DESC:
FIELD OF INVENTION

The present invention relates to an improved process for the preparation of Voxelotor and its key intermediate (2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol.

BACKGROUND OF THE INVENTION

Voxelotor is chemically known as 2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde and has the structural formula(I):

-

Formula-I

Voxelotor is approved by USFDA as Oxbryta tablet for oral administration for treatment of sickle cell disease. Upon administration, Voxelotor targets and covalently binds to the N-terminal valine of the alpha chain of HbS. This stabilizes HbS, thereby improving oxygen binding affinity. The binding of Voxelotor to HbS prevents HbS polymerization, reduces sickling, decreases red blood cell (RBC) damage and increases the half-life of RBCs. This improves blood flow and decreases hemolytic anemia.

Voxelotor was first disclosed in US patent No. 9,018,210 B2 (herein after referred as ‘210). This patent discloses the process for preparation of Voxelotor as follows.

US patent No. 9,248,199 B2 (herein after referred as ‘199) discloses alternate processes for preparation of Voxelotor as follows:

These prior art processes involves the condensation by using 2,6-dihydroxybenzaldehyde, which leads to bisalkylated product as side products and thereby produced Voxelotor with low yields.

ACS Medicinal Chemistry Letters (2017), 8(3), 321-326 discloses the preparation of Voxelotor using 2-Hydroxy-6-(methoxymethoxy)benzaldehyde, which avoids the formation of bisalkylated side product as shown below:

Most of the prior art processes involves the column purification for Voxelotor as well as its intermediate compounds, which are tedious and not suitable for large scale preparations.

The prior art process involves the use of pd(dppf)Cl2 in Suzuki coupling reaction, which is pyrophoric and expensive. Further the amount of the expensive pd(dppf)Cl2 catalyst needed to carry out the Suzuki reaction effectively is high, around 5 mole %, which in-turn makes the process more expensive. Further the byproducts formed during the Suzuki coupling reaction using pd(dppf)Cl2 requires tedious work up process.

The process for preparation of key intermediate (2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol used in the preparation of Voxelotor, suffers from several draw backs such as the preparation involves column purification and costly pd(dppf)Cl2 reagents, which are not suitable for commercial preparation as the byproducts generated during the preparation requires several distillation steps and recovery of catalyst is low as well as separation of product from the reaction mass becomes cumbersome.

In view of the above, the present invention provides convenient and economically viable process for preparation of Voxelotor. Moreover, the reagents of the present invention are not pyrophoric and easy to handle and therefore desirable to solve the problems associated with the prior art processes by employing less expensive and less hazardous reagents for preparation of Voxelotor.

OBJECTIVES OF THE INVENTION

The objective of the present invention is to provide commercially and industrially feasible process for preparation of Voxelotor.

The objective of the present invention is to provide a process for the preparation of Voxelotor
using palladium acetate with high yield and high purity.

Another objective of the present invention is to provide a process for preparation of intermediate useful in the preparation of Voxelotor

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Voxelotor, a compound of Formula I,

-

Formula I
which comprises:
a) reacting (2-Halopyridin-3-yl)methanol compound of Formula II,

-
Formula II
wherein X is halo such as chloro or bromo,
with 1-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole compound of
Formula III,

-

Formula-III
in presence of palladium (II) acetate, triphenyl phosphine and a base to obtain a compound of
Formula IV;

-

Formula IV

b) reacting the compound of Formula IV with chlorinating agent to obtain 3-(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine compound of Formula V;

-

Formula V

c) condensing 3-(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine compound of
Formula V with 2-Hydroxy-6-(methoxymethoxy)benzaldehyde compound of Formula VI,

