WO2017015793A1 - Procédé pour séparer un diastéréo-isomère a de bédaquiline - Google Patents

Procédé pour séparer un diastéréo-isomère a de bédaquiline Download PDF

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Publication number
WO2017015793A1
WO2017015793A1 PCT/CN2015/085075 CN2015085075W WO2017015793A1 WO 2017015793 A1 WO2017015793 A1 WO 2017015793A1 CN 2015085075 W CN2015085075 W CN 2015085075W WO 2017015793 A1 WO2017015793 A1 WO 2017015793A1
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WO
WIPO (PCT)
Prior art keywords
aqueous solution
diastereomer
solvent
acid
reaction
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PCT/CN2015/085075
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English (en)
Chinese (zh)
Inventor
张福利
潘林玉
朱津津
王新增
赵立
任重
宋颖
Original Assignee
浙江海正药业股份有限公司
上海医药工业研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 浙江海正药业股份有限公司, 上海医药工业研究院 filed Critical 浙江海正药业股份有限公司
Priority to PCT/CN2015/085075 priority Critical patent/WO2017015793A1/fr
Priority to CN201580081471.2A priority patent/CN107848978B/zh
Publication of WO2017015793A1 publication Critical patent/WO2017015793A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/02—Lithium compounds

Definitions

  • the present invention relates to the field of pharmaceuticals, and more particularly to a method for isolating Bidaquinoline diastereomer A.
  • Bedaquinine is an anti-tuberculosis drug with the structural formula shown in Figure 1:
  • bedaquinoline is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-2-butanol, the first drug developed by Johnson & Johnson to inhibit mycobacterial adenosine triphosphate (ATP) synthase, was first marketed in the United States in December 2012 for the treatment of adult multidrug-resistant tuberculosis.
  • the trade name is Sirturo.
  • Bedaquinoline shows strong selectivity for ATP synthase of Mycobacterium tuberculosis, and its new mechanism of action makes it resistant to cross-resistance with other anti-tuberculosis drugs, which will greatly reduce the resistance of Mycobacterium tuberculosis. It shows good activity against multidrug-resistant tuberculosis in macrophages, suggesting that it has the effect of shortening the treatment time.
  • the ratio of diastereomer B to diastereomer A obtained by the method is between 1:1 and 1:3, for the next chiral decomposing. It has an impact; sometimes even the conversion rate is as low as 50%.
  • the conversion rate is as low as 50%, since the amount of the product in the reaction liquid is small, the separation product can hardly be purified by the method of the patent WO2006125769, even if the product is separated and purified by the purification method disclosed in the patent, the final The purity of the resulting diastereomer A is also very low.
  • the present invention provides a method for separating bedaquinoline diastereomer A which is simple in operation and stable in method. Regardless of the reaction conversion rate of the prepared betaxazoline, the method can make the betadarquinoline diastereomer B and the desired diastereomer A The ratio is between 1:8-1:23, thus ensuring the high purity and yield of the desired diastereomer A, which facilitates the next chiral resolution and successfully achieves the non-antagonism of the betaxipaline. Separation of isomer A.
  • the present invention provides a method for isolating bead quinoline diastereomer A comprising the steps of:
  • the diastereomer B precipitated in the step (1) is removed to obtain a diastereomer A;
  • the diastereomer A is:
  • the diastereomer B is:
  • the reverse phase solvent is an organic solvent miscible with the solvent of the betadarquinoline reaction solution.
  • the reverse phase solvent is a non-polar or weakly polar solvent.
  • the reverse phase solvent is a C5-C16 alkane, or a C4-C8 ether solvent, or a mixture of a C5-C16 alkane and a C4-C8 ether solvent.
  • the C5-C16 alkane is n-heptane or n-hexane;
  • the C4-C8 ether solvent is isopropyl ether, petroleum ether or methyl tert-butyl ether.
  • the C5-C16 alkane is n-heptane; the C4-C8 ether solvent is isopropyl ether.
  • the solvent of the bead quinoline reaction solution is tetrahydrofuran; and the betadaquinoline reaction solution is obtained by reacting a reaction raw material with lithium diisopropylamide (LDA) in tetrahydrofuran.
  • LDA lithium diisopropylamide
  • the reaction raw materials are 3-benzyl-6-bromo-2-methoxyquinoline and 3-dimethylamino-1-(naphthalen-5-yl)acetone.
  • a weak acid aqueous solution is first added to the bead quinoline reaction solution to remove the residual starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and then the anti-addition is added.
  • Phase solvent is added.
  • the bead quinoline reaction solution is added to the reverse phase solvent to precipitate the diastereomer B, and further subjected to an ice water bath step to further precipitate the diastereomer B.
  • the ice water bath step is carried out at 0-5 °C.
  • a weak acid aqueous solution is added to the solution after removing the diastereomer B precipitated in the step (1) to remove the residual starting material 3-dimethylamino-1-(naphthalene). -5-yl)acetone; then a strong acid aqueous solution was added to remove the residual starting material 3-benzyl-6-bromo-2-methoxyquinoline to give the diastereomer A.
  • the step (2) after adding a strong acid aqueous solution to remove the raw material 3-benzyl-6-bromo-2-methoxyquinoline, it is made alkaline with an alkaline solution, and added and diastereomeric
  • the organic solvent which is mutually miscible and water-immiscible is extracted and concentrated to obtain diastereomer A; preferably, the alkaline solution is ammonia water or sodium hydroxide, and the diastereomer
  • the organic solvent in which A is mutually soluble and immiscible with water is toluene or dichloromethane.
  • the diastereomer A has a purity of at least 88%; further preferably, the purity is 88-96%.
