DESC:Field of the Invention
The present invention relates to a process for preparation of chiral intermediates of long-acting ß2-adrenoceptor agonists (LABAs) such as Vilanterol, Salmeterol, Salbutamol, Indacaterol, Abediterol, Carmoterol, Oladaterol and Arformoterol by chiral sulfide mediated epoxidation.

Background of the Invention
ß2-adrenoceptor agonists are the agents used in the treatment of bronchial asthma, chronic bronchitis, asthmatic bronchitis, emphysema, and other obstructive airways difficulty breathing disorder caused. A variety of ß2-adrenoceptor agonists with long half-lives, also called ultra long-acting ß2-adrenoceptor agonists (ultra-LABAs; Vilanterol, Salmeterol, Salbutamol, Indacaterol, Abediterol, Carmoterol, Oladaterol, Arformoterol, LAS100977 and PF-610355) are currently under development with the hopes of achieving once-daily dosing. Its pharmacological effect is attributable to stimulation of intracellular adenylyl cyclase which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cAMP). Increase in cyclic AMP are associated with relaxation of bronchial smooth muscle and inhibition of release of hypersensitivity mediators from mast cells in the lungs. Over the last decade, the development of high potency, high selectivity, rapid onset, long duration of action, is administered once daily ß2-adrenoceptor agonists caused great concern in the pharmaceutical industry.

There is a growing interest on the development of cost effective and environmentally friendly processes for non-steroidal anti-asthma agents or ß2-adrenoceptor agonists.

There are known processes for the preparation of intermediates of certain ß2-adrenoceptor agonists such as Vilanterol, Salmeterol, Salbutamol, Indacaterol, Abediterol, Carmoterol, Oladaterol and Arformoterol. However, said processes result in moderate enantioselectivity, extended reaction times, cryogenic conditions and unsatisfactory conversions. Further, such processes use expensive chiral agents.

Thus, there is a need for an industrially feasible process for preparation of chiral intermediates of Vilanterol, Salmeterol, Salbutamol, Indacaterol, Abediterol, Carmoterol, Oladaterol and Arformoterol with improved yield and purity, and reduction in production cost.

Summary of the invention
In one aspect, the present invention relates to a process for preparation of chiral compound of formula (XXXVI) by reacting a compound of Formula (XXXIV) with a chiral sulfide compound of Formula (XXXV) in presence of a first base and first solvent.

Formula (XXXIV) Formula (XXXV) Formula (XXXVI)

wherein, when R2 is -O-Benzene, R1 is selected from -NO2, -COOCH3, fused at positions a and b, fused at positions a and b,

or
R1 and R2 together is .

In another aspect of the invention, a process of preparing a compound having formula (XXXVIII) is disclosed. The process comprises the steps of reacting a compound of formula (XXXIV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XXXVI);
reacting the compound of formula (XXXVI) with a first catalyst in presence of a second solvent and a reagent to form a compound of formula (XXXVII); and
reacting the compound of formula (XXXVII) in presence of a third solvent with a second catalyst to obtain the compound of formula (XXXVIII).

Formula (XXXIV) Formula (XXXV) Formula (XXXVI)

Formula (XXXVII) Formula (XXXVIII)
wherein, when R2 is -O-Benzene, R1 is selected from -NO2, -COOCH3, fused at positions a and b, fused at positions a and b,
or
R1 and R2 together is

In another aspect the present invention relates to a process for preparation of compound of formula (VI), an intermediate of Vilanterol, Salbutamol, Salmeterol.

Formula (VI)
In another aspect the present invention relates to a process for preparation of compound of formula (XII) an intermediate of Vilanterol, Salbutamol, Salmeterol.

Formula (XII)
In another aspect the present invention relates to a process for preparation of compound of formula (XIX), an intermediate of Indacterol, Abediterol, Carmoterol.

Formula (XIX)
In another aspect the present invention relates to a process for preparation of compound of formula (XXVI), an intermediate of Oladaterol.

Formula (XXVI)
In another aspect the present invention relates to a process for preparation of compound of formula (XXXII), an intermediate of Arformoterol.

Formula (XXXII)
Detailed description of the invention
In an embodiment, the present invention relates to a process for preparation of a chiral compound of Formula (XXXVI) by reacting a compound of formula (XXXIV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent.

Formula (XXXIV) Formula (XXXV) Formula (XXXVI)
wherein, when R2 is -O-Benzene, R1 is selected from -NO2, -COOCH3, fused at positions a and b, fused at positions a and b
or
R1 and R2 together is .

The process includes a step of stirring the reaction mixture. The first base is selected from potassium hydroxide, sodium hydroxide lithium hydroxide, and the first solvent is selected from methanol, isopropyl alcohol, tert-butyl alcohol. The process is carried out at a temperature of at least 20°C, preferably the temperature is in a range from 20°C to room temperature.

In another embodiment, the present invention relates to a process for preparation of a chiral compound having formula (XXXVIII) by reacting a compound of formula (XXXIV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XXXVI);
reacting the compound of formula (XXXVI) with a first catalyst in presence of a second solvent and a reagent to form a compound of formula (XXXVII); and
reacting the compound of formula (XXXVII) in presence of a third solvent with a second catalyst to obtain the compound of formula (XXXVIII).

Formula (XXXIV) Formula (XXXV) Formula (XXXVI)

Formula (XXXVII) Formula (XXXVIII)
wherein, when R2 is -O-Benzene, R1 is selected from -NO2¬, -COOCH3, fused at positions a and b, fused at positions a and b,
or
R1 and R2 together is .

The first base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, the first solvent is selected from methanol, isopropyl alcohol, tert-butyl alcohol, the first catalyst is selected from MgI2 etherate, iodine, lithium perchlorate, sodium iodide lithium chloride, the second solvent is selected from tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, the reagent selected from benzyl isocyanate, p-methoxyphenyl isocyanate sodium cyanate, the third solvent is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, the second catalyst is selected from Pd/C, Pd/BaSO4, Raney nickel/Hydrogen.

The compound of formula (XXXIV) is reacted with compound of formula (XXXV) at a temperature of at least 20°C, preferably the temperature is in a range from 20°C to room temperature to form the compound of formula (XXXVI) and the compound of formula (XXXVI) is reacted at a temperature of at least 75°C, preferably the temperature is in a range from 75°C to 80°C.

The present invention also discloses a process to prepare compound of formula (XXXIV). The process comprises the steps of reacting a compound of formula (XXXIX) in presence of the second solvent with a second base and a fourth solvent to form a compound of formula (XXXIV).

Formula (XXXIX) Formula (XXXIV)
wherein, when R2 is -O-Benzene, R1 is selected from -NO2, -COOCH3, fused at positions a and b, fused at positions a and b,
or
R1 and R2 together is .

The second solvent is selected from tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, the second base is selected from n-butyl lithium, s-butyl lithium, lithium diisopropyl amide, potassium bis(trimethylsilyl) amide, and the fourth solvent is N, N-dimethylformamide and tetrahydrofuran in a ratio of at least 1:1. The temperature of the reaction is at least -78°C.

The process for preparation of compound of Formula (XXXIX) having a structure as formula (III) comprises the steps of:
reacting a compound of formula (I) with a reducing agent in presence of the second solvent and a halide to form a compound of formula (II);
reacting the compound of formula (II) with a third catalyst in presence of a fifth solvent and a dehydrating agent to form a compound of formula (III);

Formula (I) Formula (II) Formula (III)

The second solvent is selected from tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, the halide is selected from iodine compound, lithium chloride, lithium bromide, nickel chloride, zinc chloride, the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, sodium bis 2(-methoxy ethoxy) aluminium hydride, lithium aluminium hydride, borane dimethyl sulfide complex, the third catalyst is selected from p-toluene sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, the fifth solvent is selected from dichloromethane, dichloroethane chloroform, and the dehydrating agent is 2,2-dimethoxy propane. The temperature of the reaction is at least -5°C, preferably the temperature is in a range from 0°C to -5°C.

The process of preparation of compound of Formula (XXXIX) having a structure as formula (IX) comprises the steps of
reacting compound of formula (I) in presence of a third solvent with a first acid to form a compound of formula (VIII); and
reacting the compound of formula (VIII) in presence of a sixth solvent with a third base and a benzylating agent to form the compound of formula (IX).

Formula (I) Formula (VIII) Formula (IX)

The third solvent is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, the first acid is selected from concentrated sulfuric acid, hydrochloric acid, acetyl chloride, thionyl chloride, the sixth solvent is selected from acetone, dimethyl formamide, tetrahydrofuran, the third base is selected from potassium carbonate, sodium carbonate, caesium carbonate, and the benzylating agent is selected from benzyl bromide, benzyl chloride, benzyl iodide. The temperature of the reaction is at least 65°C, preferably 65°C to 70°C.

