WO2013132514A2 - 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 - Google Patents

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 Download PDF

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WO2013132514A2
WO2013132514A2 PCT/IN2013/000052 IN2013000052W WO2013132514A2 WO 2013132514 A2 WO2013132514 A2 WO 2013132514A2 IN 2013000052 W IN2013000052 W IN 2013000052W WO 2013132514 A2 WO2013132514 A2 WO 2013132514A2
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group
compound
process according
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acid addition
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WO2013132514A3 (en
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Davuluri Ramamohan RAO
Ponnaiah Ravi
Praveen Kumar Neela
Bathani GURUSWAMY
Kallepally SUDEER
Mutyala SWETHA
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Rao Davuluri Ramamohan
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    • 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 a novel process for the preparation of Indacaterol Maleate employing novel intermediate.
  • Indacaterol chemically known as (R)-5-[2-[(5, 6-Diethyl-2, 3-dihydro-lH- inden-2-yl) amino]- 1 -hydroxy ethyl]-8-hydroxyquinolin-2(lH)-one, is an ultra long acting beta-adrenoceptor agonist developed by Novartis and has the following structural formula:
  • Indacaterol maleate is a long acting inhaled ⁇ 2- agonist. Indacaterol maleate is marketed under the trade name Arcapta Neohaler in US and Onbrez in Europe.
  • Indacaterol maleate was disclosed in US6878721 by Novartis. The process for Indacaterol is depicted below.
  • Indacaterol maleate involves the step of reacting 8 substituted oxy-5-(R)-oxiranyl-(lH)-quinolin-2-one (III) with 2-amino- (5,6-diethyl)-indan (IV) to form a intermediate 5-[(R)-2-(5,6-diethyl-indan-2- ylamino)-l-hydroxy-ethyl]-8-substituted oxy-(lH)-quinolin-2-one (V).
  • This epoxide ring opening is not region specific thereby along with 5-[(R)-2-(5,6- diethyl-indan-2-ylamino)- 1 -hydroxy-ethyl]-8-substituted oxy-( 1 H)-quinol intone, below mentioned products are being produced as impurities.
  • the above reaction mixture contains only about 60% of desired compound i.e. 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-substituted oxy- (lH)-quinolin-2-one.
  • desired compound i.e. 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-substituted oxy- (lH)-quinolin-2-one.
  • the purification of this intermediate is done using silica gel chromatography which is tedious and requires large amounts of solvents, not suitable for industrial synthesis.
  • the main objective of the present invention is to provide a novel process for the preparation of Indacaterol or its pharmaceutical acceptable salts.
  • In one object of the present invention involves a process for the preparation of Indacaterol or its pharmaceutically acceptable salts comprising the steps of:
  • R is hydrogen or hydroxy protecting group
  • L is a leaving group
  • preferable leaving groups include bromo, iodo, tosylate and mesylate; other leaving groups known in the state of art may be used; with the compound of formula II A or its acid addition salts
  • acid herein is any pharmaceutically suitable acid.
  • Another object of the present invention provides a novel process for the preparation of Indacaterol or its pharmaceutical acceptable salts comprising the steps of:
  • R is hydrogen or hydroxy protecting group
  • L is a leaving group
  • preferable leaving groups are bromo, iodo, tosylate and mesylate; other leaving groups known in the state of art may be used, with compound of formula VIIIA or its acid addition salts,
  • acid herein is any pharmaceutically suitable acid.
  • Figure 1 Amorphous form of Indacaterol Maleate
  • the present invention involves a novel process for the preparation of indacaterol or its pharmaceutically acceptable salts thereof employing novel intermediates thereof.
  • In one embodiment of the present invention involves a process for the preparation of Indacaterol or its pharmacetically acceptable salts comprising the steps of:
  • R is a hydrogen or hydroxy protecting group
  • L is a leaving group; preferable, leaving groups are bromo, iodo, tosylate and mesylate; other leaving groups known in the state of art may be used, with the compound of formula II A or its acid addition salts,
  • acid is any pharmaceutically suitable acid.
  • the hydroxy protecting group employed in step i) of the above process is selected from the group included but not limited to silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl, haloalkyl and benzyl.
  • the base employed in the step i) of the above process is selected from the group of organic base or inorganic base, wherein the organic base is selected from the C I to C6 cyclic or acyclic amines included but not limited to isopropyl amine, diisopropyl amine, diisopropyl ethyl-amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine, DBU, DABCO and triethylamine.
