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WO2016161956A1 - Procédé de préparation d'indacatérol ou du sel de celui-ci - Google Patents

Procédé de préparation d'indacatérol ou du sel de celui-ci Download PDF

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Publication number
WO2016161956A1
WO2016161956A1 PCT/CN2016/078777 CN2016078777W WO2016161956A1 WO 2016161956 A1 WO2016161956 A1 WO 2016161956A1 CN 2016078777 W CN2016078777 W CN 2016078777W WO 2016161956 A1 WO2016161956 A1 WO 2016161956A1
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Prior art keywords
formula
acid
compound
salt
indacaterol
Prior art date
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Ceased
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PCT/CN2016/078777
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English (en)
Chinese (zh)
Inventor
王小宁
刘飞
张喜全
顾红梅
陈智林
张洪英
江金凤
刘艳妮
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to CN201680024493.XA priority Critical patent/CN107531636B/zh
Publication of WO2016161956A1 publication Critical patent/WO2016161956A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • 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

Definitions

  • the present invention belongs to the field of pharmaceutical synthesis, and in particular, the present invention provides a process for preparing indacaterol or a salt thereof.
  • the CAS number of indatrol is 312753-06-3, and the compound name is (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl ]-8-Hydroxy-1H-quinolin-2-one, having the structural formula shown below:
  • Indacaterol is an enantiomerically pure compound which, when prepared, is intermediate (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy- Indaprolol can be obtained by removing the protecting group R from ethyl]-8-substituted oxy-1H-quinolin-2-one.
  • This intermediate can be prepared by the following reaction:
  • One of the objects of the present invention is to provide a process for preparing indacaterol or a salt thereof, by which high-purity indacaterol or a salt thereof can be obtained, the content of impurities is remarkably reduced, and the safety of the drug is ensured.
  • Another object of the present invention is to provide an intermediate for the preparation of indacaterol or a salt thereof and use thereof.
  • the present invention provides a process for the preparation of indacaterol or a salt thereof, the method comprising the steps of:
  • R is a phenolic hydroxyl protecting group
  • HX is salicylic acid, acetylsalicylic acid and/or oxalic acid
  • the compound of formula IV is present in an amount from 5 to 20%; in some embodiments, the compound of formula IV is present in an amount from 10 to 20%; in some embodiments, the compound of formula III is present in an amount from 10 to 25% In some embodiments, the compound of formula III is present in an amount from 15 to 20%; in some embodiments, the compound of formula II is present in an amount from 55 to 85%; in some embodiments, the compound of formula II is present in an amount from 60 to 75 %. In some embodiments, the compound of formula II is present in an amount from 10% to 20%, the compound of formula III is from 15% to 25%, and the compound of formula IV is present in an amount from 55% to 70%.
  • the “content” as used in the present invention means the content obtained by the area normalization method as measured by HPLC analysis.
  • the HPLC analysis method is, for example, the method described in the specific examples.
  • the solvent in the step (i) is capable of dissolving the mixture and the salicylic acid, acetylsalicylic acid and/or Or oxalic acid; preferably, the solvent includes, but is not limited to, one or more of a C 1-6 alkyl alcohol, dichloromethane, dimethylformamide, and tetrahydrofuran; further preferably, the C 1-6
  • the alkyl alcohol includes one or more of methanol, ethanol, propanol, butanol, and pentanol; more preferably, the solvent is n-butanol and/or ethanol.
  • the solvent is ethanol.
  • the solvent is n-butanol and ethanol.
  • a molar excess of salicylic acid or acetylsalicylic acid is used in step (i) relative to the compound of formula II.
  • the reaction is carried out with and/or oxalic acid; for example, using 1 to 10 moles of the salicylic acid, acetylsalicylic acid and/or oxalic acid; preferably, a 2-fold molar amount is used.
  • the reaction temperature in the step (i) is from 0 ° C to 90 ° C, preferably from 60 ° C to 90 ° C, further preferably from 70 ° C to 90 ° °C.
  • the solvent used in the step (i) is as described above, and the amount of salicylic acid, acetylsalicylic acid and/or oxalic acid is used.
  • the solvent in the step (i) is n-butanol and/or ethanol, and the salicylic acid, acetylsalicylic acid and/or oxalic acid are used in an amount of from 1 to 4 moles relative to the moles of the compound of the formula II. Carry out the reaction.
