CN114751857A - Preparation method of indacaterol impurity - Google Patents

Preparation method of indacaterol impurity Download PDF

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CN114751857A
CN114751857A CN202210467095.2A CN202210467095A CN114751857A CN 114751857 A CN114751857 A CN 114751857A CN 202210467095 A CN202210467095 A CN 202210467095A CN 114751857 A CN114751857 A CN 114751857A
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吕冠宝
胡永铸
张池
刘春�
徐一鸣
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Tlc Nanjing Pharmaceutical Research And Development Co ltd
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    • 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
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Abstract

The invention discloses a preparation method of indacaterol impurity, which takes 8- (benzyloxy) -5- ((5, 6-diethyl-2, 3-dihydro-1H-inden-2-yl) glycyl) quinoline-2 (1H) -ketone as a raw material to realize the synthesis of the indacaterol impurity through six-step reaction. The prepared indacaterol has high impurity purity, and provides important basis for scientific evaluation of quality, safety and efficiency of the indacaterol.

Description

Preparation method of indacaterol impurity
Technical Field
The invention relates to a preparation method of an impurity, and particularly relates to a preparation method of an indacaterol impurity.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a common respiratory disease characterized by persistent limitation of airflow and is currently one of the five leading causes of patient death worldwide. Bronchodilators are mainly used clinically to relieve the symptoms of the patient's urgency. Commonly used bronchodilators are mainly classified into three categories: anticholinergics, methylxanthines, and beta 2 receptor agonists. The most widespread of them is β 2 receptor agonist, which activates intracellular adenylate cyclase by activating β 2 receptors widely distributed in tracheal smooth cells, thereby catalyzing the synthesis of intracellular cyclic adenosine monophosphate (cAMP), and further tries smooth muscle relaxation to relax the bronchi. The beta 2 receptor agonist can be divided into 3 types of short-acting, long-acting and super-long-acting according to the action time. The latest development of the ultra-long-acting beta 2 receptor agonist (LABA) -Indacaterol (Indacaterol) makes the daily administration of the drug by a patient 1 time possible, greatly facilitates the life of the patient and improves the life quality.
Indacaterol was developed by Novartis, switzerland, first marketed in germany 12 months in 2009, approved by the FDA in the united states for marketing in 7 months in 2011, and marketed in china in 6 months in 2012 under the commercial name "angrun" (Onbrez). The indacaterol is the first novel clinical ultra-long-acting beta 2 receptor agonist, has quick response and long action duration, and can well control the asthma symptoms of patients with chronic obstructive disease and bronchial asthma and improve the lung function only once a day. In addition, indacaterol causes little systemic untoward reaction and has slight degree, so that the indacaterol is an ideal medicament for treating chronic obstructive pulmonary diseases and bronchial asthma. The molecular formula of the indacaterol is as follows: c24H28N2O3The relative molecular mass is 392.50, and the structural formula is shown as follows:
Figure BDA0003624812300000011
with the progress of times and the improvement of technology level, people have more sufficient understanding on the importance of scientific evaluation of the quality, safety and efficacy of medicines before the medicines come into the market, wherein the control of impurities contained in the medicines is closely related to the quality of the medicines. Impurities often have a direct relationship with drug safety. The pharmacopoeia of various countries strictly stipulate the content and the type of the medicament impurities, and some indacaterol impurities are not reported yet.
Disclosure of Invention
The invention aims to: the invention aims to provide a method for synthesizing high-purity indacaterol impurity.
The technical scheme is as follows: the preparation method of the indacaterol impurity comprises the following steps:
(1) taking a compound I: dissolving 8- (benzyloxy) -5- [ (5, 6-diethyl-2, 3-dihydro-1H-inden-2-yl) glycyl ] quinolin-2 (1H) -one in an organic solvent, adding di-tert-butyl dicarbonate and alkali, and reacting to obtain a compound II;
(2) dissolving the compound II in an organic solvent, adding quaternary phosphonium salt and alkali, and reacting to obtain a compound III;
(3) suspending the compound III in a solvent, adding an oxidant, and reacting to obtain a compound IV;
(4) dissolving the compound IV in a solvent, adding a reducing agent, and reacting to obtain a compound V;
(5) dissolving the compound V in an organic solvent, adding acid, reacting and purifying to obtain a compound VI;
(6) dissolving a compound VI in an organic solvent, adding a catalyst, and reacting and purifying to obtain a compound VII;
the synthetic route is as follows:
Figure BDA0003624812300000021
further, in the step (1), the molar mass ratio of the compound I, the base and the di-tert-butyl dicarbonate is 1: 1-2: 1-2; the reaction temperature is 0-40 ℃, and the reaction time is 3-24 hours; the organic solvent is dichloromethane, tetrahydrofuran, methanol or ethanol; the base is triethylamine, N, N-diisopropylethylamine, DMAP or DBU.
