WO2016161956A1

WO2016161956A1 - Preparation method of indacaterol or salt thereof

Info

Publication number: WO2016161956A1
Application number: PCT/CN2016/078777
Authority: WO
Inventors: 王小宁; 刘飞; 张喜全; 顾红梅; 陈智林; 张洪英; 江金凤; 刘艳妮
Original assignee: 正大天晴药业集团股份有限公司
Priority date: 2015-04-09
Filing date: 2016-04-08
Publication date: 2016-10-13
Also published as: CN107531636A; CN107531636B

Abstract

The present invention relates to a preparation method of indacaterol or a salt thereof. The method comprises: in the presence of solvent, employing salicylic acid, acetylsalicylic acid and/or oxalic acid to react with a mixture containing a compound of formula II, so as to obtain a compound of formula I, wherein the mixture also contains compound(s) of formula III and/or formula IV, and definitions of formula I to formula IV are described in the specification; converting the obtained compound of formula I into indacaterol or a salt thereof. Indacaterol or a salt thereof having high purity can be prepared via the method, with greatly reduced impurities, and guaranteed medication safety.

Description

Method for preparing indaprol or its salt

Technical field

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.

Background technique

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:

It is a drug developed by Novartis for the treatment of chronic obstructive pulmonary disease and asthma, which produces anti-inflammatory and dilated bronchial effects by stimulating the β2 supraventricular receptor. Since 2009, the product has been listed in European countries for the treatment of adult patients with chronic obstructive pulmonary disease airflow obstruction, including the treatment of chronic bronchitis and / or emphysema. In 2011, the product was listed in Japan under the trade name Onbrize. In March 2012, the product was listed in the US.

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:

However, this reaction produces more disubstituted and main impurities of the positional isomer. Although some purification methods have been disclosed in the prior art, there is still a need to develop a method for preparing high enantiomeric purity of indacaterol or a salt thereof, thereby minimizing the content of impurities and ensuring the safety of administration.

Summary of the invention

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.

It is still another object of the present invention to provide a process for the preparation of the intermediate.

In order to achieve the above object, in one aspect, the present invention provides a process for the preparation of indacaterol or a salt thereof, the method comprising the steps of:

(i) reacting a mixture of salicylic acid, acetylsalicylic acid and/or oxalic acid with a compound containing a compound of formula II in the presence of a solvent to produce a compound of formula I, said mixture further comprising a compound of formula III and / or formula IV ;

In the compounds of formulae I to IV, R is a phenolic hydroxyl protecting group;

In the compound of formula I, HX is salicylic acid, acetylsalicylic acid and/or oxalic acid;

(ii) converting the resulting compound of formula I to indacaterol or a salt thereof.

In some embodiments, 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%.

Unless otherwise specified, 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.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, 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. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is n-butanol and ethanol.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, 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.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, 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.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, 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. As mentioned above. For example, 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.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, the solvent used in the step (i) is as described above, and the reaction temperature is as described above. For example, the solvent in the step (i) is n-butanol and/or ethanol, and the reaction temperature is from 0 ° C to 90 ° C. In some embodiments, 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.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, 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.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, the R includes an alkyl group, an aryl group, an alkoxy group, an aralkyl group, a halogenated alkyl group or a substituted silyl group. Preferably, the R is selected from benzyl or tert-butyldimethylsilyl.

According to a specific embodiment of the present invention, in the preparation method of indaprol or a salt thereof according to the present invention, the mixture 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;

The definition of R in the compound of formula VI is the same as the definition of R in the compound of formula II. For example, R is benzyl or tert-butyldimethylsilyl.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, after the step (i), 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.

