WO2022062401A1 - Procédé de préparation de tianagliflozine - Google Patents

Procédé de préparation de tianagliflozine Download PDF

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Publication number
WO2022062401A1
WO2022062401A1 PCT/CN2021/090928 CN2021090928W WO2022062401A1 WO 2022062401 A1 WO2022062401 A1 WO 2022062401A1 CN 2021090928 W CN2021090928 W CN 2021090928W WO 2022062401 A1 WO2022062401 A1 WO 2022062401A1
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WIPO (PCT)
Prior art keywords
compound
preparation
temperature
tagagliflozin
add
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PCT/CN2021/090928
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English (en)
Chinese (zh)
Inventor
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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Publication of WO2022062401A1 publication Critical patent/WO2022062401A1/fr

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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
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Definitions

  • the application belongs to the technical field of medicine, and specifically relates to a preparation method of tagagliflozin.
  • Diabetes is a metabolic disease characterized by hyperglycemia due to insulin secretion defect or insulin action disorder.
  • the drugs in the prior art are mainly based on the source of blood sugar or/and the destination of blood sugar as the breakthrough point.
  • the kidney also plays an important role in the regulation of blood sugar. Studies have shown that: 180g of glucose is filtered from the glomerulus every day, but it is completely reabsorbed by the renal tubule, so there is no urine in the urine.
  • SGLT-2 inhibitors include taipagliflozin, dapagliflozin, regpagliflozin, segagliflozin, canagliflozin, apagliflozin, etc. 2 inhibitors, providing another strong and effective option for clinical treatment.
  • Tagagliflozin has the structure:
  • the application provides a preparation method of tagagliflozin and tagagliflozin prepared by the preparation method.
  • compound N-10-a is used as the starting material, by first preparing compound N-10-a, then preparing compound N-11, and then reacting with Lewis acid to obtain Tagagliflozin with high yield and low impurity content net.
  • the present application provides a method for preparing taipagliflozin, wherein the taipagliflozin is reacted with compound N-9, n-butyllithium and compound N-8 to obtain compound N-10-a, and then adding three Ethylsilane and boron trifluoride ether react to obtain compound N-11, and then add Lewis acid to react to obtain;
  • the preparation method of described Taipagliflozin comprises the following steps:
  • step S2 The compound N-10-a of step S1 is diluted and dissolved with dichloromethane, triethylsilane is added, the temperature is lowered to -30°C under nitrogen protection, and boron trifluoride ether is added dropwise. Keep the temperature at -30 °C until the reaction is completed under TLC monitoring; control the temperature to below -20 °C, add saturated sodium bicarbonate solution dropwise and stir for 0.5 to 1 h, let stand for separation, take the organic phase, wash with saturated brine, dry, and concentrate under reduced pressure to no The fractions were added with n-heptane and stirred for crystallization, filtered and dried to obtain compound N-11; and
  • step S3 Mix and stir the compound N-11, compound A and dichloromethane of step S2 until dissolved, cool down and control the temperature to -50°C ⁇ -45°C, add the dichloromethane solution of Lewis acid, and keep stirring for 0.5 ⁇ 1h to monitor the reaction by TLC; control the temperature to below -20°C, add triethylamine dropwise to terminate the reaction, wash with saturated sodium bicarbonate solution, wash with purified water, dry, concentrate under reduced pressure until no fractions, add n-heptane and stir to crystallize , filtered and dried to obtain the product.
  • the equivalent ratio of compound N-9, n-butyllithium and compound N-8 is (1-1.5):(1-1.5):1.
  • the equivalent ratio of compound N-9, n-butyllithium and compound N-8 is 1.25:1.25:1.
  • the equivalent ratio of the compound N-9, triethylsilane and boron trifluoride ether is (1-1.5):(1.5-2):(1-1.5).
  • the equivalent ratio of the compound N-9, triethylsilane and boron trifluoride ether is 1.2:2:1.2.
  • the equivalent ratio of compound N-11 and Lewis acid is 1:(5-10).
  • step S3 the equivalent ratio of compound N-11 and Lewis acid is 1:5.
  • the Lewis acid includes boron trichloride, boron trifluoride and boron tribromide.
  • step S3 the equivalent ratio of compound N-11 and compound A is 1:(3-8).
  • step S3 the equivalent ratio of compound N-11 and compound A is 1:4.
  • R1, R2, R3, R4 and R5 are independently selected from at least one of -H, -(CH 2 ) n CH 3 or -O(CH 2 ) n CH 3 , and R1, R2, R3, R4 and R5 are not simultaneously -H, and n is an integer 0-10.
  • the compound A is trimethylbenzene, 1,2,4,5-tetramethylbenzene, trimethylbenzene, anisole, phenethyl ether or 1,3-dimethoxybenzene.
  • the compound A is pentamethylbenzene.
  • step S3 the equivalent ratio of compound N-11 and triethylamine is 1:3.