Further, in the step (2), the reaction solvent is toluene, tetrahydrofuran, chloroform or DMF; the alkali is sodium hydride, potassium tert-butoxide, sodium bistrimethylsilyl amide or lithium diisopropylamide; the molar mass ratio of the compound II to the quaternary phosphonium salt to the alkali is 1: 1-5: 1-5; the reaction temperature is 0-80 ℃; the reaction time is 0.5-8 hours.
Further, in the step (3), the solvent is water, tetrahydrofuran, dichloromethane or chloroform, and the oxidant is osmium tetroxide, potassium permanganate, hydrogen peroxide or tert-butyl alcohol peroxide; the molar mass ratio of the compound III to the oxidant is 1: 0.5-3, the solvent amount is 5-30 times of the solid raw material volume; the reaction time is 4-72 hours; the reaction temperature is 0-80 ℃.
Further, in the step (4), the solvent is selected from dichloromethane, chloroform, tetrahydrofuran or trifluoroacetic acid; the molar mass ratio of the compound IV to the reducing agent is 1: 2-15 at 15-80 deg.c for 3-48 hr; the organic solvent is ethyl acetate, methanol, diethyl ether or dioxane; the acid is hydrochloric acid, ethyl acetate hydrogen chloride solution, methanol hydrogen chloride solution or ether hydrogen chloride solution.
Further, in the step (5), the molar mass ratio of the compound V to the acid is 1: 0.5 to 5; the reaction temperature is 0-50 ℃, and the reaction time is 1-24 hours.
Further, the reaction solvent in the step (6) is toluene, tetrahydrofuran, methanol or ethanol; the catalyst is platinum dioxide, palladium hydroxide, palladium chloride or palladium carbon; the reducing agent is iron powder, ammonium formate, zinc powder, hydrazine hydrate or hydrogen; the molar mass ratio of the compound VI to the catalyst to the reducing agent is 1: 0.05-0.5: 3-8; the reaction temperature is 20-100 ℃; the reaction time is 2-20 hours.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages: (1) the synthesis process is reasonable in design and strong in operability; the reagent used in the synthesis method is simple and easy to obtain, and the indacaterol impurity with higher purity can be obtained. The purity of the product can reach more than 99 percent by HNMR, MS and HPLC; (2) the indacaterol impurity obtained by the preparation method can provide a test sample and a reference sample for quality control of raw material indacaterol, and has important application value in drug declaration.
Drawings
FIG. 1 is a synthesis scheme of the indacaterol impurity (Compound VII) provided by the present invention;
FIG. 2 is a nuclear magnetic spectrum of compound V of example 1;
FIG. 3 is a mass spectrum of compound VI of example 1;
FIG. 4 is a nuclear magnetic spectrum of Compound VI of example 1;
FIG. 5 is a liquid phase spectrum of Compound VI of example 1;
FIG. 6 is a mass spectrum of an indacaterol impurity (compound VII) provided by the present invention;
FIG. 7 is a nuclear magnetic spectrum of an indacaterol impurity (compound VII) provided by the present invention;
FIG. 8 is a liquid phase spectrum of the indacaterol impurity (compound VII) provided by the present invention.
Detailed Description
The technical scheme of the invention is further explained by combining the attached drawings.
Example 1
The preparation method of the indacaterol impurity specifically comprises the following steps, and the synthetic route is shown in figure 1:
preparation of Compound II Compound I (4.00g) was dissolved in 20mL of tetrahydrofuran, and triethylamine (2.3mL) and di-tert-butyl dicarbonate (3.62g) were added to stir at room temperature for 16 hours. The solvent was evaporated to dryness, and the solid was precipitated by stirring with diethyl ether and filtered to give 4.70g of compound II as a white solid with a yield of 97.51%.
