Claims:1. A method to prepare a compound of formula I, the method comprising the steps of;
(I)
a. heating a mixture of compound of formula II and water to a temperature of 60-90°C;
(II)
b. reacting the heated mixture in step a. in a reaction mixture with Sodium dithionite dissolved in water at a temperature of 60-90°C for 40-50 hours to obtain compound of formula I; and
c. isolating and purifying the compound of formula I from the reaction mixture in step b. with a solvent
2. The method as claimed in claim 1 wherein the yield of compound of formula I is 50-55%.
3. The method as claimed in claim 1 wherein the purity of compound of formula I is at least 98% as determined by HPLC.
4. The method as claimed in claim 1 wherein the compound of formula I is stable for at least two years.
5. The method as claimed in claim 1, wherein the mixture in step a. contains 40-60% w/v of compound of formula II.
6. The method as claimed in claim 1, wherein the reaction in step b. contains 25-45.0 % w/v of sodium dithionite.
7. The method as claimed in claim 1, wherein the solvent is isopropyl alcohol, ethyl acetate or isopropyl acetate.
8. The method as claimed in claim 7, wherein the solvent is isopropyl alcohol.
9. The method as claimed in claim 1, wherein the mixture in step a. is heated to a temperature of 80-85°C.
10. The method as claimed in claim 1, wherein the reaction in step b. is continued for 48 hours.
11. The method as claimed in claim 1, wherein in step b. sodium dithionite is dissolved in water at a temperature of 80-85°C.
12. The method as claimed in claim 1, wherein the isolation of the compound of formula I in step c. is done by cooling the reaction mixture from step b. followed by filtration or centrifugation of the solids to isolate the compound of formula I.
13. The method as claimed in claim 1, wherein purification of the compound of formula I in step c. is done by drying the filtered or centrifuged solids at 40-45 °C for 5-6 hrs after addition of the solvent.
14. The method as claimed in claim 1 wherein the compound of formula I is obtained in a solid form.
15. The compound of formula I obtained by the method as claimed in claim 1.
16. The method as claimed in claim 1 further comprising the step of reacting compound of formula I with trimethyl orthobenzoate in presence of acetic anhydride followed by reaction with a piperidine intermediate to produce Nintedanib.
, Description:FIELD OF INVENTION
The current invention relates to the field synthesis of methyl 2-oxoindoline-6-carboxylate, an intermediate in the synthesis of Nintedanib or salt thereof using sodium dithionate as catalyst. The current invention enables one pot reduction, hydrolysis and cyclization of the precursor compound to obtain the methyl 2-oxoindoline-6-carboxylate
BACKGROUND
Nintedanib is a small molecule known for its use in treatment of idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease. Nintedanib is a triple angiokinase inhibitor and competitively targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). These RTKs are known to have a role in lung fibrosis and tumour angiogenesis, thus these are used in the treating of proliferative diseases such as idiopathic pulmonary fibrosis, non-small cell lung cancer, and systemic sclerosis-associated interstitial lung disease.
Methyl 2-oxoindoline-6-carboxylate is a known intermediate for synthesis of Nintedanib. Indian patent application no. 201721031509 discloses method of making Nintedanib using the compound of (methyl 2-oxoindoline-6-carboxylate) as intermediate.

