。
与现有技术相比，本申请具有以下优势：
(1)本申请简化了合成路线，现有技术公开的合成路线需要七步反应，而本申请提供的合成路线仅需要五步反应，反应步骤的减少使得产率的显著提高，经实验证实，由本申请提供的方法总产率可达56％，成绩斐然。
(2)本申请避免了现有技术由于采用选择性硅基保护伯醇，导致苄基保护三个仲醇只能采用NaH而易爆炸的危险，为了避免使用NaH和DMF体系上苄基保护，调整了反应路线，先将伯醇碘代还原成甲基，此时排除了保护基干扰，就可以采用廉价的NaOH，BnBr上保护，避免了NaH和DMF体系的使用。
(3)现有技术采用NaH和DMF体系上苄基保护，需要NaH和BnBr的长时间反应，导致成本大量增加，特别是反应中产生了大量高沸点苄醚，而中间体及终产物在苄醚中的溶解度较好使得在苄醚中溶解，因而需要进一步通过柱层析除去，给合成操作带来了麻烦，而本申请简化了并调整了合成路线，不需要柱层析就能通过结晶得到高产率的最终产品。
(4)本申请提供的方法步骤简单、没有高低温反应及危险试剂，所用原材料易于获得，适用于大规模生产，成本仅为目前报道过的路线的1/2-1/3，具有显著的优势，应用前景广泛。
附图说明
图1是采用实施例3的合成方法得到的泰格列净中间体的纯度的色谱图。
图2是采用实施例3的合成方法得到的泰格列净中间体的的核磁共振波谱图。
具体实施方式
以下通过实施例形式的具体实施方式，将本申请的所述内容做进一步解释。但本申请上述主题的范围不仅限于以下实施例，并需要说明的是，本申请中所用的仪器和试剂均为市售的公知化产品。
实施例1、一种泰格列净中间体的合成方法
一种泰格列净中间体的合成方法，所述合成方法包括：
S1：以化合物A为原料，通过伯羟基碘代后，用乙酸酐/三乙胺乙酰化反应得到前处理后的产物，并经过后处理制得化合物B：
1)前处理：将化合物A 52.9g、三苯基膦88.2g、咪唑29.4g和300mL四氢呋喃加入到反应瓶中，加热至回流，将碘63.5g加入到150mL四氢呋喃中溶解后，缓慢滴入反应瓶中，滴加时间为2.5h，滴加完成后，保温反应0.5h，反应完成后，降温至20℃，加入146g吡啶后快速滴入189g酸酐，在35℃水浴控温，反应12h，取样通过薄层色谱法检测(展开剂为DCM/MEOH＝10/1；2mL；并再加1滴醋酸)，经检测化合物A基本消失，得到前处理后的产物；
2)后处理：将步骤S1所得前处理后的产物降温至25℃，加入720mL乙酸乙酯和480mL质量分数为10％的氯化钠水溶液，搅拌10min，分液，所得有 机相用360mL质量分数为10％的氯化钠水溶液洗涤1次，所述氯化钠水溶液含有108mL的浓盐酸，有机相再用质量分数为10％氯化钠水溶液480mL(含24g五水合硫代硫酸钠)洗涤1次，浓缩除去有机溶剂，加入400mL异丙醇，抽滤，滤饼用异丙醇洗涤，干燥，得到的白色固体即为化合物B 85.5g；
S2：将化合物B通过还原反应制得化合物C：
将步骤S1制得的化合物B 85.5g、钯碳催化剂4.8g、二异丙基乙基胺33.6g和1L甲醇加入反应瓶中，通入H 2置换反应3次，在室温下反应直至通过薄层色谱法(展开剂为EA/PE＝1/5；2mL)检测化合物B基本消失，过硅藻土抽滤，滤饼用甲醇洗涤，滤液浓缩干燥，用100mL甲醇打浆，抽滤，滤饼干燥得白色固体，制得化合物C 62.5g；
S3：将化合物C通过催化量甲醇钠脱去乙酰基保护，然后采用NaOH/BnBr体系上苄基保护得到前处理后的产物，并经过后处理制得化合物D：
