WO2014139485A1

WO2014139485A1 - A method for the preparation of 5-[(r)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]- 8-hydroxy-(1h)-quinolin-2-one (indacaterol)

Info

Publication number: WO2014139485A1
Application number: PCT/CZ2014/000023
Authority: WO
Inventors: Ludek Meca; Pavla VANKOVA
Original assignee: Zentiva, K.S.
Priority date: 2013-03-15
Filing date: 2014-03-03
Publication date: 2014-09-18
Also published as: CZ2013192A3; CZ306252B6

Abstract

The invention relates to a new method of synthesis of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)- 1-hydroxyethyl]-8-hydroxy-(1H)-quinolin-2-one of formula (R)-2, known under the generic name indacaterol, which is used for the treatment of chronic obstructive pulmonary disease (COPD). The method comprises preparation of the racemic intermediate 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-(1H)-quinolin-2-one of formula 1, which is further, in an arbitrary order, chirally resolved and debenzylated, and subsequently indacaterol of formula (R)-2 is isolated.

Description

A method for the preparation of 5-[(R)-2-(5,6-diethyl-Lndan-2-ylamino)-l-hydroxyethyl]- 8-hydroxy-(lH)-quinoIin-2-one (indacaterol)

Technical Field

The invention relates to a new method for the synthesis of 5-[(i?)-2-(5,6-diethyl-indan-2- ylamino)-l-hydroxyethyl]-8-hydroxy-(lH)-quinolin-2-one of formula (R)-2,

known under the generic name indacaterol, which is used for the treatment of chronic obstructive pulmonary disease (COPD).

Background Art

WO 0075114 Al is the first to describe preparation of indacaterol ((i?)-2) (Scheme 1).

Scheme 1 The synthesis is a follow-up of the previously published method for the preparation of 8- benzyloxy-5-(i?)-oxiranyl-(lH)-quinolin-2-one, published in WO 9525104 Al.This synthesis of indacaterol ((i?)-2) was further modified un WO 04076422 Al, WO 04087668 Al and WO 05123684 A2 to be better applicable for the industrial production. A weak point of the above mentioned synthesis is the use of the expensive benzyl trichloromethyl dichloroiodate as the chlorination agent in the first step. A considerable weak point of the above mentioned synthesis is the formation of undesired side products during the reaction of 8-benzyloxy-5-(R)- oxiranyl-(lH)-quinolin-2-one with 2-amino-5,6-diethylindane (Scheme 2).

Scheme 2

Crude 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2- one ((i?)-l) can be purified from these undesired side products by conversion to the benzoate, which is then re-crystallized, reduced with hydrogen, converted to indacaterol maleinate, which is finally re-crystallized. According to WO 04076422 Al, WO 04087668 Al and WO 05123684 A2, the yield of 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl]-8- benzyloxy-(lH)-quinolin-2-one ((i?)-l) benzoate from 8-benzyloxy-5-(i?)-oxiranyl-(lH)- quinolin-2-one is only 67%.

Disclosure of Invention

A method for the preparation of 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- hydroxy-(lH)-quinolin-2-one of formula (R)-2

which comprises preparation of the racemic intermediate

5 - [2-(5 ,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl] -8 -benzyloxy-( 1 H)-quinolin-2-one of formula 1,

which is further, in an arbitrary order, chirally resolved and debenzylated, and subsequently indacaterol of formula (R -2 is isolated.

Detailed Description of the Invention

The invention provides a method for the preparation of indacaterol of formula (R)-2) from the racemic intermediate 5 - [2-(5 ,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl] - 8-benzyloxy-( 1 H)- quinolin-2-one of formula 1, consisting of debenzylation of the intermediate of formula 1 to give 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-hydroxy-(lH)-quinolin-2-one of formula 2, and subsequent resolution and isolation of indacaterol of formula (R)-2.

The invention further includes preparation of indacaterol of formula (i?)-2) from the racemic intermediate 5- [2-(5 ,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl]-8-benzyloxy-( 1 H)-quinolin- 2-one of formula 1, wherein first resolution is carried out and the compound of formula (R)-l is isolated, followed by debenzylation of the compound (R)-l to obtain indacaterol of formula (R)-2.

Debenzylation of 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)- quinolin-2-one (1) to 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-hydroxy-(lH)- quinolin-2-one (2), as well as debenzylation of 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l- hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2-one ((i?)-l) to indacaterol ((R)-2) can be carried out, e.g., under a hydrogen atmosphere in the presence of palladium on carbon.

