WO2014008640A1 - Indacaterol intermediate and method for synthesizing indacaterol - Google Patents

Description

 Synthesis method of indaprol intermediate and indacaterol

 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.

 Background technique

 The chemical name of 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.

 In the prior art, the synthesis of indacaterol, such as W02004/76422, W02005/123684, US687872U US2011/118469, etc., is reported as a compound 5-(2/$ -2-epoxyethenyl-8-benzyl) Oxidation of oxy-2(1^)-quinolinone with 5,6-diethyl-2,3-dihydro-I 茚-2-amine. The reaction formula is as follows -

By-products are inevitably produced in the synthesis of the above intermediates, including: isomer by-products (formula a), by-products of molecular guanamine and two molecules of epoxy condensation (formula b), and two by-products Accounting for 8% and 12%, the structure is as follows:

 a ( 8%) b ( 12%)

 Therefore, 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.

 Summary of the invention

 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.

 In order to solve the above technical problems, the intermediate of the synthetic indacaterol of the present invention has the structural formula shown in Formula IV:

 IV

 Wherein 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.

 In order to solve the above technical problems, the method for synthesizing the indacaterol intermediate of the present invention comprises the following steps:

2) 式 II化合物与式 III化合物 （制备方法见 W02008/104781 )进行耦合反应得到式 IV化合 物；

1) reacting a compound of formula I (for preparation, see Journal of Medicinal Chemistry; vol. 53; nb. 9; (2010); 3675-3684 and U.S. Patent 6,687,721) with benzaldehyde to give a compound of formula II;

2) a compound of the formula II is reacted with a compound of the formula III (for preparation, see WO2008/104781) to give a compound of the formula IV;

 II ΙΠ IV

 In the above step 1), the solvent is selected from an alcohol solvent of Cl~4 (for example, methanol, ethanol) or an ether or a cyclic ether solvent.

(eg tetrahydrofuran). The reaction temperature is _25°. ~80°〇. 0 重量。 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 .}

(Sodium borohydride), NaBH ₃ CN (sodium cyanoborohydride) or NaBH (0Ac) ₃ (triacetoxy sodium boron hydride), 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.

In the above step 2), 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. In order to enhance the reaction effect, 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.

 In order to solve the above technical problem, the indacaterol synthesis method of the present invention comprises the following steps:

 1) Reduction of the compound of formula IV to give a chiral compound of formula V:

2) Debenzylation of a compound of formula V to give indacaterol of formula VI:

 V VI

In the above step 1), 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垸 dimethyl sulfide complex) or (-) - diisopinyl chloroboron; the catalyst can be (R) _2-methyl-CBS-oxazolboron or (l/ζ 25) - ( +) - cis-1-amino-2-nonanol; reaction temperature is _10 ° 〇 10 ° 〇. Among them, 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 重量。 0. 8〜2. 0当量。 The amount of the compound is 0. 8~2. 0 equivalent.

 In the above step 2), it is preferred to use hydrogen debenzylation, and 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. Among them, 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 following intermediates (X and XI) exist in the reaction:

 X XI

上述反应中， 式 VI化合物与马来酸反应的物质的量比为 1： 1 ; 溶剂可以选自 C1〜C6的 醇， 例如乙腈、 异丙醇、 甲醇、 二氯甲垸、 乙醇、 四氢呋喃或它们的混合溶剂， 优选乙醇； 反应温度为 0〜80°C。 The prepared indacaterol can be further reacted with maleic acid to obtain an indazidine salt represented by the formula νπ by recrystallization:

In the above reaction, 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. In order to solve the above technical problem, the method for synthesizing the racemic indacaterol of the present invention comprises the following steps:

 1) Reduction of the compound of formula IV to give a ring racemic compound:

2) Decyclase of the ring racemic compound to give a racemic formula of IX:

 Ring IX

In the above step 1), 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.

本发明以式 IV化合物为中间体合成茚达特罗及其马来酸盐， 开辟了茚达特罗的合成新路 线， 其合成方法不仅操作简单、 成本低、 适合产业化， 而且可以避免目前已知的用环氧和伯 胺反应的方法在合成茚达特罗过程中所产生的各种副产物。 In the step 2), 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) (Π 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.

 detailed description

 The invention is further illustrated by the following examples. It is to be understood that the following examples are intended to illustrate the invention and not to limit the invention.