-

Formula VI
in presence of a base to obtain a compound of Formula VII,

-

Formula VII

d) deprotecting the compound of Formula VII to obtain Voxelotor compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an process for the preparation voxelotor which comprises reacting (2-Halopyridin-3-yl)methanol compound of Formula II with 1-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole compound of Formula III in presence of palladium (II) acetate, triphenyl phosphine and a base selected from the group comprising of alkali metal carbonate and bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate in s solvent selected from of polar aprotic solvents, non-polar solvents, polar solvents, wherein polar aprotic solvent is selected from group comprising of acetonitrile, tetrahydrofuran; non-polar solvent is selected from group comprising of toluene, ethyl acetate, dioxane and polar solvents is selected from group comprising of water or mixture thereof to obtain (2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol compound of Formula IV; converting (2-(1-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole compound of Formula IV to 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine compound of Formula V in presence of chlorinating agent selected from the group comprising thionyl chloride, hydrochloric acid, oxalyl chloride, phosphorous oxychloride, phosphorous trichloride, phosphorous pentachloride, phosgene, triphosgene in a solvent selected from group comprising of aromatic hydrocarbon solvents, halogenated solvents, nitrile solvents wherein aromatic hydrocarbon solvents selected from group comprising of toluene, xylene, halogenated solvents selected from group comprising of dichloromethane, chloroform, ethylene dichloride, nitrile solvents selected from group comprising of acetonitrile; condensing 3-(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine compound of Formula V with 2-Hydroxy-6-(methoxymethoxy)benzaldehyde compound of Formula VI in presence of a base selected from group comprising of inorganic base such as alkali metal carbonate and bicarbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate in a solvent selected from the group comprising of polar aprotic solvent selected from dimethylformamide; dimethylsulfoxide to obtain compound of formula VII; deprotecting the compound of formula VII with a deprotecting reagent agent is hydrochloric acid in a solvent selected from the group comprising of alcohol solvents such as methanol, ethanol and polar aprotic solvents such as tetrahydrofuran to obtain Voxelotor compound of Formula I.

In another embodiment of the present invention, involves the use of Pd(OAc)2, which is less expensive, less pyrophoric and the molar ratio of pd catalyst w.r.to (2-haloropyridin-3-yl)methanol compound of formula-II needed to carry out the reaction is as low as from about 0.0001 to about 0.3 mol%, preferably from about 0.001 to 0.005 mol%; more preferably 0.003 mol %.

The use of water-soluble palladium(0)-TPP ligand in water-acetonitrile mixture makes the system biphasic allowing easy separation of the catalyst from the product during the work-up. After completion of the reaction, the catalyst stays in the aqueous phase and can be recycled without substantial loss of activity. The product is isolated from acetonitrile phase is easy without the need of any distillation steps.

2-((2-(1-isoporpyl-1H-pyrazol-5-yl)pyridine-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde Intermediate compound (referred as compound of formula VII in present application) produced by the prior art-process disclosed in ACS Medicinal Chemistry Letters (2017), 8(3), 321-326, has low yield around 25.5%. However, the present invention provides compound of formula VII with an yield around 69.6%, which in-turn enhances the yield of final product Voxelotor.

The use of Pd(OAc)2 in Suzuki coupling reaction makes the process more cost-effective and amenable for large scale preparation, which avoid pyrophoric and costly reagents w.r.t known prior art process. Further the advantages of the present invention w.r.to prior art process is as follows:
Prior-art process Present invention
% Yield of Compound-VII 25.5% 69.6%

% Yield of Voxelotor 35.6% 86%
Molar ratio of pd catalyst 5% 0.01 mol %.
Cost Involves expensive reagents Involves less expensive reagents
Work-up process Involves tedious work up processes Involves simple work up processes
Column purification Involves column purifications Avoids column purifications

The present inventors carried out the above process i.e., reacting (2-chloropyridin-3-yl)methanol compound of formula IIa with 1-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole compound of formula III in presence of different palladium catalysts using mole ratio 0.01%, which are reported in prior art literature references, and the obtained purities of compound of formula IV and VII are as represented below:

Pd catalyst Compound of formula IIa content in compound IV Purity by HPLC of compound IV Purity by HPLC of compound VII
Pd(dppf)Cl2 4.68 % 83.05 % 91.73%
Pd(PPh3)4 6.7 % 84.44 % 94.96 %
Pd(OAc)2 Not detected 85.92% 97.95 %

Therefore use of Pd(OAc)2 in the present invention is more advantageous and provides highly pure compounds IV and VII, which in-turn provides highly pure Voxelotor as well as yields Voxelotor and compound VII in high yields.