  • drying agent used for drying in the steps S1, S2 and S3 is anhydrous sodium sulfate.
  • the preparation method of Taipagliflozin also includes recrystallization, and the specific steps of the recrystallization are: mixing the product of step S3 with a mixed solvent, heating to 60° C. to dissolve and clarify, hot filtration, and slowly cooling to 25 ⁇ 30°C and control the cooling time to be 4 ⁇ 6h, filter and dry to get it.
  • the mixed solvent is composed of ethyl acetate and n-heptane in a mass ratio of 2:1.
  • the present application provides tagagliflozin prepared by the preparation method.
  • the present application uses compound N-10-a as the starting material, reacts with n-butyllithium and compound N-8 to obtain compound N-10-a, and then adds triethylsilane and boron trifluoride ether to react Compound N-11 was obtained, and then Lewis acid was added to react to obtain tagagliflozin.
  • the synthesis steps were reduced from 5 steps to 3 steps, which greatly shortened the synthesis route.
  • Test 1 showed that the yield of tagagliflozin was high, reaching 90%. % or more, and the purified tagagliflozin yield after recrystallization of tagagliflozin reaches more than 80%.
  • compounds may be represented in a stereoscopic or non-stereoscopic manner, which does not represent a limitation on the compounds.
  • Embodiment 1 a kind of preparation method of Taipagliflozin
  • step S2 control the temperature to below -20°C, add dropwise 600mL, 10wt% ammonium chloride aqueous solution, return the temperature to 10°C, extract with 1600mL dichloromethane, take the organic phase, wash with 1500mL saturated brine, and dry over anhydrous sodium sulfate, Concentrate under reduced pressure until there is no fraction, to obtain 250 g of compound N-10-a, which is continuously added to step S2 at a yield of 100%.
  • step S1 250 g of compound N-10-a in step S1 was diluted and dissolved with 1200 mL of dichloromethane, 64.4 g of triethylsilane (0.554 mol, 2.0 eq) was added, the temperature was lowered to -30 °C to -20 °C under nitrogen protection, and added dropwise.
  • step S3 Mix the 75g product TY702 of step S3 with 1500mL mixed solvent (the composition of ethyl acetate and n-heptane according to the mass ratio of 2:1), heat up to 60°C to dissolve and clarify, filter with heat, slowly cool down to 25°C and control the cooling time to 4h , filtered and dried to obtain 63g of Tagagliflozin.
  • 1500mL mixed solvent the composition of ethyl acetate and n-heptane according to the mass ratio of 2:1
  • Embodiment 2 ⁇ 3 a kind of preparation method of tagagliflozin
  • Example 1 The difference from Example 1 is that the raw material feeding amounts of the Examples 2 to 3 are different, see Table 1 for details.
  • the preparation method is similar to Example 1.
  • the preparation method is carried out according to the following synthetic route:
  • the intermediate 3 obtained above was mixed with 1500 mL of mixed solvent (the composition of ethyl acetate and n-heptane according to the mass ratio of 2:1), the temperature was raised to 60 ° C for dissolving and clarification, hot filtered, slowly cooled to 25 ° C and the cooling time was controlled to be 4h , filtered, and dried to obtain Tagagliflozin 1.
  • mixed solvent the composition of ethyl acetate and n-heptane according to the mass ratio of 2:1
  • the intermediate 5 obtained above was mixed with 1500 mL of mixed solvent (the composition of ethyl acetate and n-heptane according to the mass ratio of 2:1), the temperature was raised to 60 ° C to dissolve and clarify, hot filtered, slowly cooled to 25 ° C and the cooling time was controlled to be 4h , filtered, and dried to obtain Tagagliflozin 2.
  • mixed solvent the composition of ethyl acetate and n-heptane according to the mass ratio of 2:1
  • the product TY702 obtained in Examples 1-3 namely tagagliflozin
  • the purified tagagliflozin obtained after recrystallization also has a high yield.
  • Pentamethylbenzene was not added in Comparative Example 2
  • the resulting product TY702 and the purified tagagliflozin yield after recrystallization were lower, and the yields of Comparative Example 3 and Comparative Example 4 were also lower than those of the implementation.
  • Example 2 low.
  • the structure of the known impurity TY702-Bn is Its origin is due to the binding reaction effect of compound N-11 during debenzylation.
  • Table 1 the contents of known impurities TY702-Bn, the largest single impurity and total impurities in Examples 1 to 3 are less, while compared with Example 1, the addition of pentamethylbenzene in Comparative Example 2 resulted in known impurities
  • the content of impurity TY702-Bn is relatively large, which shows that adding pentamethylbenzene in step S3 of the synthesis route can effectively suppress the production of known impurity TY702-Bn, and also shows that recrystallization cannot remove known impurity TY702-Bn;
  • the content of the known impurity TY702-Bn in the example 3 is relatively high; the content of the known impurity TY702-Bn in the comparative example 4 is relatively small, indicating that the known impurity TY702-Bn can be removed after the acetylation and deacety

