VADADUSTAT

CAS 1000025-07-9

[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxamido]acetic acid

N-[[5-(3-Chlorophenyl)-3-hydroxy-2-pyridinyl]carbonyl]glycine

MF C14H11ClN2O4 , 306.0407

for Treatment of Anemia associated with Chronic Kidney Disease (CKD)

• Originator Procter & Gamble
• Developer Akebia Therapeutics
• Class Antianaemics; Chlorophenols; Pyridines; Small molecules
• Mechanism of Action Hypoxia-inducible factor-proline dioxygenase inhibitors

• Phase III Anaemia

• 01 Aug 2016 Akebia Therapeutics initiates the phase III INNO2VATE trial for Anaemia in USA (NCT02865850)
• 23 May 2016 Interim drug interactions and adverse events data from a phase I trial (In volunteers) Chronic kidney disease released by Akebia
• 05 May 2016 Akebia completes a clinical trial (ethnobridging study) in Healthy volunteers

PATENT

CN 105837502

HIF inhibitor Vadadustat (Code AKB-6548) The chemical name N- [5- (3- chlorophenyl) -3-hydroxypyridine-2-carbonyl] glycine,

Vadadustat is a treatment for anemia associated with chronic kidney disease oral HIF inhibitor, is an American biopharmaceutical company Akebia Therapeutics invention in the research of new drugs, has completed Phase II pivotal clinical trial treatment studies, successfully met the researchers set given the level of hemoglobin in vivo target and good security, a significant effect, and phase III clinical trials.

 U.S. Patent Publication US20120309977 synthetic route for preparing a Vadadustat: A 3-chlorophenyl boronic acid and 3,5_-dichloro-2-cyanopyridine as starting materials, by-catalyzed coupling methoxy substituted, cyano hydrolysis and condensation and ester hydrolysis reaction Vadadustat, process route is as follows:

Since the entire synthetic route 12 steps long, complicated operation, high cost.U.S. Patent No. 1 2 ^ ¥ disclosed 20070299086 & (^ (Scheme 3 1118 seven seven to 3,5-dichloro-2-cyanopyridine starting material, first-dichloro substituted with benzyloxy, then cyano hydrolysis, condensation, hydrogenation and deprotection trifluorosulfonyl, to give N- [5- trifluoromethanesulfonyloxy-3-hydroxypyridine-2-carbonyl) glycine methyl ester, 3-chlorophenyl and then boronic acid catalyzed coupling reactions, the final ester hydrolysis reaction Vadadustat, process route is as follows:

The synthesis steps long, intermediate products and final products contain more impurities and byproducts, thus purified requires the use of large amounts of solvents, complicated operation, low yield, and because the hydrogenation reaction is a security risk on the production, not conducive to the promotion of industrial production, it is necessary to explore a short process, simple operation, low cost synthetic method whereby industrial production Vadadus tat fit.

Example 1

A) Preparation of N- (3,5_-dichloro-2-carbonyl) glycine methyl ester:

3,5-dichloro-2-pyridinecarboxylic acid (19.2g, 0.10mol) and N, N’_ carbonyldiimidazole (24.3g, 0.15mol) was dissolved in N, N- dimethylformamide (100 mL ), was added glycine methyl ester hydrochloride (15.18,0.12111〇1), 11 was added dropwise diisopropylethylamine (51.7g, 0.40mol), the reaction mixture was stirred 35 ° C for 8 hours, TLC determined the completion of reaction gussets The reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was adjusted to neutral by adding ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, and recrystallized from methanol to give N- (3,5- dichloro-pyridin-2 – carbonyl) glycine methyl ester, an off-white solid (21.6g), a yield of 82.0%, this reaction step is as follows:

1234567 B) Preparation of N- [5- (3- chlorophenyl) -3-chloropyridine-2-carbonyl] glycine methyl ester: 2

1 (3,5-dichloro-2-carbonyl) glycine methyl ester (20 (^, 〇1 76111111), 3-chlorophenyl boronic acid (13.18, 3 83.7mmol), [l, l’- bis (diphenylphosphino) ferrocene] dichloropalladium (2.8g, 3.8mmol), potassium carbonate (14.2g, 4 0. lmo 1) and N, N- dimethylformamide (75mL) was added The reaction flask, the reaction mixture was heated to 60 ° C for 20 hours the reaction was stirred for 5:00, point TLC plates to determine completion of the reaction, the reaction solution was cooled to room temperature, was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, washed with brine, sulfuric acid 6 magnesium dried and concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane was recrystallized to give N- [5- (3- chlorophenyl) -3-7-chloro-2-carbonyl] glycine methyl ester, white solid (19.7g), yield 76.4%, this reaction step is as follows:

C) Preparation of N_ [5- (3- chlorophenyl) -3-methoxy-pyridine-2-carbonyl] glycine:

N- [5- (3- chlorophenyl) -3-chloropyridine-2-carbonyl] glycine methyl ester (19 (^, 56111 111〇1) and sodium methoxide (7.6g, 0.14mol) was dissolved in methanol (150 mL), the reaction mixture was heated to 65 ° C, the reaction was stirred at reflux for 24 hours, TLC determined gussets completion of the reaction the reaction solution was cooled to room temperature, water (300mL) was stirred for 3h, cooled to 0 ° C, stirred for 2h, precipitated solid was filtered, the filter cake was dried to give N- [5- (3- chlorophenyl) -3-methoxy-pyridine-2-carbonyl] glycine, off-white solid (17.4 g of), a yield of 96.5%, of the reaction steps are as follows:

D) Preparation Vadadustat:

N- [5- (3- chlorophenyl) -3-methoxy-pyridine-2-carbonyl] glycine (16.68,51.7111111〇1) and 48% hydrobromic acid solution (52mL, 0.46mol) added to the reaction bottle, the reaction mixture was heated to 100 ° C, the reaction was stirred at reflux for 24 hours, TLC determined gussets completion of the reaction the reaction solution cooled square ~ 5 ° C, was slowly added 50% sodium hydroxide solution was adjusted to pH 2 at 0 -5 ° C under crystallization 3h, the filter cake washed with ethyl acetate and n-hexane mixed solvent of recrystallization, in finished Vadadustat, off-white solid (15.6g), a yield of 98.0%, this reaction step is as follow

PATENT

WO-2016153996

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016153996&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescriptiohttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016153996&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

WO 2015073779

https://www.google.com/patents/WO2015073779A1?cl=en

Form A of Compound (I):

(I),

which has an X-ray powder diffraction pattern as shown in FIG. 1. In certain embodiments, Form A of Compound (I) has an X-ray powder diffraction pattern comprising one, two, three, four, or five peaks at approximately 18.1 , 20.3, 22.9, 24.0, and 26.3 °2Θ; and wherein the crystalline Compound (I) is substantially free of any other crystalline form of Compound (I).

PATENT

US 20120309977

• FIG. 1 depicts an outline of one embodiment for preparing the disclosed prolyl hydroxylase inhibitors.
  FIG. 2 depicts an outline of one embodiment for preparing the disclosed prolyl hydroxylase inhibitor ester prodrugs.
  FIG. 3 depicts an outline of one embodiment for preparing the disclosed prolyl hydroxylase inhibitor amide prodrugs.

Example 1 describes a non-limiting example of the disclosed process for the preparation of a prolyl hydroxylase ester pro-drug

EXAMPLE 1Methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate (4)

Preparation of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine (1): To a 100 mL round bottom flask adapted for magnetic stirring and equipped with a nitrogen inlet was charged (3-chlorophenyl)boronic acid (5 g, 32 mmol), 3,5-dichloro-2-cyanopyridine (5.8 g, 34 mmol), K₂CO₃ (5.5 g, 40 mmol), [1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCl₂(dppf)] (0.1 g, 0.13 mmol), dimethylformamide (50 mL) and water (5 mL). The reaction solution was agitated and heated to 45° C. and held at that temperature for 18 hours after which the reaction was determined to be complete due to the disappearance of 3,5-dichloro-2-cyanopyridine as measured by TLC analysis using ethyl acetate/methanol (4:1) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction solution was then cooled to room temperature and the contents partitioned between ethyl acetate (250 mL) and saturated aqueous NaCl (100 mL). The organic phase was isolated and washed a second time with saturated aqueous NaCl (100 mL). The organic phase was dried for 4 hours over MgSO₄, the MgSO₄ removed by filtration and the solvent removed under reduced pressure. The residue that remained was then slurried in methanol (50 mL) at room temperature for 20 hours. The resulting solid was collected by filtration and washed with cold methanol (50 mL) then hexanes (60 mL) and dried to afford 5.8 g (73% yield) of an admixture containing a 96:4 ratio of the desired regioisomer. ¹H NMR (DMSO-d₆) δ 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H)