Compound III was prepared by suspending methyl triphenyl phosphonium bromide (5.50g) in toluene, adding potassium tert-butoxide (1.73g) and stirring at room temperature for 1 hour to give ylide reagent. Compound II (4.5g) was dissolved in 45.0mL of toluene, and ylide reagent was added thereto and stirred at room temperature for 3 hours. Water was added, extraction was performed with ethyl acetate, and column chromatography purification was performed to obtain 3.76g of compound III as a yellow solid with a yield of 84.49%.
Compound IV was prepared by suspending compound III (3.50g) in 52.5mL of water, adding 30% hydrogen peroxide (2.04g) and sodium hydroxide (0.72g), and stirring at room temperature for 15 hours. Quenching with 10% sodium thiosulfate, extraction and column chromatography gave compound IV as a pale yellow solid, 2.71g, 73.84% yield, nuclear magnetic resonance as shown in fig. 2.
Compound V was prepared by dissolving compound IV (2.50g) in 50.0mL of methylene chloride, adding triethylsilane (1.19g) and boron trifluoride etherate (1.45g) and reacting at 40 ℃ for 5 hours. Water was added and the mixture was extracted with dichloromethane and purified by column chromatography to give compound V as a white solid (1.96 g) in 80% yield.
Preparation of Compound VI Compound V (1.80g) was dissolved in diethyl ether (18.0mL), ethereal hydrogen chloride solution (2M,4.5mL) was added, stirred overnight at room temperature, filtered under suction, and the solid was dried to give Compound VI as a white solid (1.55 g), liquid phase purity 99.9226%, yield 96.94%. The mass spectrum, nuclear magnetic spectrum and liquid phase spectrum are respectively shown in figure 3, figure 4 and figure 5.
Preparation of Compound VII Compound VI (1.40g) was dissolved in ethanol (14.0mL), 10% palladium on carbon (0.28g) and ammonium formate (0.82g) were added, the mixture was stirred at 75 ℃ for 5 hours, filtered under suction, and the filtrate was recrystallized from acetonitrile to give Compound VII as a white solid (1.01 g), which was 99.2090% in liquid phase purity and 87.83% in yield. The mass spectrum, nuclear magnetic spectrum and liquid phase spectrum are respectively shown in figure 6, figure 7 and figure 8.
Example 2
The preparation method of the indacaterol impurity specifically comprises the following steps, and the synthetic route is shown in figure 1:
preparation of Compound II Compound I (20.00g) was dissolved in 100mL of dichloromethane, and N, N-diisopropylethylamine (14.5mL) and di-tert-butyl dicarbonate (18.2g) were added to the solution, followed by stirring at room temperature for 16 hours. The solvent was evaporated to dryness, and then ether was added thereto, and the resulting mixture was stirred to precipitate a solid which was then filtered to obtain 21.60g of a white solid of Compound II, with a yield of 87.45%.
Compound III was prepared by suspending methyl triphenyl phosphonium bromide (13.23g) in tetrahydrofuran, adding potassium tert-butoxide (6.92g), and stirring at room temperature for 1 hour to give ylide reagent. Compound II (21.50g) was dissolved in 215mL of tetrahydrofuran, and then the resulting solution was added to ylide reagent and stirred at room temperature for 3 hours. Water was added, extraction was performed with ethyl acetate, and column chromatography purification was performed to obtain 10.10g of compound III as a yellow solid with a yield of 47.14%.
Preparation of Compound IV Compound III (10.00g) was suspended in 150.0mL of water, and potassium permanganate (5.46g) and sodium hydroxide (1.38g) were added, followed by stirring at room temperature for 15 hours. Quenching with 10% sodium thiosulfate, extraction and column chromatography gave compound IV as a pale yellow solid, 6.30g, 61.10% yield.
Preparation of Compound V Compound IV (6.10g) was dissolved in 91.5mL of methylene chloride, and triethylsilane (1.74g) and boron trifluoride etherate (2.12g) were added thereto and reacted at 40 ℃ for 5 hours. Adding water, extracting with dichloromethane, and purifying by column chromatography to obtain compound V white solid 3.62g with yield 60.94%.