1)前处理：将步骤S2所得化合物C 62.5g、甲醇钠1.3g和400mL无水甲醇加入到反应瓶中，在25℃的条件下搅拌0.5h，通过薄层色谱法(展开剂为DCM/MEOH＝10/1；2mL；并加1滴醋酸)检测化合物C基本消失，加0.48g水淬灭反应，浓缩干燥，加入100mL 2-甲基四氢呋喃，在40℃的条件下反应0.5h，再次浓缩干燥，并再加入相同体积的2-甲基四氢呋喃重复操作1次，得浓缩物(为脱去三个乙酰基保护的中间体)，将浓缩物加入550mL 2-甲基四氢呋喃中加热溶解，转入反应瓶中，加入62g氢氧化钠、9.6g四丁基碘化铵，加热至回流后反应0.5h，除去分水器中的储液，将126.6g溴苄用300mL 2-甲基四氢呋喃稀释后缓慢滴加至反应瓶中，滴加时间为3h，保温反应6h，通过薄层色谱法(展开剂为DCM/MEOH＝10/1；2mL；并加1滴醋酸)检测到浓缩物基本消失，得到前处理后的产物；
2)后处理：将步骤S3所得前处理后的产物降温至25℃，加入200mL乙酸乙酯和300mL 10℃的水，分液，水相用100mL乙酸乙酯萃取1次，合并有机相，用150mL 1mol/L的盐酸洗涤1次，再用饱和食盐水洗涤1次，浓缩干燥，所得浓缩物加入50mL 1,4-二氧六环，再次浓缩干燥，所得淡黄色油状物即为化合物D 100.5g；
S4：将化合物D通过硫酸溶液、醋酸溶液和1,4-二氧六环加热水解，并经过后处理制得化合物E：
1)前处理：将步骤S3制得的化合物D 100.5g与硫酸溶液(102g浓硫酸用水稀释成350mL)、醋酸溶液(279g醋酸用水稀释成体积分数为80％的醋酸水溶液350mL)和460mL 1,4-二氧六环加入到反应瓶中，加热至100℃，回流反应10h，通过薄层色谱法(展开剂为EA/PE＝5/1；2mL)检测化合物D基本消失，得到前处理后的产物；
2)后处理：将步骤S4所得前处理后的产物降温至20℃，加入1L水和200mL乙酸乙酯，分液，水相用200mL乙酸乙酯萃取2次，合并乙酸乙酯相，依次用100mL水洗涤1次，300mL饱和碳酸氢钠洗涤1次，200mL饱和食盐水洗涤1次，浓缩干燥，向所得浓缩物中加入乙醇溶液，浓缩干燥，所得类白色固体，即为化合物E 51.1g；
S5：将化合物E通过Swern氧化反应后制得化合物F的粗品：
将400mL DMSO加入反应瓶中，并控温20℃滴加200mL酸酐，再将步骤S4所得化合物E 51.1g溶于160mL DMSO后滴入反应瓶中，在20℃的条件下反应，通过薄层色谱法(展开剂为EA/PE＝5/1；2mL)检测化合物E基本消失，将反应液倒入2L冰水中淬灭反应，搅拌0.5h，用200mL乙酸乙酯萃取3次，乙酸乙酯相用100mL质量分数为10％的氯化钠水溶液洗涤2次，300mL饱和碳酸氢钠溶液洗涤1次，200mL饱和食盐水洗涤1次，浓缩干燥，制得化合物F的粗品；和
S6：将步骤S5所得化合物F的粗品加入到200mL乙醇中，加热至回流溶解，降温结晶，抽滤，得到纯化的化合物F 38.1g。
实施例2、一种泰格列净中间体的合成方法
一种泰格列净中间体的合成方法，所述合成方法包括：
S1：以化合物A为原料，通过伯羟基碘代后，用乙酸酐/三乙胺乙酰化反应得到前处理后的产物，并经过后处理制得化合物B：
1)前处理：将化合物A 67.6g、三苯基膦94.08g、咪唑29.4g和300mL四氢呋喃加入到反应瓶中，加热至回流，将碘108.2g加入到150mL四氢呋喃中溶解后，缓慢滴入反应瓶中，滴加时间为3.2h，滴加完成后，保温反应1h，反应完成后，降温至25℃，加入146g吡啶后快速滴入189g酸酐，在40℃水浴控温，反应15h，取样通过薄层色谱法检测(展开剂为DCM/MEOH＝10/1；2 mL；并再加1滴醋酸)，经检测化合物A基本消失，得到前处理后的产物；
2)后处理：将步骤S1所得前处理后的产物降温至30℃，加入720mL乙酸乙酯和480mL质量分数为10％的氯化钠水溶液，搅拌10min，分液，所得有机相用360mL质量分数为10％的氯化钠水溶液洗涤1次，所述氯化钠水溶液含有180mL的浓盐酸，有机相再用质量分数为10％氯化钠水溶液480mL(含24g五水合硫代硫酸钠)洗涤1次，浓缩除去有机溶剂，加入400mL异丙醇，抽滤，滤饼用异丙醇洗涤，干燥，得到的白色固体即为化合物B 115g；