  • the volume ratio of the reverse phase solvent to the solvent of the betadarquinoline reaction solution is from 1:10 to 10:1; preferably, the volume ratio is from 1:5 to 5:1; further preferably, The volume ratio is from 1:2 to 2:1.
  • the percentage concentration of the weak acid aqueous solution is 10%-60%, the percentage concentration of the strong acid aqueous solution is 5%-40%; further preferably, the weak acid aqueous solution has a percentage concentration of 30%-50%, The percentage concentration of the aqueous strong acid solution is 15%-25%.
  • the weak acid aqueous solution is an aqueous formic acid solution, an aqueous solution of acetic acid or an aqueous solution of propionic acid; and the aqueous solution of strong acid is an aqueous solution of sulfonic acid, an aqueous solution of hydrochloric acid, an aqueous solution of sulfuric acid or an aqueous solution of phosphoric acid.
  • the weak acid aqueous solution is an aqueous acetic acid solution
  • the strong acid aqueous solution is an aqueous hydrochloric acid solution.
  • the separation method used in the present invention has more industrial value than the separation and purification by column chromatography;
  • the separation product can hardly be purified by the method of the patent WO2006125769, even if the product is separated and purified by the purification method disclosed in the patent, and finally The purity of the resulting diastereomer A is also very low.
  • the undesired diastereomer B is precipitated from the betaacene racemate by adding a reverse phase solvent to the betadarquinoline reaction solution, regardless of the conversion conversion rate of the prepared betaxazoline.
  • the ratio of the betaactoline diastereomer B to the desired diastereomer A can be between 1:8 and 1:23 to ensure the desired diastereomer.
  • A has higher purity and yield, which is beneficial to the next chiral separation.
  • the bidaquinoline diastereomer B is removed, and then the raw material is removed by pickling, thereby achieving the purpose of further purification, compared with the patent.
  • the ethanol pulping and purifying method used in the step C of the embodiment part of WO2006125769 is more advantageous, on the one hand, the product residue is prevented from causing loss in the beating mother liquor; on the other hand, when the conversion rate of the prepared betaxazoline reaction is not good, the reaction end point is caused.
  • the diastereomer A obtained by the method of the present invention is further resolved to obtain a qualified end product of betaxaquinoline having a purity of ⁇ 99.0%, wherein the diastereomer impurity is ⁇ 0.1%. Therefore, the invention has more application value than the prior art in practical applications, and is simple in operation and stable in method.
  • the diastereomer A isolated by the method of the present invention can be resolved by a prior art method to further obtain the betaxipaquinine of the desired configuration.
  • the separation method of the invention has more industrial value than the separation and purification by the conventional column chromatography
  • the separation method of the present invention can overcome the technical problem that the reaction conditions of the betaxazoline are severe, the conversion rate is difficult to be ensured, and the amount of the product is small when the conversion rate is low, and it is difficult to purify and separate it;
  • the reverse phase solvent is added to precipitate the undesired diastereomer B from the beta-quinoline racemate, and the beta-quinoline diastereomeric can be ensured regardless of the reaction conversion rate of the prepared betaxazoline.
  • the ratio of isomer B to the desired diastereomer A is between 1:8 and 1:23, thereby ensuring that the desired diastereomer A has higher purity and yield, which is advantageous for the next Step chiral splitting;
  • the separation method of the invention can easily remove the residue of the raw material, the yield is high, the purity of the diastereomer A is also high, and the separation is facilitated, and the qualified bedaquinoline can be prepared by further resolution.
  • the product has a purity of ⁇ 99.0%, wherein the diastereomer impurity is ⁇ 0.1%.
  • the separation method of the present invention is simple in operation and stable in method.
  • the obtained filtrate was washed with a 50% aqueous acetic acid solution to remove the starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and a 15% aqueous hydrochloric acid solution was added to the organic layer to stir to form a salt in the aqueous layer. In the middle of precipitation. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded.
  • the filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to basic with aqueous ammonia, extracted with toluene, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure to obtain a product.
  • Isomer A (4.9 g), purity 89%.
  • the obtained diastereomer A was resolved by the method of WO2006125769 to obtain the desired bedaquinoline.
  • the specific method is as follows:
  • the split salt (2.07 g), toluene (37 ml), potassium carbonate (1.51 g) and water (13 ml) were mixed, heated to 90 ° C and stirred until fully dissolved; hot layered, the organic layer was treated with 10% aqueous potassium carbonate solution ( 5 ml), 1 time, the organic layer was monitored by TLC; washed with purified water until pH was neutral (20 ml ⁇ 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.5 g); The mixture was stirred and stirred at room temperature for 0.5 h to precipitate a solid, which was stirred for 1 hour in ice-water bath, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to obtain bedaquinoline (1.07 g) with an HPLC purity of >99%. .
  • the obtained filtrate was washed with a 10% aqueous solution of formic acid to remove the starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and a 5% aqueous solution of sulfuric acid was added to the organic layer to stir to form a salt in the aqueous layer. In the middle of precipitation. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the starting material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded.
