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
  • C07D215/24—Oxygen atoms attached in position 8
  • C07D215/26—Alcohols; Ethers thereof

Definitions

• the present invention relates to the field of pharmaceutical synthesis, and in particular to an intermediate of indacaterol, a preparation method of the intermediate, and a method for synthesizing indacaterol using the intermediate.
• Indacaterol Maleate is: 5_ ⁇ (1R) _2_ [(5, 6_Diethyl-2, 3-dihydro-1H-indan-2-yl)Ammonia] 1-hydroxyethyl ⁇ -8-hydroxy-1H-quinolin-2-one maleate, the structural formula is as follows:
• Indacaterol maleate is a novel ultra long-acting beta 2 receptor agonist developed by Novartis AG. It was approved by the US FDA on July 1, 2011 and is marketed under the trade name Ar Ca pta.
• the finished drug is an inhaled hard capsule for the treatment of patients with chronic bronchial obstruction (C0PD) airflow obstruction, including chronic bronchitis or emphysema, but not for the treatment of acute exacerbation of chronic bronchial obstruction and asthma.
• C0PD chronic bronchial obstruction
• the prepared preparation method has many types of impurities, and the impurity content is large, which increases the difficulty of separation and purification of the product, the product yield is low, the production cost is high, and the sales price of the preparation product is pushed up from the cost level. Adding an economic burden to patients.
• One of the technical problems to be solved by the present invention is to provide an intermediate for synthesizing indacaterol, and synthesizing indacaterol with the intermediate can reduce by-products of the synthesis reaction.
• the intermediate of the synthetic indacaterol of the present invention has the structural formula shown in Formula IV:
• Bn (benzyl) is an amine protecting group.
• the second technical problem to be solved by the present invention is to provide a synthesis method of the above indacaterol intermediate.
• the method for synthesizing the indacaterol intermediate of the present invention comprises the following steps:
• the solvent is selected from an alcohol solvent of Cl ⁇ 4 (for example, methanol, ethanol) or an ether or a cyclic ether solvent.
• the reaction temperature is _25°. ⁇ 80° ⁇ . 0 ⁇
• the amount of the compound is 0. 6 ⁇ 2. 0 eq.
• the reducing agent may be used in the reaction, and the reducing agent may be selected from those capable of reducing the imine to an amine, such as NaBH 4 .
• an amount of reducing agent is preferably used in an amount of a compound of formula I 0.5 5 ⁇ 5 0 Equivalent; In some embodiments, this step of the reaction can also be reduced using catalytic hydrogenation.
• the reaction may be carried out in a medium-free system, and an acetonitrile, a C3-C6 ketone solvent (e.g., acetone) or a C2 to C8 ether solvent (e.g., tetrahydrofuran) may be selected as the reaction medium.
• the reaction temperature is _25 ° C to 80 ° C.
• the molar ratio of the compound of the formula II to the compound of the formula III is preferably 1: 0. 7 ⁇ 1: 1. 3.
• a base may be added, and the base may be selected from K 2 C0 3 (potassium carbonate), N3 ⁇ 4C0 3 (sodium carbonate), triethylamine or diisopropylethylamine, preferably triethylamine; base and compound of formula III
• the amount of the compound is 0. 6 ⁇ 2. 0 equivalent.
• the third technical problem to be solved by the present invention is to provide a method for synthesizing indacaterol using the above intermediate, which is simple in operation, low in cost, and suitable for industrialization.
• the indacaterol synthesis method of the present invention comprises the following steps:
• the reaction medium is preferably an ether solvent such as methyl tert-butyl ether or tetrahydrofuran;
• the reducing agent may be selected from the group consisting of BH 3 . THF (boron tetrahydrofuran complex), BH 3 . Me 2 S (boron ⁇ dimethyl sulfide complex) or (-) - diisopinyl chloroboron;
• the catalyst can be (R) _2-methyl-CBS-oxazolboron or (l/ ⁇ 25) - ( +) - cis-1-amino-2-nonanol; reaction temperature is _10 ° ⁇ 10 ° ⁇ .
• BH 3 THF in an amount of a compound of formula IV is used in an amount of 0. 0 3 ⁇ 3 equivalents;.
• (R) -2- methyl-oxazole--CBS- embankment amount of boron compound of formula IV is used in an amount of 0. 1 ⁇ 1 ⁇ 0. 8 ⁇ 2. 0 ⁇ The amount of the compound is 0. 8 ⁇ 2. 0 equivalent.
• the reaction medium may be selected from the group consisting of an ester solvent ethyl acetate, acetic acid, water, a C1 to C4 alcohol solvent (for example, methanol, ethanol), and an ether solvent (for example, tetrahydrofuran). , one of dichloromethane or a mixed solvent thereof; the catalyst may be a palladium catalyst; the hydrogen source may be hydrogen, formic acid, ammonium formate, a single hydrogen source or a mixed hydrogen source thereof; the reaction temperature is 25 ° C to 65 ° C.