According to a specific embodiment of the present invention, the preparation method of the indacaterol or the salt thereof of the present invention comprises the following steps:

(a) 8-substituted oxy-5-(R)-oxiranyl-1H-quinolin-2-one of the formula VI in the presence of a solvent and 5,6- represented by the formula V Diethyl-2,3-dihydro-1H-inden-2-amine is reacted to obtain a mixture containing a compound of formula II;

(b) treating the mixture of step (a) with salicylic acid, acetylsalicylic acid and/or oxalic acid to provide a compound of formula I;

(c) isolating and crystallizing the compound of formula I;

(d) removing a phenolic hydroxyl protecting group R from a compound of formula I to provide a compound of formula VII;

(e) treating the compound of formula VII with an acid to directly obtain a salt of indacaterol represented by formula VIII. Preferably, 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;

Wherein 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.

In the compound of formula VIII, HY is the acid used in the acid treatment;

Preferably, 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.

According to a specific embodiment of the present invention, in the preparation method of the indacaterol or the salt thereof of the present invention, in the step (a), 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.

According to a specific embodiment of the present invention, in the method for producing indacaterol or a salt thereof of the present invention, 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:

Converting it to indacaterol with a base treatment of a compound of formula VII, optionally converting the indacaterol to its salt, or

Direct conversion of the compound of formula VII to an indacaterol salt, optionally, converting the indacaterol salt to indacaterol; preferably, 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.

According to a specific embodiment of the present invention, in the method for preparing indacaterol or a salt thereof of the present invention, step (ii) Including the following steps:

Conversion of a compound of formula I to a compound of formula IX using a base:

Removal of the phenolic hydroxyl protecting group R in the compound of formula IX affords indacaterol; alternatively, the indacaterol can be converted to its salt.

According to a specific embodiment of the present invention, in the method for preparing indacaterol or a salt thereof of the present invention, the step (ii) comprises the steps of:

Converting it to a compound of formula X by acid treatment of a compound of formula I, preferably 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;

Removal of the phenolic hydroxyl protecting group R in the compound of formula X gives a salt of indacaterol; alternatively, the indaprolol salt is converted to indacaterol.

In another aspect, 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:

In the compound of formula I, 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;

In the compound of formula I or formula VII, HX is salicylic acid, acetylsalicylic acid and/or oxalic acid.

According to a specific embodiment of the present invention, 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:

In a further aspect, the invention provides a crystallization of a compound of formula 1-1, wherein, in the use of Cu-Kα radiation, in an X-ray powder diffraction pattern, at a degree of 2θ 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 2θ 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 2θ 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, 27.64, 28.98, 32.69; more preferably, when using Cu-Kα radiation, the XRD spectrum of the crystal of the compound of formula I-1 is shown in FIG.

In still another aspect, the present invention provides a crystallization of a compound of formula 1-2, wherein, in the use of Cu-Kα radiation, it has an X-ray powder diffraction pattern at about 2,427, 10.69, 21.57, 22.98, 24.64 degrees of 2θ. 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 2θ 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-Kα radiation, the compound of formula I-2 The spectrum of the crystallized XRD is shown in Fig. 2.

Unless otherwise stated, "about" in the present invention means fluctuation within a range of ± 0.2 given a specific value. For example, a degree of 2θ of about 7.06 means that 2θ is 7.06±0.2.

In a further aspect, 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.

In a further aspect, the invention provides a process for the preparation of a compound of formula I, which comprises the steps of:

(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

(C) isolating and crystallizing the compound of formula I;

Wherein R is a phenolic hydroxyl protecting group,

HX is salicylic acid, acetylsalicylic acid and/or oxalic acid.

According to a particular embodiment of the invention, in the process for the preparation of the compound of the formula I according to the invention, 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.

According to a specific embodiment of the present invention, in the preparation method of the compound of the formula I of the present invention, 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.