Preparation of 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine (2): To a 500 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, 1, (10 g, 40 mmol), sodium methoxide (13.8 mL, 60 mmol) and methanol (200 mL). With stirring, the reaction solution was heated to reflux for 20 hours. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction mixture was cooled to room temperature and combined with water (500 mL). A solid began to form. The mixture was cooled to 0° C. to 5° C. and stirred for 3 hours. The resulting solid was collected by filtration and washed with water, then hexane. The resulting cake was dried in vacuo at 40° C. to afford 9.4 g (96% yield) of the desired product as an off-white solid. ¹H NMR (DMSO-d₆) δ 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).

Preparation of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid (3): To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser was charged 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine, 2, (1 g, 4 mmol) and a 48% aqueous solution of HBr (10 mL). While being stirred, the reaction solution was heated to reflux for 20 hours. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction contents was then cooled to 0° C. to 5° C. with stirring and the pH was adjusted to approximately 2 by the slow addition of 50% aqueous NaOH. Stirring was then continued at 0° C. to 5° C. for 3 hours. The resulting solid was collected by filtration and washed with water, then hexane. The resulting cake was dried in vacuo at 40° C. to afford 1.03 g (quantitative yield) of the desired product as an off-white solid. ¹H NMR (DMSO-d₆) δ 8.52 (d, 1H), 7.99 (d, 1H), 7.95 (s, 1H) 7.81 (t, 1H), 7.57 (s, 1H), and 7.55 (s, 1H).

Preparation of methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate (4): To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a nitrogen inlet tube was charged 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (1 gm, 4 mmol), N,N′-carbonyldiimidazole (CDI) (0.97 g, 6 mmol) and dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 45° C. for about 1 hour then cooled to room temperature. Glycine methyl ester hydrochloride (1.15 g, 12 mmol) is added followed by the dropwise addition of diisopropylethylamine (3.2 mL, 19 mmol). The mixture was then stirred for 2.5 hours at room temperature after which water (70 mL) was added. The contents of the reaction flask was cooled to 0° C. to 5° C. and 1N HCl was added until the solution pH is approximately 2. The solution was extracted with dichloromethane (100 mL) and the organic layer was dried over MgSO₄ for 16 hours. Silica gel (3 g) is added and the solution slurried for 2 hours after which the solids are removed by filtration. The filtrate is concentrated to dryness under reduced pressure and the resulting residue was slurried in methanol (10 mL) for two hours. The resulting solid was collected by filtration and washed with cold methanol (20 mL) then hexane and the resulting cake is dried to afford 0.85 g of the desired product as an off-white solid. The filtrate was treated to afford 0.026 g of the desired product as a second crop. The combined crops afford 0.88 g (68% yield) of the desired product. ¹H NMR (DMSO-d₆) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).

The formulator can readily scale up the above disclosed synthesis. Disclosed herein below is a synthesis wherein the disclosed process is scaled up for commercial use

EXAMPLE 2Methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate (4)