• Pd/C may be 10% wet-based Pd/C, and the amount thereof is preferably 10% to 80% w/w of the compound of the formula V.
• the hydrogen pressure is preferably from 1 to 20 atm.
• the prepared indacaterol can be further reacted with maleic acid to obtain an indazidine salt represented by the formula ⁇ by recrystallization:
• the ratio of the compound of the formula VI to the maleic acid is 1:1;
• the solvent may be selected from a C1 to C6 alcohol such as acetonitrile, isopropanol, methanol, dichloromethane, ethanol, tetrahydrofuran or A mixed solvent thereof, preferably ethanol;
• the reaction temperature is 0 to 80 °C.
• the fourth technical problem to be solved by the present invention is to provide a method for synthesizing racemic indacaterol using an intermediate of formula IV.
• the method for synthesizing the racemic indacaterol of the present invention comprises the following steps:
• the reaction medium is preferably an ether solvent such as methyl tert-butyl ether or tetrahydrofuran;
• the reducing agent is BH 3 ⁇ THF, BH 3 ⁇ Me 2 S 3 or NaBH 4 , and the reducing agent is used in the formula IV.
• the compound is used in an amount of from 0. 8 to 6. 0 equivalents; and the reaction temperature is from 25 ° C to 80 ° C.
• the reaction medium may be selected from the group consisting of an ester solvent ethyl acetate, acetic acid, water, a C1 to C4 alcohol solvent (for example, methanol, ethanol), an ether solvent (for example, tetrahydrofuran), and dichloromethane. Or a mixed solvent thereof; a palladium catalyst may be used as the catalyst; a hydrogen source, a formic acid, a single hydrogen source of ammonium formate or a mixed hydrogen source thereof may be used as the hydrogen source; and the reaction temperature is 25 ° C to 65 ° C.
• the following intermediates (formula) ( ⁇ and formula XIII) are present in the reaction:
• the invention synthesizes indacaterol and its maleate by using the compound of formula IV as an intermediate, and opens up a new synthetic route of indacaterol.
• the synthesis method is not only simple in operation, low in cost, suitable for industrialization, but also can avoid current Various by-products produced by the reaction of epoxy and primary amines in the synthesis of indacaterol are known.
• the 250ml three-necked bottle is equipped with a three-way, respectively connected to an argon or hydrogen balloon, a thermometer (measuring temperature range of 0 ⁇ 100 °C), and a plug.
• argon three times
• hydrogen three times
• the 250ml three-necked bottle is equipped with a tee, which is connected to an argon or hydrogen balloon, a thermometer (measuring temperature range is 0 ⁇ 100 °C), and a plug. It was replaced with argon three times and then replaced with hydrogen three times.
• Adding ethanol 100.
• 00g 17.5 excitation 1 ), 10% Pd/C 8.
• the 250ml three-necked bottle is equipped with a tee, which is connected to an argon or hydrogen balloon, a thermometer (temperature range 0 100 ° C), and a plug.
• a tee which is connected to an argon or hydrogen balloon
• thermometer temperature range 0 100 ° C
• plug a plug
• acetic acid 100.00ml 5_ ⁇ (2_[( N-benzyl-5 6-diethyl-2 3-dihydro-1H-indan-2- Amino]-1-hydroxyethyl ⁇ -8-benzyloxy-1H-quinolin-2-one (cyclic compound) lO.OOg (17.50 1 10% Pd/C 5.00 g (water content 50%)
• Hydrogenation hydrogen pressure lamt.
• the temperature was lowered to 70 ° C to 80 ° C, 9.36 g (76.71 mmol) of benzoic acid was added, and pale yellow crystals were precipitated in about 10 minutes. The crystals were kept for 3 hours, and more crystals were precipitated.
• the mixture was stirred at room temperature for 10 hours, and cooled to 0 ° in an ice bath. After stirring at C to 5 ° C for 3 hours, suction filtration through a Buchner funnel and elution with 20 ml of ethanol gave a pale yellow powdery solid. Recrystallization from 300 ml of ethanol gave a pale yellow near white solid (weight 6.2 g, yield 20%, high-performance liquid phase content greater than 99%).

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (2)

Applications Claiming Priority (1)

Publications (1)

Family

ID=49915317

Family Applications (1)

Country Status (2)

Cited By (3)

Citations (3)

Family Cites Families (1)

• 2012
  • 2012-07-11 WO PCT/CN2012/078500 patent/WO2014008640A1/fr not_active Ceased
  • 2012-07-11 CN CN201280071638.3A patent/CN104379566B/zh active Active

Patent Citations (3)

Also Published As

Similar Documents

Legal Events