WO2009071523A1 discloses process to manufacture indoline derivatives in several steps. The patent discloses synthesis of Methyl-2-oxoindoline-6-carboxylate in multiple steps in the presence of Palladium (Pd) catalysts.
In fact, most of the reduction reactions of nitro to amine compounds have been reported using metal catalysts such as Palladium (Pd), Raney Nickel (Ni) or Iron (Fe). Metal catalysts like Pd are very costly and require high pressure hydrogenation for the conversion which is not cost effective and pose safety issues including high toxicity risk as well. The reaction product usually sticks with most of the metal catalysts thus requiring repeated washings with solvents to separate the product from the metal catalyst.
Sodium dithionite is a white crystalline powder and is known as a reducing agent. The reducing capability of sodium dithionite has been deployed in various industries being inexpensive and safe. It is also known for its chemo selectivity. It is also known for phase transfer catalysis of unsaturated ketones. Sodium dithionite has been known for regiospecific reduction of unsaturated ketones.
The prior art lacks an efficient, green approach to synthesize 2-oxoindoline-6-carboxylate, an intermediate in synthesis of Nintedanib. The current invention fills in the gap as it encompasses an efficient, one pot method to synthesize the Nintedanib intermediate by reducing the number of reaction steps by utilizing sodium dithionite as a catalyst instead of metal catalysts like Pd, Ni .The current invention thereby eliminates the need of a high pressure hydrogenation step for synthesis of the Nintedanib intermediate , as is required by catalysis with metal catalysts. The current invention eliminates the need of washing the reaction products in multiple cycles by a solvent as the reaction product sticks to metal catalysts when catalysis utilizes metal catalysts.
The current invention discloses a preparation method of making a Nintedanib intermediate, methyl 2-oxoindoline-6-carboxylate via one pot reduction, hydrolysis and cyclisation by using sodium dithionate as a reducing agent in water. The method disclosed in the invention renders the process operationally efficient and simpler, with significant cost saving and resource conservation.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1 shows the schematic for converting compound of formula II to formula I.

SUMMARY
The current invention discloses a one pot method of synthesis of methyl 2-oxoindoline-6-carboxylate, an intermediate in the synthesis of Nintedanib or salt thereof using sodium dithionate as catalyst.
One embodiment of the current invention is a method to prepare a compound of formula I, the method comprising the steps of;
(I)
a. heating a mixture of compound of formula II and water to a temperature of 60-90°C;
(II)

b. reacting the heated mixture in step a. in a reaction mixture with Sodium dithionite dissolved in water at a temperature of 60-90°C for 40-50 hours to make compound of formula I ; and
c. isolating and purifying the compound of formula I from the reaction mixture in step b. with a solvent.
In one embodiment of the invention, the yield of compound of formula I produced by the method disclosed herein is 50-55%. In one embodiment of the invention, the yield of compound of formula I obtained by the method disclosed herein is 55%. In one embodiment of the invention, the purity of compound of formula I is at least 98% as determined by HPLC.
In one embodiment of the invention, the compound of formula I is stable for at least two years. In one embodiment of the invention, the mixture of formula II with water in step a. contains 40-60% w/v of compound of formula II. In one embodiment of the invention the reaction mixture in step b. contains 25-45.0 % w/v of sodium dithionite. In one embodiment of the invention the solvent used for purifying in step c. is isopropyl alcohol, ethyl acetate or isopropyl acetate. In one embodiment of the invention, the solvent is isopropyl alcohol.
In one embodiment of the invention, the mixture in step a. is heated to a temperature of 80-85°C.In one embodiment of the invention the reaction in step b. is continued for 48 hours. In one embodiment of the invention, in step b. sodium dithionite is dissolved in water at a temperature of 80-85°C.
In one embodiment of the invention, the compound of formula I is obtained in a solid form in step c.
One embodiment of the invention is compound of formula I obtained by the method encompassed in the invention.
In one embodiment of the invention, the method further comprises of the step of making Nintedanib from the compound of formula I wherein the compound of formula I is reacted with trimethyl orthobenzoate in presence of acetic anhydride followed by reaction with a piperidine intermediate to produce Nintedanib.
DETAILED DESCRIPTION
The current invention encompasses a method of preparation of compound of Formula I, using sodium dithionate as catalyst.
Synthesis of compound of formula I has been reported in the prior art in multiple steps.
WO2009071523A1 discloses synthesis of 6-methoxycarbonyl-2-oxindole.