The process of preparation of compound of Formula (XXXIX) having a structure as formula (XL) comprises the steps of reacting a compound of formula (XLI) in presence of the sixth solvent with the third base and the benzylating agent to form a compound of formula (XLII);
reacting the compound of formula (XLII) with a second acid and a brominating agent to form a compound of formula (XL);

Formula (XLI) Formula (XLII) Formula (XL)
wherein the compound of formula (XL) has a structure as Formula XVI or Formula XXIII

Formula (XVI) Formula (XXIII)

The benzylation step is carried out at a temperature of at least 60°C, preferably the temperature is in a range from 60°C to 65°C, bromination is carried out at a temperature at least 0°C, preferably the temperature is in a range from 0°C to room temperature, the sixth solvent is selected from acetone, dimethyl formamide, tetrahydrofuran, the third base is selected from potassium carbonate, sodium carbonate, caesium carbonate, and the benzylating agent is selected from benzyl bromide, benzyl chloride, benzyl iodide, the second acid is selected from formic acid, acetic acid hydrobromic acid, and the brominating agent is selected from N-bromosuccinimide, dibromohydantoin.

The process of preparation of compound of Formula (XXXIX) having a structure as formula (XXIX) comprises reacting compound of formula (XXVIII) in presence of a sixth solvent with a third base and a benzylating agent to form compound of formula (XXIX).

Formula (XXVIII) Formula (XXIX)

The compound of formula (III), the compound of formula (IX), the compound of formula (XVI), the compound of formula (XXIII) the compound of formula (XXIX) is used as a reactant to form the compound of formula (XXXIV).

The present invention also discloses a process for preparation of a chiral intermediate compound of Formula (VI), an intermediate of Vilanterol, Salmeterol, and Salbutamol using a chiral sulfide intermediate compound of Formula (XXXV).The process comprises the steps of reacting a compound of formula (I) with a reducing agent in presence of a second solvent and a halide to form a compound of formula (II);
reacting the compound of formula (II) in presence of a third catalyst with a fifth solvent and a dehydrating agent to form a compound of formula (III);
reacting the compound of formula (III) in presence of a second solvent with a second base and a fourth solvent to form a compound of formula (IV);
reacting the compound of formula (IV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (V);
reacting the compound of formula (V) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (VII); and
reacting the compound of formula (VII) in presence of a third solvent with a second catalyst to obtain the compound of formula (VI).

The present invention discloses a process for preparation of a chiral intermediate compound of Formula (XII), an intermediate of Vilanterol, Salmeterol, and Salbutamol using a chiral sulfide intermediate compound of Formula (XXXV).
The process comprises the steps of:
reacting compound of formula (I) in presence of a third solvent with a first acid to form a compound of formula (VIII);
reacting the compound of formula (VIII) in presence of a sixth solvent with a third base and a benzylating agent to form the compound of formula (IX);
reacting a compound of formula (IX) in presence of a second solvent with a second base and a fourth solvent to form a compound of formula (X);
reacting a compound of formula (X) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XI);
reacting the compound of formula (XI) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (XIII); and
reacting the compound of formula (XIII) in presence of a third solvent with a second catalyst to obtain compound of formula (XII).

The present invention discloses a process for preparation of a chiral intermediate compound of Formula (XIX), an intermediate of Indacaterol, Abediterol, and Carmoterol using a chiral sulfide intermediate compound of Formula (XXXV) is disclosed. The process comprises the steps of:
reacting compound of formula (XIV) in presence of a sixth solvent with a third base and a benzylating agent to form a compound of formula (VX);
reacting the compound of formula (XV) with a second acid and a brominating agent to form a compound of formula (XVI);
reacting a compound of formula (XVI) in presence of a second solvent with a second base and a fourth solvent to form a compound of formula (XVII).
reacting the compound of formula (XVII) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XVIII);
reacting the compound of formula (XVIII) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (XX); and
reacting the compound of formula (XX) in presence of a third solvent with a second catalyst to obtain compound of formula (XIX).

The present invention also discloses a process for preparation of a chiral intermediate compound of Formula (XXVI) of Oladaterol using a chiral sulfide intermediate compound of Formula (XXXV). The process comprises the steps of:
reacting compound of formula (XXI) in presence of a sixth solvent with a third base and a benzylating agent to form compound of formula (XXII);
reacting the compound of formula (XXII) with a second acid and a brominating agent form a compound of formula (XXIII);
reacting a compound of formula (XIII) in presence of a second solvent with a second base and a fourth solvent to form a compound of formula (XVI);
reacting a compound of formula (XXIV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XXV);
reacting the compound of formula (XXV) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (XXVII); and
reacting the compound of formula (XXVII) in presence of a third solvent with a second catalyst to obtain compound of formula (XXVI).

The present invention also discloses a process for preparation of a chiral intermediate compound of Formula (XXXII), an intermediate of Arformoterol using a chiral sulfide intermediate compound of Formula (XXXV). The process comprises the steps of:
reacting compound of formula (XXVIII) in presence of a sixth solvent with a third base and a benzylating agent to form a compound of formula (XXIX);
reacting a compound of formula (XXIX) in presence of a second solvent with a second base and a fourth solvent to form compound of formula (XXX);
reacting a compound of formula (XXX) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XXXI);
reacting the compound of formula (XXXI) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (XXXIII); and
reacting the compound of formula (XXXIII) in presence of a third solvent with a second catalyst to obtain the compound of formula (XXXII).
The first solvent is selected from methanol, isopropyl alcohol, tert-butyl alcohol, the second solvent is selected from tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether diethyl ether, the third solvent is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, the fourth solvent is N,N-dimethylformamide and tetrahydrofuran in a ratio of at least 1:1, the fifth solvent is selected from dichloromethane, dichloroethane, chloroform, the sixth solvent is selected from acetone, dimethyl formamide, tetrahydrofuran, the first base is selected from potassium hydroxide, sodium hydroxide lithium hydroxide, the second base is selected from n-butyl lithium, s-butyl lithium, lithium diisopropyl amide, potassium bis(trimethylsilyl) amide, the third base is selected from potassium carbonate, sodium carbonate, caesium carbonate, the first catalyst is selected from MgI2 etherate, iodine, lithium perchlorate, sodium iodide lithium chloride, the second catalyst is selected from Pd/C, Pd/BaSO4, Raney nickel/Hydrogen, the third catalyst is selected from p-toluene sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, the reagent selected from benzyl isocyanate, p-methoxyphenyl isocyanate sodium cyanate, the benzylating agent is selected from benzyl bromide, benzyl chloride, benzyl iodide, the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, sodium bis 2(-methoxy ethoxy) aluminium hydride, lithium aluminium hydride, borane dimethyl sulfide complex, the halide is selected from iodine compound, lithium chloride, lithium bromide, nickel chloride, zinc chloride, the dehydrating agent is 2,2-dimethoxy propane, the first acid is selected from concentrated sulfuric acid, hydrochloric acid, acetyl chloride, thionyl chloride, the second acid is selected from formic acid, acetic acid hydrobromic acid, and the brominating agent is selected from N-bromosuccinimide, dibromohydantoin.

The present invention discloses a process for preparation of a chiral intermediate compound of Formula (VI), an intermediate of Vilanterol, Salmeterol, and Salbutamol using a chiral sulfide intermediate compound of Formula (XXXV) comprising the steps of:
a) reducing a compound of Formula (I) with a reducing agent in presence of a solvent at a temperature followed by adding a halide and refluxing for a time and at a temperature to obtain a compound of Formula (II);

b) reacting the compound of Formula (II) with a catalyst in presence of a solvent followed by adding a dehydrating agent in presence of the solvent to form a compound of Formula (III);

c) dissolving the compound of Formula (III) in a solvent and cooling to a temperature followed by adding a strong base and stirring at a temperature for a time to obtain a reaction mixture;
d) treating the above reaction mixture with a mixture of solvent at a ratio and stirring the reaction mixture at a temperature for a time to obtain a compound of Formula (IV);

e) reacting the compound of Formula (IV) with a chiral sulfide intermediate compound of Formula (XXXV) in presence of a strong base and a solvent and stirring at temperature for a time to form a chiral epoxide compound of Formula (V);

f) adding the compound of Formula (V) to a catalyst in presence of a solvent followed by adding a reagent at a temperature to obtain a reaction mixture and then heating the reaction mixture to a temperature for a time to obtain a compound of Formula (VII); and

g) adding the compound of Formula (VII) to a solvent in presence of a catalyst followed by charging a gas at a pressure and stirring for a time at a temperature to obtain a chiral intermediate compound of Formula (VI) of Vilanterol, Salmeterol and Salbutamol.

