CN105837502A - Synthesis method of Vadadustat - Google Patents
Synthesis method of Vadadustat Download PDFInfo
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- CN105837502A CN105837502A CN201610206230.2A CN201610206230A CN105837502A CN 105837502 A CN105837502 A CN 105837502A CN 201610206230 A CN201610206230 A CN 201610206230A CN 105837502 A CN105837502 A CN 105837502A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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Abstract
The invention discloses a synthesis method of Vadadustat. The method comprises the following steps: carrying out a condensation reaction on 3,5-dichloro-2-picolinic acid and glycine methyl ester hydrochloride; carrying out a catalytic coupling reaction on above obtained methyl N-(3,5-dichloropyridyl-2-carbonyl)glycinate and 3-chlorophenylboronic acid; carrying out a methoxy substitution reaction on above obtained methyl N-[5-(3-chlorophenyl)-3-chloropyridyl-2-carbonyl)glycinate and sodium methoxide; and hydrolyzing obtained N-[5-(3- chlorophenyl)-3-methoxy pyridyl-2-carbonyl)]glycine to obtain the finished product Vadadustat. The synthesis method has the advantages of short route steps, operation simplification, low cost, environmental protection, and suitableness for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to the synthetic method of a kind of Vadadustat.
Background technology
The entitled N-of chemistry [5-(3-the chlorphenyl)-3-pyridone-2-of HIF inhibitor Vadadustat (code name AKB-6548)
Carbonyl] glycine, its chemical structural formula is:
Vadadustat is a kind of oral HIF inhibitor treating anemia and chronic kidney disease, is the biopharmaceutical company of the U.S.
Akebia Therapeutics invention grinding new drug, the most having completed the key clinical II phase studies therapeutic test, successfully reaches
Target and the good safeties such as the internal hemoglobin level that research worker sets, evident in efficacy, and will carry out the III phase
Clinical trial.
A kind of synthetic route preparing Vadadustat disclosed in United States Patent (USP) US20120309977: with 3-chlorophenylboronic acid and 3,5-
Two chloro-2-cyanopyridines are initiation material, by catalytic coupling, methoxy substitution, cyan-hydrolysis, condensation and ester hydrolysis reaction
Obtaining Vadadustat, process route is as follows:
Owing to whole synthetic route step is longer, complex operation, relatively costly.
The synthetic route of Vadadustat disclosed in United States Patent (USP) US20070299086, with 3,5-bis-chloro-2-cyanopyridine is
Beginning raw material, first replaces dichloro with benzyloxy, then by cyan-hydrolysis, be condensed, hydrogenate deprotection and trifluoro sulfonylation is anti-
Should, obtain N-[5-trifluoro-methanesulfonyl oxy-3-pyridone-2-carbonyl) glycine methyl ester, then be catalyzed with 3-chlorophenylboronic acid
Coupling reaction, last ester hydrolysis reaction obtains Vadadustat, and process route is as follows:
This synthesis step is longer, and midbody product and final products are impure more with by-product, thus purification needs to use greatly
Amount solvent, complex operation, yield is relatively low, simultaneously because hydrogenation exists the security risk on producing, is unfavorable for industrialization
Produce and promote, it is therefore necessary to exploration technological process is short, simple to operate, with low cost and uses applicable industrialized production
The synthetic method of Vadadustat.
Summary of the invention
For the deficiencies in the prior art and defect, it is an object of the invention to provide the synthetic method of a kind of Vadadustat,
The method process route is reasonable, simple to operate, reagent is easy to get and total recovery high and is satisfied industrial amplification production and requires also
Excellent environmental protection effect can be embodied.