  • the solvent used in the step (i) is as described above, and the reaction temperature is as described above.
  • the solvent in the step (i) is n-butanol and/or ethanol, and the reaction temperature is from 0 ° C to 90 ° C.
  • the solvent in step (i) is ethanol; in some embodiments, the solvent in step (i) is n-butanol and ethanol; in some embodiments, the volume ratio of n-butanol to ethanol is 1:1. ⁇ 10; In some embodiments, the volume ratio of n-butanol to ethanol is from 1:3 to 6.
  • the solvent used in the step (i) is as described above; the amounts of salicylic acid, acetylsalicylic acid and/or oxalic acid are as above Said; and the reaction temperature is as described above.
  • the R in the method for producing indacaterol or a salt thereof of the present invention, includes an alkyl group, an aryl group, an alkoxy group, an aralkyl group, a halogenated alkyl group or a substituted silyl group.
  • the R is selected from benzyl or tert-butyldimethylsilyl.
  • the mixture in the preparation method of indaprol or a salt thereof according to the present invention, can be prepared as follows: in the presence of a solvent, 5,6-di-B represented by Formula V Base-2,3-dihydro-1H-indol-2-amine and 8-substituted oxy-5-(R)-oxiranyl-1H-quinolin-2-one of formula VI Reacting to obtain the mixture;
  • R in the compound of formula VI is the same as the definition of R in the compound of formula II.
  • R is benzyl or tert-butyldimethylsilyl.
  • the method further comprises separating and/or crystallizing the obtained compound of the formula I, preferably Separation and crystallization; preferably, crystallization is carried out using an alcohol solvent, and further preferably, the alcohol solvent is ethanol.
  • the preparation method of the indacaterol or the salt thereof of the present invention comprises the following steps:
  • step (b) treating the mixture of step (a) with salicylic acid, acetylsalicylic acid and/or oxalic acid to provide a compound of formula I;
  • the acid used in the acid treatment is an organic carboxylic acid such as benzoic acid, maleic acid, fumaric acid or tartaric acid. Preferred; maleic acid;
  • R in the compound of formula I, formula II or formula VI is a phenolic hydroxy protecting group, preferably said R comprises an alkyl group, an aryl group, an alkoxy group, an arylalkyl group, a haloalkyl group or a substituted silyl group; further preferably The R is selected from benzyl or tert-butyldimethylsilyl.
  • HX is salicylic acid, acetylsalicylic acid and/or oxalic acid
  • HY is the acid used in the acid treatment
  • the salicylic acid, acetylsalicylic acid and/or oxalic acid described in step (b) may be directly mixed with the mixture of step (a), or salicylic acid, acetylsalicylic acid and/or oxalic acid are dissolved in the solvent. (eg, ethanol) is then mixed with the mixture of step (a) to form a salt in a molar excess of salicylic acid, acetylsalicylic acid and/or oxalic acid relative to the compound of formula VI at a temperature of from 0 ° C to 90 ° °C.
  • solvent eg, ethanol
  • n-butanol and/or ethanol is used as a solvent, and the molar ratio of the compound of the formula V to the compound of the formula VI is 1.15 to 1.3:1, the reaction temperature is 95 ° C to 120 ° C.
  • the step (ii) comprises the step of removing the phenolic hydroxyl protecting group R from the compound of the formula I to obtain a compound of the formula VII:
  • Direct conversion of the compound of formula VII to an indacaterol salt optionally, converting the indacaterol salt to indacaterol;
  • the acid used in the acid treatment is an organic carboxylic acid, such as benzene Formic acid, maleic acid, fumaric acid or tartaric acid; maleic acid is further preferred.
  • step (ii) Including the following steps:
  • the step (ii) comprises the steps of:
  • the acid used in the acid treatment is an organic carboxylic acid such as benzoic acid, maleic acid, fumaric acid or tartaric acid; preferably maleic acid;
  • HY is the acid used in the acid treatment
  • the invention provides an intermediate for the preparation of indacaterol or a salt thereof, the intermediate being a compound of formula I or a compound of formula VII:
  • R is a phenolic hydroxy protecting group, preferably R comprises an alkyl, aryl, alkoxy, aralkyl, haloalkyl or substituted silyl group; preferably, said R is benzyl Or tert-butyldimethylsilyl;
  • HX is salicylic acid, acetylsalicylic acid and/or oxalic acid.
  • the intermediate for preparing indacaterol or a salt thereof of the present invention has a formula Structure shown in I-1, Formula I-2 or Formula I-3:
  • the invention provides a crystallization of a compound of formula 1-1, wherein, in the use of Cu-K ⁇ radiation, in an X-ray powder diffraction pattern, at a degree of 2 ⁇ degrees of about 7.06, 10.66, 12.13, 19.78, 23.33, 24.25 a diffraction peak; preferably, a diffraction peak at a degree of 2 ⁇ degrees of about 7.06, 10.66, 11.56, 12.13, 12.55, 13.89, 15.39, 16.43, 17.01, 17.66, 18.41, 19.33, 19.78, 21.69, 23.33, 24.25, 25.25; Further preferably, the degrees of 2 ⁇ are about 7.06, 7.87, 10.66, 11.56, 12.13, 12.55, 13.89, 15.39, 15.62, 16.43, 17.01, 17.66, 18.41, 19.33, 19.78, 20.19, 21.00, 21.69, 23.33, 24.25, 25.25, There are diffraction peaks at 26.14, 27.
  • the present invention provides a crystallization of a compound of formula 1-2, wherein, in the use of Cu-K ⁇ radiation, it has an X-ray powder diffraction pattern at about 2,427, 10.69, 21.57, 22.98, 24.64 degrees of 2 ⁇ .
  • a diffraction peak preferably, having diffraction peaks at about 2:27, 7.24, 10.69, 11.74, 14.16, 17.84, 20.21, 21.57, 22.98, 24.64, 28.86; further preferably, at a degree of 2 ⁇ of about 5.27, 7.24, 10.69, 11.74, 12.82, 14.16, 17.00, 17.84, 18.26, 20.21, 20.57, 21.57, 22.10, 22.98, 23.41, 24.64, 28.86 have diffraction peaks; more preferably, when using Cu-K ⁇ radiation, the compound of formula I-2 The spectrum of the crystallized XRD is shown in Fig. 2.
  • the invention provides the use of an intermediate of the invention, a crystallization of a compound of formula 1-1 or a crystallization of a compound of formula 1-2 in the preparation of indacaterol or a salt thereof.
  • the invention provides a process for the preparation of a compound of formula I, which comprises the steps of:
  • step (B) treating the mixture obtained in step (A) with salicylic acid, acetylsalicylic acid and/or oxalic acid to obtain the corresponding salt of the compound of formula II, ie a compound of formula I; and optionally
  • R is a phenolic hydroxyl protecting group
  • HX is salicylic acid, acetylsalicylic acid and/or oxalic acid.
  • the R is selected from the group consisting of alkyl, aryl, alkoxy, aralkyl, haloalkyl and substituted silyl; preferred R is selected from benzyl or tert-butyldimethylsilyl.
  • the molar ratio of the compound of the formula V to the compound of the formula VI is 1.15 to 1.3 in the step (A) using n-butanol and/or ethanol as a solvent. : 1, the temperature is 95 ° C ⁇ 120 ° C.
  • the invention provides a process for the preparation of a compound of formula I, comprising:
  • the present invention provides a method for preparing an indacaterol salt, comprising:
  • R is a protecting group
  • HX and HY are each a corresponding acid.
  • the protecting group R of the present invention is a protecting group for a phenolic hydroxyl group known to those skilled in the art.
  • R is selected from the group consisting of alkyl, aryl, alkoxy, aralkyl, haloalkyl and substituted silyl. More preferably, R is selected from benzyl or tert-butyldimethylsilyl.
  • step (1) step (a) or step (A)
  • a suitable solvent which is capable of dissolving the mixture of step (1), step (a) or step (A), including but not It is limited to C 1 to 6 alkyl alcohols (for example, methanol, ethanol, propanol, butanol, pentanol), dichloromethane, dimethylformamide, tetrahydrofuran.
  • the solvent is ethanol.
  • step (1) step (a) or step (A), in some embodiments of the invention, the solvent is n-butanol and/or ethanol.
  • the molar ratio of the reactants it is preferred to use an excess of the compound of formula V with respect to the compound of formula VI.
  • the molar ratio of the compound of Formula VI to the compound of Formula V is from 1:1.15 to 1.3; in a preferred embodiment, the molar ratio of the compound of Formula VI to the compound of Formula V is 1:1.2.
  • the temperature of the reaction is from 50 ° C to 140 ° C; in some embodiments, the temperature of the reaction is from 95 ° C to 120 ° C; in some specific embodiments, the temperature of the reaction is 100 °C ⁇ 110 °C.
  • the 8-substituted oxy-5-(R)-oxiranyl-1H-quinolin-2-one is 8-benzyloxy-5-(R)-ethylene oxide Base-1H-quinolin-2-one.
  • the step (a) or the step (A) the molar ratio of the compound of the formula VI to the compound of the formula V is 1:1.15 to 1.3, using n-butanol and/or ethanol as a solvent.
  • the temperature is from 95 ° C to 120 ° C
  • the reaction of the step (1), the step (a) or the step (A) can be completed in a short period of time, for example, within 10 hours, and in a specific embodiment, The reaction was completed in 8 hours, and the compound of formula VI was not detected by TLC in the mixture, and other impurity spots were less.
  • step (1) step (a) or step (A)
  • the amine acts as a nucleophile to attack the epoxy, and two impurities are formed depending on the ring opening direction of the epoxy compound: a positional isomer and a disubstituted impurity (
  • the structural formula is as follows).