In one aspect, the invention provides a process for the preparation of a compound of formula I, comprising:

(1) 8-substituted oxy-5-(R)-oxiranyl-1H-quinolin-2-one (formula VI) and 5,6-diethyl-2, in the presence of a solvent, 3-Dihydro-1H-indol-2-amine (Formula V) is reacted to give a mixture containing a compound of formula II;

(2) treating the mixture prepared in the step (1) with salicylic acid, acetylsalicylic acid and/or oxalic acid to obtain a corresponding salt of the compound of the formula II, ie a compound of the formula I; and optionally

(3) The compound of formula I is isolated and crystallized.

In another aspect, the present invention provides a method for preparing an indacaterol salt, comprising:

(2) treating the mixture prepared in the step (1) with salicylic acid, acetylsalicylic acid and/or oxalic acid to obtain the corresponding salt of the compound of the formula II, that is, the compound of the formula I;

(3) separating and crystallizing the compound of formula I;

(4) removing the protecting group of formula I to give a compound of formula VII;

(5) treating a compound of the formula VII with an acid to obtain a salt of indacaterol represented by the formula VIII,

Wherein R is a protecting group, and 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. Preferably, 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.

In step (1), step (a) or step (A), one skilled in the art can select 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. In a specific embodiment, the solvent is ethanol.

In step (1), step (a) or step (A), in some embodiments of the invention, the solvent is n-butanol and/or ethanol. With regard to 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. In some embodiments, 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. With respect to the temperature of the reaction, in some embodiments, 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. In some embodiments, the 8-substituted oxy-5-(R)-oxiranyl-1H-quinolin-2-one is 8-benzyloxy-5-(R)-ethylene oxide Base-1H-quinolin-2-one.

In a preferred embodiment of the step (1), 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. When 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.

In 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.

In step (2), step (i), step (b) or step (B), one skilled in the art can directly mix salicylic acid, acetylsalicylic acid and/or oxalic acid with the mixture, or alternatively a solvent capable of dissolving salicylic acid, acetylsalicylic acid and/or oxalic acid of step (2), step (i), step (b) or step (B), including but not limited to C _1-6 alkane Alcohol (eg methanol, ethanol, propanol, butanol, pentanol), dichloromethane, dimethylformamide, tetrahydrofuran. In a specific embodiment, the solvent is ethanol.

In step (2), step (b) or step (B), a molar excess (for example, 1 to 5 moles) of salicylic acid, acetylsalicylic acid and/or oxalic acid is used relative to the compound of formula VI. To form a salt; in some embodiments, the reaction is carried out using a 2-fold molar acid. The temperature to be used is preferably 0 ° C to 90 ° C.

In 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.

In 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. In some embodiments of the invention, Formula I is a salicylate. In some embodiments, the compound of Formula I is acetylsalicylate. In some embodiments, the compound of Formula I is an oxalate salt.

Removal of the protecting group or phenolic hydroxyl protecting group of the present invention, such as the removal of the protecting group of the salt of formula I in step (4), can be removed by those skilled in the art according to the prior art. For example, when the protecting group 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. In some embodiments of the invention, the compound of formula VII is a salicylate. In some embodiments of the invention, the compound of formula VII is acetylsalicylate. In some embodiments of the invention, 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. Preferably, the acid is maleic acid.

As used herein, "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. For example, 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.

The "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.

The "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.

The "aryl group" means an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system, preferably having 6 to 14 carbon atoms, more preferably 6 to 12 carbon atoms. Most preferably, it has 6 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The "aralkyl group" means an aryl-substituted alkyl group, wherein the definitions of "aryl" and "alkyl" are the same as defined above.

In another aspect, 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. Moreover, purification using salicylic acid, acetylsalicylic acid or oxalic acid as the salt-forming acid makes the compound of formula I easier to separate, and when the temperature of the solution is lowered, for example, to room temperature, there is a large amount of solid form of formula I. The crude product of the compound is precipitated and the operation is simpler.

DRAWINGS

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.

detailed description

The technical solutions of the present invention will be described in detail below with reference to the specific embodiments and the accompanying drawings. The scope of the invention.