Preparation of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine (1): A 20 L reactor equipped with a mechanical stirrer, dip tube, thermometer and nitrogen inlet was charged with (3-chlorophenyl)boronic acid (550 g, 3.52 mol), 3,5-dichloro-2-cyanopyridine (639 g, 3.69 mol), K₂CO₃ (5.5 g, 40 mmol), [1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCl₂(dppf)] (11.5 g, 140 mmol), and dimethylformamide (3894 g, 4.125 L). The reaction solution was agitated and purged with nitrogen through the dip-tube for 30 minutes. Degassed water (413 g) was then charged to the reaction mixture while maintaining a temperature of less than 50° C. 25 hours. The reaction was determined to be complete due to the disappearance of 3,5-dichloro-2-cyanopyridine as measured by TLC analysis using ethyl acetate/methanol (4:1) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction solution was then cooled to 5° C. and charged with heptane (940 g, 1.375 L) and agitated for 30 minutes. Water (5.5 L) was charged and the mixture was further agitated for 1 hour as the temperature was allowed to rise to 15° C. The solid product was isolated by filtration and washed with water (5.5 L) followed by heptane (18881 g, 2750 ML). The resulting cake was air dried under vacuum for 18 hours and then triturated with a mixture of 2-propanol (6908 g, 8800 mL0 and heptane (1 g, 2200 mL0 at 50° C. for 4 hours, cooled to ambient temperature and then agitated at ambient temperature for 1 hour. The product was then isolated by filtration and washed with cold 2-propanol (3450 g, 4395 mL) followed by heptane (3010 g, 4400 mL). The resulting solid was dried under high vacuum at 40° C. for 64 hours to afford 565.9 g (65% yield) of the desired product as a beige solid. Purity by HPLC was 98.3. ¹H NMR (DMSO-d₆) δ 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H).

Preparation of 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine (2): A 20 L reactor equipped with a mechanical stirred, condenser, thermometer and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, 1, (558 g, 2.24 mol) and sodium methoxide (25% solution in methanol, 726.0 g, 3.36 mol). With agitation, the reaction solution was heated to reflux for 24 hours, resulting in a beige-colored suspension. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction mixture was cooled to 5° C. and then charged with water (5580 mL). The resulting slurry was agitated for 3 hours at 5° C. The solid product was isolated by filtration and washed with water (5580 mL) until the filtrate had a pH of 7. The filter cake was air dried under vacuum for 16 hours. The filter cake was then charged back to the reactor and triturated in MeOH (2210 g, 2794 mL) for 1 hour at ambient temperature. The solid was collected by filtration and washed with MeOH (882 g, 1116 mL, 5° C.) followed by heptane (205 mL, 300 mL), and dried under high vacuum at 45° C. for 72 hours to afford 448 g (82% yield) of the desired product as an off-white solid. Purity by HPLC was 97.9%. ¹H NMR (DMSO-d₆) δ 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).

Preparation of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid (3): A 20 L reactor equipped with a mechanical stirrer, condenser, thermometer, nitrogen inlet and 25% aqueous NaOH trap was charged 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine, 2, (440.6 g, 1.8 mol) and 37% aqueous solution of HCl (5302 g). While being agitated, the reaction solution was heated to 102° C. for 24 hours. Additional 37% aqueous HCl (2653 g) was added followed by agitation for 18 hours at 104° C. The reaction contents was then cooled to 5° C., charged with water (4410 g) and then agitated at 0° C. for 16 hours. The resulting precipitated product was isolated by filtration and washed with water until the filtrate had a pH of 6 (about 8,000 L of water). The filter cake was pulled dry under reduced pressure for 2 hours. The cake was then transferred back into the reactor and triturated in THF (1958 g, 2201 mL) at ambient temperature for 2 hours. The solid product was then isolated by filtration and washed with THF (778 g, 875 mL) and dried under reduced pressure at 5° C. for 48 hours to afford 385 g (89% yield) of the desired product as an off-white solid. HPLC purity was 96.2%. ¹H NMR (DMSO-d₆) δ 8.52 (d, 1H), 7.99 (d, 1H), 7.95 (s, 1H) 7.81 (t, 1H), 7.57 (s, 1H), and 7.55 (s, 1H).

Preparation of methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate (4): A 20 L reactor equipped with a mechanical stirrer, condenser, thermometer and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (380 g, 1.52 mol) and diisopropylethylamine (DIPEA) (295 g, 2.28 mol). With agitation, the solution was cooled to 3° C. and charged with trimethylacetyl chloride (275.7 g, 2.29 mol) while maintaining a temperature of less than 11° C., The mixture was then agitated at ambient temperature for 2 hours. The mixture was then cooled to 10° C. and charged with a slurry of glycine methyl ester HCl (573.3 g, 4. 57 mol) and THF (1689 g, 1900 mL), then charged with DIPEA (590.2 g, 4.57 mol) and agitated at ambient temperature for 16 hours. The mixture was then charged with EtOH (1500 g, 1900 mL) and concentrated under reduced pressure to a reaction volume of about 5.8 L. The EtOH addition and concentration was repeated twice more. Water (3800 g) was then added and the mixture was agitated for 16 hours at ambient temperature. The resulting solid product was isolated by filtration and washed with a mixture of EtOH (300 g, 380 mL) and water (380 g), followed by water (3800 g), dried under reduced pressure for 18 hours at 50° C. to afforded 443 g (91% yield) of the desired product as an off-white solid. Purity by HPLC was 98.9%. ¹H NMR (DMSO-d₆) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).