In an embodiment, the compound of Formula (I) in step (a) is 5-bromo-2-hydroxybenzoic acid. In step (a) the reducing agent is selected from a group of sodium borohydride (NaBH4), sodium cyanoborohydride, sodium bis(2-methoxyethoxy) aluminium hydride (Red-Al), lithium aluminum hydride (LAH), Borane dimethyl sulfide complex (BH3.SMe2) or like. The solvent is selected from a group of tetrahydrofuran (THF), methyl tert-butyl ether, diisopropyl ether, diethyl ether or like. The temperature is -5°C to 0°C. The halide compound is selected from a group of iodine compound, lithium chloride (LiCl), lithium bromide (LiBr), nickel chloride (NiCl2), zinc chloride ZnCl2), or like. Refluxing is done for a temperature of 0°C to 80°C for a time of 8 hours to 12 hours.
In step (b) the catalyst is selected from the group of p-toluene sulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, or like. The solvent is selected from the group of dichloromethane, dichloroethane, chloroform, or like. The dehydrating agent is 2,2-dimethoxypropane.
In step (c) the solvent is tetrahydrofuran (THF), methyl tert-butylether, diisopropyl ether, diethyl ether, or like. The cooling is done to a temperature from 0°C to -78°C. The strong base is selected from the group of n-butyl lithium, s-butyl lithium, lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), or like. Further the stirring is done at a temperature from -70°C to -78°C and for a time of 2 hours to 3 hours.
In step (d) the mixture of solvent is N, N-dimethylformamide and tetrahydrofuran at a ratio of 1:1. Stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 45 minutes to 1 hour.
In step (e) the strong base is selected from the group of potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), or like. The solvent is selected from the group of tert-butyl alcohol, isopropyl alcohol, methanol, or like. Stirring is done at temperature of 20°C to room temperature for a time of 42 hours to 48 hours.
In step (f) the catalyst is selected from MgI2 etherate (MgI2.OEt2), Iodine (I2), lithium perchlorate (LiClO4), sodium iodide (NaI), lithium chloride (LiCl) or like. The solvent is selected from the group of tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, or like. The reagent is selected from the group of benzyl isocyanate, p-methoxyphenyl isocyanate, sodium cyanate, or like. The temperature under is 20°C to room temperature. Heating of the reaction mixture is done at temperature of 75°C to 80°C for a time of 2 hours to 4 hours.
In step (g) the solvent is selected from the group of methanol, ethanol, Isopropyl alcohol, ethyl acetate, or like. The catalyst is selected from palladium supported on Carbon (Pd/C), Pd/BaSO4, Raney nickel, or like. The gas is hydrogen gas and is charged at a pressure of 100 psi to 150 psi.
In an embodiment, the chiral intermediate compound of Formula (VI) of Vilanterol, Salmeterol and Salbutamol has a purity of 98% to 99% HPLC purity and yield of 90% to 95% yield.

In a further embodiment, a process for preparation of a chiral sulfide intermediate compound of Formula (XXXV) used in step (e) is disclosed. the process comprises the steps of:

A) adding an elemental sulfur to a compound of Formula (1) along with a compound of Formula (2) or compound of Formula (3) and heating to a temperature under vigorous stirring for a time to obtain a compound of Formula (4); and

B) preparing a solution of the compound of Formula (4) in a solvent and adding the solution to a methylating agent in presence of a catalyst to obtain a reaction mixture and stirring the reaction mixture at room temperature for a time to form a compound of Formula (XXXV).

In an embodiment, the compound of Formula (1) is (R)-Limonene, the compound of Formula (2) is 1,4-cyclohexadiene and the compound of Formula (3) is ?-terpinene. In step (A) the heating is done to a temperature under vigorous stirring from 105°C to 110°C for a time of 12 hours to 15 hours.
In step (B) the solvent is selected from the group of acetone, acetonitrile, dichloromethane, dichloroethane, or like. The methylating agent is selected from the group of methyl bromide, methyl iodide, or like. The catalyst is selected from the group of silver perchlorate, sodium perchlorate, or like. Stirring of the reaction mixture is done for a time of 0.5 hours to 1 hour.
In this embodiment, the chiral sulfide intermediate compound of Formula (XXXV) has a purity of 99.2% to 99.8% HPLC purity and yield of 65 % to 70% yield.

In a preferred embodiment, the process for preparation of a chiral intermediate compound of Formula (XII) of Vilanterol, Salmeterol, and Salbutamol using a chiral sulfide intermediate compound of Formula (XXXV) comprising the steps of:
1) dissolving a compound of Formula (I) in a solvent and adding a strong acid at a temperature to obtain a reaction mixture;
2) heating the above reaction mixture to a temperature for a time and followed by cooling the reaction mixture to a temperature to obtain a compound of Formula (VIII);

3) adding the compound of Formula (VIII) in a solvent followed by adding a base and a benzylating agent at a temperature followed by stirring and refluxing for a time and at a temperature to obtain a compound of Formula (IX);

4) dissolving the compound of Formula (IX) in a solvent and cooling to a temperature followed by adding a strong base and stirring the above reaction mixture at a temperature for a time to obtain a reaction mixture;
5) treating the above reaction mixture with a mixture of solvent at a ratio and stirring the reaction mixture at a temperature for a time to obtain a compound of Formula (X);

6) reacting the compound of Formula (X) with a chiral sulfide intermediate compound of Formula (XXXV) in presence of a strong base and a solvent and stirring at temperature for a time to form a chiral epoxide compound of Formula (XI);

7) adding the compound of Formula (XI) to a catalyst in presence of a solvent followed by adding a reagent at a temperature to obtain a reaction mixture and then heating the reaction mixture to a temperature for a time to obtain a compound of Formula (XIII); and

8) adding the compound of Formula (XIII) to a solvent in presence of a catalyst followed by charging a gas at a pressure and stirring for a time at a temperature to obtain a chiral intermediate compound of Formula (XII) of Vilanterol, Salmeterol, and Salbutamol.

In an embodiment, the compound of Formula (I) in step (1) is 5-bromo-2-hydroxybenzoic acid. In step (1) the solvent is selected from methanol, ethanol, isopropanol or like. The strong acid is selected from conc. sulfuric acid, hydrochloric acid (HCl), Acetyl chloride (CH3COCl), thionyl chloride (SOCl2) or like and the addition is done at a temperature of 0°C to 5°C.
In step (2), heating of the reaction mixture is done at a temperature of 65°C to 70°C for a time of 15 hours to 20 hours. The cooling is done to a temperature of 25°C to 27°C.
In step (3), the solvent is selected from acetone, dimethyl formamide (DMF), tetrahydrofuran (THF) or like. The base is selected from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), caesium carbonate (Cs2CO3) or like. The benzylating agent is selected from benzyl bromide, benzyl chloride, benzyl iodide, or like. The addition is done at a temperature of 0°C to 5°C. The stirring and refluxing is done at a time of 8 hours to 12 hours and at a temperature of 60°C to 65°C.
In step (4) the solvent is tetrahydrofuran (THF), methyl tert-butylether, diisopropyl ether, diethyl ether, or like. The cooling is done to a temperature from 0°C to -78°C.

The strong base is selected from the group of n-butyl lithium, s-butyl lithium, lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), or like. Further the stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 2 hours to 3 hours.
In step (5) the mixture of solvent is N, N-dimethylformamide and tetrahydrofuran at a ratio of 1:1. Stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 45 minutes to 1 hour.
In step (6) the strong base is selected from the group of potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), or like. The solvent is selected from the group of tert-butyl alcohol, isopropyl alcohol, methanol, or like. Stirring is done at temperature of 20°C to room temperature for a time of 42 hours to 48 hours.
In step (7) the catalyst is selected from MgI2 etherate (MgI2.OEt2), Iodine (I2), lithium perchlorate (LiClO4), sodium iodide (NaI), lithium chloride (LiCl) or like. The solvent is selected from the group of tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, or like. The reagent is selected from the group of benzyl isocyanate, p-methoxyphenyl isocyanate, sodium cyanate, or like. The temperature under is 20°C to room temperature. Heating of the reaction mixture is done at temperature of 75°C to 80°C for a time of 2 hours to 4 hours.
In step (8) the solvent is selected from the group of methanol, ethanol, Isopropyl alcohol, ethyl acetate, or like. The catalyst is selected from palladium supported on Carbon (Pd/C), Pd/BaSO4, Raney nickel, or like. The gas is hydrogen gas and is charged at a pressure of 100 psi to 150 psi.