 Example 1

 1. Synthesis of N-benzyl-5,6-diethyl-2,3-dihydro-1H-indole-2-amine (compound of formula II)

 00克苯苯。 4. 00g 5,6-diethyl-2,3-dihydro-1H-indol-2-amine (compound of formula I), 60. 00ml of methanol and 4. 50g of benzene Formaldehyde, the oil bath was heated to 65 ° C for 4 hours. Then slowly cool down to _25 ° C, add 4. 80 g of sodium borohydride in portions, keep the internal temperature less than 25 ° C, add, slowly warm to room temperature, and react overnight. The methanol was removed by steaming, and 50. 00 ml of water was added dropwise to the residue. Then, 50. 00 ml of ethyl acetate was added and the aqueous phase was back-extracted three times with 20.00 ml of ethyl acetate. Dry over anhydrous sodium sulfate, filter, concentrate and remove most of solvent. To the obtained solid-liquid mixture, 50 ml of HCl/MeOH (wt=32%) was slowly added dropwise, and the mixture was stirred for 1 hour and then filtered to give a white solid (yield: 7.83 g, yield 78.3%, purity 97%) ).

_3⁄4 NMR (400MHz, CD ₃ 0D): δ 7. 61-7· 45 (m, 5H), 7. 10 (s, 2H), 4. 31 (s, 2H), 4. 17-4· 07 ( m, 1H), 3. 42 (dd, 2H, =16, J ₂ =8Hz), 3. 14 (dd, 2H, =16, J ₂ =8Hz), 2. 67 (q, 4H, J =8Hz ), 1. 21 (t, 6H, J=8Hz).

 2. 5-{2-[(N-Benzyl-5,6-diethyl-2,3-dihydro-1H_indan-2-yl)amino]-acetyl}-8-benzyloxy Synthesis of _1H_quinolin-2-one (compound of formula IV)

Add 8-benzyloxy-5-bromoacetyl-1H-quinolin-2-one to the reaction flask at -25 ° C (dry ice-ethanol bath) </ RTI> 00g, N-benzyl-5,6-diethyl-2,3-dihydro-1H-indol-2-amine (compound of formula II) 2·10g, triethylamine 0. 85g, Potassium iodide 0. 16g, acetone 150. 00ml, reflux reaction for 24 hours. The solution was slowly cooled to room temperature, filtered, and the filter cake was washed twice with 2,500 ml of acetone. The solvent was evaporated to remove the solvent, and 100. 00 ml (0. 50 N) of aqueous HCl solution was added dropwise to 250 ml of dichloromethane. The liquid phase was separated and the aqueous phase was stripped with methylene chloride. The organic phase is combined, washed with a saturated aqueous solution of 100. 00 ml, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness to give a yellow powdery solid product 13.10 g (yield 81%). ; mass spectrum [ESI] M+l=571.

 3⁄4 NMR (400MHz, DMS0): δ 10. 53 (s, 1Η), 7. 85 (d, 1H, J=8Hz), 7. 56 (d, 2H, J=8Hz), 7. 37 (t, 2H , J=8Hz), 7. 30 (t, 1H, J=8Hz), 7. 26-7· 16 (m, 5H), 7. 13 (d, 1H, J=8Hz), 7. 03 (d , 1H, J=8Hz), 6. 93 (s, 1H), 6. 87 (s, 1H) , 6. 37 (d, 1H, J=12 Hz), 5. 28 (s, 2H), 3 · 80—3· 51 (m, 5H), 2. 95-2. 80 (m, 4H), 2. 65-2· 49 (m, 4H), 1. 14-1· 07 (m, 6H) .