Scheme II herein below outlines and Example 2 describes a non-limiting example of the disclosed process for preparing a prolyl hydroxylase inhibitor from an ester prodrug.

EXAMPLE 3{[5-(3-Chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetic acid (5)

Preparation of {[5-(3 -chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetic acid (5): To a 50 mL flask is charged methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}-acetate, 4, (0.45 g, 1.4 mmol), tetrahydrofuran (4.5 mL) and 1 M NaOH (4.5 mL, 4.5 mmol). The mixture was stirred for 2 hours at room temperature after which it was determined by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components that the reaction was complete. The reaction solution was adjusted to pH 1 with concentrated HCl and the solution was heated at 35° C. under vacuum until all of the tetrahydrofuran had been removed. A slurry forms as the solution is concentrated. With efficient stirring the pH is adjusted to ˜2 with the slow addition of 1 M NaOH. The solid which forms was collected by filtration, washed with water, followed by hexane, then dried under vacuum to afford 0.38 g (88% yield) of the desired product as a white solid. ¹H NMR (DMSO-d₆) δ 12.84 (s, 1H), 12.39 (s, 1H), 9.39 (t, 1H), 8.56 (d, 1H), 7.94 (s, 1H), 7.81 (m, 2H), 7.55 (q, 2H), and 4.02 (d, 2H).

The formulator can readily scale up the above disclosed synthesis. Disclosed herein below is a synthesis wherein the disclosed process is scaled up for commercial use.

EXAMPLE 4{[5-(3-Chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetic acid (5)

Preparation of {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetic acid (5): To a 20 L reactor equipped with a mechanical stirrer, condenser, thermometer and nitrogen inlet was charged methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}-acetate, 4, (440 g, 1.42 mol), tetrahydrofuran (3912 g, 4400 mL) and 1 M NaOH (4400 mL). The mixture was stirred for 2 hours at room temperature after which it was determined by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components that the reaction was complete. The reaction solution was acidified to a pH of 2 with slow addition of 2M HCl (2359 g). The resulting mixture was concentrated under reduced pressure to a volume of about 7.5 L. Ware (2210 g) was added and the solution cooled to ambient temperature and agitated for 18 hours. The solid product was isolated by filtration and washed with water (6 L). the crude product was transferred back into the reactor and triturated with 2215 g o deionized water at 70° C. for 16 hours. The mixture was cooled to ambient temperature, The solid product was isolated by filtration and washed with water (500 mL) and dried under reduced pressure at 70° C. for 20 hours to afford 368 g (87% yield) of the desired product as an off-white solid. Purity by HPLC was 99.3%. ¹H NMR (DMSO-d₆) δ 12.84 (s, 1H), 12.39 (s, 1H), 9.39 (t, 1H), 8.56 (d, 1H), 7.94 (s, 1H), 7.81 (m, 2H), 7.55 (q, 2H), and 4.02 (d, 2H).

Scheme III herein below outlines and Example 3 describes a non-limiting example of the disclosed process for preparing a prolyl hydroxylase amide prodrug.

EXAMPLE 55-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide

Preparation of 5-(3-chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide (6): To a solution of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (749 mg, 3 mmol) in DMF (20 mL) at room temperature under N₂ is added 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (0.925 g, 5.97 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.806 g, 5.97 mmol). The resulting solution is stirred for 15 minutes then 2-aminoacetamide hydrochloride (0.66 g, 5.97 mmol) and diisopropylethylamine (1.56 ml, 8.96 mmol) are added. The reaction is monitored by TLC and when the reaction is complete the reaction mixture is concentrated under reduced pressure and H₂O added. The product can be isolated by normal work-up: The following data have been reported for compound (6). ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.46 (1H, s), 9.17 (1H, t, J=5.9 Hz), 8.55 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=0.9 Hz), 7.75-7.84 (2H, m), 7.49-7.60 (3H, m), 7.18 (1H, s), 3.91 (2H, d, J=5.9 Hz). HPLC-MS: m/z 306 [M+H]⁺.