  • the organic base is selected from the C I to C6 cyclic or acyclic amines included but not limited to isopropyl amine, diisopropyl amine, diisopropyl ethyl-amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine, DBU, DABCO and triethylamine.
  • Inorganic base may be selected from the group consisting of alkali metals such as sodium, potassium, lithium or alkali metal carbonates like sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides like sodium hydroxide, calcium hydroxide, potassium hydroxide, metal alkoxides like alkoxides of sodium, lithium or potassium, sodium tert-butoxide and sodium hydride, including the combination of above organic and inorganic bases in any ratio.
  • alkali metals such as sodium, potassium, lithium or alkali metal carbonates like sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides like sodium hydroxide, calcium hydroxide, potassium hydroxide, metal alkoxides like alkoxides of
  • the organic solvent employed in step i)of the above process is selected from the group but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, isobutyl alcohol, tertiary-butyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like; ketones such as acetone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tertiary- butyl ether and the like; esters such as ethyl acetate, h-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; hydrocarbons such as hexane
  • the reducing agent employed in step ii) of the above process is selected from the group included but not limited to asymmetric reducing agents such as boranes like BH 3 -THF, Borane DMS, Diborane with chiral catalyst Methyl CBS, phenyl CBS.
  • asymmetric reducing agents such as boranes like BH 3 -THF, Borane DMS, Diborane with chiral catalyst Methyl CBS, phenyl CBS.
  • the reduction also carried out using DIP chloride, Diethyl methoxy borane and sodium borohydride, lithium aluminum hydride.
  • the acid employed in step iv) of the above process is selected from the group of inorganic acids such as HCl, HBr, HI, H2S04, HN03, H3P04 or organic acids such as C2 to C4 carbons containing organic acid like maleic acid, formic acid, oxalic acid.
  • inorganic acids such as HCl, HBr, HI, H2S04, HN03, H3P04 or organic acids such as C2 to C4 carbons containing organic acid like maleic acid, formic acid, oxalic acid.
  • the another embodiment of the present invention provides novel process for the preparation of Indacaterol or its pharmaceutical acceptable salts comprising the steps of:
  • R is hydrogen or hydroxy protecting group
  • L is a leaving group
  • preferable leaving groups are bromo, iodo, tosylate and mesylate; other leaving groups known in the state of art may be used, with compound of formula VIIIA or its acid addition salts,
  • the acid is any pharmaceutically suitable acid.
  • the hydroxy protecting groups employed in step i) of the above process is from the group included but not limited to silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl, haloalkyl and hydrogen.
  • protecting group is silyl or benzyl.
  • the nitrogen protecting groups employed in step i) of the above process is selected from the group of silyl, benzyl, benzoyl, carbobenzyloxy, acetyl, tosy!.
  • the base employed in the step i) of the above process is selected from the group of organic base or inorganic base, wherein the organic base is selected from the C I to C6 cyclic or acyclic amines included but not limited to isopropyl amine, diisopropyl amine, diisopropyl ethyl-amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine, DBU, DABCO and triethylamine.
  • the organic base is selected from the C I to C6 cyclic or acyclic amines included but not limited to isopropyl amine, diisopropyl amine, diisopropyl ethyl-amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine, DBU, DABCO and triethylamine.
  • Inorganic base may be selected from the group consisting of alkali metals such as sodium, potassium, lithium or alkali metal carbonates like sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides like sodium hydroxide, calcium hydroxide, potassium hydroxide, metal alkoxides such as alkoxides of sodium, lithium or potassium, sodium tert-butoxide and sodium hydride, including the combination of above organic and inorganic bases in any ratio .
  • alkali metals such as sodium, potassium, lithium or alkali metal carbonates like sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides like sodium hydroxide, calcium hydroxide, potassium hydroxide, metal alkoxides such as alkoxid
  • the organic solvent employed in step i) of the above process is selected from the group but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, isobutyl alcohol, tertiary-butyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like; ketones such as acetone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tertiary- butyl ether and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; hydrocarbons such as hexane
  • the reducing agent employed in step ii) of the above process is selected from the group included but not limited to asymmetric reducing agents such as boranes like BH 3 -THF, Borane DMS, Diborane with chiral catalyst Methyl CBS, phenyl CBS.
  • asymmetric reducing agents such as boranes like BH 3 -THF, Borane DMS, Diborane with chiral catalyst Methyl CBS, phenyl CBS.
  • the reduction also carried out using DIP chloride, Diethyl methoxy borane and sodium borohydride, lithium aluminum hydride.