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Example 1: Preparation of 2-((2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde

Step- a) Preparation of 2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (Formula-IV)
A mixture of (2-chloropyridin-3-yl)methanol (100.0 g) compound of formula-II, acetonitrile (350 ml), water (350 ml) and potassium carbonate (230.68 g) was heated to 70-75°C. palladium(II)acetate (1.53 g) and triphenyl phosphine (5.48 g) were added to the above reaction mixture at 70-75°C and stirred for 10 minutes. 1-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (230.24 g) compound of formula-III in acetonitrile (200 ml) was added to reaction mixture at 70-75°C and stirred for 4 hours. After the completion of reaction, cooled the reaction mixture 55-60°C and separated the organic layer and dried to get (2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol as thick viscous liquid.

Purity by HPLC: 85.92 %;
Content of compound of Formula II: Not detected.

Step-b) Preparation of 3-(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine (Formula-Va)

A solution of (2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol compound of formula-IV obtained in step-a) in dichloromethane (1050 ml) was cooled to 0-5°C and thionyl chloride (98.60 g) was added slowly. Raised the temperature to 25-30°C and stirred for 6 hours. Added dichloromethane (450 ml) to above reaction mixture, co-distilled with toluene and dried to get 3-(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine as a solid, which can be used for next step without purification.

Step-c) Preparation of 2-((2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxy methoxy)benzaldehyde (Formula-VII)

A solution of 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine compound of formula-Va obtained in step-b) in dimethylsulfoxide (300 ml) was added to a mixture of 2-hydroxy-6-(methoxymethoxy)benzaldehyde compound of formula-VI (100.16 g), potassium carbonate (288.36 g) and dimethylsulfoxide (450 ml) at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 7 hours. Cooled the reaction mixture to 25-30°C, water (3750 ml) was added to and stirred for 6 hours. Filtered the solid and dried to yiedl 2-((2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxy methoxy)benzaldehyde.

Yield: 185 g ; Yield % : 69.6%; purity by HPLC: 97.95%

Exmaple-2: Preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy) benzaldehyde (Formula-I)

Step-a) Preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl) methoxy) benzaldehyde (Formula-I)

Conc.HCl (214.5 ml) was added to a mixture of 2-((2-(1-Isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde (195.0 g) compound of formula-VII and tetrahydrofuran (1950 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30oC and stirred for 6 hours. Treated the reaction mixture with aq. sodium bicarbonate solution and stirred for 8 hours at 25-30°C. Filtered the solid and dried to get 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy) benzaldehyde.

Step-b) Purification of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl) methoxy)benzaldehyde (Formula-I)

A mixture of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy) benzaldehyde obtained in step-a) and Isopropyl alcohol (1150 ml) was heated to 75-80°C. Treated with carbon and stirred and filtered. The solid thus obtained was added methanol, water and stirred, filtered and dried the yield pure 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.

Yield: 149 g ; Yield %: 86% purity by HPLC: 99.98%
,CLAIMS:We claim:

1. A process for the preparation of Voxelotor, a compound of Formula I,

-

Formula I
which comprises:
a) reacting (2-Halopyridin-3-yl)methanol compound of Formula II,

-
Formula II
wherein X is halo such as chloro or bromo,
with 1-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole compound of Formula III,

-

Formula-III
in presence of palladium (II) acetate, triphenyl phosphine and a base to obtain a compound of Formula IV;

-

Formula IV

b) reacting the compound of Formula IV with chlorinating agent to obtain -(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine compound of Formula V;

-

Formula V

c) condensing 3-(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine compound of
Formula V with 2-Hydroxy-6-(methoxymethoxy)benzaldehyde compound of Formula VI,

-

Formula-VI
in presence of a base to obtain a compound of Formula VII,

-

Formula VII

d) deprotecting the compound of Formula VII to obtain Voxelotor compound of Formula I.

2. The process as claimed in claims 1, wherein the base is selected from alkali metal carbonate and alkali metal bicarbonate selected from the group comprising of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate.

3. The process as claimed in claims 1, wherein the solvent is selected from group comprising of methanol, ethanol, isopropyl alcohol, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, toluene, xylene, ethyl acetate, dioxane, dichloromethane, chloroform, ethylene dichloride, water and /or mixture of solvents thereof.

4. The process as claimed in claim 1, wherein the chlorinating reagent is selected from group comprising of thionyl chloride, hydrochloric acid, oxalyl chloride, phosphorous oxychloride, phosphorous trichloride, phosphorous pentachloride, phosgene and triphosgene.

5. The process as claimed in claim 1, wherein deprotecting agent is hydrochloric acid.