The purity and impurity content of the compounds in the examples were tested by HPLC method. Specifically, the purity measurement conditions (HPLC) were as follows:

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);

Chromatographic conditions: using octadecylsilane bonded silica as a filler [Waters XBridge C18 (4.6 mm × 250 mm, 5 μm)], with phosphate buffer (take 2.72 g of potassium dihydrogen phosphate, add 1000 ml of water to dissolve, use phosphoric acid Adjust the pH to 2.0 ± 0.1) - water - acetonitrile (200: 700: 100) for mobile phase A, phosphate buffer - acetonitrile (200: 800) for mobile phase B, flow rate of 1.0 ml per minute, as shown below A linear gradient elution was performed with a detection wavelength of 210 nm and a column temperature of 30 °C.

时间(分钟)Time (minutes)	流动相A(％)Mobile phase A (%)	流动相B(％)Mobile phase B (%)
00	8080	2020
2020	4040	6060
3030	4040	6060
3131	8080	2020
3636	8080	2020

Method of operation: According to the "High Performance Liquid Chromatography Operating Procedures" (Q/SOP ZL059), accurately measure 10 μl of the test solution into the liquid chromatograph (1 injection per injection) and record the chromatogram. Calculated according to the peak area normalization method, the purity and impurity content of the test sample are obtained.

Example 1 (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinoline-2- Preparation of ketone salicylate

This embodiment is prepared as follows:

To the reaction flask was added 29.3 g of 8-benzyloxy-5-(R)-oxiranyl-1H-quinolin-2-one and 22.7 g of 5,6-diethyl-2,3-dihydrogen. -1H-indole-2-amine and 200 ml of n-butanol, stirred uniformly, heated to 105 ± 5 ° C, and reacted for 10 h. When the reaction solution is concentrated under reduced pressure at 50-60 ° C to about 1/3 of the original volume, 300 ml of ethanol is added, heated to 70-78 ° C, and stirred to dissolve; HPLC shows that the content of the positional isomer is 11.94%, disubstituted The content of impurities was 16.55%, (R)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quina The content of oxa-2-one was 62.98%. Then add a solution of salicylic acid in ethanol (add 30g of salicylic acid to 200ml of ethanol, stir and dissolve), stir at room temperature for 16h, precipitate a large amount of solids, and extract by filtration to obtain (R)-5-[2-(5,6- Crude diethyldihydroindo-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinolin-2-one salicylate. The crude product was recrystallized from 500 ml of ethanol to give 36.9 g of (R)-5-[2-(5,6-diethyldihydroindol-2-ylamino)-1-hydroxyethyl]-8-benzyloxy -1H-quinolin-2-one salicylate pure product, which is a pale yellow solid powder, and XRD is shown in Fig. 1. (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinoline-2 as determined by HPLC - the purity of the ketone salicylate is 99.60%, the content of the positional isomer is 0.08%, the content of the disubstituted substance is 0.01%, and the retention time of the salicylic acid in the test solution is compared with the salicylic acid reference solution. The retention time of the main peak is the same.

Example 2(R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinoline-2- Preparation of ketoacetyl salicylate

To the reaction flask was added 14.7 g of 8-benzyloxy-5-(R)-oxiranyl-1H-quinolin-2-one and 11.4 g of 5,6-diethyl-2,3-dihydrogen. -1H-indole-2-amine and 100 ml of n-butanol, stirred uniformly, heated to 105 ± 5 ° C, and reacted for 10 h. When the reaction solution is concentrated under reduced pressure at 50-60 ° C to about 1/3 of the original volume, 150 ml of ethanol is added, heated to 70-78 ° C, and stirred to dissolve; HPLC shows that the content of the positional isomer is 10.28%, disubstituted The content of impurities was 14.33%, (R)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quina The content of the oxa-2-one was 60.5%. Further, an ethanol solution of acetylsalicylic acid (20 g of acetylsalicylic acid was added to 100 ml of ethanol, and the mixture was stirred and dissolved), and stirred at room temperature for 16 hours, a large amount of solid was precipitated, and (R)-5-[2-(5, Crude 6-diethylindoline-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinolin-2-one acetylsalicylate. The crude product was recrystallized from 300 ml of ethanol to give 15.5 g of (R)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy -1H-quinolin-2-one acetylsalicylate pure product, which is a pale yellow solid powder. (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.