  • the acid employed in step iv) of the above process is selected from the group of inorganic acids such as HCl, HBr, HI, H2S04, HN03, H3P04 or organic acids such as C2 to C4 carbons containing organic acidsalts such as maleic acid, formic acid, oxalic acid.
  • inorganic acids such as HCl, HBr, HI, H2S04, HN03, H3P04
  • organic acids such as C2 to C4 carbons containing organic acidsalts such as maleic acid, formic acid, oxalic acid.
  • the process of the present invention provides pure Indacaterol maleate having purity not less than 98% and more than 99.5% is obtained.
  • the process of the present invention provides Indacaterol maleate free of dimer and regioisomer.
  • the process of the present invention provides an amorphous form of Indacaterol maleate depicted in Figure 1.
  • novel intermediates or its acid addition salts of the present invention may also prepared by known methods in the state of the art.
  • the deprotection process of present invention may be done by the known methods in the state of the art.

Abstract

The present invention relates to a novel process for preparation of Indacaterol Maleate by employing novel intermediates of the formula [IIIA] and [IXA].

Description

Title of the Invention
A novel process for the preparation of (R)-5-[2-[(5, 6-diethyl-2, 3-dihydro-lH- inden-2-yl) amino]- 1 -hydroxyethyl]-8-hydroxy quinolin-2( 1 H)-one
Cross reference to related application:
[0001] This application claims priority from the provisional specification No. 890/CHE/2012 filed on 09.03. 2012.
Field of the Invention
[0002] The present invention relates to a novel process for the preparation of Indacaterol Maleate employing novel intermediate.
Background of the Invention
[0003] Indacaterol chemically known as (R)-5-[2-[(5, 6-Diethyl-2, 3-dihydro-lH- inden-2-yl) amino]- 1 -hydroxy ethyl]-8-hydroxyquinolin-2(lH)-one, is an ultra long acting beta-adrenoceptor agonist developed by Novartis and has the following structural formula:
Figure imgf000003_0001
[0004] Indacaterol maleate is a long acting inhaled β2- agonist. Indacaterol maleate is marketed under the trade name Arcapta Neohaler in US and Onbrez in Europe.
[0005] Indacaterol maleate was disclosed in US6878721 by Novartis. The process for Indacaterol is depicted below.
Figure imgf000004_0001
Indacaterol Maleate
VII
[0006] In the above process for preparing Indacaterol maleate involves the step of reacting 8 substituted oxy-5-(R)-oxiranyl-(lH)-quinolin-2-one (III) with 2-amino- (5,6-diethyl)-indan (IV) to form a intermediate 5-[(R)-2-(5,6-diethyl-indan-2- ylamino)-l-hydroxy-ethyl]-8-substituted oxy-(lH)-quinolin-2-one (V). This epoxide ring opening is not region specific thereby along with 5-[(R)-2-(5,6- diethyl-indan-2-ylamino)- 1 -hydroxy-ethyl]-8-substituted oxy-( 1 H)-quinol intone, below mentioned products are being produced as impurities.
Figure imgf000005_0001
[0007] The above reaction mixture contains only about 60% of desired compound i.e. 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-substituted oxy- (lH)-quinolin-2-one. The purification of this intermediate is done using silica gel chromatography which is tedious and requires large amounts of solvents, not suitable for industrial synthesis.
[0008] To overcome the above draw backs of the process for preparing Indacaterol, the patent US7534890 discloses a process that avoids the column purification by the formation of acid addition salts of intermediate (formula - IV).
Therefore, there exists a need to develop a novel process for the preparation of indacaterol maleate.
Summary of the Invention
[0009] The main objective of the present invention is to provide a novel process for the preparation of Indacaterol or its pharmaceutical acceptable salts.
[0010] In one object of the present invention involves a process for the preparation of Indacaterol or its pharmaceutically acceptable salts comprising the steps of:
i) treating the compound of formula IA or its acid addition salts,
Figure imgf000006_0001
wherein R is hydrogen or hydroxy protecting group; L is a leaving group; preferable leaving groups include bromo, iodo, tosylate and mesylate; other leaving groups known in the state of art may be used; with the compound of formula II A or its acid addition salts
Figure imgf000006_0002
in an organic solvent, optionally in the presence of a base to obtain a compound of formula IIIA or its acid addition salts,
Figure imgf000006_0003
ii) treating the compound of formula IIIA or its acid addition salts with reducin agent to obtain the compound of formula IVA or its acid addition salts,
Figure imgf000006_0004
iii) optionally, deprotecting the compound of formula IVA or its acid salts to obtain a compound of formula VA or its acid addition salts,
Figure imgf000007_0001
iv) optionally treating the compound of formula VA with an acid in presence of solvent to obtain the com ound of formula VIA,
Figure imgf000007_0002
wherein acid herein is any pharmaceutically suitable acid.