In an embodiment, the chiral intermediate compound of Formula (XII) of Vilanterol, Salmeterol, and Salbutamol has a purity of 98% to 99.9% HPLC purity and yield of 89% to 92% yield.

In a preferred embodiment, the process for preparation of a chiral intermediate compound of Formula (XIX) of Indacaterol, Abediterol, and Carmoterol using a chiral sulfide intermediate comprising the steps of:
I) adding a compound of Formula (XIV) in a solvent followed by adding a base and a benzylating agent at a temperature followed by stirring and refluxing for a time and at a temperature to obtain a compound of Formula (XV);

II) dissolving the compound of Formula (XV) in an acid and adding a brominating agent in presence of an acid to make a reaction mixture and stirring the reaction mixture at a temperature for a time to obtain a compound of Formula (XVI);

III) dissolving the compound of Formula (XVI) in a solvent and cooling to a temperature followed by adding a strong base and stirring the above reaction mixture at a temperature for a time to obtain a reaction mixture;
IV) treating the above reaction mixture with a mixture of solvent at a ratio and stirring the reaction mixture at a temperature for a time to obtain a compound of Formula (XVII);

V) reacting the compound of Formula (XVII) with a chiral sulfide intermediate compound of Formula (XXXV) in presence of a strong base and a solvent and stirring at temperature for a time to form a chiral epoxide compound of Formula (XVIII);

VI) adding the compound of Formula (XVIII) to a catalyst in presence of a solvent followed by adding a reagent at a temperature to obtain a reaction mixture and then heating the reaction mixture to a temperature for a time to obtain a compound of Formula (XX); and

VII) adding the compound of Formula (XX) to a solvent in presence of a catalyst followed by charging a gas at a pressure and stirring for a time at a temperature to obtain a chiral intermediate compound of Formula (XIX) of Indacaterol, Abediterol, and Carmoterol.

In an embodiment, the compound of Formula (XIV) in step (I) is 8-Hydroxyquinolin-2-(1H)-one. In step (I), the solvent is selected from acetone, THF, DMF or like. The base is selected from potassium carbonate (K2CO3), Na2CO3, Cs2CO3 or like. The benzylating agent is selected from benzyl bromide, benzyl chloride, benzyl iodide, or like. The addition is done at a temperature of 0°C to 5°C. The stirring and refluxing is done at a time of 10 hours to 12 hours and at a temperature of 60°C to 65°C.
In step (II) the acid is selected from acetic acid, formic acid (HCO2H), hydrobromic acid (HBr), or like. The brominating agent is selected from bromine, 1,3-dibromohydantoin, NBS or like. The stirring of the reaction mixture is done at a temperature of 0°C to room temperature and for a time of 3 hours to 4 hours.
In step (III) the solvent is tetrahydrofuran (THF), methyl tert-butylether, diisopropyl ether, diethyl ether, or like. The cooling is done to a temperature from 0°C to -78°C. The strong base is selected from the group of n-butyl lithium, s-butyl lithium, lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), or like. Further the stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 2 hours to 3 hours.
In step (IV) the mixture of solvent is N, N-dimethylformamide and tetrahydrofuran at a ratio of 1:1. Stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 45 minutes to 1 hour.
In step (V) the strong base is selected from the group of potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), or like. The solvent is selected from the group of tert-butyl alcohol, isopropyl alcohol, methanol, or like. Stirring is done at temperature of 20°C to room temperature for a time of 42 hours to 48 hours.
In step (VI) the catalyst is selected from MgI2 etherate (MgI2.OEt2), Iodine (I2), lithium perchlorate (LiClO4), sodium iodide (NaI), lithium chloride (LiCl) or like. The solvent is selected from the group of tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, or like. The reagent is selected from the group of benzyl isocyanate, p-methoxyphenyl isocyanate, sodium cyanate, or like. The temperature under is 20°C to room temperature. Heating of the reaction mixture is done at temperature of 75°C to 80°C for a time of 2 hours to 4 hours.
In step (VII) the solvent is selected from the group of methanol, ethanol, Isopropyl alcohol, ethyl acetate, or like. The catalyst is selected from palladium supported on Carbon (Pd/C), Pd/BaSO4, Raney nickel, or like. The gas is hydrogen gas and is charged at a pressure of 100 psi to 150 psi.
In an embodiment, the chiral intermediate compound of Formula (XIX) of Indacaterol, Abediterol, and Carmoterol has a purity of 98% to 99.9% HPLC purity and yield of 90% to 96% yield.

In a preferred embodiment, the process for preparation of a chiral intermediate compound of Formula (XXVI) of Oladaterol using a chiral sulfide intermediate compound of Formula (XXXV) comprising the steps of:
i) adding a compound of Formula (XXI) in a solvent followed by adding a base and a benzylating agent at a temperature followed by stirring and refluxing for a time and at a temperature to obtain a compound of Formula (XXII);

ii) dissolving the compound of Formula (XXII) in an acid and adding a brominating agent in presence of an acid to make a reaction mixture and stirring the reaction mixture at a temperature for a time to obtain a compound of Formula (XXIII);

iii) dissolving the compound of Formula (XXIII) in a solvent and cooling to a temperature followed by adding a strong base and stirring the above reaction mixture at a temperature for a time to obtain a reaction mixture;
iv) treating the above reaction mixture with a mixture of solvent at a ratio and stirring the reaction mixture at a temperature for a time to obtain a compound of Formula (XXIV);

v) reacting the compound of Formula (XXIV) with a chiral sulfide intermediate compound of Formula (XXXV) in presence of a strong base and a solvent and stirring at temperature for a time to form a chiral epoxide compound of Formula (XXV);

vi) adding the compound of Formula (XXV) to a catalyst in presence of a solvent followed by adding a reagent at a temperature to obtain a reaction mixture and then heating the reaction mixture to a temperature for a time to obtain a compound of Formula (XXVII); and

vii) adding the compound of Formula (XXVII) to a solvent in presence of a catalyst followed by charging a gas at a pressure and stirring for a time at a temperature to obtain a chiral intermediate compound of Formula (XXVI) of Oladaterol.

In an embodiment, the compound of Formula (XXI) in step (i) is 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one. In step (i), the solvent is selected from acetone, DMF, THF or like. The base is selected from potassium carbonate (K2CO3), Na2CO3, Cs2CO3-- or like. The benzylating agent is selected from benzyl bromide, benzyl bromide, benzyl chloride, benzyl iodide, or like. The addition is done at a temperature of 0°C to 5°C. The stirring and refluxing is done at a time of 8 hours to 10 hours and at a temperature of 60°C to 65°C.
In step (ii) the acid is selected from acetic acid, HCO2H, HBr, or like. The brominating agent is selected from bromine, N-Bromosuccinimide (NBS), or dibromohydantoin like. The stirring of the reaction mixture is done at a temperature of 0°C to room temperature and for a time of 3 hours to 4 hours.
In step (iii) the solvent is tetrahydrofuran (THF), methyl tert-butylether, diisopropyl ether, diethyl ether, or like. The cooling is done to a temperature from 0°C to -78°C. The strong base is selected from the group of n-butyl lithium, s-butyl lithium, lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), or like. Further the stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 2 hours to 3 hours.
In step (iv) the mixture of solvent is N, N-dimethylformamide and tetrahydrofuran at a ratio of 1:1. Stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 45 minutes to 1 hour.
In step (v) the strong base is selected from the group of potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), or like. The solvent is selected from the group of tert-butyl alcohol, isopropyl alcohol, methanol, or like. Stirring is done at temperature of 20°C to room temperature for a time of 42 hours to 48 hours.
In step (vi) the catalyst is selected from MgI2 etherate (MgI2.OEt2), Iodine (I2), lithium perchlorate (LiClO4), sodium iodide (NaI), lithium chloride (LiCl) or like. The solvent is selected from the group of tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, or like. The reagent is selected from the group of benzyl isocyanate, p-methoxyphenyl isocyanate, sodium cyanate, or like. The temperature under is 20°C to room temperature. Heating of the reaction mixture is done at temperature of 75°C to 80°C for a time of 2 hours to 4 hours.
In step (vii) the solvent is selected from the group of methanol, ethanol, Isopropyl alcohol, ethyl acetate, or like. The catalyst is selected from palladium supported on Carbon (Pd/C), Pd/BaSO4, Raney nickel, or like. The gas is hydrogen gas and is charged at a pressure of 100 psi to 150 psi.
In an embodiment, the chiral intermediate compound of Formula (XXVI) of Oladaterol has a purity of 98% to 99.9% HPLC purity and yield of 90% to 94% yield.