The prior art lacks an efficient, green approach to synthesize Nintedanib intermediate, 2-oxoindoline-6-carboxylate. The current invention fills in the gap as it encompasses an efficient, one pot method to synthesize the Nintedanib intermediate by reducing the number of reaction steps by utilizing sodium dithionite as a catalyst instead of metal catalysts like Pd,Ni (Nickel) The current invention thereby eliminates the need of a high pressure hydrogenation step for synthesis of the Nintedanib intermediate , as is required by catalysis with metal catalysts. The current invention eliminates the need of washing the reaction products in multiple cycles by a solvent as the reaction product sticks to metal catalysts when catalysis utilizes metal catalysts.
The current invention discloses a preparation method of making a Nintedanib intermediate, methyl 2-oxoindoline-6-carboxylate via one pot reduction, hydrolysis and cyclisation by using sodium dithionate as a reducing agent in water. The method disclosed in the invention renders the process operationally efficient and simpler, with significant cost saving and resource conservation.
Definitions:
As used herein the term "Nintedanib" refers to compounds Nintedanib esylate, Nintedanib free base, CAS no. 656247-17-5, salts and polymorphs thereof.
As used herein the term "Sodium Dithionite" refers to compounds with CAS no. 7775-14-6, molecular formula Na2S2O4.
As used herein, the term “isolated” with reference to compounds of the present invention to the form physically separated from the reaction mixture, where it is formed. Isolation of the compound of the invention can be carried out by any of the techniques known in literature, and including, without limitation, filtration, crystallization.
As used herein, the term "mixture" refers to a homogenous or a heterogenous solution, aqueous or non-aqueous of one or more components or reactants or catalysts.
As used herein, "dissolving/dissolution in water" implies dissolving in water, wherein the water may have additives like salt, minerals present. The resulting mixture cmay be a homogenous or heterogenous solution.
As used herein, the term “purification” refers to removing impurities from the isolated compounds from the reaction mixture. Purification of the compound of the invention can be carried out by techniques including distillation, re-crystallization, sublimation, differential extraction, chromatography.
As used herein, the term "w/v" (weight/ volume) refers to amount of solute in grams in 100ml of solvent including water or other organic solvents like isopropyl alcohol.
As used herein, the term "yield" refers to purified/dried amount of compound of formula I