[0011] Another object of the present invention provides a novel process for the preparation of Indacaterol or its pharmaceutical acceptable salts comprising the steps of:
i) treating the compound of formula IA or its acid addition salts,
Figure imgf000007_0003
where in R is hydrogen or hydroxy protecting group; L is a leaving group; preferable leaving groups are bromo, iodo, tosylate and mesylate; other leaving groups known in the state of art may be used, with compound of formula VIIIA or its acid addition salts,
VIIIA
Figure imgf000008_0001
wherein Rl is N-protected group, in an organic solvent, optionally in the presence of a base to obtain a compound of formula IXA or its acid addition salts,
Figure imgf000008_0002
ii) treating the compound of formula IXA or its acid addition salt in the presence of a reducing agent to obtain a compound of formula XA or its acid addition salts,
Figure imgf000008_0003
iii) treating the compound of formula XA or acid or its addition salt with palladium catalyst to obtain the compound of formula VA or its acid addition salts,
Figure imgf000009_0001
iv) optionally treating the compound of formula VA with acid in a solvent to obtain compound of formula VIA,
Figure imgf000009_0002
wherein acid herein is any pharmaceutically suitable acid.
Brief description of the Drawings
[0012] Figure 1 : Amorphous form of Indacaterol Maleate
Detailed Description of the Invention
[0013] The present invention involves a novel process for the preparation of indacaterol or its pharmaceutically acceptable salts thereof employing novel intermediates thereof.
[0014] In one embodiment of the present invention involves a process for the preparation of Indacaterol or its pharmacetically acceptable salts comprising the steps of:
i) treating the compound of formula IA or its acid addition salts,
Figure imgf000010_0001
where in R is a hydrogen or hydroxy protecting group;
L is a leaving group; preferable, leaving groups are bromo, iodo, tosylate and mesylate; other leaving groups known in the state of art may be used, with the compound of formula II A or its acid addition salts,
Figure imgf000010_0002
in an organic solvent optionally in presence of a base to obtain a compound of formula IIIA or its acid addition salts
Figure imgf000010_0003
ii) treating the compound of formula IIIA or its acid addition salts with reduc agent to obtain the compound of formula IVA or its acid addition salts,
Figure imgf000010_0004
iii) optionally, deprotecting the compound of formula IVA or its acid addition salts to obtain a compound of formula VA or its acid addition salts,
Figure imgf000011_0001
iv) optionally treating the compound of formula VA with an acid in presence of solvent to obtain the compound of formula VIA,
Figure imgf000011_0002
wherein acid is any pharmaceutically suitable acid.
[0015] The hydroxy protecting group employed in step i) of the above process is selected from the group included but not limited to silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl, haloalkyl and benzyl.
[0016] The base employed in the step i) of the above process is selected from the group of organic base or inorganic base, wherein the organic base is selected from the C I to C6 cyclic or acyclic amines included but not limited to isopropyl amine, diisopropyl amine, diisopropyl ethyl-amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine, DBU, DABCO and triethylamine. Inorganic base may be selected from the group consisting of alkali metals such as sodium, potassium, lithium or alkali metal carbonates like sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides like sodium hydroxide, calcium hydroxide, potassium hydroxide, metal alkoxides like alkoxides of sodium, lithium or potassium, sodium tert-butoxide and sodium hydride, including the combination of above organic and inorganic bases in any ratio.
[0017] The organic solvent employed in step i)of the above process is selected from the group but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, isobutyl alcohol, tertiary-butyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like; ketones such as acetone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tertiary- butyl ether and the like; esters such as ethyl acetate, h-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; hydrocarbons such as hexane, benzene,xylene, toluene and the like and aprotic polar solvents such as dimethyl sulfoxide, Ν,Ν-dimethylformamide, N,N-dimethylacetamide and the like, any solvent or mixture of solvents or their combination with water or any of the solvents from the classes mentioned above is acceptable.
[0018] The reducing agent employed in step ii) of the above process is selected from the group included but not limited to asymmetric reducing agents such as boranes like BH3-THF, Borane DMS, Diborane with chiral catalyst Methyl CBS, phenyl CBS. The reduction also carried out using DIP chloride, Diethyl methoxy borane and sodium borohydride, lithium aluminum hydride. [0019] The acid employed in step iv) of the above process is selected from the group of inorganic acids such as HCl, HBr, HI, H2S04, HN03, H3P04 or organic acids such as C2 to C4 carbons containing organic acid like maleic acid, formic acid, oxalic acid.