In order to realize foregoing invention purpose, the technical solution used in the present invention is:
The synthetic route of described Vadadustat is:
Specifically comprising the following steps that of the synthetic method of Vadadustat
(1) N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester is prepared: first by 3,5-dichloro-2-pyridyl formic acid and glycine first
Ester hydrochloride carries out condensation reaction in the system that condensing agent, acid binding agent alkali, solvent form, and obtains N-(3,5-dichloropyridine-2-
Carbonyl) glycine methyl ester；
(2) N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester is prepared: by N-(3,5-dichloropyridine-2-carbonyl)
Glycine methyl ester and 3-chlorophenylboronic acid are at double (diphenylphosphino) ferrocene of 1,1'-] body that constitutes of palladium chloride, inorganic salt, solvent
System carries out catalyzed coupling reaction, obtains N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester；
(3) N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine is prepared: by N-[5-(3-chlorphenyl)-3-chloropyridine
-2-carbonyl] glycine methyl ester and Feldalat NM carry out methoxy substitution reaction in methanol, obtains N-[5-(3-chlorphenyl)-3-methoxy
Yl pyridines-2-carbonyl] glycine；
(4) Vadadustat is prepared: by N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine in mass percent
Concentration be 48% hydrobromic acid aqueous solution in be hydrolyzed reaction, obtain Vadadustat.
Preferably, the condensing agent described in step (1) is N, N '-carbonyl dimidazoles (CDI), 1-(3-dimethylamino-propyl)-3-
Ethyl carbodiimide (EDCI), 1-hydroxy benzo triazole (HOBt), N, N '-dicyclohexylcarbodiimide (DCC) or
N, N '-DIC (DIC)；Described acid binding agent alkali be N, N-diisopropylethylamine, triethylamine, diethylamine,
Trimethylamine, pyridine, piperidines, DMAP, 2,6-lutidines, aniline, N, N-dimethylaniline, N, N-diethyl
Base aniline, Tris(isopropylamine)., tri-n-butylamine, tetramethyl guanidine, N-methylmorpholine or two cyclohexyl amines；Described solvent is
N,N-dimethylformamide (DMF) or DMAC N,N' dimethyl acetamide (DMA)；Wherein, described 3,5-dichloro-2-pyridyl first
Mol ratio between acid, glycine methyl ester hydrochloride, condensing agent, acid binding agent alkali, solvent is 1.0: (1.1～1.5): (1.1～1.8):
(3.5～5.5): (10.0～25.0).
Preferably, the inorganic salt described in step (2) is potassium carbonate or potassium phosphate；Described solvent is N, N-dimethyl methyl
Amide (DMF), DMAC N,N' dimethyl acetamide (DMA), 1,4-dioxane, oxolane, methyl tertiary butyl ether(MTBE) or second
Nitrile；Wherein, described N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester, 3-chlorophenylboronic acid, 1, double (diphenylphosphino) two of 1'-
Cyclopentadienyl ferrum] palladium chloride, inorganic salt, mol ratio between solvent be 1.0: (1.1～1.5): (0.025～0.075): (1.15～2.25):
(5.0～25.0).
Preferably, N-[5-(3-the chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester described in step (3), Feldalat NM and
The mol ratio of methanol three is 1.0: (2.2～4.0): (40.0～80.0).
Preferably, step (4) described N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine and hydrobromic mole
Ratio is 1.0: (5.0～15.0).
Preferably, the temperature of the condensation reaction described in step (1) is 25～60 DEG C, and the response time is 6～24 hours；Step
(2) temperature of the catalyzed coupling reaction described in is 50～90 DEG C, and the response time is 18～30 hours；Described in step (3)
The temperature of methoxy substitution reaction is 60～70 DEG C, and the response time is 20～30 hours；Hydrolysis described in step (4)
Temperature is 95～105 DEG C, and the response time is 20～30 hours.
The present invention is first with 3, and 5-dichloro-2-pyridyl formic acid and glycine methyl ester hydrochloride, as raw material, carry out condensation reaction, no
Need the protection of group and de-protected process, directly obtain highly purified condensation reaction midbody compound, and be conducive to
Next step catalyzed coupling reaction, obtains next step intermediate that purity is higher, methoxy substitution reaction the most down and water
Solve reaction, obtain finished product Vadadustat.
The technical scheme that the present invention provides has following technical effect that one, only makees routinely after having reacted due to each step
Post processing and purification without column chromatography, impurity is less, can directly carry out next step reaction, therefore simplify behaviour
Making, the most each step can obtain higher yield；Its two, the process route agents useful for same of the present invention is easy to get, technical scheme
Rationally, can produce in a large number and meet the use demand of crude drug, it is adaptable to industrialized production；Its three, owing to preparing
Journey will not produce pollutant, thus environmental protection effect can be embodied.