 3. 5- { (lR) -2- [(N-benzyl-5,6-diethyl-2,3-dihydro-1H_indan-2-yl)ammonia]-1-hydroxyethyl } Synthesis of -8-benzyloxy-1H-quinolin-2-one (compound of formula V)

To the reaction flask was added 0.15 g (wt = 33.3%) of a toluene solution of (R)-Me-CBS and 5. OOml of THF, and 2.00 ml of BH ₃ 'THF was added dropwise with stirring. Then, the ice salt bath was cooled to _10 ° C, and 10.00 g of 5- {2- [ ( N-benzyl-5, 6-diethyl-2,3-dihydro-111-indane-2-) was added dropwise. 10. OOmlTHF of amino)-acetyl}-8-benzyloxy-111-quinolin-2-one (formula of formula 1)

(tetrahydrofuran) solution. After the addition is completed in about 1 hour, the mixture is slowly warmed to room temperature, reacted for 24 hours, and lowered to 0 ° C. A 2% aqueous solution of HCl was added dropwise to quench the reaction, which was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was spin-dried to give a yellow powdery solid product 5.10 g (yield: 51%).

3⁄4 NMR (400MHz, CDC1 ₃ ): δ 9. 12 (s, 1H), 7. 49 (d, 1H, J=8Hz), 7. 32 (s, 10H), 7. 12 (d, 1H, J= 8Hz), 7. 03 (s, 1H), 7. 01 (s, 1H), 6. 95 (d, 1H, J=8Hz), 6. 48 (d, 1H, J=8 Hz), 5. 14 (s, 2H), 4. 80 (br, 1H), 4. 02—3. 65 (m, 4H), 3. 20—2. 87 (m, 4H), 2. 81—2. 70 ( m, 2H), 2. 59 (q, 4H, J=4Hz), 2. 19 (t, 6H, J=4Hz).

 4. 5- { (lR) -2- [(5, 6-Diethyl-2,3-dihydro-1H_indan-2-yl)ammonia]-1-hydroxyethyl}-8-hydroxyl Synthesis of _1H_quinolin-2-one (compound of formula VI)

250ml three-neck bottle assembly tee, respectively connected to argon or hydrogen balloon, thermometer (temperature range 0~100 °C), tumbling Plug. Firstly replaced with argon three times, then replaced with hydrogen three times, adding acetic acid 100.00ml 5-{(lR)-2_[(N-benzyl-5 6-diethyl-2 3-dihydro-1H-茚Full-2-yl)amino]-1-hydroxyethyl}-8-benzyloxy-1H-quinolin-2-one (compound of formula V) lO.OOg (17.50 1 10%Pd/C 5.00g (aqueous The ratio is 50%), hydrogenation at 40 ° C (hydrogen pressure 20 atm.) 10-24 hours, TLC (thin layer chromatography) is monitored until the reaction is completed. Palladium on carbon is removed by filtration, and acetic acid is removed by rotary evaporation to obtain indacaterol ( Compound of formula VI).

 3⁄4 NMR (400MHz, DMS0) δ 1.10(t, 6H J=7.5Hz) 2.51 (q, 4H J = 7· 5 Hz) 2.53—2.62 (m 2H) 2.68-2.76 (m 2H) 2.90-3.03 (m 2H) 3.48-3.55 (m 1H) 4.97-5.04 (m 1H), 6.49 (d 1H J=ll.0Hz) , 6.90 (d 1H J=9.1Hz) 6.91 (s 2H) 7.07 (d, 1H J= 9.1 Hz) 8.17 (d 1H J=ll.0Hz) Example 2

 1. Synthesis of N-benzyl-5 6-diethyl -2 3-dihydro -1H-indole-2-amine (compound of formula II)

6.00 g of 5 6-diethyl-2 3-dihydro-1H-indole-2-amine (compound of formula I) was added to the reaction flask at -25 ° C (cooled with dry ice-acetone bath) under nitrogen. 60.00 ml of ethanol and 2.00 g of benzaldehyde, 1.00 g of NaBH ₃ CN, and the oil bath was heated to 80 ° C for 4 hours. Steaming, removing most of the ethanol, adding 50.00 ml of water to the residue, and then adding 50.00 ml of ethyl acetate, the aqueous phase was back-extracted 3 times with 20.00 ml of ethyl acetate, and the organic phase was combined with anhydrous sulfuric acid. The sodium is dried, filtered and concentrated to remove most of the solvent. To the obtained solid-liquid mixture, 50.001111 of 11 (1/3⁄46011 (wt=32%) was slowly added dropwise, and the mixture was stirred for 1 hour and then filtered to give a white solid (dry weight: 5.50 g, yield: 91%, purity: 99%) .