[0020] The another embodiment of the present invention provides novel process for the preparation of Indacaterol or its pharmaceutical acceptable salts comprising the steps of:
i) treating the compound of formula IA or its acid addition salts,
Figure imgf000013_0001
in which R is hydrogen or hydroxy protecting group; L is a leaving group; preferable leaving groups are bromo, iodo, tosylate and mesylate; other leaving groups known in the state of art may be used, with compound of formula VIIIA or its acid addition salts,
VIIIA
Figure imgf000013_0002
wherein Rlis N-protected group, in an organic solvent, optionally in the presence of a base to obtain a compound of formula IXA or its acid addition salts,
Figure imgf000013_0003
ii) treating the compound of formula IXA or its acid addition salts with a reducing agent to obtain a compound of formula XA or its acid addition salts,
Figure imgf000014_0001
iii) treating the compound of formula XA or its acid addition salts with palladiu catalyst to obtain the compound of formula VA or its acid addition salts,
Figure imgf000014_0002
iv) optionally treating the compound of formula V with acid in a solvent to obtain compound of formula VI
Figure imgf000014_0003
wherein the acid is any pharmaceutically suitable acid.
[0021] The hydroxy protecting groups employed in step i) of the above process is from the group included but not limited to silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl, haloalkyl and hydrogen. Preferably, protecting group is silyl or benzyl. [0022] The nitrogen protecting groups employed in step i) of the above process is selected from the group of silyl, benzyl, benzoyl, carbobenzyloxy, acetyl, tosy!. The base employed in the step i) of the above process is selected from the group of organic base or inorganic base, wherein the organic base is selected from the C I to C6 cyclic or acyclic amines included but not limited to isopropyl amine, diisopropyl amine, diisopropyl ethyl-amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine, DBU, DABCO and triethylamine. Inorganic base may be selected from the group consisting of alkali metals such as sodium, potassium, lithium or alkali metal carbonates like sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides like sodium hydroxide, calcium hydroxide, potassium hydroxide, metal alkoxides such as alkoxides of sodium, lithium or potassium, sodium tert-butoxide and sodium hydride, including the combination of above organic and inorganic bases in any ratio .
[0023] The organic solvent employed in step i) of the above process is selected from the group but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, isobutyl alcohol, tertiary-butyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like; ketones such as acetone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tertiary- butyl ether and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; hydrocarbons such as hexane, benzene, xylene, toluene and the like and aprotic polar solvents such as dimethyl sulfoxide, N,N-dimethylformamide, Ν,Ν-dimethylacetamide and the like, any solvent or mixture of solvents or their combination with water or any of the solvents from the classes mentioned.
[0024] The reducing agent employed in step ii) of the above process is selected from the group included but not limited to asymmetric reducing agents such as boranes like BH3-THF, Borane DMS, Diborane with chiral catalyst Methyl CBS, phenyl CBS. The reduction also carried out using DIP chloride, Diethyl methoxy borane and sodium borohydride, lithium aluminum hydride.
[0025] The acid employed in step iv) of the above process is selected from the group of inorganic acids such as HCl, HBr, HI, H2S04, HN03, H3P04 or organic acids such as C2 to C4 carbons containing organic acidsalts such as maleic acid, formic acid, oxalic acid.
[0026] The process of the present invention provides pure Indacaterol maleate having purity not less than 98% and more than 99.5% is obtained. The process of the present invention provides Indacaterol maleate free of dimer and regioisomer. The process of the present invention provides an amorphous form of Indacaterol maleate depicted in Figure 1.
[0027] The novel intermediates or its acid addition salts of the present invention may also prepared by known methods in the state of the art. The deprotection process of present invention may be done by the known methods in the state of the art.
[0028] The following examples are provided to enable one skilled in the art to practice the invention and merely illustrate the process of the invention. However, it is not intended in any way to limit the scope of the present invention.