  • the mixture of step (1), step (a) or step (A) contains a positional isomer and a disubstituted impurity.
  • step (2) step (i), step (b) or step (B)
  • the solvent is ethanol.
  • step (2) step (b) or step (B)
  • a molar excess for example, 1 to 5 moles
  • the reaction is carried out using a 2-fold molar acid.
  • the temperature to be used is preferably 0 ° C to 90 ° C.
  • step (2) step (i), step (b) or step (B), in a specific embodiment, the solvent used is n-butanol and/or ethanol in a molar excess of salicylic acid, acetyl Salicylic acid and / or oxalic acid to form a salt, the temperature is 0 ° C ⁇ 90 ° C.
  • step (3) step (c) or step (C)
  • the salt of formula I is isolated and crystallized.
  • the salt of formula I is very easy to separate, and when the temperature of the solution is lowered, for example to room temperature, a large amount of crude form of the salt of the formula I is precipitated.
  • Formula I is a salicylate.
  • the compound of Formula I is acetylsalicylate.
  • the compound of Formula I is an oxalate salt.
  • the protecting group or phenolic hydroxyl protecting group of the present invention can be removed by those skilled in the art according to the prior art.
  • the protecting group when it is a benzyl group, it can be hydrogenated in the presence of a catalyst. Catalysts which may be mentioned include palladium, palladium hydroxide, platinum, Raney nickel, or palladium (palladium carbon) supported on activated carbon.
  • the compound of formula VII is a salicylate.
  • the compound of formula VII is acetylsalicylate.
  • the compound of formula VII is an oxalate salt.
  • the acid in step (5) or step (e) is an organic carboxylic acid such as benzoic acid, maleic acid, fumaric acid or tartaric acid.
  • the acid is maleic acid.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond.
  • the alkyl group may have 1 to 6 carbon atoms (indicated by C 1-6 alkyl groups), preferably 1 to 4 carbon atoms.
  • Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl Base, n-hexyl.
  • haloalkyl group refers to an alkyl group substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine, and iodine, wherein the alkyl group is as defined above.
  • alkoxy refers to an -O-alkyl group wherein the alkyl group is the same as defined above.
  • the alkoxy group may have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
  • Non-limiting examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy , 2-methylbutoxy, neopentyloxy, n-hexyloxy.
  • aryl group means an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system, preferably having 6 to 14 carbon atoms, more preferably 6 to 12 carbon atoms. Most preferably, it has 6 carbon atoms.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • aralkyl group means an aryl-substituted alkyl group, wherein the definitions of "aryl” and “alkyl” are the same as defined above.
  • the invention provides compounds of formula I and formula VII, and their use in the preparation of indacaterol; wherein HX is salicylic acid, acetylsalicylic acid and/or oxalic acid, and R is benzyl ,
  • the present application uses salicylic acid, acetylsalicylic acid and/or oxalic acid as a salt-forming acid to purify a mixture containing positional isomers and/or disubstituted impurities, which may be positional isomers and/or disubstituted.
  • the content of the substance is reduced to less than 0.2%, and a compound of the formula I having an enantiomeric purity of 99% or more and even 99.5% or more is obtained, which ensures the safety of the marketed drug.
  • Figure 1 is (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-benzyloxy-1H-quinoline-2 XRD pattern of ketone salicylate;
  • Figure 2 is (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-benzyloxy-1H-quinoline-2 - XRD pattern of ketooxalate.
  • HPLC purity measurement conditions
  • Test solution Take the appropriate amount of test sample, accurately weighed, add 50% acetonitrile solution to dissolve and quantitatively dilute to make a solution containing about 0.25mg per 1ml, that is, the test solution (1 part);
  • (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinoline-2 as determined by HPLC - ketoacetylsalicylate has a purity of 99.47%, a positional isomer content of 0.08%, a disubstituted content of 0.01%, and a retention time of acetylsalicylic acid in the test solution with acetylsalicylic acid The retention time of the main peak of the reference solution was consistent.
  • reaction solution When concentrated under reduced pressure at 50-60 ° C to about 1/3 of the original volume, 100 ml of ethanol was added, heated to 70-78 ° C, and stirred to dissolve; HPLC showed that the content of the positional isomer was 12.11%, and the content of the disubstituted impurity was 16.75%, (R)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinoline-2- The ketone content was 63.0%.