_3⁄4 NMR (400MHz, CD ₃ 0D) δ 7.61-7· 45 (m 5H) 7.10 (s 2H) 4.31 (s 2H) 4.17-4· 07 (m 1H), 3.42 (dd 2H, =16 J ₂ =8Hz ) 3.14 (dd 2H, =16 J ₂ =8Hz) 2.67 (q 4H J =8Hz) 1.21 (t 6H J=8Hz)

 2. 5- {2-[(N-Benzyl-5 6-diethyl-2 3-dihydro-1H_indan-2-yl)amino]-acetyl}-8-benzyloxy_1H_ Synthesis of quinolin-2-one (compound of formula IV)

To the reaction flask was added 8-benzyloxy-5-bromoacetyl-1H-quinolin-2-one (compound of formula III) at -25 ° C (dry ice-ethanol bath) 10.00 g N-benzyl-5 6 -diethyl-2 3-dihydro-1H-indol-2-amine (compound of formula II) 2.10g N3⁄4C0 ₃ L 60g Potassium iodide 0.16 g, acetonitrile 150.00 ml, and reacted at 80 ° C for 24 hours. The mixture was slowly cooled to room temperature, filtered, and the filter cake was washed twice with 25.00 ml of acetone, and the filtrate was evaporated to remove solvent. To the obtained viscous material, 100.00 ml (0.50 N) of an aqueous HCl solution was added dropwise, and 250.00 ml of dichloromethane was separated, and the aqueous phase was back-extracted with dichloromethane, and the organic phase was combined and washed once with 100.00 ml of saturated brine. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness.

 3⁄4 NMR (400MHz, DMS0): δ 10.53 (s, 1H), 7.85 (d, 1H, J=8Hz), 7.56 (d, 2H, J=8Hz), 7.37 (t, 2H, J=8Hz), 7.30 ( t, 1H, J=8Hz), 7.26-7· 16 (m, 5H), 7.13 (d, 1H, J=8Hz), 7.03 (d, 1H, J=8Hz), 6.93 (s, 1H), 6.87 (s, 1H), 6.37 (d, 1H, J=12 Hz), 5.28 (s, 2H), 3· 80—3· 51 (m, 5H), 2.95-2.80 (m, 4H), 2.65-2 · 49 (m, 4H), 1.14-1· 07 (m, 6H).

 3. 5-{(lR)-2-[(N-Benzyl-5,6-diethyl-2,3-dihydro_1H_indan-2-yl)ammonia]-1-hydroxyethyl } Synthesis of -8-benzyloxy-1H-quinolin-2-one (compound of formula V)

0.26 _δ (1/ζ 25)-(+)-cis-1-amino-2-nonanol and 5. OO ml of THF were added to the reaction flask, and 2.00 ml of BH ₃ 'THF was added dropwise with stirring. Then the ice salt bath was cooled to _5 ° C, and 10.00 g of 5-{2-[(N-benzyl-5,6-diethyl-2,3-dihydro-1H-indan-2-yl) was added dropwise. Ammonia]-acetyl}-8-benzyloxy-1H-quinolin-2-one (compound of formula IV) in a solution of 10. OOml of THF, added over 1 hour, slowly warmed to room temperature, reacted for 24 hours, reduced to At 0 ° C, a 2% aqueous solution of HCl was added dropwise to carry out a quenching reaction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness.

3⁄4 NMR (400MHz, CDC1 ₃ ): δ 9.12(s, 1H), 7.49 (d, 1H, J=8Hz), 7.32 (s, 10H), 7.12 (d, 1H, J=8Hz), 7.03 (s, 1H) ), 7.01 (s, 1H), 6.95 (d, 1H, J=8Hz), 6.48(d, 1H, J=8 Hz), 5.14 (s, 2H), 4.80 (br, 1H), 4.02—3.65 ( m, 4H), 3.20—2.87 (m, 4H), 2.81—2.70 (m, 2H), 2.59 (q, 4H, J=4Hz), 2.19(t, 6H, J=4Hz).