Detailed description of the invention
Below in conjunction with specific embodiment, technical scheme is further elaborated, it is clear that protection scope of the present invention
It is not limited to embodiment, other embodiments of the present invention that those skilled in the art are done, broadly fall into the scope of protection of the invention.
Embodiment 1
A) N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester is prepared:
3,5-dichloro-2-pyridyl formic acid (19.2g, 0.10mol) and N, N '-carbonyl dimidazoles (24.3g, 0.15mol) are dissolved in N, N-
Dimethylformamide (100mL), adds glycine methyl ester hydrochloride (15.1g, 0.12mol), drips N, N-diisopropyl second
Amine (51.7g, 0.40mol), reactant mixture 35 DEG C stirring reaction 8 hours, TLC point plate determines that reaction is complete, reactant liquor
Concentrated by rotary evaporation, to dry, add dilute hydrochloric acid and regulates to neutral, add ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry,
Recrystallizing methanol, obtains N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester, off-white color solid (21.6g), yield 82.0%,
The reaction equation of this step is as follows:
B) N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester is prepared:
N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester (20.0g, 76mmol), 3-chlorophenylboronic acid (13.1g, 83.7mmol),
[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (2.8g, 3.8mmol), potassium carbonate (14.2g, 0.1mol) and N, N-
Dimethylformamide (75mL) adds in reaction bulb, and reactant mixture is heated to 60 DEG C of stirring reactions 20 hours, TLC point
Plate determines that reaction is complete, and reactant liquor is down to room temperature, and concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and salt is washed, magnesium sulfate
Being dried, concentrated by rotary evaporation is to dry, and ethyl acetate and normal hexane mixed solvent carry out recrystallization, obtain N-[5-(3-chlorphenyl)-3-chlorine pyrrole
Pyridine-2-carbonyl] glycine methyl ester, off-white color solid (19.7g), yield 76.4%, the reaction equation of this step is as follows:
C) N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine is prepared:
N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester (19.0g, 56mmol) and Feldalat NM (7.6g, 0.14mol)
Being dissolved in methanol (150mL), reactant mixture is heated to 65 DEG C, and return stirring reacts 24 hours, and TLC point plate determines reaction
Complete, reactant liquor is down to room temperature, adds water (300mL) stirring 3h, is cooled to 0 DEG C, stirs 2h, separate out solid, mistake
Filter, filtration cakes torrefaction, obtain N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine, off-white color solid (17.4g), receive
Rate 96.5%, the reaction equation of this step is as follows:
D) Vadadustat is prepared:
N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine (16.6g, 51.7mmol) and 48% hydrobromic acid solution
(52mL, 0.46mol) adds in reaction bulb, and reactant mixture is heated to 100 DEG C, and return stirring reacts 24 hours, TLC
Point plate determines that reaction is complete, and reactant liquor is down to 0～5 DEG C, and being slowly added to 50% sodium hydroxide solution regulation pH value is 2,
Crystallize 3h at 0-5 DEG C, filters, and filter cake ethyl acetate and normal hexane mixed solvent carry out recrystallization, obtain finished product Vadadustat,
Off-white color solid (15.6g), yield 98.0%, the reaction equation of this step is as follows:
Embodiment 2
A) N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester is prepared:
3,5-dichloro-2-pyridyl formic acid (20.5g, 0.107mol) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (26.5g,
0.17mol) it is dissolved in N,N-dimethylacetamide (130mL), adds glycine methyl ester hydrochloride (17.4g, 0.139mol),
Dropping triethylamine (54.0g, 0.53mol), reactant mixture 25 DEG C stirring reaction 10 hours, TLC point plate determines that reaction is complete,
Reactant liquor concentrated by rotary evaporation, to dry, add dilute hydrochloric acid and regulates to neutral, add ethyl acetate extraction, and magnesium sulfate is dried, rotation inspissation
It is reduced to do, recrystallizing methanol, obtains N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester, off-white color solid (24.0g), yield
85.4%, the reaction equation of this step is with embodiment 1；
B) N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester is prepared:
N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester (26.3g, 0.10mol), 3-chlorophenylboronic acid (24.0g, 0.15mol),
[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (5.1g, 7.0mmol), potassium phosphate (48.8g, 0.23mol) and tetrahydrochysene
Furan (190mL) adds in reaction bulb, and reactant mixture is heated to 55 DEG C of stirring reactions 24 hours, and TLC point plate determines