Example 3(R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinoline-2- Preparation of oxalate

To the reaction flask was added 9.8 g of 8-benzyloxy-5-(R)-oxiranyl-1H-quinolin-2-one and 7.6 g of 5,6-diethyl-2,3-dihydrogen. -1H-indole-2-amine and 70 ml of n-butanol, stirred uniformly, heated to 105 ± 5 ° C, and reacted for 10 h. The 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%. Then add oxalic acid in ethanol solution (5.5 g of oxalic acid was added to 70 ml of ethanol, stir and dissolve), stir at room temperature for 16 h, a large amount of solid precipitated, and suction filtration to obtain (R)-5-[2-(5,6-diethyl) A crude product of dihydroindol-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinolin-2-one oxalate. The obtained crude product was recrystallized from 160 ml of ethanol to give 9.2 g of (R)-5-[2-(5,6-diethyldihydroindol-2-ylamino)-1-hydroxyethyl]-8-benzyloxy -1H-quinolin-2-one oxalate pure product, which is a pale yellow solid powder, and XRD is shown in FIG. (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinoline-2 as determined by HPLC - the purity of the ketooxalate is 99.58%, the content of the positional isomer is 0.05%, the content of the disubstituted substance is 0.02%, and the retention time of the oxalic acid in the test solution is consistent with the retention time of the main peak of the oxalic acid reference solution. .

Example 4 Preparation of indacaterol maleate (using Example 1 as an intermediate)

To the hydrogenation reactor was added 30 g of (R)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H- Quinoline-2-one salicylate and 300 ml of acetic acid. 3 grams of 10% palladium on carbon was added and the reaction was hydrogenated for 2-6 hours until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure at 50 ° C. The residue was dissolved in 300 ml of ethanol and heated to 60 ° C. A solution of maleic acid in ethanol (6.9 g of maleic acid dissolved in 35 ml of ethanol) was added and stirring was continued. After 30 minutes, the product was crystallized by slow cooling to 0-5 °C. It was dried by suction filtration to obtain 22.5 g of indacaterol maleate as a white crystalline powder.

Characteristic peaks of ¹ H-NMR (CDCl ₃ ): δ 7.04 (1H, d, J = 8.2), 7.22 (1H, d, J = 8.2), 6.60 (1H, d, J = 10.0), 8.25 (1H) , d, J = 10.0), 7.00 (2H, s), 2.51 to 2.57 (4H, m), 1.12 (6H, t, J = 7.5), 6.08 (2H, s), 5.41 (brd, J = 9.2) , 9-12 (brs, 4H), 9-12 (brs, 4H) disappeared after heavy water exchange, indicating the presence of active hydrogen.

It is to be noted that the above embodiments are only used to explain the implementation process and features of the present application, and do not limit the technical solutions of the present application. Although the present application is described in detail with reference to the above embodiments, those skilled in the art should understand that: Modifications or equivalent substitutions of the present application may be made without departing from the spirit and scope of the invention.