 4. 5-{(lR)-2-[(5,6-Diethyl-2,3-dihydro_1H_indan-2-yl)ammonia]-1-hydroxyethyl}-8-hydroxyl Synthesis of _1H_quinolin-2-one (compound of formula VI)

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. First, replace it with argon three times, then replace it with hydrogen three times, add 100.00ml of ethanol, 5-{(lR)-2_[(N-benzyl-5, 6-Diethyl-2,3-dihydro-1H-indan-2-yl)amino]-1-hydroxyethyl}-8-benzyloxy-1H-quinolin-2-one (compound of formula V) lO. OOg ( 17. 50 excitation 1 ), 20% Pd (OH) ₂ /C 2· 00g, hydrogenation at 65 ° C (hydrogen pressure 5 atm.) 10-24 hours, TLC monitoring until the reaction is completed. The palladium hydroxide charcoal was removed by filtration, and ethanol was removed by rotary evaporation to obtain indaprol (the compound of the formula VI).

 3⁄4 NMR (400 MHz, DMS0): δ 1. 10 (t, 6H, J=7. 5Hz), 2. 51 (q, 4H, J = 7· 5 Hz), 2. 53-2. 62 (m, 2H) , 2. 68-2. 76 (m, 2H) , 2. 90-3. 03 (m, 2H) , 3. 48-3. 55 (m, 1H) , 4. 97-5. 04 ( m, 1H), 6. 49 (d, 1H, J=l l. 0Hz) , 6. 90 (d, 1H, J=9. 1Hz) , 6. 91 (s, 2H) , 7. 07 (d , 1H, J= 9. 1 Hz) , 8. 17 (d, 1H, J=l l. 0Hz). Example 3

 1. Synthesis of N-benzyl-5,6-diethyl-2,3-dihydro-1H-indole-2-amine (compound of formula II)

Under a nitrogen atmosphere, -25 ° C (cooled with a dry ice-acetone bath) was added to the reaction flask to 6. 00 g of 5,6-diethyl-2,3-dihydro-1H-indole-2-amine (Form I Compound), 60·OOmlTHF and 6.70 g benzaldehyde, 34·00 g NaBH (0Ac) ₃ , the oil bath was heated to 80 ° C for 4 hours. The THF was removed by steaming, and 50. 00 ml of water was added dropwise to the residue, followed by the addition of 50.0 ml of ethyl acetate. The aqueous phase was back-extracted 3 times with 00 ml of ethyl acetate, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to remove most solvent. /3⁄46011 (wt=32%), after completion, the mixture was stirred for 1 hour and filtered to give a white solid (dry weight 5.50 g, yield 91%, purity 99%).

_3⁄4 NMR (400MHz, CD ₃ 0D) : δ 7. 61-7· 45 (m, 5H) , 7. 10 (s, 2H) , 4. 31 (s, 2H) , 4. 17-4· 07 ( m, 1H), 3. 42 (dd, 2H, =16, J ₂ =8Hz) , 3. 14 (dd, 2H, =16 , J ₂ =8Hz) , 2. 67 (q, 4H, J =8Hz ), 1. 21 (t, 6H, J=8Hz).

 2. 5-{2-[(N-Benzyl-5,6-diethyl-2,3-dihydro-1H_indan-2-yl)amino]-acetyl}-8-benzyloxy Synthesis of _1H_quinolin-2-one (compound of formula IV)

To the reaction flask was added 8-benzyloxy-5-bromoacetyl-1H-quinolin-2-one (compound of formula III) 10. 00 g, N-benzyl-5,6-diethyl-2,3 Dihydro-1H-indol-2-amine (Compound of formula II) 2. 10 g, diisopropylethylamine 0. 60 g, potassium iodide 0.16 g, acetonitrile 150. 00 ml, reacted at 80 ° C for 24 hours. The mixture was slowly cooled to room temperature, filtered, and the filter cake was washed twice with 2,500 ml of acetone. The solvent was evaporated to remove the solvent, and 100. 00 ml (0.5 N) of HCl aqueous solution was added dropwise, 250. 00 ml of dichloromethane was separated, and the aqueous phase was dichloromethane, and the organic phase was combined. The granules were washed once with a saturated aqueous solution of sodium chloride (100 ml) (yield 70%).