Reacting complete, reactant liquor is down to room temperature, and concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and salt is washed, and magnesium sulfate is dried,
Concentrated by rotary evaporation is to dry, and ethyl acetate and normal hexane mixed solvent carry out recrystallization, obtain N-[5-(3-chlorphenyl)-3-chloropyridine-2-
Carbonyl] glycine methyl ester, off-white color solid (34.5g), yield 79.7%, the reaction equation of this step is with embodiment 1；
C) N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine is prepared:
N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester (34.5g, 0.10mol) and Feldalat NM (19.2g,
0.36mol) being dissolved in methanol (200mL), reactant mixture is heated to 66 DEG C, and return stirring reacts 28 hours, TLC point
Plate determines that reaction is complete, and reactant liquor is down to room temperature, adds water (400mL) stirring 3h, is cooled to 0 DEG C, stirs 2h, analysis
Go out solid, filter, filtration cakes torrefaction, obtain N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine, off-white color solid
(30.8g), yield 94.5%, the reaction equation of this step is with embodiment 1；
D) Vadadustat is prepared:
N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine (30.0g, 93mmol) and 48% hydrobromic acid solution
(107mL, 0.93mol) adds in reaction bulb, and reactant mixture is heated to 100 DEG C, and return stirring reacts 24 hours, TLC
Point plate determines that reaction is complete, and reactant liquor is down to 0-5 DEG C, and being slowly added to 50% sodium hydroxide solution regulation pH value is 2, at 0～5 DEG C
Lower crystallize 3h, filters, and filter cake ethyl acetate and normal hexane mixed solvent carry out recrystallization, obtain finished product Vadadustat, class
White solid (28.2g), yield 98.5%, the reaction equation of this step is with embodiment 1.
Embodiment 3
A) N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester is prepared:
3,5-dichloro-2-pyridyl formic acid (30.0g, 0.16mol) and 1-hydroxy benzo triazole (35.9g, 0.27mol) are dissolved in N, N-
Dimethylformamide (220mL), adds glycine methyl ester hydrochloride (26.6g, 0.21mol), drips DMAP
(105.0g, 0.86mol), reactant mixture 30 DEG C stirring reaction 12 hours, TLC point plate determines that reaction is complete, reactant liquor
Concentrated by rotary evaporation, to dry, add dilute hydrochloric acid and regulates to neutral, add ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry,
Recrystallizing methanol, obtains N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester, off-white color solid (33.6g), yield 81.7%,
The reaction equation of this step is with embodiment 1；
B) N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester is prepared:
N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester (33.6g, 0.13mol), 3-chlorophenylboronic acid (25.9g, 0.17mol),
[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (5.6g, 7.7mmol), potassium carbonate (26.4g, 0.19mol) and methyl
Tertbutyl ether (150mL) adds in reaction bulb, and reactant mixture is heated to 75 DEG C of stirring reactions 18 hours, TLC point plate
Determining that reaction is complete, reactant liquor is down to room temperature, and concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and salt is washed, and magnesium sulfate is done
Dry, concentrated by rotary evaporation is to dry, and ethyl acetate and normal hexane mixed solvent carry out recrystallization, obtain N-[5-(3-chlorphenyl)-3-chloropyridine
-2-carbonyl] glycine methyl ester, off-white color solid (32.0g), yield 74.0%, the reaction equation of this step is with embodiment 1；
C) N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine is prepared:
N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester (32.0g, 94mmol) and Feldalat NM (15.3g,
0.28mol) being dissolved in methanol (235mL), reactant mixture is heated to 69 DEG C, and return stirring reacts 20 hours, TLC point
Plate determines that reaction is complete, and reactant liquor is down to room temperature, adds water (370mL) stirring 3h, is cooled to 0 DEG C, stirs 2h, analysis
Go out solid, filter, filtration cakes torrefaction, obtain N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine, off-white color solid
(28.8g), yield 95.0%, the reaction equation of this step is with embodiment 1；
D) Vadadustat is prepared:
N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine (28.8g, 0.09mol) and 48% hydrobromic acid solution
(124mL, 1.09mol) adds in reaction bulb, and reactant mixture is heated to 95 DEG C, and return stirring reacts 28 hours, TLC
Point plate determines that reaction is complete, and reactant liquor is down to 0-5 DEG C, and being slowly added to 50% sodium hydroxide solution regulation pH value is 2, at 0～5 DEG C
Lower crystallize 3h, filters, and filter cake ethyl acetate and normal hexane mixed solvent carry out recrystallization, obtain finished product Vadadustat, class
White solid (27.2g), yield 98.9%, the reaction equation of this step is with embodiment 1.