Preparation of Compound VI Compound V (3.50g) was dissolved in methanol (35.0mL), methanolic hydrogen chloride solution (2M,5.9mL) was added, stirred overnight at room temperature, and crystallized from ethyl acetate on a rotary press to give compound VI as a white solid, 2.64g, 84.34% yield.
Preparation of Compound VII Compound VI (2.50g) was taken up in ethanol (25.0mL), 10% palladium on carbon (0.25g) and ammonium formate (1.48g) were added, stirred overnight at 20 deg.C, filtered under suction, and the filtrate was recrystallized from acetonitrile to give Compound VII as a white solid (1.35 g) with a yield of 64.90%.
Example 3
The preparation method of the indacaterol impurity specifically comprises the following steps, and the synthetic route is shown in figure 1: preparation of Compound II Compound I (10.00g) was dissolved in 50mL of methanol, and triethylamine (2.89mL) and di-tert-butyl dicarbonate (4.54g) were added and the mixture was stirred at room temperature for 8 hours. The solvent was evaporated to dryness, diethyl ether was added, the solid was stirred and filtered to give compound II as a white solid 9.12g with 75.37% yield.
Compound III was prepared by suspending methyltriphenylphosphine bromide (16.61g) in tetrahydrofuran, adding sodium hydride (60%, 1.86g) and stirring at room temperature for 1 hour to give ylide reagent. Compound II (9.00g) was dissolved in 90.0mL of tetrahydrofuran, and the resulting solution was added to ylide reagent and stirred at 40 ℃ for 5 hours. Water was added, extraction was performed with ethyl acetate, and column chromatography purification was performed to obtain 6.64g of compound III as a yellow solid, which was 74.02% in yield.
Preparation of Compound IV Compound III (6.50g) was suspended in 65.0mL of water, potassium permanganate (5.32g) and sodium hydroxide (1.34g) were added, and the mixture was stirred at room temperature for 15 hours. Quenching with 10% sodium bisulfite, extraction by column chromatography gave compound IV as a pale yellow solid, 3.23g, 47.08% yield.
Preparation of Compound V Compound IV (3.20g) was dissolved in 32.0mL of tetrahydrofuran, and triethylsilane (2.12g) and boron trifluoride etherate (2.58g) were added thereto and reacted at 70 ℃ for 3 hours. Water was added, extraction was performed with ethyl acetate, and purification was performed by column chromatography to obtain compound V as a white solid (2.10 g), with a yield of 67.74%.
Preparation of Compound VI Compound V (2.00g) was dissolved in ethyl acetate (20.0mL), ethyl acetate-HCl solution (2M,3.4mL) was added, stirred at room temperature for 8 hours, filtered with suction, and the solid was dried to give Compound VI as a white solid 1.63g, 90.05% yield.
Preparation of Compound VII Compound VI (1.60g) was dissolved in tetrahydrofuran (267.0mL), 20% palladium hydroxide (0.48g) was added, the mixture was stirred at room temperature for 7 hours under a hydrogen balloon, filtered with suction, and the filtrate was recrystallized from acetonitrile to give Compound VII as a white solid (0.97 g), in 72.93% yield.

Claims (10)

1. A preparation method of indacaterol impurity is characterized by comprising the following steps:
(1) Taking a compound I: dissolving 8- (benzyloxy) -5- [ (5, 6-diethyl-2, 3-dihydro-1H-inden-2-yl) glycyl ] quinoline-2 (1H) -ketone in an organic solvent, adding di-tert-butyl dicarbonate and alkali, and reacting to obtain a compound II;
(2) dissolving the compound II in an organic solvent, adding quaternary phosphonium salt and alkali, and reacting to obtain a compound III;
(3) suspending the compound III in a solvent, adding an oxidant, and reacting to obtain a compound IV;
(4) dissolving the compound IV in a solvent, adding a reducing agent, and reacting to obtain a compound V;
(5) dissolving the compound V in an organic solvent, adding acid, reacting and purifying to obtain a compound VI;
(6) dissolving a compound VI in an organic solvent, adding a catalyst, and reacting and purifying to obtain a compound VII;
the synthetic route is as follows:
Figure FDA0003624812290000011
2. the preparation method according to claim 1, wherein in the step (1), the molar mass ratio of the compound I, the base and the di-tert-butyl dicarbonate is 1: 1-2: 1-2; the reaction temperature is 0-40 ℃, and the reaction time is 3-24 hours; the organic solvent is dichloromethane, tetrahydrofuran, methanol or ethanol; the base is triethylamine, N, N-diisopropylethylamine, DMAP or DBU.