S2：将化合物B通过还原反应制得化合物C：
将步骤S1制得的化合物B 115g、0.5L水、锌粉24g加入到反应瓶中，加热至90℃，滴加醋酸，反应，通过薄层色谱法(展开剂为EA/PE＝1/5；2mL)检测化合物B基本消失，抽滤，滤饼用少量乙酸乙酯洗涤，所得滤液用150mL乙酸乙酯萃取一次，萃取后的乙酸乙酯相用100mL水洗1次、100mL饱和碳酸钠洗涤1次，200mL饱和食盐水洗涤1次，浓缩干燥，固体用100mL甲醇打浆，抽滤，滤饼干燥得白色固体，得化合物C 81.5g；
S3：将化合物C通过催化量甲醇钠脱去乙酰基保护，然后采用NaOH/BnBr体系上苄基保护得到前处理后的产物，并经过后处理制得化合物D：
1)前处理：将步骤S2所得化合物C 81.5g、甲醇钠1.3g和400mL无水甲醇加入到反应瓶中，在30℃的条件下搅拌0.5h，通过薄层色谱法(展开剂为DCM/MEOH＝10/1；2mL；并加1滴醋酸)检测化合物C基本消失，加0.48g水淬灭反应，浓缩干燥，加入100mL 2-甲基四氢呋喃，在50℃的条件下反应0.5h，再次浓缩干燥，并再加入相同体积的2-甲基四氢呋喃重复操作1次，得浓缩物(为脱去三个乙酰基保护的中间体)，将浓缩物加入550mL 2-甲基四氢呋喃中加热溶解，转入反应瓶中，加入62g氢氧化钠、9.6g四丁基碘化铵，加热至回流后反应0.5h，除去分水器中的储液，将126.6g溴苄用300mL 2-甲基四氢呋喃稀释后缓慢滴加至反应瓶中，滴加时间为3h，保温反应8h，通过薄层色谱法(展开剂为DCM/MEOH＝10/1；2mL；并加1滴醋酸)检测到浓缩物基本消失，得到前处理后的产物；
2)后处理：将步骤S3所得前处理后的产物降温至30℃，加入200mL乙酸乙酯和300mL 15℃的水，分液，水相用100mL乙酸乙酯萃取1次，合并有机相，用150mL 1mol/L的盐酸洗涤1次，再用饱和食盐水洗涤1次，浓缩干 燥，所得浓缩物加入50mL 1,4-二氧六环，再次浓缩干燥，所得淡黄色油状物即为化合物D 139g；
S4：将化合物D通过硫酸溶液、醋酸溶液和1,4-二氧六环加热水解，并经过后处理制得化合物E：
1)前处理：将步骤S3制得的化合物D 139g与硫酸溶液(102g浓硫酸用水稀释成350mL)、醋酸溶液(279g醋酸用水稀释成体积分数为80％的醋酸水溶液350mL)和460mL 1,4-二氧六环加入到反应瓶中，加热至100℃，回流反应12h，通过薄层色谱法(展开剂为EA/PE＝5/1；2mL)检测化合物D基本消失，得到前处理后的产物；
2)后处理：将步骤S4所得前处理后的产物降温至25℃，加入1L水和200mL乙酸乙酯，分液，水相用200mL乙酸乙酯萃取2次，合并乙酸乙酯相，依次用100mL水洗涤1次，300mL饱和碳酸氢钠洗涤1次，200mL饱和食盐水洗涤1次，浓缩干燥，向所得浓缩物中加入乙醇溶液，浓缩干燥，所得类白色固体，即为化合物E 76.2g；
S5：将化合物E通过Swern氧化反应后制得化合物F的粗品：
将400mL DMSO加入反应瓶中，并控温25℃滴加200mL酸酐，再将步骤S4所得化合物E 76.2g溶于160mL DMSO后滴入反应瓶中，在25℃的条件下反应，通过薄层色谱法(展开剂为EA/PE＝5/1；2mL)检测化合物E基本消失，将反应液倒入2L冰水中淬灭反应，搅拌0.5h，用200mL乙酸乙酯萃取3次，乙酸乙酯相用100mL质量分数为10％的氯化钠水溶液洗涤2次，300mL饱和碳酸氢钠溶液洗涤1次，200mL饱和食盐水洗涤1次，浓缩干燥，制得化合物F的粗品；和
S6：将步骤S5所得化合物F的粗品加入到200mL乙醇中，加热至回流溶解，降温结晶，抽滤，得到纯化的化合物F 58.3g。
