HK40064146B - Process for preparing 6- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide - Google Patents

Description

Process for preparing 6-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide

Invention Field

This invention relates to a process for preparing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide.

Background of the Invention

6-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (Compound I) is a substituted nicotinamide Bruton's tyrosine kinase (BTK) inhibitor. Compound I may be used to treat cancer, inflammation, and autoimmune diseases (WO2015/028662). WO2015/028662 discloses a method for preparing approximately 50 grams of Compound I.

There is a need for an efficient and controllable process for preparing compound I, especially for large-scale preparations exceeding 1 kg.

Detailed Description of the Invention

This invention relates to a process for the high-purity and high-yield preparation of 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (compound I). The process is suitable for large-scale production (more than 1 kg, preferably more than 2 kg, more than 4 kg, or more than 10 kg). The process provides compound I with a purity ≥90%, ≥95%, ≥98%, or ≥99%.

Compound I

In the first embodiment A, compound I is prepared from 6-chloro-2-(4-phenoxyphenyl)nicotinamide (INA) using a tert-butoxycarbonyl (t-Boc) group as a protecting group. The process includes the following steps:

(a) A mixture of INA, SMC, and the first palladium catalyst was heated at 60–140 °C to yield INB.

PG is a tert-butoxycarbonyl protecting group;

(b) INB was hydrogenated under _H2 using a second palladium catalyst to give 1NC;

(c) INC is deprotected in HCl solution to obtain solid IND-HCl salt;

        

(d) IND-HCl salt reacts with acryloyl chloride or 3-chloropropionyl chloride under alkaline conditions to give 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide.

In step (a), 6-chloro-2-(4-phenoxyphenyl)nicotinamide (INA), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (SMC), and a suitable palladium catalyst are reacted in an alkaline aqueous/organic solvent mixture in a reactor under low oxygen content (<2%) to give crude 5-carbamoyl-6-(4-phenoxyphenyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylic acid tert-butyl ester (INB). The reaction temperature is 60–140 °C, preferably 60–100 °C, more preferably 75–85 °C. The reaction time is typically 1–4 hours. The Pd loading (molar ratio of Pd catalyst to reactant INA) is 0.5–5%. Higher Pd loading accelerates the reaction but also increases cost and impurities. Crude INB can be further purified to at least 90% purity without column chromatography by recrystallization and/or pulping (e.g., with tetrahydrofuran and ethyl acetate).

Suitable palladium catalysts used in this application include organopalladium compounds such as tris(dibenzylacetone)palladium(O) ( _Pd₂ (dba) _₃ ), tetra(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II) dichloride (Pd( _PPh₃ ) _₂Cl₂ ), [1,1′- _bis (diphenylphosphine)ferrocene]palladium(II) dichloride (Pd(dppf) _Cl₂ ) and inorganic palladium compounds, including Pd(OAc) _₂ and various ligands such as _Ph₃P , _Ph₂CyP , and _Cy₃P - _HBF₄ .

In step (b), the organic solution of INB is catalytically hydrogenated in a reactor under hydrogen atmosphere using a suitable palladium catalyst to yield crude 4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridine-2-tert-butyl ester)-piperidine-1-carboxylic acid ester (INC). The reaction temperature is 15–50 °C, preferably 20–45 °C. The reaction time is typically 2–10 hours. The palladium catalyst can be Pd/C or Pd(OH) _₂ /C, preferably Pd(OH) _₂ /C, which is more suitable for the process.

In step (c), HCl gas or HCl solution is added to the organic solution of INC, and the mixture is stirred at 10–40°C for 4–9 hours to remove the protecting group (t-Boc) and generate 2-(4-phenoxyphenyl)-6-(piperidin-4-yl)nicotinamide (IND)-HCl salt solid. IND-HCl precipitates from the reaction medium and is easily collected by filtration or centrifugation, making it suitable for large-scale production. In one embodiment, HCl gas is bubbled into the INC solution. In another embodiment, an organic solution of HCl (e.g., HCl in ethyl acetate or ethanol) is added to the organic solution of INC (e.g., INC in ethanol or dichloromethane). Alternatively, the organic solution of INC is added to the organic solution of HCl. The IND-HCl solid can be pulped in ethyl acetate to achieve a purity of at least 90%, preferably at least 95%.