Claims

A method for preparing indaprol or a salt thereof, the method comprising the steps of:

(i) reacting a mixture of salicylic acid, acetylsalicylic acid and/or oxalic acid with a compound containing a compound of formula II in the presence of a solvent to produce a compound of formula I, said mixture further comprising a compound of formula III and / or formula IV ;

In the compounds of formulae I to IV, R is a phenolic hydroxyl protecting group;

In the compound of formula I, HX is salicylic acid, acetylsalicylic acid and/or oxalic acid;

(ii) converting the resulting compound of formula I to indacaterol or a salt thereof.
The method according to claim 1, wherein said solvent in step (i) is capable of dissolving said mixture and said salicylic acid, acetylsalicylic acid and/or oxalic acid; preferably, said solvent comprises C1 ~ 6 one or more alkyl alcohols, dichloromethane, dimethylformamide and tetrahydrofuran; more preferably, the C 1 ~ 6 alkyl alcohols include methanol, ethanol, propanol, butanol and amyl alcohol One or more; more preferably, the solvent is n-butanol and/or ethanol.
The method according to claim 1, wherein the reaction is carried out in step (i) using a molar excess of salicylic acid, acetylsalicylic acid and/or oxalic acid relative to the number of moles of the compound of formula II; for example, from 1 to 10 The reaction of the salicylic acid, acetylsalicylic acid and/or oxalic acid in moles is carried out; preferably, a 2-fold molar number is used.
The method according to claim 1, wherein 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 method according to claim 1, wherein said R comprises an alkyl group, an aryl group, an alkoxy group, an aralkyl group, a halogenated alkyl group or a substituted silyl group; preferably, said R is selected from a benzyl group or a tertiary group. Butyldimethylsilyl.
The method according to any one of claims 1 to 5, wherein the mixture is prepared as follows: 5,6-diethyl-2,3-dihydrogen of the formula V in the presence of a solvent -1H-indol-2-amine and 8-substituted oxy group represented by formula VI -5-(R)-oxiranyl-1H-quinolin-2-one is reacted to obtain the mixture;

The definition in R in Formula VI is the same as the definition of R in Claim 1 or Claim 5.
The method according to claim 1, wherein after the step (i), the method further comprises separating and/or crystallizing the obtained compound of the formula I; preferably, crystallization is carried out using an alcohol solvent, further preferably, The alcohol solvent is ethanol.
The method of claim 1 wherein the method comprises the steps of:

(a) 8-substituted oxy-5-(R)-oxiranyl-1H-quinolin-2-one of the formula VI in the presence of a solvent and 5,6- represented by the formula V Diethyl-2,3-dihydro-1H-inden-2-amine is reacted to obtain a mixture containing a compound of formula II;

(b) treating the mixture of step (a) with salicylic acid, acetylsalicylic acid and/or oxalic acid to provide a compound of formula I;

(c) isolating and crystallizing the compound of formula I;

(d) removing the phenolic hydroxyl protecting group R of the compound of formula I to give a compound of formula VII;

(e) treating the compound of formula VII with an acid to directly obtain a salt of indacaterol represented by formula VIII. Preferably, 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;

Wherein R in the compound of formula I, formula II or formula VI is a phenolic hydroxy protecting group, preferably said R comprises an alkyl, aryl, alkoxy, aralkyl, haloalkyl or substituted silyl group; preferably R is selected from benzyl or tert-butyldimethylsilyl;

HX in formula I is salicylic acid, acetylsalicylic acid and/or oxalic acid;

In Formula VIII, HY is the acid used in the acid treatment;

Preferably, the salicylic acid, acetylsalicylic acid and/or oxalic acid described in step (b) are directly mixed with the mixture of step (a), or salicylic acid, acetylsalicylic acid and/or oxalic acid are dissolved in the solvent. Further mixing with the mixture of step (a); further preferably, the salt is formed 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. .
The method according to claim 8, wherein in step (a), 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 from 1.15 to 1.3:1, and the reaction temperature is from 95 ° C to 120. °C.
The method of claim 1 wherein step (ii) comprises the step of removing the phenolic hydroxyl protecting group R from the compound of formula I to produce a compound of formula VII:

Converting it to indacaterol with a base treatment of a compound of formula VII, optionally converting the indacaterol to its salt, or

Directly converting it to an indacaterol salt by acid treatment of a compound of formula VII, optionally converting the indacaterol salt to indacaterol; preferably, 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.
The method of claim 1 wherein step (ii) comprises the steps of:

Conversion of a compound of formula I to a compound of formula IX using a base:

Removal of the phenolic hydroxyl protecting group R in the compound of formula IX affords indacaterol; alternatively, the indacaterol can be converted to its salt.
The method of claim 1 wherein step (ii) comprises the steps of:

Converting it to a compound of formula X by acid treatment of a compound of formula I, preferably 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;

Removal of the phenolic hydroxyl protecting group R in the compound of formula X gives a salt of indacaterol; alternatively, the indaprolol salt is converted to indacaterol.
An intermediate for the preparation of indacate or a salt thereof, the intermediate being a compound of formula I or a compound of formula VII:

In the compound of formula I, 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;

In the compound of formula I or formula VII, HX is salicylic acid, acetylsalicylic acid and/or oxalic acid.
The intermediate according to claim 13, wherein the intermediate has the structure of Formula I-1, Formula I-2 or Formula I-3:
The crystallization of the compound of the formula I-1 in the intermediate according to claim 14, wherein, in the case of using Cu-Kα radiation, in the X-ray powder diffraction pattern, the degree of 2θ is about 7.06, 10.66, 12.13, 19.78, There are diffraction peaks at 23.33 and 24.25; preferably, when Cu-Kα radiation is used, in the X-ray powder diffraction pattern, there are diffraction peaks at 2θ degrees of about 7.06, 10.66, 12.13, 19.78, 23.33, 24.25; Ground, having diffraction peaks at 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; more preferably, at 2θ Degrees approximately 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, 26.14, 27.64, 28.98, There is a diffraction peak at 32.69; more preferably, when using Cu-Kα radiation, the XRD spectrum of the crystal of the compound of the formula I-1 is shown in Fig. 1.
The crystallization of the compound of the formula I-2 in the intermediate according to claim 14, wherein in the X-ray powder diffraction pattern, when the Cu-Kα radiation is used, the degree of 2θ is about 7.24, 10.69, 21.57, 22.98, There are diffraction peaks at 24.64; preferably, there are diffraction peaks at 2θ degrees of about 5.27, 7.24, 10.69, 11.74, 14.16, 17.84, 20.21, 21.57, 22.98, 24.64, 28.86; further preferably, the degree of 2θ is 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-Kα radiation, formula I- The XRD spectrum of the crystal of the 2 compound is shown in Fig. 2.
Use of the intermediate according to claim 13 or 14 or the crystallization of the compound of the formula I-1 according to claim 15 or the crystallization of the compound of the formula I-2 according to claim 16 for the preparation of indacaterol or a salt thereof .
A process for the preparation of a compound of formula I according to claim 13 for the preparation of an intermediate of indacaterol or a salt thereof, comprising the steps of:

(A) 8-substituted oxy-5-(R)-oxiranyl-1H-quinolin-2-one of the formula VI in the presence of a solvent and 5,6- represented by the formula V Diethyl-2,3-dihydro-1H-inden-2-amine is reacted to obtain a mixture containing a compound of formula II;

(B) treating the mixture obtained in step (A) with salicylic acid, acetylsalicylic acid or oxalic acid to obtain the corresponding salt of the compound of formula II, ie a compound of formula I; and optionally

(C) isolating and crystallizing the compound of formula I;

Wherein R is a phenolic hydroxyl protecting group,

HX is salicylic acid, acetylsalicylic acid and/or oxalic acid.
The method according to claim 18, wherein said R is selected from the group consisting of alkyl, aryl, alkoxy, aralkyl, haloalkyl and substituted silyl; preferably, R is selected from benzyl or tert-butyl Dimethylsilyl.
The method according to claim 18 or 19, wherein the molar ratio of the compound of the formula V to the compound of the formula VI in the step (A) is n-butanol and/or ethanol, and the temperature is from 95 to 1200. °C.