实施例3、一种泰格列净中间体的合成方法
一种泰格列净中间体的合成方法，所述合成方法包括：
S1：以化合物A为原料，通过伯羟基碘代后，用乙酸酐/三乙胺乙酰化反应得到前处理后的产物，并经过后处理制得化合物B：
1)前处理：将化合物A 60g、三苯基膦89g、咪唑29.4g和300mL四氢 呋喃加入到反应瓶中，加热至回流，将碘86.3g加入到150mL四氢呋喃中溶解后，缓慢滴入反应瓶中，滴加时间为3h，滴加完成后，保温反应0.8h，反应完成后，降温至20℃，加入146g吡啶后快速滴入189g酸酐，在35℃水浴控温，反应13h，取样通过薄层色谱法检测(展开剂为DCM/MEOH＝10/1；2mL；并再加1滴醋酸)，经检测化合物A基本消失，得到前处理后的产物；
2)后处理：将步骤S1所得前处理后的产物降温至28℃，加入720mL乙酸乙酯和480mL质量分数为10％的氯化钠水溶液，搅拌10min，分液，所得有机相用360mL质量分数为10％的氯化钠水溶液洗涤1次，所述氯化钠水溶液含有150mL的浓盐酸，有机相再用质量分数为10％氯化钠水溶液480mL(含24g五水合硫代硫酸钠)洗涤1次，浓缩除去有机溶剂，加入400mL异丙醇，抽滤，滤饼用异丙醇洗涤，干燥，得到的白色固体即为化合物B 106g；
S2：将化合物B通过还原反应制得化合物C：
将步骤S1制得的化合物B 106g、钯碳催化剂5g、二异丙基乙基胺38.2g和1L甲醇加入反应瓶中，通入H 2置换反应3次，在室温下反应直至通过薄层色谱法(展开剂为EA/PE＝1/5；2mL)检测化合物B基本消失，过硅藻土抽滤，滤饼用甲醇洗涤，滤液浓缩干燥，用100mL甲醇打浆，抽滤，滤饼干燥得白色固体，制得化合物C 79g；
S3：将化合物C通过催化量甲醇钠脱去乙酰基保护，然后采用NaOH/BnBr体系上苄基保护得到前处理后的产物，并经过后处理制得化合物D：
1)前处理：将步骤S2所得化合物C 79g、甲醇钠1.3g和400mL无水甲醇加入到反应瓶中，在28℃的条件下搅拌0.5h，通过薄层色谱法(展开剂为DCM/MEOH＝10/1；2mL；并加1滴醋酸)检测化合物C基本消失，加0.48g水淬灭反应，浓缩干燥，加入100mL 2-甲基四氢呋喃，在40℃的条件下反应0.5h，再次浓缩干燥，并再加入相同体积的2-甲基四氢呋喃重复操作1次，得浓缩物(为脱去三个乙酰基保护的中间体)，将浓缩物加入550mL 2-甲基四氢呋喃中加热溶解，转入反应瓶中，加入62g氢氧化钠、9.6g四丁基碘化铵，加热至回流后反应0.5h，除去分水器中的储液，将126.6g溴苄用300mL 2-甲基四氢呋喃稀释后缓慢滴加至反应瓶中，滴加时间为3h，保温反应8h，通过薄层色谱法(展开剂为DCM/MEOH＝10/1；2mL；并加1滴醋酸)检测到浓缩物基本消失，得到前处理后的产物；
2)后处理：将步骤S3所得前处理后的产物降温至25℃，加入200mL乙酸乙酯和300mL 12℃的水，分液，水相用100mL乙酸乙酯萃取1次，合并有机相，用150mL 1mol/L的盐酸洗涤1次，再用饱和食盐水洗涤1次，浓缩干燥，所得浓缩物加入50mL 1,4-二氧六环，再次浓缩干燥，所得淡黄色油状物即为化合物D 140g；
S4：将化合物D通过硫酸溶液、醋酸溶液和1,4-二氧六环加热水解，并经过后处理制得化合物E：
1)前处理：将步骤S3制得的化合物D 140g与硫酸溶液(102g浓硫酸用水稀释成350mL)、醋酸溶液(279g醋酸用水稀释成体积分数为80％的醋酸水溶液350mL)和460mL 1,4-二氧六环加入到反应瓶中，加热至100℃，回流反应12h，通过薄层色谱法(展开剂为EA/PE＝5/1；2mL)检测化合物D基本消失，得到前处理后的产物；