In step (d), the IND-HCl salt ^reacts with acryloyl chloride in an alkaline solution ( ^pH 8–14, e.g. ^, bicarbonate solution _HCO3- , carbonate solution _CO32- , phosphate solution _PO4- , and hydroxide solution OH-) at low temperature (0–8°C or 2–6°C) to reduce impurity formation and obtain compound I. The solvent of the solution can be an organic solvent (e.g., THF or dichloromethane), aqueous or anhydrous. The reaction time is typically 1–5 hours or 1–3 hours. Alternatively, in step (d), the IND-HCl salt first reacts with 3-chloropropionyl chloride in a moderately alkaline solution (pH 10–12, e.g., carbonate or phosphate solution) to generate intermediate INE, and then the pH is increased to a strongly alkaline solution (e.g., hydroxide solution) to 14 to generate compound I. The solvent of the solution can be an aqueous or anhydrous organic solvent (e.g., THF or dichloromethane).

Compound I can be further purified by THF/water slurrying to increase the purity to at least 90%, preferably at least 95%.

In the second embodiment B, compound I is prepared from 6-chloro-2-(4-phenoxyphenyl)nicotinic acid/ester (INA′) and t-Boc is used as a protecting group. The process includes the following steps:

(a) A mixture of INA′, SMC, and the first palladium catalyst was heated to 60–140 °C to obtain INB′.

Where R is H or _C1-4 alkyl,

PG is a tert-butoxycarbonyl protecting group;

(b) When R is H, INB′ reacts with oxaloyl chloride first, and then reacts with ammonia to be amidated to obtain INB; or when R is _C1-4 alkyl, INB′ reacts with ammonia to be amidated to obtain INB.

(c) INB is hydrogenated under _H₂ using a second palladium catalyst to give INC;

(d) INC is deprotected in HCl solution to obtain a solid IND-HCl salt; and

(e) IND-HCl salt reacts with acryloyl chloride or 3-chloropropionyl chloride under alkaline conditions to give compound I.

Implementation scheme B is similar to scheme A, with the following differences. In implementation scheme B, the starting material is INA′ (acid or ester), not INA (amide). The product of step (a) is INB′ (acid or ester), which needs to be amidated to INB before hydrogenation. In step (b), when R is H, INB′ is first reacted with oxalyl chloride in an organic solvent (e.g., THF) at 15–50°C for 2–10 hours to obtain an acyl chloride intermediate, and then reacted with a 20–35% (w/w) aqueous ammonia solution at 15–50°C for 1–5 hours. In step (b), when R is _C1-4 alkyl, the organic solution of INB′ (e.g., THF) is reacted with a 20–35% (w/w) aqueous ammonia solution at 15–75°C for 4–20 hours.

In the third embodiment C, compound I is prepared from 6-chloro-2-(4-phenoxyphenyl)nicotinamide (INA) using a benzyl or benzyloxycarbonyl group as a protecting group. The process includes the following steps:

(a) A mixture of INA, SMC′, and the first palladium catalyst was heated at 60–140 °C to yield INB.

PG ₁ is a benzyl or benzyloxycarbonyl protecting group;

(b) INB is hydrogenated under _H2 using a second palladium catalyst to yield IND;

(c) IND reacts with acryloyl chloride or 3-chloropropionyl chloride under alkaline conditions to give 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide.

Implementation scheme C is similar to A, except that in step (a) implementation scheme C uses a different protecting group, benzyl or benzyloxycarbonyl, as a reagent. This protecting group is unstable during hydrogenation and is deprotected in step (b) to generate IND. IND can then react with acryloyl chloride or 3-chloropropionyl chloride under alkaline conditions to generate compound I. Optionally, after step (b), an HCl solution can be added to the IND to generate a solid IND-HCl salt, which is then reacted with acryloyl chloride or 3-chloropropionyl chloride.