Separation of indacaterol ((i?)-2) from 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- hydroxy-(lH)-quinolin-2-one (2), as well as separation of 5-[(i?)-2-(5,6-diethyl-indan-2- ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2-one ((R)-l) from 5-[2-(5,6-diethyl- indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2-one (1) can be carried out, e.g., by repeated crystallization of diastereomeric addition compounds with suitable chiral substances or by means of HPLC using a chiral stationary phase.

We have observed that 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy- (lH)-quinolin-2-one (1) can be quantitatively resolved into individual enantiomers using HPLC. Suitable stationary phases are, e.g., Chiralcel OD-3R and Chiralcel OZ-3R; very suitable stationary phases are Chiralcel AS-V and Chiralcel AS-3R. We have also found out that 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyemyl]-8-hydroxy-(lH)-quinolin-2-one (2) can be quantitatively resolved into individual enantiomers using HPLC. A suitable stationary phase is, e.g,. Chiralcel OZ-H; very suitable stationary phases are Chiralcel OJ and Chiralcel OJ-H.

HPLC columns of the trade mark Chiralcel are filled with silica gel particles with the size of 3- 20 μιη, which are coated with a cellulose derivative. For example, the Chiralcel OJ-H column contains silica gel particles with the size of 5 μηι, coated with a cellulose derivative, which is cellulose tris (4-methylbenzoate). The invention also includes a method for the preparation of the racemic intermediate 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy- (lH)-quinolin-2-one of formula 1, which is useful for the preparation of indacaterol. The preparation of the compound of formula 1 consists in reaction of 8-benzyloxy-5-(2,2- dihydroxyacetyl)-lH-quinolin-2-one with 2-amino-5,6-diethylindane in a suitable solvent in the presence of a suitable reducing agent. The starting compound, 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one, was described in the patent publication US 2004167167 Al; however, use of this compound for the preparation of indacaterol has not been described yet.

The product of formula 1 is obtained in a surprisingly high yield (94 - 99%). Solvents suitable for the reaction are dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide and similar dipolar aprotic solvents, as well as methanol and other C2 to C4 aliphatic alcohols, dichloromethane and similar halogenated solvents,or tetrahydrofuran and other ethers. Suitable reducing agents are borohydride reducing agents such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium triethylborohydride, as well as borane, diborane, diisobutyl aluminium hydride, lithium aluminium hydride, sodium bis(2- methoxyethoxy)aluminium hydride, or their lithium, sodium and potassium salts.

A suitable temperature for performing this reaction is -20 to 50°C.

The invention further includes the use of the compound 8-benzyloxy-5-(2,2-dihydroxyacetyl)- 1H-quinolin-2-one for the preparation of indacaterol.

The entire sequence of synthesis of indacaterol in accordance with the invention is

summarized in Scheme 3.

Scheme 3 An advantage of this procedure for the synthesis of indacaterol as compared to the prior art is a lower number of steps (four compared to five, starting from the same 5-acetyl-8- (phenylmethoxy)-lH-quinolin-2-one as WO 0075114 Al) and a high yield of the synthesis of the intermediate of formula 1. The synthesis is also beneficial from the economic point of view as the use of the expensive benzyl trichloromethyl dichloroiodate as the chlorination agent is eliminated. The synthesis is also more efficient compared to the prior art from the point of view of formation of undesired products. Examples

HPLC analyses of the various batches of 5-[(i-)-2-(5,6-diethyl-indan-2-ylamino)-l- hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2-one ((i?)-l) were conducted with UV detection at 257 nm, column length of 150 mm, column internal diameter of 4.6 mm, stationary phase Chiralcel AS-3R (3 um), temperature of 25°C, flow rate of 1 ml/min, mobile phase A:

phosphate buffer (1.15 g of NH₄H₂P0₄ dissolved in 1000 ml of water, adjusted to pH 6.0 with triethylamine), mobile phase B: acetonitrile, isocratic elution 20% A + 80% B. The typical retention time of the compound S)-l under these conditions was 3.5 min and that of the compound (j?)-l under these conditions was 7.3 min.

HPLC analyses of the various batches of indacaterol ((R)-2) were conducted with UV detection at 261 nm, column length of 250 mm, column internal diameter of 4.6 mm, stationary phase Chiralcel OJ-H (5 μηι), temperature of 30 °C, flow rate of 1 ml/min, mobile phase A: 500 ml of hexane + 1 ml of triethylamine, mobile phase B: ethanol, isocratic elution 82%) A + 18%) B. The typical retention time of the compound (S)-2 under these conditions was 7.8 min and that of the compound (i?)-2 under these conditions was 13.3 min.