 3⁄4 NMR (400MHz, DMS0) : δ 10. 53 (s, 1H) , 7. 85 (d, 1H, J=8Hz) , 7. 56 (d, 2H, J=8Hz) , 7. 37 (t, 2H , J=8Hz), 7. 30 (t, 1H, J=8Hz), 7. 26-7· 16 (m, 5H), 7. 13 (d, 1H, J=8Hz) , 7. 03 (d , 1H, J=8Hz), 6. 93 (s, 1H) , 6. 87 (s, 1H) , 6. 37 (d, 1H, J=12 Hz) , 5. 28 (s, 2H) , 3 · 80—3· 51 (m, 5H) , 2. 95-2. 80 (m, 4H) , 2. 65-2· 49 (m, 4H) , 1. 14-1· 07 (m, 6H) .

 3. 5- { (lR) -2- [(N-benzyl-5,6-diethyl-2,3-dihydro-1H_indan-2-yl)ammonia]-1-hydroxyethyl } Synthesis of -8-benzyloxy-1H-quinolin-2-one (compound of formula V)

To the reaction flask was added 9.30 g of (-)-diisopinyl chloroboron (60% wt% in CH ₂ C1 ₂ ) and 5. OO ml of THF, and then the ice salt bath was cooled to 10 ° C, and dropped dropwise. OOg 5- {2-[(N-benzyl-5,6-diethyl-2,3-dihydro-1H-indan-2-yl)amino]-acetyl}-8-benzyloxy- 1 OO ml THF solution of 1H-quinolin-2-one (compound of formula IV). After about 1 hour of addition, slowly rise to room temperature, react for 24 hours, drop to 0 ° C, and add concentrated aqueous ammonia to quench the reaction. The product was extracted with chloroformic acid, and the organic phase was dried over anhydrous sodium sulfate.

3⁄4 NMR (400MHz, CDC1 ₃ ) : δ 9. 12 (s, 1H) , 7. 49 (d, 1H, J=8Hz) , 7. 32 (s, 10H) , 7. 12 (d, 1H, J= 8Hz), 7. 03 (s, 1H), 7. 01 (s, 1H), 6. 95 (d, 1H, J=8Hz), 6. 48 (d, 1H, J=8 Hz), 5. 14 (s, 2H) , 4. 80 (br, 1H) , 4. 02—3. 65 (m, 4H) , 3. 20—2. 87 (m, 4H) , 2. 81—2. 70 ( m, 2H) , 2. 59 (q, 4H, J=4Hz), 2. 19 (t, 6H, J=4Hz).

 4. 5- { (lR) -2- [(5, 6-Diethyl-2,3-dihydro-1H_indan-2-yl)ammonia]-1-hydroxyethyl}-8-hydroxyl Synthesis of _1H_quinolin-2-one (compound of formula VI)

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. 00ml, 5- { (lR) -2_ [(N-benzyl-5,6-diethyl-2,3-dihydro-1H-indan-2-yl)ammonia]-1- Hydroxyethyl} -8-benzyloxy-1H-quinolin-2-one (compound of formula V) 10. 00g ( 17.5 excitation 1 ), 10% Pd/C 8. 00g, hydrogenated at 25 ° C ( Hydrogen pressure 1 atm.) 10-24 hours, TLC supervision It is measured until the reaction is completed. The palladium on carbon was removed by filtration, and ethanol was removed by rotary evaporation to obtain indaprol (the compound of the formula VI).