Examples
Example -1 Preparation of compound of IIIA, wherein R is Benzyl
Figure imgf000018_0001
[0029] The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 - 30°C. The triethylamine (0. 1 mol) was added to above contents slowly, following by added sodium iodide (0.03 mol) at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lhour at 25 - 30°C and filtered to obtain the title compound. Yield: 76%
Example -2 Preparation of compound of IIIA, wherein R is Benzyl
Figure imgf000019_0001
[0030] The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 - 30°C. Potassium carbonate (0. 1 mol) was added to above contents slowly, following by added sodium iodide (0.03 mol) at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lhour at 25 - 30 °C and filtered to obtain the title compound. Yield: 82%
Exam le -3 Preparation of compound of IIIA, wherein R is Benzyl
Figure imgf000019_0002
[0031] The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 - 30°C, then Sodium iodide (0.03 mol) was added to the reaction mixture at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lho'ur at 25 - 30 °C and filtered to obtain the title compound. Yield: 84%
Exam le -4 Preparation of compound of IVA, wherein R is Benzyl
Figure imgf000020_0001
[0032] The Borane-dimethyl sulfide (0.11 mol) was added at 0-5°C, followed by addition of R - (2)-Methyl CBS (0.01 mol) and stirred the contents for 10 minutes at same temperature. The compound of example-1 (20 gm) was dissolved in methylene chloride (200 ml) at same temperature and stirred the reaction mixture for 1.0 hour. The methanol was added to the reaction mixture followed by addition of 5% hydrogen peroxide (0.01 mol) at 0-5 °C and stirred the contents for 15 minutes at same temperature, gradually increased the temperature to 20- 30°C. The 6. ON sulfuric acid (10 ml) solution was added to the reaction mixture and stirred for 15 minutes.The layers were separated. The separated organic layer was washed with 2. ON sulfuric acid solution followed by washings with water, then distilled and dissolved in ethyl acetate. The contents were stirred for 1.0 hour, filtered and dried at 60°C. Yield: 85%; E.e: > 95%.
Example -5 Preparation of compound of formula VA (Indacaterol)
[0033] The compound of example-4 (10 gm) was dissolved in methanol (100 ml), followed by addition of acetic acid (50 ml) to the reaction mixture. The 5% Pd/C was added to the reaction mixture and applied hydrogen pressure 3-4 Kg/cm3' and then the contents were stirred for 4.0 hours at 25-30°C, filtered and distilled. The residue was dissolved in ethyl acetate, stirred for 10 min and distilled to obtain the compound. Yield: 79%
Example -6 Preparation of Indacaterol Maleate
[0034] To a methanolic solution of Indacaterol, maleic acid (0.9 mol) in methanol was slowly added at 25 -30°C and stirred the isolated compound for 2.0 hours at same temperature. The reaction mass was cooled to 0 -10°C and maintained for 2.0 hrs at same temperature. The contents were filtered, washed with methanol and dried at 60 -65 °C. Yield: 93%; E.e: >99%.
Example -7 Preparation of compound of formula IXA, wherein R and Rl is benzyl
Figure imgf000022_0001
[0035] The (Bromo compound) of formula I (25 gm) was dissolved in DMF (150 ml) and stirred the contents for 15 min. The 5,6-Diethyl indane N-benzyl amine (0.9 mol) was added to the above mixture at 25 -30°C, followed by the slow addition of triethylamine, then the reaction mixture was stirred for 5.0 min. The sodium iodide (0.01 mol) was added to the reaction mixture at same temperature and stirred for 3 hours at same temperature. The purified water was added to the reaction mixture, and then the contents were filtered and washed with water. The wet compound was dissolved in methanol then water was added to the contents and stirred for lhour at 25 -30 °C. The contents were filtered and dried the compound at 60 °C. Yield: 70%.
Example -8 Preparation of compound of formula XA, wherein R and Rl is benzyl
[0036] A mixture of Borane-dimethyl sulfide (0.11 mol), R-(2)-Methyl CBS (0.01 mol) and methylene chloride was stirred for 10 minutes at 0-5 C. The compound of example-7 (20 gm) was dissolved in methylene chloride (200 ml) and was added to the reaction mixture at same temperature. The reaction mixture was stirred for 1.0 hour. The methanol was added to the reaction mixture followed by addition of 5% hydrogen peroxide (0.01 mol) at 0-5 C. Stirred the contents for 15 minutes at same temperature, gradually increased the temperature to 20-30°C. The 6. ON sulfuric acid (10 ml) solution was added to the reaction mixture and stirred for 5minutes.The layers were separated. The organic layer was washed with 2. ON sulfuric acid solution followed by washing with water. The organic layer was distilled and dissolved in ethyl acetate. Stirred the contents for 1.0 hour and filtered the compound. The compound was dried at 60°C. Yield: 80%; Purity E.e: > 95%.