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Abstract

La présente invention concerne un procédé de préparation d'indacatérol ou du sel de celui-ci. Le procédé comprend : en présence d'un solvant, l'utilisation d'acide salicylique, d'acide acétylsalicylique et/ou d'acide oxalique pour la mise en réaction avec un mélange contenant un composé de formule II, afin d'obtenir un composé de formule I, où le mélange contient également le(s) composé(s) de formule III et/ou de formule IV, et les définitions de la formule I à la formule IV sont décrites dans la description ; la conversion du composé obtenu de formule I en indacatérol ou sel de celui-ci. L'indacatérol ou son sel présentant une pureté élevée peuvent être préparés via le procédé, les impuretés étant grandement réduites, et l'innocuité du médicament étant garantie.
PCT/CN2016/078777 2015-04-09 2016-04-08 Procédé de préparation d'indacatérol ou du sel de celui-ci Ceased WO2016161956A1 (fr)

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CN109721534A (zh) * 2018-09-25 2019-05-07 四川海思科制药有限公司 一种马来酸茚达特罗中间体及其制备方法和用途
CN110229078A (zh) * 2019-05-22 2019-09-13 博诺康源(北京)药业科技有限公司 一种茚达特罗起始原料开环杂质的制备
CN111808021A (zh) * 2019-04-10 2020-10-23 上海谷森医药有限公司 茚达特罗及其盐的制备方法

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CN114591236A (zh) * 2020-12-02 2022-06-07 四川海思科制药有限公司 一种茚达特罗的改进制备方法

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CN109721534A (zh) * 2018-09-25 2019-05-07 四川海思科制药有限公司 一种马来酸茚达特罗中间体及其制备方法和用途
CN109721534B (zh) * 2018-09-25 2022-05-20 四川海思科制药有限公司 一种马来酸茚达特罗中间体及其制备方法和用途
CN111808021A (zh) * 2019-04-10 2020-10-23 上海谷森医药有限公司 茚达特罗及其盐的制备方法
CN110229078A (zh) * 2019-05-22 2019-09-13 博诺康源(北京)药业科技有限公司 一种茚达特罗起始原料开环杂质的制备

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