  • the filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to a weak basic with sodium hydroxide, extracted with dichloromethane, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure.
  • the product diastereomer A (5.7 g) was obtained with a purity of 92%.
  • the obtained diastereomer A was resolved by the method of WO2006125769 to obtain the desired bedaquinoline.
  • the specific method is as follows:
  • the obtained filtrate was washed with a 60% aqueous solution of propionic acid to remove the starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and 40% aqueous methanesulfonic acid was added to the organic layer to stir to form a salt. Precipitated in the water layer. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded.
  • the filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to a weak basic with sodium hydroxide, extracted with dichloromethane, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure.
  • the product diastereomer A (6.0 g) was obtained with a purity of 94%.
  • the obtained diastereomer A was resolved by the method of WO2006125769 to obtain the desired bedaquinoline.
  • the specific method is as follows:
  • the split salt (2.59g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90 ° C and stirred until fully dissolved; layered hot, the organic layer was treated with 10% potassium carbonate solution ( Washed once with 5 ml), washed with purified water until the pH was neutral (20 ml ⁇ 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.7 g); toluene (1 ml) Stir at room temperature for 0.5h The solid was precipitated, stirred in an ice water bath for 1 h, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to give bedaquinoline (1.20 g) with HPLC purity >99%.
  • the obtained filtrate was washed with a 30% aqueous solution of acetic acid to remove the raw material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and a 25% aqueous phosphoric acid solution was added to the organic layer to stir to form a salt in the aqueous layer. In the middle of precipitation. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded.
  • the filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to a weak basic with sodium hydroxide, extracted with dichloromethane, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure.
  • the product diastereomer A (5.72 g) was obtained with a purity of 88%.
  • the obtained diastereomer A was resolved by the method of WO2006125769 to obtain the desired bedaquinoline.
  • the specific method is as follows:
  • the split salt (2.43g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90 ° C and stirred until fully dissolved; hot layered, the organic layer was treated with 10% potassium carbonate solution ( Washed once with 5 ml), washed with purified water until the pH was neutral (20 ml ⁇ 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.5 g); toluene (1 ml) The solid was precipitated by stirring at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to obtain bedaquinoline (1.16 g) with HPLC purity >99%.
  • the obtained filtrate was washed with a 40% aqueous solution of acetic acid to remove the raw material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and a 20% aqueous hydrochloric acid solution was added to the organic layer to stir to form a salt in the aqueous layer. In the middle of precipitation. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded.
  • the filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to a weak basic with sodium hydroxide, extracted with dichloromethane, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure.
  • the product diastereomer A (6.1 g) was obtained with a purity of 96%.
  • the obtained diastereomer A was resolved by the method of WO2006125769 to obtain the desired bedaquinoline.
  • the specific method is as follows:
  • split salt (2.69 g), toluene (40 ml), potassium carbonate (1.60 g) and water (14 ml) were mixed, heated to 90 ° C and stirred until fully dissolved; hot layered, organic layer with 10% aqueous potassium carbonate solution ( Washed once with 5 ml), washed with purified water until the pH was neutral (20 ml ⁇ 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.8 g); toluene (1 ml) The solid was precipitated by stirring at room temperature for 0.5 h, stirred in an ice water bath for 1 h, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to obtain bedaquinoline (1.28 g) with an HPLC purity of >99%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour séparer un diastéréo-isomère A de bédaquiline. Le procédé comprend les étapes suivantes, consistant à : (1) ajouter un solvant à phase inversée dans un liquide de réaction de bédaquiline, comprenant les diastéréo-isomères A et B, de manière à séparer par précipitation le diastéréo-isomère B ; et (2) éliminer le diastéréo-isomère B séparé par précipitation dans l'étape (1), de manière à obtenir le diastéréo-isomère A. Le procédé de séparation de la présente invention est facile à exploiter, stable et présente une valeur d'industrialisation plus élevée par rapport à une séparation et une purification dans un procédé de chromatographie sur colonne classique et permet de résoudre les problèmes de la difficulté de purification et de séparation de la bédaquiline en raison de la petite quantité d'un produit provoquée par un taux de conversion excessivement faible, étant donné que les conditions de préparation de la bédaquiline sont dures et que le taux de conversion est difficile à assurer ; les résidus de matières premières peuvent être facilement éliminés, le rendement est élevé et la pureté du diastéréo-isomère A est élevée, ce qui facilite la séparation ; la séparation peut en outre être mise en oeuvre pour obtenir un produit de bédaquiline certifié, présentant une pureté supérieure ou égale à 99,0 %, les impuretés des diastéréo-isomères étant inférieures ou égales à 0,1 %.
PCT/CN2015/085075 2015-07-24 2015-07-24 Procédé pour séparer un diastéréo-isomère a de bédaquiline WO2017015793A1 (fr)