In the fourth embodiment D, compound I is prepared from 6-chloro-2-(4-phenoxyphenyl)nicotinic acid/ester (INA′) using a benzyl or benzyloxycarbonyl group as a protecting group. The process includes the following steps:

(a) A mixture of INA′, SMC′, and the first palladium catalyst was heated at 60–140 °C to obtain INB′.

Where R is H or _C1-4 alkyl,

PG ₁ is a benzyl or benzyloxycarbonyl protecting group;

(b) When R is H, INB′ reacts with oxaloyl chloride first, and then with ammonia; or when R is a _C1-4 alkyl group, INB′ reacts with ammonia to give INB.

(c) INB is hydrogenated under _H2 using a second palladium catalyst to give IND;

(d) IND reacts with acryloyl chloride or 3-chloropropionyl chloride under alkaline conditions to give 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide.

Implementation scheme D is similar to C, with the following differences. In implementation scheme D, the starting material is INA′ (acid or ester), not INA (amide). The product of step (a) is INB′ (acid or ester), which needs to be amidated to INB before hydrogenation. In step (b), when R is H, INB′ is first reacted with oxalyl chloride in an organic solvent (e.g., THF) at 15–50°C for 2–10 hours to obtain an acyl chloride intermediate, and then reacted with a 20–35% (w/w) ammonia solution at 15–50°C for 1–5 hours. In step (b), when R is _C1-4 alkyl, the organic solution of INB′ (e.g., THF) is reacted with a 20–35% (w/w) ammonia solution at 15–75°C for 4–20 hours.

The raw material INA can be prepared by heating 2,6-dichloronicotinamide (SMA), SMB and palladium catalyst in an alkaline solvent or solvent mixture (e.g. sodium carbonate or potassium carbonate, 1,4-dioxane, dimethylacetamide, ethanol/methanol) at 60–140 °C for 8–12 hours to obtain INA.

The raw material INA′ can be prepared by heating 2,6-dichloronicotinic acid/ester (SMA′), SMB and palladium catalyst in an alkaline solvent or solvent mixture (e.g. sodium carbonate or potassium carbonate, 1,4-dioxane, dimethylacetamide) at 60–140 °C for 8–12 hours to obtain INA′.

In the preparation of INA or INA′, the borate ester of SMB is used. SMB reacts better than the corresponding boric acid, reducing bicoupling side reactions and improving the regioselectivity of chlorine. Crude INA can be further pulped in tetrahydrofuran to improve purity to at least 90%.

2,6-Dichloronicotinamide (SMA) can be obtained from the supplier. Alternatively, SMA can be prepared by reacting 2,6-dichloronicotinic acid (SM1) with oxaloyl chloride (COCl) ₂ at 10–30°C for 4–12 hours, followed by reacting it with ammonia in an organic solvent at 10–30°C for 1–3 hours.

2,6-Dichloronicotinic acid/ester (SMA′) can be obtained from the supplier.

This method provides a high yield of compound I. The overall yield from INA or INA′ to compound I is approximately 55–70%, and the overall yield from SMA or SMA to compound I is approximately 30–50%.

The following embodiments further illustrate the present invention. These embodiments are for illustrative purposes only and should not be construed as limiting the invention.

Example

Examples 1-6 are summarized in Scheme A.

Example 1. Preparation of 2,6-dichloronicotinamide (SMA)