3. The method according to claim 1, wherein in the step (2), the organic solvent is toluene, tetrahydrofuran, chloroform or DMF; the alkali is sodium hydrogen, potassium tert-butoxide, sodium bistrimethylsilyl amide or lithium diisopropylamide; the molar mass ratio of the compound II to the quaternary phosphonium salt to the base is 1: 1-5: 1-5; the reaction temperature is 0-80 ℃; the reaction time is 0.5-8 hours.
4. The preparation method according to claim 1, wherein in the step (3), the solvent is water, tetrahydrofuran, dichloromethane or chloroform, and the oxidant is osmium tetroxide, potassium permanganate, hydrogen peroxide or tert-butyl peroxide.
5. The method according to claim 1, wherein in step (3), the molar mass ratio of the compound III to the oxidizing agent is 1: 0.5-3, the solvent amount is 5-30 times of the volume of the solid raw material; the reaction time is 4-72 hours; the reaction temperature is 0-80 ℃.
6. The method according to claim 1, wherein in the step (4), the solvent is dichloromethane, chloroform, tetrahydrofuran or trifluoroacetic acid; the molar mass ratio of the compound IV to the reducing agent is 1: 2-15 deg.C, 15-80 deg.C, and reaction time 3-48 hr.
7. The method according to claim 1, wherein in the step (5), the organic solvent is ethyl acetate, methanol, diethyl ether or dioxane; the acid is hydrochloric acid, ethyl acetate hydrogen chloride solution, methanol hydrogen chloride solution or ether hydrogen chloride solution.
8. The method according to claim 1, wherein in the step (5), the molar mass ratio of the compound V to the acid is 1: 0.5 to 5; the reaction temperature is 0-50 ℃, and the reaction time is 1-24 hours.
9. The process according to claim 1, wherein the reaction solvent in the step (6) is toluene, tetrahydrofuran, methanol or ethanol; the catalyst is platinum dioxide, palladium hydroxide, palladium chloride or palladium carbon; the reducing agent is iron powder, ammonium formate, zinc powder, hydrazine hydrate or hydrogen.
10. The preparation method according to claim 1, wherein in the step (6), the molar mass ratio of the compound VI to the catalyst to the reducing agent is 1: 0.05-0.5: 3-8; the reaction temperature is 20-100 ℃; the reaction time is 2-20 hours.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002045703A2 (en) * 2000-12-04 2002-06-13 Novartis Ag Mixtures or organic compounds for the treatmentof airway diseases
CN1774423A (en) * 2003-04-02 2006-05-17 诺瓦提斯公司 A process for the preparation of 5-(haloacetyl)-8-(substituted oxy)-(1h)-quinolin-2-ones
WO2013132514A2 (en) * 2012-03-09 2013-09-12 Rao Davuluri Ramamohan A novel process for the preparation of (r)-5-[2-[(5, 6-diethyl-2, 3-dihydro-1h-inden-2-yl) amino]-1-hydroxyethyl]-8-hydroxy quinolin-2(1h)-one
CN107735390A (en) * 2015-01-20 2018-02-23 欧伦股份公司 The preparation method of indane amine derivative and new synthetic intermediate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002045703A2 (en) * 2000-12-04 2002-06-13 Novartis Ag Mixtures or organic compounds for the treatmentof airway diseases
CN1774423A (en) * 2003-04-02 2006-05-17 诺瓦提斯公司 A process for the preparation of 5-(haloacetyl)-8-(substituted oxy)-(1h)-quinolin-2-ones
WO2013132514A2 (en) * 2012-03-09 2013-09-12 Rao Davuluri Ramamohan A novel process for the preparation of (r)-5-[2-[(5, 6-diethyl-2, 3-dihydro-1h-inden-2-yl) amino]-1-hydroxyethyl]-8-hydroxy quinolin-2(1h)-one
CN107735390A (en) * 2015-01-20 2018-02-23 欧伦股份公司 The preparation method of indane amine derivative and new synthetic intermediate

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