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PCT/CN2015/085075 WO2017015793A1 (fr) 2015-07-24 2015-07-24 Procédé pour séparer un diastéréo-isomère a de bédaquiline
CN201580081471.2A CN107848978B (zh) 2015-07-24 2015-07-24 一种分离贝达喹啉非对映异构体a的方法

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107857727A (zh) * 2017-10-26 2018-03-30 江苏天和制药有限公司 一种（1r，2s）和（1s，2r）‑贝达喹啉的制备方法
CN109422679A (zh) * 2017-08-30 2019-03-05 武汉武药科技有限公司 一种贝达喹啉的纯化及稳定晶型的制备方法
CN114085185A (zh) * 2020-07-01 2022-02-25 东亚St 株式会社 制备贝达喹啉及其药学上可接受的盐的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101180302A (zh) * 2005-05-25 2008-05-14 詹森药业有限公司 制备(αS,βR)-6-溴-α-[2-(二甲基氨基)乙基]-2-甲氧基-α-1-萘基-β-苯基-3-喹啉乙醇的方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2301544E (pt) * 2002-07-25 2012-12-10 Janssen Pharmaceutica Nv Novos inibidores de micobactérias

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101180302A (zh) * 2005-05-25 2008-05-14 詹森药业有限公司 制备(αS,βR)-6-溴-α-[2-(二甲基氨基)乙基]-2-甲氧基-α-1-萘基-β-苯基-3-喹啉乙醇的方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109422679A (zh) * 2017-08-30 2019-03-05 武汉武药科技有限公司 一种贝达喹啉的纯化及稳定晶型的制备方法
CN109422679B (zh) * 2017-08-30 2021-06-25 武汉武药科技有限公司 一种贝达喹啉的纯化及稳定晶型的制备方法
CN107857727A (zh) * 2017-10-26 2018-03-30 江苏天和制药有限公司 一种（1r，2s）和（1s，2r）‑贝达喹啉的制备方法
CN114085185A (zh) * 2020-07-01 2022-02-25 东亚St 株式会社 制备贝达喹啉及其药学上可接受的盐的方法

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