In a preferred embodiment, the process for preparation of a chiral intermediate compound of Formula (XXXII) of Arformoterol using a chiral sulfide intermediate compound of Formula (XXXV) is prepared as follows:
01) adding a compound of Formula (XXVIII) in a solvent followed by adding a base and a benzylating agent at a temperature followed by stirring and refluxing for a time and at a temperature to obtain a compound of Formula (XXIX);

02) dissolving the compound of Formula (XXIX) in a solvent and cooling to a temperature followed by adding a strong base and stirring the above reaction mixture at a temperature for a time to obtain a reaction mixture;
03) treating the above reaction mixture with a mixture of solvent at a ratio and stirring the reaction mixture at a temperature for a time to obtain a compound of Formula (XXX);

04) reacting the compound of Formula (XXX) with a chiral sulfide intermediate compound of Formula (XXXV) in presence of a strong base and a solvent and stirring at temperature for a time to form a chiral epoxide compound of Formula (XXXI);

05) adding the compound of Formula (XXXI) to a catalyst in presence of a solvent followed by adding a reagent at a temperature to obtain a reaction mixture and then heating the reaction mixture to a temperature for a time to obtain a compound of Formula (XXXIII); and

06) adding the compound of Formula (XXXIII) to a solvent in presence of a catalyst followed by charging a gas at a pressure and stirring for a time at a temperature to obtain a chiral intermediate compound of Formula (XXXII) of Arformoterol.

In an embodiment, the compound of Formula (XXVIII) in step (01) is 4-bromo-2-nitro-phenol. In step (01), the solvent is selected from acetone, DMF, THF or like. The base is selected from potassium carbonate (K2CO3), Na2CO3, Cs2CO3-- or like. The benzylating agent is selected from benzyl bromide, -benzyl chloride, benzyl iodide, or like. The addition is done at a temperature of 0°C to 5°C. The stirring and refluxing is done at a time of –8 hours to 10 hours and at a temperature of 60°C to 65°C.
In step (02) the solvent is tetrahydrofuran (THF), methyl tert-butylether, diisopropyl ether, diethyl ether, or like. The cooling is done to a temperature from 0°C to -78°C. The strong base is selected from the group of n-butyl lithium, s-butyl lithium, lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), or like. Further the stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 2 hours to 3 hours.
In step (03) the mixture of solvent is N, N-dimethylformamide and tetrahydrofuran at a ratio of 1:1. Stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 45 minutes to 1 hour.
In step (04) the strong base is selected from the group of potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), or like. The solvent is selected from the group of tert-butyl alcohol, isopropyl alcohol, methanol, or like. Stirring is done at temperature of 20°C to room temperature for a time of 42 hours to 48 hours.
In step (05) the catalyst is selected from MgI2 etherate (MgI2.OEt2), Iodine (I2), lithium perchlorate (LiClO4), sodium iodide (NaI), lithium chloride (LiCl) or like. The solvent is selected from the group of tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, or like. The reagent is selected from the group of benzyl isocyanate, p-methoxyphenyl isocyanate, sodium cyanate, or like. The temperature under is 20°C to room temperature. Heating of the reaction mixture is done at temperature of 75°C to 80°C for a time of 2 hours to 4 hours.
In step (06) the solvent is selected from the group of methanol, ethanol, Isopropyl alcohol, ethyl acetate, or like. The catalyst is selected from palladium supported on Carbon (Pd/C), Pd/BaSO4, Raney nickel, or like. The gas is hydrogen gas and is charged at a pressure of 100 psi to 150 psi.
In an embodiment, the chiral intermediate compound of Formula (XXXII) of Arformoterol as a purity of 98% to 99.9% HPLC purity and yield of 90% to 96% yield.

The reaction scheme for preparation of a chiral intermediate compound of Formula (VI) of Vilanterol, Salmeterol, and Salbutamol is represented below:

The reaction scheme for preparation of a chiral intermediate compound of Formula (XII) of Vilanterol, Salmeterol, and Salbutamol is represented below:

The reaction scheme for preparation of a chiral intermediate compound of Formula (XIX) of Indacaterol, Abediterol, and Carmoterol is represented below:

The reaction scheme for preparation of a chiral intermediate compound of Formula (XXVI) of Oladaterol is represented below:

The reaction scheme for preparation of a chiral intermediate compound of Formula (XXXII) of Arformoterol is represented below:

EXAMPLES
The following examples illustrate the invention without limiting its scope.

Example 1: Preparation of the chiral intermediate compound of Formula (VI) of Vilanterol, Salmeterol, and Salbutamol:

1) To a solution of 5-bromo-2-hydroxybenzoic acid (I) (5.0g, 0.023 mol.) in dry THF (50 mL) were added NaBH4 (2.0g, 0.053mol) at 0 °C followed by a solution of iodine (5.8g, 0.023mol.) in dry THF (30 mL) drop wise. The mixture was heated to reflux overnight and then quenched with MeOH (˜200 mL) until a clear solution. The solvents were removed and the mixture was diluted with water and extracted with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3x200 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the compound (II) 76% yield as a white solid.
2) To a suspension of 4-bromo-2-(hydroxymethyl)phenol (II) (3.0g, 0.015mol) and p-toluenesulfonic acid (0.03g, 0.0002 mol) in 40 ml of dichloromethane was added a solution of 2,2-dimethoxypropane (2.0mL, 0.016 mol) in dichloromethane (15 ml) in drop wise manner. The suspension was stirred vigorously until it becomes homogeneous (light yellow). The mixture was quenched with sat. NaHCO3 solution. The organic phase was separated and dried over MgSO4. The solvent was evaporated under reduced pressure to give the acetonide (III) in 84% yield.
3) The above bromo acetonide (III) (4.0 g, 0.017mol.) was dissolved in dry THF, cooled to -78 °C and a 1.6 M solution of n-butyl lithium (21.25 mL, 1.6 M in hexane, 0.034 mol.) was added drop wise. The mixture was stirred at -78 °C for 2 h and then treated with dry N,N-dimethylformamide (18.7 mL, 0.26 mol) as a 1:1 solution in dry THF. The resulting mixture was stirred at -78 °C for 0.75 h and warmed slowly up to room temperature. Then the mixture was diluted with diethyl ether, washed with water followed by a brine solution and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatograph on silica gel to give the required compound (IV) (70% yield).
4) A mixture of aldehyde (IV) (3.0g, 0.016mol), sulfonium perchlorate (5.5g, 0.019mol) and powdered KOH (1.1g, 0.019mol) in tert-butyl alcohol (40 mL) was stirred at room temperature for 48 h. Then the mixture was quenched with water and extracted with dichloromethane (30 mL x 3). The combined extracts were washed with sat. NaCl and dried over MgSO4. Evaporation of the solvent followed by purification on silica gel using a mixture of EtOAc - hexane as an eluent gave the epoxide (V) in 83% yield.
5) To a stirred solution of freshly prepared MgI2.OEt2 (0.0048 mol) in THF (25 mL) was added (R)-2,2-dimethyl-6-(oxiran-2-yl)-4H-benzo[d][1,3]dioxine (V) (2.5g, 0.012 mol) in dropwise manner followed by addition of the benzyl isocyanate (1.3g, 0.0097 mol) at room temperature under nitrogen. After complete addition, the mixture was allowed to warm to 80 °C and stirred for 4 h. The resulting homogeneous mixture was quenched with saturated aqueous Na2SO3 solution and extracted with CH2Cl2 and purified by flash chromatography on silica gel using a gradient mixture of ethyl acetate-n-hexane to give the compound (VII) (78% yield) as a pale yellow solid.
6) To the above compound (VII) (1.5g, 0.0044 mol) in 30 ml of methanol was added 10% Pd/C (150 mg). The solution was placed in a stainless steel reactor, which was then charged with hydrogen gas (150 psi). After being stirred for 24 h at room temperature, the mixture was filtered through Celite to remove the catalyst. The filtrate thus obtained was evaporated to give the product (VI) (95% yield).