The starting 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one and 2-amino-5,6- diethylindane were prepared according to US 2004167167 Al and F. Baur et al. J. Med.

Chem. 2010, 53, 3675-3684. Example 1. Preparation of 5-[2-(5,6-diethyI ndan-2-yIamino)-l-hydroxyethyl]-8- benzyloxy-(lH)-quinoIin-2-one (1)

A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (1,15 g), 2-amino-5,6- diethylindane (0.83 g) and dimethyl sulfoxide (5 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and methanol (5 ml) was added at this temperature. Finely triturated NaB¾ (0.39 g) was added at 0°C and the resulting clear solution was stirred at 20°C for 16 hours. Water (20 ml) was added to the mixture and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 1.68 g (98%) of beige powder.

Example 2. Preparation of 5- [2-(5,6-diethyl-indan-2-yIamino)-l -hydrox ethyl] -8- benzyloxy-(lH)-quinolin-2-one (1) A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (1.95 g), 2-amino-5,6- diethylindane (1.25 g), dimethyl sulfoxide (8 ml) and acetic acid (0.05 ml) was stirred at 20°C for 2 h. The resulting suspension was cooled down to 0°C and methanol (8 ml) was added at this temperature. Finely triturated NaBH (1.13 g) was added at 0°C and the produced clear solution was stirred at 20°C for 3 h. Water (32 ml) was added to the mixture and the mixture was stirred at 20°C for 16 h. The product was filtered off, washed with water and air-dried. The yield was 2.75 g (95%) of beige powder.

Example 3. Preparation of 5-[2-(5,6-diethyI-indan-2-ylamino)-l-hydroxyethyI]-8- benzyloxy-(lH)-quinolin-2-one (1)

A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (115 mg), 2-amino-5,6- diethylindane (83 mg) and dimethyl acetamide (0.5 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and methanol (0.5 ml) was added at this temperature. Finely triturated NaBHU (39 mg) was added at 0°C and the obtained clear solution was stirred at 20°C for 16 h. Water (2 ml) was added to the mixture and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 160 mg (94%) of beige powder. Example 4. Preparation of 5-[2-(5,6-diethyI-indan-2-ylamino)-l-hydroxyethyI]-8- benzyloxy-(lH)-quinoLm-2-one (1)

A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (115 mg), 2-amino-5,6- diethylindane (83 mg) and dichloromethane (2 ml) was stirred at 20°C for 2 h. Finely triturated NaBH(OAc)₃ (250 mg) was added at 20°C. The resulting mixture was stirred at 20°C for 16 h and then evaporated until dry. Water (2 ml) was added to the evaporation product and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 164 mg (96%) of beige powder.

Example 5. Preparation of 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- benzyloxy-(li?)-quinolin-2-one (1)

A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (33 mg), 2-amino-5,6- diethylindane (21 mg) and tetrahydrofuran (1 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and 1 M BH₃ in tetrahydrofuran (0.5 ml) was added at this temperature. The produced clear solution was stirred at 20°C for 16 h and then evaporated until dry. Water (1 ml) was added to the evaporation product and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 48 mg (99%) of beige powder.

Example 6. Preparation of 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- hydroxy-(l/Z)-quinolin-2-one (2) A mixture of 5-[2-(5,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl]-8-benzyloxy-(lH)-quinolin- 2-one (1) (1.21 g), ethanol (100 ml) and 5 % Pd / C (80 mg) was stirred in a hydrogen atmosphere at 20°C at the pressure of 101 kPa for 2 h. A TLC analysis of the mixture showed the pure reactant, therefore the mixture was filtered and fresh 5% Pd / C (80 mg) was added to the filtrate. The mixture was stirred in a hydrogen atmosphere at 20°C at the pressure of 101 kPa for 2 h. A TLC analysis of the mixture showed the reactant accompanied by a small amount of the product, therefore the mixture was filtered and fresh 5 % Pd / C (80 mg) was again added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa for 4 h. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.97 g (99%) of yellow powder. Example 7. Preparation 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-hydroxy- (lfl)-quinoIin-2-one (2)

A mixture of 5-[2-(5,6-diemyl-indan-2-ylammo)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin- 2-one (1) (1,21 g), ethanol (100 ml) and Raney nickel (1 g) was stirred at 20°C for 2 h. The mixture was filtered and 5% Pd / C (0.1 g) was added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa at 40°C. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.96 g (98%) of yellow powder.