2)后处理：将步骤S4所得前处理后的产物降温至22℃，加入1L水和200mL乙酸乙酯，分液，水相用200mL乙酸乙酯萃取2次，合并乙酸乙酯相，依次用100mL水洗涤1次，300mL饱和碳酸氢钠洗涤1次，200mL饱和食盐水洗涤1次，浓缩干燥，向所得浓缩物中加入乙醇溶液，浓缩干燥，所得类白色固体，即为化合物E 79g；
S5：将化合物E通过Swern氧化反应后制得化合物F的粗品：
将400mL DMSO加入反应瓶中，并控温23℃滴加200mL酸酐，再将步骤S4所得化合物E 79g溶于160mL DMSO后滴入反应瓶中，在25℃的条件下反应，通过薄层色谱法(展开剂为EA/PE＝5/1；2mL)检测化合物E基本消失，将反应液倒入2L冰水中淬灭反应，搅拌0.5h，用200mL乙酸乙酯萃取3次，乙酸乙酯相用100mL质量分数为10％的氯化钠水溶液洗涤2次，300mL饱和碳酸氢钠溶液洗涤1次，200mL饱和食盐水洗涤1次，浓缩干燥，制得化合物F的粗品；和
S6：将步骤S5所得化合物F的粗品加入到200mL乙醇中，加热至回流溶解，降温结晶，抽滤，得到纯化的化合物F 62g。
实验例1、泰格列净中间体的合成方法的产率
实施例1-实施例3每步反应的产率及总反应产率如表1所示。
表1：每步反应的产率及总反应产率汇总表
Figure PCTCN2021090968-appb-000004
由表1可知，实施例3为本申请提供的最优技术方案，总产率可达56％，具有显著的进步。
实验例2、合成所得泰格列净中间体的纯度及杂质
采用实施例3的合成方法得到的泰格列净中间体的纯度和杂质含量如表2所示。采用实施例3的合成方法得到的泰格列净中间体的纯度的色谱图如图1所示，核磁共振波谱图如图2所示。
表2：实施例3最终所得泰格列净中间体的纯度和杂质含量
检测项目 实施例3
纯度 99.7％
杂质含量 单杂<0.22％
由表2和图1可知，由实施例3合成所得泰格列净中间体纯度可达99.7％，而单杂(主要为二苄醚)<0.22％，充分证实了本申请提供的合成路线能够获得高纯度的泰格列净中间体，由图2可知，采用本申请实施例3合成所得泰格列净中间体确为化合物F，具有广泛的应用前景。

Claims (9)

  1. 一种具有式F所示结构的泰格列净中间体的合成方法，其包括以下步骤：
    S1：以化合物A为原料，通过伯羟基碘代后，用乙酸酐/三乙胺乙酰化反应得到前处理后的产物，并经过后处理制得化合物B；
    S2：将化合物B通过还原反应制得化合物C；
    S3：将化合物C通过催化量甲醇钠脱去乙酰基保护，然后采用NaOH/BnBr体系上苄基保护得到前处理后的产物，并经过后处理制得化合物D；
    S4：将化合物D通过硫酸溶液、醋酸溶液和1,4-二氧六环加热水解得到前处理后的产物，并经过后处理制得化合物E；
    S5：将化合物E通过Swern氧化反应后制得化合物F的粗品；和
    S6：将步骤S5所得化合物F的粗品加入到乙醇中，加热至回流溶解，降温结晶，抽滤，得到纯化的化合物F，
    其中，反应式如下所示：
    Figure PCTCN2021090968-appb-100001
  2. 如权利要求1所述泰格列净中间体的合成方法，其中，所述步骤S1将化合物A制得化合物B用到的原料包括化合物A、三苯基膦、咪唑、四氢呋喃和碘，所述化合物A、三苯基膦和咪唑的质量比为1.8-2.3:3:1，所述碘的质量为1.2-1.6倍化合物A的质量。
  3. 如权利要求1所述泰格列净中间体的合成方法，其中，所述步骤S1中所述后处理为：将经过伯羟基碘代和乙酸酐/三乙胺乙酰化反应后的产物降温至25-30℃，加入乙酸乙酯和质量分数为10％的氯化钠水溶液，搅拌10min，分液，有机相用质量分数为10％的氯化钠水溶液洗涤1次，所述氯化钠水溶液含有30％-50％体积的浓盐酸，有机相再用含有五水合硫代硫酸钠和氯化钠的水溶液 洗涤1次，浓缩除去有机溶剂，加入异丙醇，抽滤，滤饼用异丙醇洗涤，干燥，得到化合物B。