 3⁄4 NMR (400 MHz, DMS0): δ 1. 10 (t, 6H, J=7. 5Hz), 2. 51 (q, 4H, J = 7· 5 Hz), 2. 53-2. 62 (m, 2H), 2. 68-2. 76 (m, 2H), 2. 90-3. 03 (m, 2H), 3. 48-3. 55 (m, 1H), 4. 97-5. 04 ( m, 1H), 6. 49 (d, 1H, J=l l. 0Hz) , 6. 90 (d, 1H, J=9. 1Hz), 6. 91 (s, 2H), 7. 07 (d , 1H, J= 9. 1 Hz), 8. 17 (d, 1H, J=l l. 0Hz). Example 4: 5-{(lR)-2-[(5,6-Diethyl-2,3-dihydro_1H_indan-2-yl)ammonia]-1-hydroxyethyl}-8 Synthesis of -hydroxy-1H-quinolin-2-one maleate (formula VE compound)

 950 mL (4. 20M), heat preservation. Add 50. 00 mL of ethanol to the residue obtained in Example 1, 2 or 3 (200 lb. After 10 minutes, a white solid precipitated spontaneously. Stir at room temperature for 24 hours. Filtered to a white solid. The ethanol was repeatedly crystallized to give 7.40 g of yttrium sulphate (formula VE compound, yield 83%, HPLC purity: 99.9%).

 3⁄4 NMR (400 MHz, DMS0): δ 10. 51 ( s, 1H), 10. 45 (br, 1H), 8. 93 (br, 2H), 8. 15 (d, 1H, J = 8 Hz), 7. 18 (d, 1H, J=8Hz), 7. 03 ( s, 2H), 6. 99 (d, 1H, J=8Hz), 6. 61 (d, 1H, J=8Hz), 6. 19 ( s, 1H), 6. 02 ( s, 2H), 5. 32 (d, 1H, J=12Hz), 4. 07 (t, 1H, J = 8 Hz), 3. 29-3. 14 (m, 3H), 3. 13-2. 98 (m, 3H), 2. 57 (q, 4H, J=8Hz), 2. 50 ( s, 1H), 1. 13 (t, 6H, J =8 Hz) Example 5: 5-{2-[(N-benzyl-5,6-diethyl-2,3-dihydro-1H-indan-2-yl)ammonia]-1-hydroxyethyl Synthesis of -8-benzyloxy-1H-quinolin-2-one (cyclic compound)

Add 5-{2-[(N-benzyl-5,6-diethyl-2,3-dihydro-1H-indan-2-yl)amino]-acetyl} _8_ benzyloxy to the reaction flask Base-1H-quinolin-2-one (compound of formula IV) 10. OOg, methanol 50. 00ml, stirred and cooled to 0 ° C, added 2. 00 g of sodium borohydride in portions, and then slowly warmed to room temperature for 24 hours. 00克(Yield 60%) A mixture of methyl tert-butyl ether and methanol (MTBE: Me0H = 6:1) was added dropwise. ). Example 6: 5-{2-[(5 6-Diethyl-2 3-dihydro-1H-indan-2-yl)amino]-1-hydroxyethyl}-8-hydroxy-1H-quino Synthesis of oxa-2-one (compound of formula IX)

 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. Firstly replaced with argon three times, then replaced with hydrogen three times, adding 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.) at 40 ° C for 10-24 hours, TLC was monitored until completion of the reaction. Palladium on carbon was removed by filtration, and acetic acid was removed by rotary evaporation to obtain racemic indazol (compound of formula IX). : 5-{(lR)-2-[(5 6-Diethyl-2 3-dihydro-1H-indan-2-yl)amino]-1-hydroxyethyl}-8-benzyloxy- Synthesis of 1H-quinolin-2-one (compound of formula X II)

 Reference is made to the method disclosed in International Patent No. WO2004/76422. 100ml three-neck bottle assembly thermometer (temperature range 0 200 °C), reflux condenser (three-way condensate tube, argon balloon), tumbling plug. Replace with argon three times. Add compound 5-(2R)-2-epoxyacetyl-8-benzyloxy-2(1H)-quinolinone (Formula III) 15.0 g (51.14 mmol), compound 5 6-diethyl-2 3-Dihydro-1H-indol-2-amine (Formula I) 12.6 (66.48 mmol), diethylene glycol dimethyl ether 50 ml, argon-protected oil bath heated to 108 ° C to 114 ° C, reaction 18 to After 24 hours, TLC was monitored until the reaction was complete. Byproducts & and 13 were produced by HPLC monitoring. 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%).