Embodiments:
One embodiment of the current invention is a method to prepare a compound of formula I, the method comprising the steps of;
(I)
a. heating a mixture of compound of formula II and water to a temperature of 60-90°C;
(II)
b. reacting the heated mixture in step a. in a reaction mixture with Sodium dithionite dissolved in water at a temperature of 60-90°C for 40-50 hours to obtain compound of formula I; and
c. isolating and purifying the compound of formula I from the reaction mixture in step b. with a solvent.
In one embodiment of the invention, the mixture in step a. contains 40-60% w/v of compound of formula II. In one embodiment of the invention, the mixture in step a. contains 50% w/v of compound of formula II. In one embodiment of the invention the mixture in step a. is heated to a temperature of 60-90°C. In one embodiment of the invention the mixture in step a. is heated to a temperature of 60-90°C to give a homogenous solution. In one embodiment of the invention in step a. is heated to a temperature of 80-85°C.
In one embodiment of the invention, the compound of formula II can be mixed with a solvent selected from water, methanol, acetic acid or mixtures thereof.
In one embodiment of the invention, the reaction in step b. contains 25.0-45.0 % w/v of sodium dithionite. In one embodiment of the invention, the reaction in step b. contains 27.0-38.0 % w/v of sodium dithionite. In one embodiment of the invention, the reaction in step b. contains 40-42 % w/v of sodium dithionite. In one embodiment of the invention the reaction in step b. is continued for 48 hours. In one embodiment of the invention sodium dithionite is dissolved in water at a temperature of 80-85°C in step b. In one embodiment, water may comprise of additives like salts or minerals or both. In one embodiment of the invention, the ratio of sodium dithionite dissolved in water in step b. to the heated mixture of compound of formula II dissolved in water in step a. is 1:4. In one embodiment of the invention, the ratio of sodium dithionite dissolved in water in step b. to the heated mixture of compound of formula II dissolved in water in step a. is 1:3.
In one embodiment of the invention, isolation of the compound of formula I in step c. is done by cooling the reaction mixture from step b. followed by filtration or centrifugation of the solids to isolate the compound of formula I. In one embodiment of the invention, the compound of formula I was precipitated from the reaction mixture from step b.
In one embodiment of the invention , the compound of formula I can be isolated by any of the techniques known in literature, and without limitation, includes filtration, centrifugation, and the like, evaporation by lyophilisation, freeze-drying, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying, agitated nutsche filter dryer, complete evaporation in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the solution, cooling the solution if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like. In one embodiment of the invention, the compound of formula I is isolated by filtration. In one embodiment of the invention, the compound of formula I is isolated by centrifugation.
In one embodiment of the invention, purification of the compound of formula I in step c. is done by drying the filtered or centrifuged solids at 40-45 °C for 5-6 hours after addition of the solvent. In one embodiment of the invention, purification of the compound of formula I in step c. is done by drying the filtered or centrifuged solids at 40-45°C for 5-6 hours after addition of isopropyl alcohol. In one embodiment of the invention, the solvent purified compound of formula I is dried in tray driers at 40-45°C for 5-6 hours. In embodiment of the invention, the compound of formula I is purified by stirring in isopropyl alcohol at room temperature for 1-2 hours.
In one embodiment of the invention the yield of compound of formula I is 30-60%. In one embodiment of the invention the yield of compound of formula I is 45%. In one embodiment of the invention the yield of compound of formula I is 50-55%. In one embodiment of the invention the yield of compound of formula I is 55%.
In one embodiment of the invention, the purity of compound of formula I is greater than 92% as determined by HPLC. In one embodiment of the invention, the purity of compound of formula I is at least 96%. In one embodiment of the invention, the purity of compound of formula I is at least 98%. In one embodiment of the invention, the purity of compound of formula I is at least 99%.
In one embodiment of the invention the compound of formula I is obtained in a solid form.
In one embodiment of the invention the compound of formula I is stable for 1-2 years. In one embodiment of the invention the compound of formula I is stable for at least 2 years. In one embodiment of the invention the compound of formula I is stable for at least 6 months.
In one embodiment of the invention, the solvent to purify compound of formula I in step c. is selected from C1-C6 alcohol, C1-C6 amide, C1-C6 ester, C1-C6 carboxylic acid, C2-C6 carboxylic anhydride, C1-C6 aliphatic ether, C1-C6 haloalkane, C6-C12 aromatic hydrocarbon or mixtures thereof. In one embodiment of the invention the solvent is isopropyl alcohol, ethyl acetate or isopropyl acetate. In one embodiment of the invention the solvent is isopropyl alcohol.
One embodiment of the invention is the compound of formula I obtained by the method of encompassed in the invention.
One embodiment of the invention, the method of making the compound of formula I further comprises the step of reacting compound of formula I with trimethyl orthobenzoate in presence of acetic anhydride followed by reaction with a piperidine intermediate to produce Nintedanib. In one embodiment of the invention, the piperidine intermediate includes N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide.
Examples
Example 1: Preparation of Compound of Formula I & Purification in Isopropyl Alcohol
The mixture of compound of formula II (100.0 gm) and water (200.0 mL) were heated to 80-85°C to get clear homogeneous solution. To this water mixture was added Sodium dithionite (3.0 equivalent, 167.0 gm) dissolved in water (400.0 mL) at 80-85 °C and heating was continued for 48 h. The reaction progress was observed by HPLC analysis. After 48 h, the reaction mixture was cooled to room temperature. The solids were filtered, washed with water (200mL) and dried under vacuum. The solid was further purified with Isopropyl alcohol (200.0 mL) to get the compound of formula I with HPLC purity > 98.0 %. Isolated Yield was 55 %

Example 2: Preparation of Compound of Formula I & Purification in Methanol
The mixture of compound of formula II (100.0 gm) and water (200.0 mL) were heated to 80-85°C to get clear homogeneous solution. To this water mixture was added Sodium dithionite (3.0 eq, 167.0 gm) dissolved in water (400.0 mL) at 80-85 °C and heating was continued for 48 h. The reaction progress was observed by HPLC analysis. After 48 h, the reaction mixture was cooled to room temperature. The solids were filtered, washed with water (1x200mL) and dried under vacuum. The solid was further purified with Methanol (200.0 mL to get the compound of formula I with HPLC purity > 96.0 %. Isolated Yield was 45 %