In a reactor under nitrogen atmosphere, 2,6-dichloronicotinic acid (SM1, 39.8 kg, 207 mol), DMF (1.9 kg, 26 mol), and THF (189.9 kg) were added. Oxaloyl chloride (36.0 kg, 283 mol) was slowly added to the above solution while maintaining the temperature between 15 and 25°C. After the addition was complete, the reaction was stirred at the same temperature for 8 hours. Maintaining the temperature below 50°C, the mixture was concentrated under reduced pressure until the volume decreased to 2.5–3.5 V. The mixture was then cooled to 20–30°C and added to a stirred solution of THF (106.1 kg) and ammonia (180.0 kg) cooled to 0–10°C. After the addition was complete, the reaction mixture was heated to 20–30°C and stirred for another 1.5 hours. The mixture was then concentrated under reduced pressure below 50°C until no more distillate was distilled off. The resulting slurry was cooled to 15–25°C, stirred for 2–4 hours, and centrifuged. The solid filter cake was washed with water (40.4 kg) and mixed with methyl tert-butyl ether (148.5 kg). The resulting mixture was heated to 45–55 °C and stirred for 3–5 hours. Then it was cooled to 20–30 °C, stirred for 1–3 hours, and centrifuged. The solid filter cake was washed with methyl tert-butyl ether (6.8 kg) and dried under reduced pressure (below -0.080 MPa) at 35–45 °C for 16 hours to obtain SMA (30.48 kg, yield 77%, purity 99.6%).

Example 2. Preparation of 6-chloro-2-(4-phenoxyphenyl)nicotinamide (INA)

SMA (30.0 kg, 157 mol) and _Na₂CO₃ (66.6 kg, 628 mol) were added to a solution of SMB (58.7 kg, 198.2 mol) in ethanol (120.0 kg) and _methanol (36.3 kg). The resulting mixture was replaced three times with _N₂ . Then _Pd₂ (dba) _₃ (tris(dibenzylacetone)dipalladium(0), 4.32 kg, 4.7 mol) was added, and _N₂ was bubbled through for 2–5 minutes. The reaction mixture was heated to 75–85 °C and stirred for 12 hours. The mixture was then cooled to 15–25 °C, stirred for 4–6 hours, and filtered. The filter cake was soaked in ethanol (30.3 kg) for 10–20 minutes and filtered. The filter cake was dissolved in THF (268.4 kg), heated to 45–55 °C, and stirred for 2–4.5 hours. The mixture was cooled to 20–30 °C and filtered. Collect the filtrate. Soak the filter cake in THF (62.4 kg) for 10–20 minutes and filter. Collect the filtrate. Soak the filter cake further in THF (60.3 kg) for 10–20 minutes and filter. Collect the filtrate, combine it with the two batches of filtrate above, and concentrate under reduced pressure below 50°C. Add ethanol (60.1 kg) to the residue and concentrate under reduced pressure below 50°C. Add another batch of ethanol (60.4 kg) to the residue and concentrate under reduced pressure below 50°C. Add ethanol (90.1 kg) to the residue, heat to 75–85°C and stir for 1.5–2.5 hours. Cool the resulting mixture to 15–25°C, stir for 4–6 hours and centrifuge. The solid filter cake was washed with ethanol (30.1 kg) and dried under reduced pressure (below -0.080 MPa) at 35–45 °C for 16 hours to obtain INA (39.23 kg, yield 77%, purity 93.1%).

Example 3. Preparation of tert-butyl 5-carbamoyl-6-(4-phenoxyphenyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylic acid (INB)

In a reactor under nitrogen atmosphere, add INA (31.7 kg, 90.7 mol, 93.1% purity), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (30.8 kg, 99.7 mol), _Na₂CO₃ (25.1 _kg , 237 mol), EtOH (118.7 kg), and _H₂O (148.2 kg). Bubble the reactor with _N₂ until the oxygen content is below 1.0%. Then add Pd( _PPh₃ ) _₂Cl₂ (1.18 _kg , 1.68 mol). Heat the reaction mixture to 75–85 °C and stir for 2.5 hours. After cooling to 15–25 °C, stir the reaction mixture for 1–3 hours and filter. The filter cake was washed successively with ethanol (26.2 kg) and _H₂O (35.8 kg), dissolved in THF (261.7 kg), and stirred at 45–55 °C for 2–4 hours. The solution was then cooled to 20–30 °C and filtered. The filtrate was collected. The filter cake was washed twice with THF (59.3 kg and 59.7 kg THF, respectively), and the filtrate was collected. The three batches of filtrate were combined and concentrated below 60 °C. Ethyl acetate (148.1 kg) was added to the residue, and the mixture was concentrated below 60 °C. Then another batch of ethyl acetate (147.5 kg) was added, and the mixture was concentrated below 60 °C. The resulting residue was added to ethyl acetate (147.5 kg), heated to 65–75 °C, and stirred for 2–4 hours. The mixture was then cooled to 15–25 °C, stirred for 2–4 hours, and centrifuged. The solid filter cake was washed with ethyl acetate (59.0 kg) and dried under reduced pressure (below -0.08 MPa) at 35–45 °C for 12–16 hours to obtain INB (30.44 kg, yield 71%, purity 98.7%).