Example 2: Preparation of the chiral intermediate compound of Formula (XII) of Vilanterol, Salmeterol, and Salbutamol:

1) 5-bromo-2-hydroxybenzoic acid (I) (5.0g, 0.023 mol.) was dissolved in 60 mL of CH3OH, and concd sulfuric acid (11 mL, 0.21 mol) was added slowly at 0°C. The reaction mixture was heated under reflux for 20 h, allowed to cool down, and then poured into 100 mL of iced water. The aqueous layer was extracted three times with CH2Cl2 (3x50 mL), the combined organic layers were dried with sodium sulphate, and the solvent was removed under vacuo to yield the crude product. Purification was achieved by distillation to give colorless liquid (VIII) with 84% Yield.
2) To a solution of (VIII) (5.0g, 0.022 mol) in acetone (35 mL) were added K2CO3 (3.6g, 0.026 mol.)) and benzyl bromide (3.2mL, 0.026mol) at 0 ?C. The mixture was stirred at reflux temperature under nitrogen. After completion, the solvent was removed under reduced pressure and quenched with 1N HCl and extracted with ethyl acetate (3x50 mL), dried over sodium sulphate, filtered and distilled under reduced pressure. The residue was purified by silica gel chromatography to give the benzyl ether (IX) as a pale yellow liquid in 94% yield.
3) The above bromo acetonide (IX) (3.5 g, 0.012mol.) was dissolved in dry THF, cooled to -78 °C and a 1.6 M solution of n-butyl lithium (13.7 mL, 1.6 M in hexane, 0.022 mol.) was added drop wise. The mixture was stirred at -78 °C for 2 h and then treated with dry N, N-dimethylformamide (14.1 mL, 0.18 mol) as a 1:1 solution in dry THF. The resulting mixture was stirred at -78 °C for 0.75 h and warmed slowly up to room temperature. Then the mixture was diluted with diethyl ether, washed with water followed by a brine solution and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatograph on silica gel to give the required compound (X) (68% yield).
4) A mixture of aldehyde (X) (2.5g, 0.0093mol), sulfonium perchlorate (3.2g, 0.011mol) and powdered KOH (0.62g, 0.011mol) in tert-butyl alcohol (40 mL) was stirred at room temperature for 48 h. Then the mixture was quenched with water and extracted with dichloromethane (30 mL x 3). The combined extracts were washed with sat. NaCl and dried over MgSO4. Evaporation of the solvent followed by purification on silica gel using a mixture of EtOAc - hexane as an eluent give the epoxide (XI) in 79% yield.
5) To a stirred solution of freshly prepared MgI2.OEt2 (0.0044 mol) in THF (25 mL) was added methyl (R)-2-(benzyloxy)-5-(oxiran-2-yl)benzoate (XI) (3.0g, 0.011 mol) in dropwise manner followed by addition of the benzyl isocyanate (1.14g, 0.0086 mol) at room temperature under nitrogen. After complete addition, the mixture was allowed to warm to 80 °C and stirred for 4 h. The resulting homogeneous mixture was quenched with saturated aqueous Na2SO3 solution and extracted with CH2Cl2 and purified by flash chromatography on silica gel using a gradient mixture of ethyl acetate-n-hexane to give the compound (XIII) (75% yield) as a pale yellow solid.
6) To the above compound (XIII) (2.0g, 0.0048 mol) in 30 ml of methanol was added 10% Pd/C (150 mg). The solution was placed in a stainless steel reactor, which was then charged with hydrogen gas (150 psi). After being stirred for 24 h at room temperature, the mixture was filtered through Celite to remove the catalyst. The filtrate thus obtained was evaporated to give the product (XII) (92% yield).

Example 3: Preparation of the chiral intermediate compound of Formula (XIX) of Indacaterol, Abediterol, and Carmoterol:

1) To a solution of 8-Hydroxyquinolin-2-(1H)-one (XIV) (5.0g, 0.031 mol) in acetone (40 mL) were added K2CO3 (5.1g, 0.037 mol) and benzyl bromide (4.4 mL, 0.037 mol) at 0 ?C. The mixture was stirred at reflux temperature under nitrogen. After completion, the solvent was removed under reduced pressure and quenched with 1N HCl and extracted with ethyl acetate (3x50 mL), dried over sodium sulphate, filtered and distilled under reduced pressure. The residue was purified by silica gel chromatography to give the benzyl ether (XV) as a colourless solid in 89% yield.
2) A solution of bromine (0.5 mL, 0.02 mol) in acetic acid (6.0 mL) was added dropwise to a solution of (XV) (4.5 g, 0.018 mol) in acetic acid (40 mL). The mixture was stirred at room temperature for 4 h and quenched with sat. Na2S2O3 solution and then extracted with EtOAc (3x40 mL). The combined organic layers were washed with sat. NaHCO3 solution followed by water and brine solution and dried over Na2SO4. The solvent was evaporated and the resulting residue was purified by flash chromatography to afford the compound (XVI) (80% yield) as a colourless solid.
3) The above bromo acetonide (XVI) (3.7 g, 0.011mol.) was dissolved in dry THF, cooled to -78 °C and a 1.6 M solution of n-butyl lithium (14.1 mL, 1.6 M in hexane, 0.022 mol.) was added drop wise. The mixture was stirred at -78 °C for 2 h and then treated with dry N, N-dimethylformamide (12.7 mL, 0.17 mol) as a 1:1 solution in dry THF. The resulting mixture was stirred at -78 °C for 0.75 h and warmed slowly up to room temperature. Then the mixture was diluted with diethyl ether, washed with water followed by a brine solution and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatograph on silica gel to give the required compound (XVII) (74% yield).
4) A mixture of aldehyde (XVII) (2.5g, 0.0089mol), sulfonium perchlorate (3.2g, 0.011mol) and powdered KOH (0.62g, 0.011mol) in tert-butyl alcohol (40 mL) was stirred at room temperature for 48 h. Then the mixture was quenched with water and extracted with dichloromethane (30 mL x 3). The combined extracts were washed with sat. NaCl and dried over MgSO4. Evaporation of the solvent followed by purification on silica gel using a mixture of EtOAc - hexane as an eluent give the epoxide (XVIII) in 80% yield.
5) To a stirred solution of freshly prepared MgI2.OEt2 (0.0034 mol) in THF (25 mL) was added (R)-8-(benzyloxy)-5-(oxiran-2-yl)quinolin-2(1H)-one (XVIII) (2.5g, 0.0085 mol) in dropwise manner followed by addition of the benzyl isocyanate (0.92g, 0.0069 mol) at room temperature under nitrogen. After complete addition, the mixture was allowed to warm to 80 °C and stirred for 4 h. The resulting homogeneous mixture was quenched with saturated aqueous Na2SO3 solution and extracted with CH2Cl2 and purified by flash chromatography on silica gel using a gradient mixture of ethyl acetate-n-hexane to give the compound (XX) (72% yield) as a pale yellow solid.
6) To the above compound (XX) (1.5g, 0.0035 mol) in 30 ml of methanol was added 10% Pd/C (150 mg). The solution was placed in a stainless steel reactor, which was then charged with hydrogen gas (150 psi). After being stirred for 24 h at room temperature, the mixture was filtered through Celite to remove the catalyst. The filtrate thus obtained was evaporated to give the product (XIX) (96% yield).

Example 4: Preparation of the chiral intermediate compound of Formula (XXVI) of Oladaterol:

1) To a solution of 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one (XXI) (5.0g, 0.030 mol) in acetone (40 mL) were added K2CO3 (5.0g, 0.036 mol) and benzyl bromide (4.3mL, 0.036 mol) at 0?C. The mixture was stirred at reflux temperature under nitrogen. After completion, the solvent was removed under reduced pressure and quenched with 1N HCl and extracted with ethyl acetate (3x50 mL), dried over sodium sulphate, filtered and distilled under reduced pressure. The residue was purified by silica gel chromatography to give the benzyl ether (XXII) as a colourless solid in 86% yield.
2) Bromine (0.44 mL, 0.018 mol) was dissolved in acetic acid (20 mL) and was added dropwise to a solution of (XXII) (4.0 g, 0.017 mol) in acetic acid (65 mL). The mixture was stirred at room temperature for 4 h. Saturated Na2S2O3 solution was added and the product was extracted with EtOAc (3x40 mL). The combined organic layers were washed with saturated NaHCO3 solution, water and brine, and dried (Na2SO4). The solvent was evaporated and purification of the crude product by flash chromatography (hexanes/EtOAc 20:1 to 10:1) yielded (XXIII) (84%) as a colorless solid.
3) The above bromo acetonide (XXIII) (4.0 g, 0.012mol.) was dissolved in dry THF, cooled to -78 °C and a 1.6 M solution of n-butyl lithium (15.1 mL, 1.6 M in hexane, 0.024 mol.) was added drop wise. The mixture was stirred at -78 °C for 2 h and then treated with dry N,N-dimethylformamide (13.8 mL, 0.18 mol) as a 1:1 solution in dry THF. The resulting mixture was stirred at -78 °C for 0.75 h and warmed slowly up to room temperature. Then the mixture was diluted with diethyl ether, washed with water followed by a brine solution and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatograph on silica gel to give the required compound (XXIV) (75% yield).
4) A mixture of aldehyde (XXIV) (2.8g, 0.0099mol), sulfonium perchlorate (3.4g, 0.012mol) and powdered KOH (0.67g, 0.012mol) in tert-butyl alcohol (30 mL) was stirred at room temperature for 48 h. Then the mixture was quenched with water and extracted with dichloromethane (30 mL x 3). The combined extracts were washed with sat. NaCl and dried over MgSO4. Evaporation of the solvent followed by purification on silica gel using a mixture of EtOAc - hexane as an eluent give the epoxide (XXV) in 76% yield.
5) To a stirred solution of freshly prepared MgI2.OEt2 (0.0027 mol) in THF (25 mL) was added (R)-5-(benzyloxy)-8-(oxiran-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (XXV) (2.0g, 0.0067 mol) in dropwise manner followed by addition of the benzyl isocyanate (0.73g, 0.0055 mol) at room temperature under nitrogen. After complete addition, the mixture was allowed to warm to 80 °C and stirred for 4 h. The resulting homogeneous mixture was quenched with saturated aqueous Na2SO3 solution and extracted with CH2Cl2 and purified by flash chromatography on silica gel using a gradient mixture of ethyl acetate-n-hexane to give the compound (XXVII) (70% yield) as a pale yellow solid.
6) To the above compound (XXVII) (1.5g, 0.0035 mol) in 30 ml of methanol was added 10% Pd/C (150 mg). The solution was placed in a stainless steel reactor, which was then charged with hydrogen gas (150 psi). After being stirred for 24 h at room temperature, the mixture was filtered through Celite to remove the catalyst. The filtrate thus obtained was evaporated to give the product (XXVI) (94% yield).