Example 8. Preparation of indacaterol ((R)-2)

Indacaterol ((i?)-2) was resolved from Z 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]- 8-hydroxy-(lH)-quinolin-2-one (2) (0.90 g) by means of preparative HPLC. Conditions of the resolution: UV detection at 260 nm, column length 500 mm, column internal diameter 50 mm, stationary phase Chiralcel OJ (20 μηι), temperature 25°C, flow rate 120 ml/min, mobile phase A: 500 ml of hexane + 1 ml triethylamine, mobile phase B: ethanol, isocratic elution 82% A + 18% B. The fractions containing indacaterol ((R)-2) were evaporated in an evaporator at a reduced pressure. The yield was 0.44 g (49%) of white powder. HPLC enantiomeric purity 99.0% ee.

Example 9. Preparation of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- benzyloxy-(lH)-quinolin-2-one ((R)-l) 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2-one ((R)-l) was resolved from 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy- (lH)-quinolin-2-one (1) (1.00 g) by means of preparative HPLC. Conditions of the resolution: UV detection at 260 nm, column length 500 mm, column internal diameter 50 mm, stationary phase Chiralcel AS-V (20 μηι), temperature 25°C, flow rate 120 ml/min, mobile phase A: phosphate buffer (1.15 g of NH₄H₂P0₄, dissolved in 1000 ml of water, adjusted to pH 6.0 with 25% aqueous NH₃), mobile phase B: acetonitrile, isocratic elution 20% A + 80% B. The fractions containing 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l -hydroxyethyl]-8-benzyloxy- (lH)-quinolin-2-one ((R)-l) were evaporated in an evaporator at a reduced pressure to the volume of about 50 ml. 25% aqueous NH₃ was added dropwise to the resulting suspension up to pH 8-9 and the product was extracted with ethyl acetate. The combined extracts were dried with Na₂S0₄ and evaporated in an evaporator at a reduced pressure. The yield was 0.48 g (48%) of white powder. HPLC enantiomeric purity 99.2% ee.

Example 10. Preparation of indacaterol ((R)-2)

A mixture of 5-[(i-)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)- quinolin-2-one ((R)-l) (0.42 g, HPLC enantiomeric purity of 99.2% ee), ethanol (50 ml) and Raney nickel (0.5 g) was stirred at 20°C for 2 h. The mixture was filtered and 5% Pd / C (0.05 g) was added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa for 4 h. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.33 g (97%) of white powder. HPLC enantiomeric purity 99.0% ee.

Claims

1. A method for the preparation of 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- hydroxy-(lH)-quinolin-2-one of formula (R)-2

which comprises preparation of the racemic intermediate

5- [2-(5 ,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl] -8-benzyloxy-( 1 H)-quinolin-2- formula 1 ,

which is further, in an arbitrary order, chirally resolved and debenzylated, and subsequently indacaterol of formula (i?)-2 is isolated.

2. The method according to claim 1 , characterized in that the racemic intermediate of formula 1 is debenzylated to obtain 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-hydroxy- (lH)-quinolin-2-one of formula 2, which subsequently chirally resolved, the undesired enantiomer is separated and indacaterol of formula (R)-2 is isolated.

3. The method according to claim 1 , characterized in that the racemic intermediate of formula 1 is chirally resolved, the undesired enantiomer is separated, 5-[(i?)-2-(5,6-diethyl-indan-2- ylamino)-l -hydroxyethyl]-8-beiizyloxy-(lif)-quinolin-2-one of formula (i?)-l is isolated, which is subsequently debenzylated to obtain indacaterol of formula (R)-2.

4. The method according to claims 2 to 3, characterized in that the chiral resolution and separation of the undesired enantiomer is carried out by means of a HPLC method.

5. The method according to claim 1, characterized in that the racemic intermediate of formula

is prepared by reaction of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one with 2- amino-5,6-diethylindane in the presence of a reducing agent.

6. The method according to claim 5, characterized in that the reducing agent is selected from the group consisting of sodium borohydride, sodium triacetoxyborohydride, sodium

cyanoborohydride, sodium triethylborohydride, as well as borane, diborane, diisobutyl aluminium hydride, lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride, or their lithium, sodium and potassium salts.

7. The method according to claims 5 to 6, characterized in that the reaction is carried out in a solvent from the group consisting of dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, l,3-dimethyl-2-imidazolidinone, Q to C₄ aliphatic alcohols, dichloromethane, 1 ,2-dichloroethane, chlorobenzene, tetrahydrofuran, dioxan, 1,2- dimethoxyethane, bis(2-methoxyethyl)ether, diethyl ether and tert-butyl methyl ether.

8. The method according to claims 5 to 7, characterized in that the reaction is carried out at a temperature in the range of -20 to 50°C.

9. Use of the compound 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one for the preparation of indacaterol.