Example 3: Preparation of Compound of Formula I & Purification in Ethyl Acetate
The mixture of compound of formula II (100.0 gm) and water (200.0 mL) were heated to 80-85°C to get clear homogeneous solution. To this water mixture was added Sodium dithionite (3.0 eq, 167.0 gm) dissolved in water (400.0 mL) at 80-85 °C and heating was continued for 48 h. The reaction progress was observed by HPLC analysis. After 48 h, the reaction mixture was cooled to room temperature. The solids were filtered, washed with water (1x200mL) and dried under vacuum. The solid was further purified with Ethyl acetate (200 mL) to get the compound of formula I with HPLC purity > 92.0 %. Isolated Yield was observed to be 38 %

Example 4: Preparation of Compound of Formula I with Acetic acid & Water(1:2)
The mixture of compound of formula II (100.0 gm), Acetic acid (100.0 mL) and water (200.0 mL) were heated to 80-85°C to get clear homogeneous solution. To this water mixture was added Sodium dithionite (3.0 equivalents, 167.0 gm) dissolved in water (400.0 mL) at 80-85 °C and heating was continued for 24 h. The reaction progress was observed by HPLC analysis. The reaction mixture was cooled to room temperature. The solids were filtered, washed with water (1x200mL) and dried under vacuum. The solid was further purified with Isopropyl (2 vol) alcohol to get the compound of formula I with HPLC purity > 95.0 %. Isolated Yield was 30 %.

Example 5: Preparation of Compound of Formula I with Reduced Reaction Time
The mixture of compound of formula II (100.0 gm) and water (200.0 mL) were heated to 80-85°C to get clear homogeneous solution. To this water mixture was added Sodium dithionite (3.0 eq, 167.0 gm) dissolved in water (400.0 mL) at 80-85 °C. To this was added potassium carbonate (14 gm) and heating was continued for 24 h. The reaction progress was observed by HPLC analysis. The reaction mixture was cooled to room temperature. The solids were filtered, washed with water (1x200mL) and dried under vacuum. The solid was further purified with Isopropyl alcohol (200 mL ) to get the compound of formula I with HPLC purity > 95.0 %. Isolated Yield was 35-40 %.

Example 6: Preparation of Compound of Formula I with Methanol at Lower Temperature; Methanol as solvent for Purification
The mixture of compound of formula II (100.0 gm) and Methanol (200.0 mL) were heated to 60-65°C to get clear homogeneous solution. To this water mixture was added Sodium dithionite (5.0 eq, 279.7 gm) dissolved in water (400.0 mL) at 60-65 °C and heating was continued for 48 h. The reaction progress was observed by HPLC analysis. After 48 h, the reaction mixture was cooled to room temperature. The solids were filtered, washed with water (1x200mL) and dried under vacuum. The solid was further purified with Methanol (2 vol) to get the compound of formula I with HPLC purity > 95.0 %. Isolated Yield was 35 %.

Example 7: Preparation of Compound of Formula I with Methanol at Lower Temperature; Isopropyl Alcohol as solvent for Purification
The mixture of compound of formula II (100.0 gm) and Methanol (200.0 mL) were heated to 60-65°C to get clear homogeneous solution. To this water mixture was added Sodium dithionite (5.0 eq, 279.7 gm) dissolved in water (400.0 mL) at 60-65 °C and solid potassium carbonate (14gm, 0.3 eq) was added. The reaction mixture was heated at 60-65 °C for 48 h. The reaction progress was observed by HPLC analysis. After 48 h, the reaction mixture was cooled to room temperature. The solids were filtered, washed with water (1x200mL) and dried under vacuum. The solid was further purified with Isopropyl alcohol (200.0 mL to get the compound of formula I with HPLC purity > 95.0 %. Isolated Yield was 40 %.