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention appartient au domaine technique des médicaments, et concerne spécifiquement un procédé de préparation de tianagliflozine. La tianagliflozine de la présente invention est obtenue par réaction d'un composé N-9, n-butyle lithium et d'un composé N-8 pour obtenir un composé N-10-a, puis ajout de triéthylsilane et d'éther de trifluorure de bore pour les faire réagir et obtenir un composé N-11, et ajout d'acide de Lewis pour réaction. Le procédé de préparation de la présente invention permet de raccourdir la voie synthétique de la tianagliflozine, et la tianagliflozine obtenue présente un rendement élevé, une faible teneur en impuretés et des propriétés stables.
PCT/CN2021/090928 2020-09-22 2021-04-29 Procédé de préparation de tianagliflozine WO2022062401A1 (fr)

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CN202011003431.5A CN112062742B (zh) 2020-09-22 2020-09-22 一种泰格列净的制备方法
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Publication number Priority date Publication date Assignee Title
CN112062742B (zh) * 2020-09-22 2021-08-20 广州市力鑫药业有限公司 一种泰格列净的制备方法

Citations (3)

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CN1802366A (zh) * 2003-03-14 2006-07-12 安斯泰来制药有限公司 C－糖苷衍生物及其盐
CN107108539A (zh) * 2014-09-15 2017-08-29 北京生命科学研究所 钠‑葡萄糖协同转运蛋白2(sglt‑2)抑制剂
CN112062742A (zh) * 2020-09-22 2020-12-11 广州市力鑫药业有限公司 一种泰格列净的制备方法

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CN110305118B (zh) * 2019-06-20 2024-04-02 四川科伦药物研究院有限公司 一种适合工业生产恩格列净的合成方法
CN110698468B (zh) * 2019-09-24 2020-11-03 杭州华东医药集团新药研究院有限公司 一种坎格列净的制备方法
CN111592515B (zh) * 2020-06-22 2022-02-08 广州市力鑫药业有限公司 一种具有降低血糖的sglt2抑制剂的制备方法

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
CN1802366A (zh) * 2003-03-14 2006-07-12 安斯泰来制药有限公司 C－糖苷衍生物及其盐
CN107108539A (zh) * 2014-09-15 2017-08-29 北京生命科学研究所 钠‑葡萄糖协同转运蛋白2(sglt‑2)抑制剂
CN112062742A (zh) * 2020-09-22 2020-12-11 广州市力鑫药业有限公司 一种泰格列净的制备方法

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Title
SHI, YONGHENG ET AL.: "A facile synthesis of 6-deoxydapagliflozin", MONATSHEFTE FUER CHEMIE, vol. 144, no. 12, 1 October 2013 (2013-10-01), XP035303911, DOI: 10.1007/s00706-013-1053-0 *

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