Claims

 Claims An intermediate for synthesizing indacaterol, characterized in that the structural formula is as shown in formula IV,

 IV  2. The method for synthesizing an intermediate according to claim 1, comprising the steps of: 1) reacting a compound of formula I with benzaldehyde to give a compound of formula II;

 II 2) The compound of formula II is coupled with a compound of formula III to give formula IV

 II ΙΠ IV  The method according to claim 2, wherein, in the step 1), the solvent is a C1 to C4 alcohol, an ether or a cyclic ether; the reaction temperature is _25 to 80; and the amount of the benzaldehyde is the amount of the compound of the formula I. 0.6 to 2.0 equivalents.  The method according to claim 2 or 3, wherein, in step 1), a reducing agent is added during the reaction, and the reducing agent is sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The dosage is 0.5~5 of the amount of the compound of formula I The method according to claim 2, wherein the reaction medium is acetonitrile, C3~C6 ketone or C2~C8 ether; the reaction temperature is _25 〜80, the compound of formula II and formula III The molar ratio of the compound is from 1:0.7 to 1:1.3. The method according to claim 2 or 5, characterized in that step 2), the reaction was added a base, the base used is K ₂ C0 _3, N¾C0 _3, triethylamine or diisopropylethylamine, an amount It is 0.6 to 2.0 equivalents of the compound of the formula II. 7. A method of synthesizing indacaterol using the intermediate of claim 1 comprising the steps of: 1) reducing a compound of formula IV to provide a chiral compound of formula V;

2) The compound of formula V is debenzylated to give the formula VI茚达特罗.

The method according to claim 7, wherein the reaction medium is methyl t-butyl ether or tetrahydrofuran; and the reducing agent is BH ₃ *THF, BH ₃ *Me ₂ S or (-) - Diisoxanyl chloroboron; the catalyst is (R) _2_methyl-CBS-oxazolboron or (l ζ 25) - (+)-cis-1-amino-2-nonanol; reaction temperature It is -10 ° C ~ 10 ° C. 9. The method according to claim 8, wherein the amount of BH ₃ * THF, BH ₃ · Me ₂ S in the compound of formula IV is used in an amount of 0. 0 3~3 equivalents; The (-) The amount of the compound of the formula IV is 0. 8~ 2. 0 equivalent; the amount of the (R) -2-methyl-CBS-oxazolboron is the amount of the compound of the formula IV. 0. 1~1 equivalent.  10. The method according to claim 7, wherein the reaction medium is one of ethyl acetate, acetic acid, water, C1 to C4 alcohol, tetrahydrofuran, dichloromethane, or a mixture thereof. Solvent; The catalyst is a palladium catalyst; the hydrogen source is hydrogen, formic acid, ammonium formate or a mixed hydrogen source; and the reaction temperature is 25 ° C to 65 ° C.  The method according to claim 10, wherein in step 2), the palladium catalyst is 10% wet-based Pd/C, and the amount is 10% to 80% by weight of the compound of formula V; For l~20atm. 12. The method according to claim 7, wherein in the reaction of step 2), the following intermediates of formula X and formula XI are present: 2) The cyclomic compound is debenzylated to give the racemic indacaterol of formula IX.

 Ring IX The method according to claim 13, wherein the reaction medium is methyl t-butyl ether or tetrahydrofuran; and the reducing agent is BH ₃ * THF, BH ₃ * Me ₂ S ₃ or NaBH ₄ . The amount of the compound of the formula IV is 0.8 to 6. 0 equivalent; and the reaction temperature is 25 ° C to 80 ° C.  The method according to claim 7, wherein the reaction medium is one of ethyl acetate, acetic acid, water, Cl~4 alcohol, tetrahydrofuran, dichloromethane or a mixture thereof. Solvent; The catalyst is a palladium catalyst; the hydrogen source is hydrogen, formic acid, ammonium formate or a mixed hydrogen source; and the reaction temperature is 25 ° C to 65 ° C.  The method according to claim 15, wherein in step 2), the palladium catalyst is 10% wet-based Pd/C, and the amount is 10% to 80% w/w of the amount of the cyclic compound; The pressure of hydrogen is l~20atm. 17. The method according to claim 13, wherein in the reaction of step 2), the following formula and formula are present

 " y t nix OOS8.0/ZlOlN3/X3d 0f9800/ 0Z O