Scheme IV herein below depicts a non-limiting example the hydrolysis of an amide pro-drug to a prolyl hydroxylase inhibitor after removal of a R¹⁰ protecting group

PATENT

US 20070299086

https://www.google.com/patents/US20070299086

REF

http://akebia.com/wp-content/themes/akebia/img/media-kit/abstracts-posters-presentations/Akebia_NKF%202016%20Poster_FINAL.pdf

Beuck S, Schänzer W, Thevis M. Hypoxia-inducible factor stabilizers and other
small-molecule erythropoiesis-stimulating agents in current and preventive doping
analysis. Drug Test Anal. 2012 Nov;4(11):830-45. doi: 10.1002/dta.390. Epub 2012
Feb 24. Review. PubMed PMID: 22362605.

Abstracts, posters, and presentations

The effect of altitude on erythropoiesis-stimulating agent dose, hemoglobin level, and mortality in hemodialysis patients

Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysisdependent chronic kidney disease

2016 ERA-EDTA: Poster
A Drug-Drug Interaction Study to Evaluate the Effect of Vadadustat on the Pharmacokinetics of Celecoxib—a CYP2C9 Substrate—in Healthy Volunteers

2016 NKF: Poster
Vadadustat — a Novel, Oral Treatment for Anemia of CKD — Maintains Stable Hemoglobin Levels in Dialysis Patients Converting From Erythropoiesis-Stimulating Agent (ESA)

2015 ASN: Posters
Vadadustat Demonstrates Controlled Hemoglobin Response in a Phase 2b Study for the Treatment of Anemia in Patients with Non-Dialysis Dependent Chronic Kidney Disease

Dose Exposure Relationship of Vadadustat is Independent of the Level of Renal Function

Vadadustat, a Novel, Oral Treatment for Anemia of CKD, Maintains Stable Hemoglobin Levels in Dialysis Patients Converting from Erythropoiesis-Stimulating Agents

Hemoglobin Response in a Phase 2b Study of Vadadustat for the Treatment of Anemia in Patients with Non-Dialysis Dependent Chronic Kidney Disease

The Effect of Altitude on Erythropoiesis-Stimulating Agent Dose, Hemoglobin Level, and Mortality in Hemodialysis Patients

Erythropoiesis-Stimulating Agent Hyporesponse Is Associated with Persistently Elevated Mortality among Hemodialysis Patients

Variability in Hemoglobin Levels in Hemodialysis Patients in the Current Era

2014 ASN: Posters
Phase 2 Study of AKB-6548, a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) in patients with end stage renal disease (ESRD) undergoing hemodialysis (HD)

Hemodialysis has minimal impact on the pharmacokinetics of AKB-6548, a once-daily oral inhibitor of hypoxia-inducible factor prolyl-hydroxylases (HIF-PHs) for the treatment of anemia related to chronic kidney disease (CKD)

2014 ERA-EDTA: Oral presentation
Controlled Hemoglobin Response in a Double-Blind, Placebo-Controlled Trial of AKB-6548 in Subjects with Chronic Kidney Disease

2012 ASN: Oral presentation
AKB-6548, A New Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, Increases Hemoglobin in Chronic Kidney Disease Patients Without Increasing Basal Erythropoietin Levels

2011 ASN: Oral presentation
AKB-6548, A Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Reduces Hepcidin and Ferritin while It Increases Reticulocyte Production and Total Iron Binding Capacity In Healthy Adults

2011 ASN: Poster
AKB-6548, A New Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Increases Hemoglobin While Decreasing Ferritin in a 28-day, Phase 2a Dose Escalation Study in Stage 3 and 4 Chronic Kidney Disease Patients With Anemia

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Akebia Reaches Agreement with FDA and EMA on Vadadustat Global Phase 3 Program

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///////////VADADUSTAT, PHASE 3, AKB-6548, PG-1016548, B-506

c1cc(cc(c1)Cl)c2cc(c(nc2)C(=O)NCC(=O)O)O