Example 5: Preparation of the chiral intermediate compound of Formula (XXXII) of Arformoterol:

1) To a solution of 54-bromo-2-nitro-phenol (XXVIII) (5.0g, 0.023 mol) in acetone (50 mL) were added K2CO3 (3.9g, 0.028 mol) and benzyl bromide (3.3mL, 0.028 mol) at 0 ?C. The mixture was stirred at reflux temperature under nitrogen. After completion, the solvent was removed under reduced pressure and quenched with 1N HCl and extracted with ethyl acetate (3x50 mL), dried over sodium sulphate, filtered and distilled under reduced pressure. The residue was purified by silica gel chromatography to give the benzyl ether (XXIX) as a colourless solid in 96% yield.
2) The above bromo acetonide (XXIX) (5.0 g, 0.016mol.) was dissolved in dry THF, cooled to -78 °C and a 1.6 M solution of n-butyl lithium (20.4 mL, 1.6 M in hexane, 0.033 mol.) was added drop wise. The mixture was stirred at -78 °C for 2 h and then treated with dry N, N-dimethylformamide (18.5 mL, 0.26 mol) as a 1:1 solution in dry THF. The resulting mixture was stirred at -78 °C for 0.75 h and warmed slowly up to room temperature. Then the mixture was diluted with diethyl ether, washed with water followed by a brine solution and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatograph on silica gel to give the required compound (XXX) (75% yield).
3) A mixture of aldehyde (XXX) (3.5g, 0.014mol), sulfonium perchlorate (4.5g, 0.016mol) and powdered KOH (0.89g, 0.016mol) in tert-butyl alcohol (35 mL) was stirred at room temperature for 48 h. Then the mixture was quenched with water and extracted with dichloromethane (30 mL x 3). The combined extracts were washed with sat. NaCl and dried over MgSO4. Evaporation of the solvent followed by purification on silica gel using a mixture of EtOAc - hexane as an eluent give the epoxide (XXXI) in 81% yield.
4) To a stirred solution of freshly prepared MgI2.OEt2 (0.0044 mol) in THF (25 mL) was added (R)-2-(4-(benzyloxy)-3-nitrophenyl)oxirane (XXXI) (3.0g, 0.011 mol) in dropwise manner followed by addition of the benzyl isocyanate (1.2g, 0.0089 mol) at room temperature under nitrogen. After complete addition, the mixture was allowed to warm to 80 °C and stirred for 4 h. The resulting homogeneous mixture was quenched with saturated aqueous Na2SO3 solution and extracted with CH2Cl2 and purified by flash chromatography on silica gel using a gradient mixture of ethyl acetate-n-hexane to give the compound (XXXIII) (75% yield) as a pale yellow solid.
5) To the above compound (XXXIII) (2.0g, 0.0050 mol) in 30 ml of methanol was added 10% Pd/C (200 mg). The solution was placed in a stainless steel reactor, which was then charged with hydrogen gas (150 psi). After being stirred for 24 h at room temperature, the mixture was filtered through Celite to remove the catalyst. The filtrate thus obtained was evaporated to give the product (XXXII) (96% yield).

Advantages of the present invention
1) The process results in high yield of the end product with maximum purity.
2) The process is an eco-friendly and a cost effective process, which minimizes formation of waste products.
3) The process provides intermediates with high yield and with maximum purity and high chirality.
4) The process is industrially feasible, simple and practical and is applied for large scale synthesis.

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

,CLAIMS:
1. A process for preparing a chiral compound having formula (XXXVI) comprising reacting a compound of formula (XXXIV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent.

Formula (XXXIV) Formula (XXXV) Formula (XXXVI)
wherein, when R2 is -O-Benzene, R1 is selected from -NO2, -COOCH3, fused at positions a and b, fused at positions a and b,

or
R1 and R2 together is .

2. The process as claimed in claim 1, wherein the first base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide and the first solvent is selected from methanol, isopropyl alcohol, tert-butyl alcohol.

3. The process as claimed in claim 1 or 2, wherein the compound of formula (XXXIV) is reacted with the compound of formula (XXXV) at a temperature of at least 20°C, preferably the temperature is in a range from 20°C to room temperature.

4. A process for preparing a chiral compound of formula (XXXVIII), the process comprising the steps:
reacting a compound of formula (XXXIV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XXXVI);
reacting the compound of formula (XXXVI) with a first catalyst in presence of a second solvent and a reagent to form a compound of formula (XXXVII); and
reacting the compound of formula (XXXVII) in presence a third solvent with a second catalyst to obtain compound of formula (XXXVIII).

Formula (XXXIV) Formula (XXXV) Formula (XXXVI)

Formula (XXXVII) Formula (XXXVIII)
wherein, when R2 is -O-Benzene, R1 is selected from -NO2, -COOCH3, fused at positions a and b, fused at positions a and b,

or
R1 and R2 together is .

5.The process as claimed in claim 4, wherein
the first base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide,
the first solvent is selected from methanol, isopropyl alcohol, tert-butyl alcohol,
the first catalyst is selected from MgI2 etherate, iodine, lithium perchlorate, sodium iodide lithium chloride,
the second solvent is selected from tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether,
the reagent selected from benzyl isocyanate, p-methoxyphenyl isocyanate sodium cyanate,

the third solvent is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate,
the second catalyst is selected from Pd/C, Pd/BaSO4, Raney nickel/Hydrogen.

6. The process as claimed in claim 4 or 5, wherein the compound of formula (XXXIV) is reacted with compound of formula (XXXV) at a temperature of at least 20°C, preferably the temperature is in a range from 20°C to room temperature to form the compound of formula (XXXVI) and the compound of formula (XXXVI) is reacted at a temperature of at least 75°C, preferably the temperature is in a range from 75°C to 80°C.

7. The process for preparing compound of formula (XXXIV) as claimed in claim 1 or 4 the process comprising the steps:
reacting a compound of formula (XXXIX) in presence of a second solvent with a second base and a fourth solvent to form a compound of formula (XXXIV).

Formula (XXXIX) Formula (XXXIV)
wherein, when R2 is -O-Benzene, R1 is selected from -NO2, -COOCH3, fused at positions a and b, fused at positions a and b

or
R1 and R2 together is .

8.The process as claimed in claim 7, wherein
the second solvent is selected from tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether,
the second base is selected from n-butyl lithium, s-butyl lithium, lithium diisopropyl amide, potassium bis(trimethylsilyl) amide, and
the fourth solvent is N, N-dimethylformamide and tetrahydrofuran in a ratio of at least 1:1.

9.The process as claimed in claim 7, wherein temperature of the reaction is at least -78°C.