Example 4. Preparation of tert-butyl 4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)piperidine-1-carboxylic acid (INC)

In a reactor under nitrogen atmosphere, Pd(OH) _₂ /C (2.03 kg, 20%) and THF (32.0 kg) were added and stirred for 5–10 minutes. Then, a THF solution of 14.85 kg (31.5 mol) of INB was added (47 kg). More THF (32.0 kg) was added, and the system temperature was maintained between 20 and 25 °C. The reaction mixture was purged three times with _N₂ , and then three times with _H₂ . The reaction mixture was heated to 35–45 °C and stirred for 4 hours under _H₂ pressure of 0.10–0.20 MPa. The mixture was then filtered, and the filter cake was washed twice with THF (30 kg × 2). The three batches of filtrate were combined to obtain a solution of crude INC (181.5 kg). Two separate reaction batches (using a total of 30.5 kg of pure INB) were combined to obtain a THF solution of INC (365.3 kg). Activated carbon (3.00 kg) was added, and the mixture was heated to 45–55 °C and stirred for 1–3 hours. The mixture was then cooled to 20–30 °C, filtered through diatomaceous earth (15.2 kg), and washed twice with THF (62.2 kg and 61.1 kg of THF, respectively). The three filtrates were combined and concentrated under reduced pressure below 50 °C. Ethanol (244.0 kg) was added to the residue and concentrated under reduced pressure below 50 °C. Ethanol (246.1 kg) was added again, and the resulting mixture was concentrated under reduced pressure below 50 °C. Ethyl acetate (262.3 kg) and ethanol (43.5 kg) were added to the residue, and the mixture was stirred at 20–55 °C until all solids dissolved, yielding a solution of INC.

Example 5. Preparation of 2-(4-phenoxyphenyl)-6-(piperidin-4-yl)nicotinamide (IND)

The above solution of INC in ethyl acetate (262.3 kg) and ethanol (43.5 kg) was replaced three times with _N2 . Then, HCl (gas, 11.7 kg) was bubbled into the solution, and the reaction mixture was stirred at 10–40 °C for 7 hours. The mixture was cooled to 15–25 °C, stirred for 1–3 hours, and centrifuged. The solid filter cake was washed with ethyl acetate (60.8 kg) and dried under reduced pressure (below -70 kPa) at 30–50 °C for 24 hours to give IND (26.3 kg, HCl salt, 99% yield, 99.4% purity).

Example 6. Preparation of 6-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (INF)