Example -9 Preparation of compound of formula VA (Indacaterol)
[0037] The compound of example-8 (10 gm) was dissolved in methanol (100 ml), followed by addition of acetic acid (50 ml) to the reaction mixture. Then 5% Pd/C was added to the reaction mixture and applied hydrogen pressure 3-4 Kg/cm3 The content was stirred for 4.0 hours at 25-30°C, filtered and the filtrate was distilled. The residue was dissolved in ethyl acetate (50 ml), stirred the contents for 10 min and distilled to obtain the compound. Yield: 80%

Claims

Claims We Claim:
1. A process for the preparation of indacaterol or its pharmaceutical acceptable salts comprising the steps of:
i) treating the compound of formula IA or its acid addition salts,
Figure imgf000024_0001
wherein R is hydrogen or hydroxy protecting group, L is a leaving group; with the compound of formula II A or its acid addition salts,
Figure imgf000024_0002
in an organic solvent optionally in the presence of a base to obtain a compound of formula IIIA or its acid addition salts,
Figure imgf000024_0003
ii) treating the compound of formula IIIA or its acid addition salt with reducing agent to obtain the compound of formula IVA or its acid addition salt,
Figure imgf000025_0001
iii) optionally, deprotecting the compound of formula IVA or its acid addition salts to obtain a compound of formula VA or its acid addition salt,
Figure imgf000025_0002
iv) optionally treating the compound of formula VA with an acid in presence of solvent to obtain the compound of formula VIA
Figure imgf000025_0003
wherein said acid is any pharmaceutically suitable acid.
2. The process according to the claim 1 wherein the hydroxy protected group is selected from the group of silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl, haloalkyl and hydrogen.
3. The process according to the claim 1 wherein the base employed is selected from the group consisting of organic base and inorganic base.
4. The process according to claim 3 wherein the organic base is selected from the group comprising of isopropyl amine, diisopropyl amine, diisopropyl ethyl- amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N- methyl pyridine, DBU, DABCO and triethylamine.
5. The process according to claim 3 wherein the inorganic base is selected from the group comprising of alkali metals, alkali metal carbonates , alkali metal bicarbonates, alkali metal hydroxides and metal alkoxides.
6. The process according to the claim 1 wherein acid is selected from the group of inorganic acids or organic acids
7. The process according to the claims 6 wherein the inorganic acid is selected from the group comprising of HC1, HBr, HI, H2S04, HN03 and H3P04.
8. The process according to the claim 6 wherein the organic acid is selected from the group comprising of C2 to C4 carbons containing organic acids.
9. The process according to the claim 1 wherein the organic solvent is selected from the group comprising of alcohols, halogenated hydrocarbons, ketones, nitriles, ethers, esters, hydrocarbons, aprotic polar solvents or mixture of solvents and their combination with water.
10. The process according to the claim 1 wherein the reducing agent is selected from the group comprising of asymmetric reducing agents.
11. The process according to the claim 10, wherein the asymmetric reducing agents is selected from the group comprising of borane-THF, borane -DMS, diborane with chiral catalyst, methyl-CBS and phenyl-CBS.
12. A process for the preparation of compound of formula IIIA or its acid addition salt,
Figure imgf000027_0001
comprising the steps of :
i) treating the compound of formula IA or its acid addition salt,
Figure imgf000027_0002
wherein R is hydrogen or hydroxy protecting group, L is a leaving group; with the compound of formula II A or its acid addition salt,
Figure imgf000027_0003
in an organic solvent, optionally in the presence of a base to obtain a compound of formula IIIA or its acid addition salt.
13. The process according to the claim 12 wherein the hydroxy protected group is selected from the group of silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl, haloalkyl and hydrogen.
14. The process according to the claim 12 wherein the base employed is selected from the group consisting of organic base and inorganic base.
15. The process according to claim 14 wherein the organic base is selected from the group comprising of isopropyl amine, diisopropyl amine, diisopropyl ethyl- amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N- methyl pyridine, DBU, DABCO and triethylamine.
16. The process according to claim 14 wherein the inorganic base is selected from the group comprising of alkali metals, alkali metal carbonates , alkali metal bicarbonates, alkali metal hydroxides and metal alkoxides.
17. The process according to claim 12 wherein the organic solvent is selected from the group comprising of alcohols, halogenated hydrocarbons, ketones, nitriles, ethers, esters, hydrocarbons, aprotic polar solvents or mixture of solvents and their combination with water.