  4. 如权利要求1所述泰格列净中间体的合成方法，其中，所述步骤S2将化合物B通过还原反应制得化合物C的步骤为，将步骤S1制得的化合物B、钯碳催化剂、二异丙基乙基胺和甲醇加入反应瓶中，通入H 2置换反应进行3次；
    或者是将步骤S1制得的化合物B、水、锌粉加入到反应瓶中，滴加醋酸反应至完全，抽滤，滤饼用乙酸乙酯洗涤，滤液用乙酸乙酯萃取1次，乙酸乙酯相用水洗1次，饱和碳酸氢钠洗涤1次，饱和食盐水洗涤1次，浓缩干燥，固体用甲醇打浆，抽滤，滤饼干燥得白色固体C，制得化合物C。
  5. 如权利要求1所述泰格列净中间体的合成方法，其中，所述步骤S3所述化合物C通过催化量甲醇钠脱去乙酰基保护用到的甲醇钠和化合物C的质量比为1：50-55。
  6. 如权利要求1所述泰格列净中间体的合成方法，其中，所述步骤S3中所述后处理的步骤为：将步骤S3前处理后的产物降温至25-30℃，加入乙酸乙酯和10-15℃的水，分液，水相用乙酸乙酯萃取1次，合并有机相，用盐酸洗涤1次，再用饱和食盐水洗涤1次，浓缩干燥，所得浓缩物加入1,4-二氧六环，再次浓缩干燥，制得化合物D。
  7. 如权利要求1所述泰格列净中间体的合成方法，其中，所述步骤S4所述化合物D通过硫酸溶液、醋酸溶液和1,4-二氧六环加热水解的反应需要加热至100℃，回流反应10-12h。
  8. 如权利要求1所述泰格列净中间体的合成方法，其中，所述步骤S4中所述后处理的步骤为：将步骤S4前处理后的产物降温至20-25℃，加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并乙酸乙酯相，用水洗涤1次，饱和碳酸氢钠洗涤1次，饱和食盐水洗涤1次，浓缩干燥，所得浓缩物加入乙醇，浓缩干燥，制得化合物E。
  9. 如权利要求1所述泰格列净中间体的合成方法，其中，所述步骤S5中所述Swern氧化反应的步骤包括：将DMSO加入反应瓶中，并控温20-25℃滴加酸酐，再将步骤S4所得化合物E溶于DMSO后滴入反应瓶中，在20-25℃的条件下进行反应。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011219401A (ja) * 2010-04-07 2011-11-04 Daiichi Sankyo Co Ltd 糖誘導体化合物の製造方法
CN103130848A (zh) * 2013-02-22 2013-06-05 中国人民解放军第二军医大学 一种大环内酯类抗菌化合物及其制备方法和应用
CN107709332B (zh) * 2015-06-23 2019-12-20 中国科学院上海药物研究所 一种c,o-螺环芳基糖苷类化合物及其制备和应用
CN112661736A (zh) * 2021-01-12 2021-04-16 广州市力鑫药业有限公司 一种泰格列净中间体的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011219401A (ja) * 2010-04-07 2011-11-04 Daiichi Sankyo Co Ltd 糖誘導体化合物の製造方法
CN103130848A (zh) * 2013-02-22 2013-06-05 中国人民解放军第二军医大学 一种大环内酯类抗菌化合物及其制备方法和应用
CN107709332B (zh) * 2015-06-23 2019-12-20 中国科学院上海药物研究所 一种c,o-螺环芳基糖苷类化合物及其制备和应用
CN112661736A (zh) * 2021-01-12 2021-04-16 广州市力鑫药业有限公司 一种泰格列净中间体的合成方法

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