10.The process as claimed in claim 7 for preparing compound of formula (XXXIX) having structure as formula (III) comprising the steps:
reacting a compound of formula (I) with a reducing agent in presence of the second solvent and a halide to form a compound of formula (II);
reacting the compound of formula (II) with a third catalyst in presence of a fifth solvent and a dehydrating agent to form a compound of formula (III);

Formula (I) Formula (II) Formula (III)

11.The process as claimed in claim 10, wherein
the second solvent is selected from tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether,
the halide is selected from iodine compound, lithium chloride, lithium bromide, nickel chloride, zinc chloride,
the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, sodium bis 2(-methoxy ethoxy) aluminium hydride, lithium aluminium hydride, borane dimethyl sulfide complex,
the third catalyst is selected from p-toluene sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid,
the fifth solvent is selected from dichloromethane, dichloroethane chloroform, and
the dehydrating agent is 2,2-dimethoxy propane.

12. The process as claimed in claim 10, wherein the compound of formula (I) is reacted at a temperature of at least -5°C, preferably the temperature is in a range from 0°C to -5°C.

13. The process as claimed in claim 7 for preparing compound of formula (XXXIX) having structure as formula (IX) comprising the steps:
reacting compound of formula (I) in presence of a third solvent with a first acid to form a compound of formula (VIII); and
reacting the compound of formula (VIII) in presence of a sixth solvent with a third base and a benzylating agent to form the compound of formula (IX).

Formula (I) Formula (VIII) Formula (IX)

14. The process as claimed in claim 13, wherein
the third solvent is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate,
the first acid is selected from concentrated sulfuric acid, hydrochloric acid, acetyl chloride, thionyl chloride,
the sixth solvent is selected from acetone, dimethyl formamide, tetrahydrofuran,
the third base is selected from potassium carbonate, sodium carbonate, caesium carbonate, and
the benzylating agent is selected from benzyl bromide, benzyl chloride, benzyl iodide.

15. The process as claimed in claim 13, wherein the temperature of the reaction is at least 65°C, preferably 65°C to 70°C.

16. The process as claimed in claim 7 for preparing compound of formula (XXXIX) having structure as formula (XL) comprising the steps:
reacting compound of formula (XLI) in presence of a sixth solvent with a third base and a benzylating agent to form compound of formula (XLII);
reacting the compound of formula (XLII) with a second acid and a brominating agent to form a compound of formula (XL);

Formula (XLI) Formula (XLII) Formula (XL)
wherein Formula (XL) has a structure of formula (XVI) or formula (XXIII)

Formula (XVI) Formula (XXIII)

17. The process as claimed in claim 16, wherein the benzylation step is carried out at a temperature of at least 60°C, preferably the temperature is in a range from 60°C to 65°C, bromination is carried out at a temperature at least 0°C, preferably the temperature is in a range from 0°C to room temperature,
the sixth solvent is selected from acetone, dimethyl formamide, tetrahydrofuran,
the third base is selected from potassium carbonate, sodium carbonate, caesium carbonate, and
the benzylating agent is selected from benzyl bromide, benzyl chloride, benzyl iodide,
the second acid is selected from formic acid, acetic acid hydrobromic acid, and
the brominating agent is selected from N-bromosuccinimide, dibromohydantoin.

18. The process as claimed in claim 7 for preparing compound of formula (XXXIX) having structure as formula (XXIX) comprising reacting compound of formula (XXVIII) in presence of a sixth solvent with a third base and a benzylating agent to form compound of formula (XXIX).

Formula (XXVIII) Formula (XXIX)
19. The process as claimed in any one of claims 7 wherein the compound of formula (III), the compound of formula (IX), the compound of formula (XVI), the compound of formula (XXIII) the compound of formula (XXIX) is used as a reactant to form the compound of formula (XXXIV).

20. A process for preparation of compound of Formula (VI), an intermediate of Vilanterol, Salmeterol and Salbutamol, the process comprising the steps of:
reacting a compound of formula (I) with a reducing agent in presence of a second solvent and a halide to form a compound of formula (II);
reacting the compound of formula (II) with a third catalyst in presence of a fifth solvent and a dehydrating agent to form a compound of formula (III);
reacting the compound of formula (III) in presence of the second solvent with a second base and a fourth solvent to form a compound of formula (IV);
reacting the compound of formula (IV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (V);
reacting the compound of formula (V) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (VII); and
reacting the compound of formula (VII) in presence of a third solvent with a second catalyst to obtain the compound of formula (VI).

21. A process for preparing compound of Formula (XII), an intermediate of Vilanterol, Salmeterol and Salbutamol, the process comprising the steps:
reacting compound of formula (I) in presence of a third solvent and a first acid to form a compound of formula (VIII);
reacting the compound of formula (VIII) in presence of a sixth solvent with a third base and a benzylating agent to form the compound of formula (IX);
reacting a compound of formula (IX) in presence of a second solvent with a second base and a fourth solvent to form a compound of formula (X);
reacting a compound of formula (X) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XI);
reacting the compound of formula (XI) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (XIII); and
reacting the compound of formula (XIII) in presence of a third solvent with a second catalyst to obtain compound of formula (XII).

22.A process for preparing compound of Formula (XIX), an intermediate of Indacaterol, Abediterol and Carmoterol, the process comprising the steps:
reacting compound of formula (XIV) in presence of a sixth solvent with a third base and a benzylating agent to form a compound of formula (VX);
reacting the compound of formula (XV) with a second acid and a brominating agent to form a compound of formula (XVI);
reacting a compound of formula (XVI) in presence of a second solvent with a second base and a fourth solvent to form a compound of formula (XVII).
reacting the compound of formula (XVII) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XVIII);
reacting the compound of formula (XVIII) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (XX); and
reacting the compound of formula (XX) in presence of a third solvent with a second catalyst to obtain compound of formula (XIX).

23. A process for preparing compound of formula (XXVI), an intermediate of Oladaterol, the process comprising the steps:
reacting compound of formula (XXI) in presence of a sixth solvent with a third base and a benzylating agent to form compound of formula (XXII);
reacting the compound of formula (XXII) with a second acid and a brominating agent form a compound of formula (XXIII);
reacting a compound of formula (XIII) in presence of a second solvent with a second base and a fourth solvent to form a compound of formula (XVI);
reacting a compound of formula (XXIV) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XXV);
reacting the compound of formula (XXV) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (XXVII); and
reacting the compound of formula (XXVII) in presence of a third solvent with a second catalyst to obtain compound of formula (XXVI).

24. A process for preparing compound of formula (XXXII), an intermediate of Arformoterol, the process comprising the steps:
reacting compound of formula (XXVIII) in presence a sixth solvent, with a third base and a benzylating agent to form a compound of formula (XXIX);
reacting a compound of formula (XXIX) in presence of a second solvent with a second base and a fourth solvent to form compound of formula (XXX);
reacting a compound of formula (XXX) with a chiral sulfide compound of formula (XXXV) in presence of a first base and a first solvent to form compound of formula (XXXI);
reacting the compound of formula (XXXI) with a first catalyst in presence of the second solvent and a reagent to form a compound of formula (XXXIII); and
reacting the compound of formula (XXXIII) in presence of a third solvent with a second catalyst to obtain the compound of formula (XXXII).

25. The process as claimed in claims 20-24, wherein
the first solvent is selected from methanol, isopropyl alcohol, tert-butyl alcohol,
the second solvent is selected from tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether diethyl ether,
the third solvent is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate,
the fourth solvent is N,N-dimethylformamide and tetrahydrofuran in a ratio of at least 1:1,
the fifth solvent is selected from dichloromethane, dichloroethane, chloroform,
the sixth solvent is selected from acetone, dimethyl formamide, tetrahydrofuran,
the first base is selected from potassium hydroxide, sodium hydroxide lithium hydroxide,
the second base is selected from n-butyl lithium, s-butyl lithium, lithium diisopropyl amide, potassium bis(trimethylsilyl) amide,
the third base is selected from potassium carbonate, sodium carbonate, caesium carbonate,
the first catalyst is selected from MgI2 etherate, iodine, lithium perchlorate, sodium iodide lithium chloride,
the second catalyst is selected from Pd/C, Pd/BaSO4, Raney nickel/Hydrogen,
the third catalyst is selected from p-toluene sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid,
the reagent selected from benzyl isocyanate, p-methoxyphenyl isocyanate sodium cyanate,
the benzylating agent is selected from benzyl bromide, benzyl chloride, benzyl iodide,
the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, sodium bis 2(-methoxy ethoxy) aluminium hydride, lithium aluminium hydride, borane dimethyl sulfide complex,
the halide is selected from iodine compound, lithium chloride, lithium bromide, nickel chloride, zinc chloride,
the dehydrating agent is 2,2-dimethoxy propane,
the first acid is selected from concentrated sulfuric acid, hydrochloric acid, acetyl chloride, thionyl chloride,
the second acid is selected from formic acid, acetic acid hydrobromic acid, and
the brominating agent is selected from N-bromosuccinimide, dibromohydantoin.