18. A process for the preparation of indacaterol or its pharmaceutical acceptable salts comprising the steps of:
i) treating the compound of formula IA or its acid addition salts,
Figure imgf000028_0001
in which R is hydrogen or hydroxy protecting group, L is a leaving group; with compound of formula VIIIA or its acid addition salt
Figure imgf000028_0002
wherein Rl is N-protected group, in an organic solvent, optionally in the of a base to obtain a compound of formula IXA or its acid addition salt,
Figure imgf000029_0001
ii) treating the compound of formula IXA or its acid addition salt with a reducing agent to obtain a compound of formula XA or its acid addition salts,
Figure imgf000029_0002
iii) treating the compound of formula XA or its acid addition salt with palladium catalyst to obtain the compound of formula VA or its acid addition salt,
Figure imgf000029_0003
iv) optionally treating the compound of formula V with acid in a solvent to obtain compound of formula VI
Figure imgf000029_0004
wherein said acid is any pharmaceutically suitable acid,
19. The process according to the claim 18 wherein the hydroxy protected group is selected from the group of silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl, haloaikyl and hydrogen.
20. The process according to the claim 18 wherein the nitrogen protecting group is selected from the group comprising of silyl, benzyl, benzoyl, carbobenzyloxy, acetyl and tosyl.
21. The process according to the claim 18 wherein the base employed is selected from the group consisting of organic base and inorganic base.
22. The process according to claim 21 wherein the organic base is selected from the group comprising of isopropyl amine, diisopropyl amine, diisopropyl ethyl- amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N- methyl pyridine, DBU, DABCO and triethylamine.
23. The process according to claim 21 wherein the inorganic base is selected from the group comprising of alkali metals, alkali metal carbonates , alkali metal bicarbonates, alkali metal hydroxides and metal alkoxides.
24. The process according to the claim 18 wherein acid is selected from the group of inorganic acids or organic acids
25. The process according to the claim 24 wherein the inorganic acid is selected from the group comprising of HC1, HBr, HI, H2S04, H 03 and H3P04.
26. The process according to the claim 24 wherein the organic acid is selected from the group comprising of C2 to C4 carbons containing organic acids.
27. The process according to the claim 18 wherein the organic solvent is selected from the group comprising of alcohols, halogenated hydrocarbons, ketones, nitriles, ethers, esters, hydrocarbons, aprotic polar solvents or mixture of solvents and their combination with water.
28. The process according to the claim 18 wherein the reducing agent is selected from the group comprising of asymmetric reducing agents.
29. The process according to the claim 28 wherein asymmetric reducing agents is selected from the group comprising of borane-THF, borane-DMS, diborane with chiral catalyst, methyl-CBS, phenyl-CBS.
30. A process for the preparation of compound of formula IXA or its acid addition salts
Figure imgf000031_0001
comprising the steps of :
i) treating the compound of formula IA or its acid addition salts
Figure imgf000031_0002
in which R is hydrogen or hydroxy protecting group, L is a leaving group; with compound of formula VIIIA or its acid addition salts
Figure imgf000032_0001
wherein Rl is N-protected group, in an organic solvent, optionally in the presence of a base to obtain a compound of formula IXA or its acid addition salts.
31. The process according to the claim 30 wherein the hydroxy protected group is selected from the group of silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl, haloalkyl and hydrogen.
32. The process according to the claim 30 wherein the nitrogen protecting group is selected from the group comprising of silyl, benzyl, benzoyl, carbobenzyloxy, acetyl and tosyl.
33. The process according to the claim 30 wherein the base employed is selected from the group consisting of organic base and inorganic base
34. The process according to claim 33 wherein the organic base is selected from the group comprising of isopropyl amine, diisopropyl amine, diisopropyl ethyl- amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N- methyl pyridine, DBU, DABCO and triethylamine.
35. The process according to claim 33 wherein the inorganic base is selected from the group comprising of alkali metals, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides and metal alkoxides.
36. The process according to claim 30 wherein the organic solvent is selected from the group comprising of alcohols, halogenated hydrocarbons, ketones, nitriles, ethers, esters, hydrocarbons, aprotic polar solvents or mixture of solvents and their combination with water.
37. A compound of formula ΙΠΑ or it's acid addition salts
Figure imgf000033_0001
wherein R is hydrogen or hydroxy protecting group.
38. A compound of formula IXA and its acid addition salts
Figure imgf000033_0002
wherein R is hydrogen or hydroxy protecting group; Rl is N-protected group.
PCT/IN2013/000052 2012-03-09 2013-01-24 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 WO2013132514A2 (en)

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CN114751857A (en) * 2022-04-29 2022-07-15 梯尔希（南京）药物研发有限公司 Preparation method of indacaterol impurity

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