In a reactor under nitrogen atmosphere, IND (10.0 kg, 24.4 mol), THF (105.5 kg), and _H₂O (125.4 kg) were added, and the mixture was stirred at 15–25 °C for 20–40 minutes. Then, _NaHCO₃ (10.3 kg, 123 mol) was added over 20–40 minutes. The reaction mixture was cooled to -2–6 °C, and acryloyl chloride (3.8 kg, 42.0 mol) was added, followed by stirring for 1–3 hours. HPLC analysis showed that IND was not completely consumed, so acryloyl chloride was added again, and stirring of the reaction mixture continued until the reaction was complete (0.68 kg of acryloyl chloride was added in three batches, with the reaction lasting 16 hours). The mixture was then heated to 5–20 °C, and water (98.9 kg) was added, followed by stirring for 20–40 minutes, and then filtered. The filter cake was washed with water (20 kg) and mixed with another batch of water (100.8 kg), and stirred at 15–25 °C for 1–2 hours. The mixture was then filtered. The filter cake was washed successively with water (21.2 kg) and ethanol (5.0 kg). The filter cake was then dissolved in dichloromethane (200.6 kg), heated to 40–45 °C, and stirred until the solution became clear. After cooling to 15–25 °C, HCl solution (300.7 kg, 0.18%) was added, and the mixture was stirred for 10–20 minutes. The liquid-liquid phase was separated. The organic layer was washed twice successively with water (51.0 kg and 50.2 kg respectively), _Na₂CO₃ aqueous solution (0.42%, adjusted pH = 8–9), and water (50.0 kg). The organic phase was concentrated under reduced pressure. Ethanol (100.0 kg) was added to the residue, and the mixture was concentrated under reduced pressure below 45 °C. Ethanol (80.0 kg) was added again to the residue, and the mixture was stirred at 15–25 °C for 1–2 hours, then filtered. The filter cake was washed with ethanol and dried under reduced pressure at 20–30°C for 14 hours to obtain INF (7.47 kg, yield 72%, purity 99.5%).

This invention, as well as the manner and process of making and using it, is now described in such complete, clear, concise, and precise terminology that any person skilled in the art to which this invention pertains can make and use it. It should be understood that preferred embodiments of the invention have been described above, and modifications may be made thereto without departing from the scope of the invention as set forth in the claims. To particularly point out and clearly claim protection for the subject matter considered inventive, the following claims summarize the specification.

Claims (5)

1. A method for preparing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (compound I), comprising: (a) A mixture of INA, SMC, and a first palladium-containing catalyst was heated at 60–140 °C to yield INB. PG is a tert-butoxycarbonyl protecting group; (b) INB is hydrogenated by a second palladium-containing catalyst under _H2 to give a first solution containing crude INC; (c) Add activated carbon to purify the crude INC, then concentrate the purified INC and dissolve it in ethyl acetate and ethanol to obtain a second solution containing the purified INC. (d) HCl gas was added to the second solution to deprotect the INC and obtain a solid IND-HCl salt; (e) Add THF, _H₂O , and _NaHCO₃ to dissolve and neutralize the IND-HCl salt; (f) IND reacts with acryloyl chloride or 3-chloropropionyl chloride under alkaline conditions to give 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide. 2. A method for preparing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (compound I), comprising: (a) A mixture of INA’, SMC, and the first palladium-containing catalyst was heated at 60–140 °C to obtain INB’. Where R is H or _C1-4 alkyl, PG is a tert-butoxycarbonyl protecting group; (b) When R is H, INB' reacts with oxaloyl chloride first, and then reacts with ammonia to be amidated to obtain INB; or when R is _C1-4 alkyl, INB' reacts with ammonia to be amidated to obtain INB. (c) INB is hydrogenated by a second palladium-containing catalyst under _H2 to give a first solution containing crude INC; (d) Add activated carbon to purify the crude INC, then concentrate the purified INC and dissolve it in ethyl acetate and ethanol to obtain a second solution containing the purified INC; (e) HCl gas is added to the second solution to deprotect the INC and obtain a solid IND-HCl salt; (f) Add THF, _H₂O , and _NaHCO₃ to dissolve and neutralize the IND-HCl salt; (g)IND reacts with acryloyl chloride or 3-chloropropionyl chloride under alkaline conditions to give 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide. 3. The method according to claim 1, further comprising the step of heating a mixture of 2,6-dichloronicotinamide (SMA), SMB, and a palladium-containing catalyst in an alkaline solvent or a solvent mixture at 60–140°C for 8–12 hours to prepare INA. 4. The method according to claim 3 further comprises the step of reacting 2,6-dichloronicotinic acid with oxalyl chloride (COCl) ₂ , and then reacting it with ammonia in an organic solvent to obtain SMA. 5. The method according to claim 2, further comprising the step of heating a mixture of 2,6-dichloronicotinic acid/ester (SMA’), SMB, and a palladium-containing catalyst in an alkaline solvent or solvent mixture at 60–140°C for 8–12 hours to prepare INA’.