Embodiment 4
A) N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester is prepared:
3,5-dichloro-2-pyridyl formic acid (42.0g, 0.22mol) and N, N '-dicyclohexylcarbodiimide (65.4g, 0.32mol) are molten
In N,N-dimethylacetamide (240mL), add glycine methyl ester hydrochloride (38.5g, 0.31mol), drip N, N-bis-
Toluidines (111.3g, 0.92mol), reactant mixture 25 DEG C stirring reaction 17 hours, TLC point plate determines that reaction is complete,
Reactant liquor concentrated by rotary evaporation, to dry, add dilute hydrochloric acid and regulates to neutral, add ethyl acetate extraction, and magnesium sulfate is dried, rotation inspissation
It is reduced to do, recrystallizing methanol, obtains N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester, off-white color solid (49.0g), yield
85.0%, the reaction equation of this step is with embodiment 1；
B) N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester is prepared:
N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester (49.0g, 0.19mol), 3-chlorophenylboronic acid (32.0g, 0.20mol),
[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (6.2g, 8.4mmol), potassium phosphate (79.2g, 0.37mol) and N, N-
Dimethyl acetylamide (300mL) adds in reaction bulb, and reactant mixture is heated to 65 DEG C of stirring reactions 28 hours, TLC
Point plate determines that reaction is complete, and reactant liquor is down to room temperature, and concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and salt is washed, sulphuric acid
Magnesium is dried, and concentrated by rotary evaporation is to dry, and ethyl acetate and normal hexane mixed solvent carry out recrystallization, obtain N-[5-(3-chlorphenyl)-3-chlorine
Pyridine-2-carbonyl] glycine methyl ester, off-white color solid (51.2g), yield 81.0%, the reaction equation of this step is with embodiment 1；
C) N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine is prepared:
N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester (50.0g, 0.15mol) and Feldalat NM (19.9g,
0.37mol) being dissolved in methanol (370mL), reactant mixture is heated to 62 DEG C, and return stirring reacts 30 hours, TLC point
Plate determines that reaction is complete, and reactant liquor is down to room temperature, adds water (600mL) stirring 3h, is cooled to 0 DEG C, stirs 2h, analysis
Go out solid, filter, filtration cakes torrefaction, obtain N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine, off-white color solid
(44.2g), yield 93.8%, the reaction equation of this step is with embodiment 1；
D) Vadadustat is prepared:
N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine (44.0g, 0.14mol) and 48% hydrobromic acid solution
(125mL, 1.1mol) adds in reaction bulb, and reactant mixture is heated to 102 DEG C, and return stirring reacts 30 hours, TLC
Point plate determines that reaction is complete, and reactant liquor is down to 0-5 DEG C, and being slowly added to 50% sodium hydroxide solution regulation pH value is 2, at 0～5 DEG C
Lower crystallize 3h, filters, and filter cake ethyl acetate and normal hexane mixed solvent carry out recrystallization, obtain finished product Vadadustat, class
White solid (40.7g), yield 96.9%, the reaction equation of this step is with embodiment 1.
Above-described embodiment is only for clearly demonstrating the invention example, and not concrete to the invention reality
Execute the restriction of mode.To those of ordinary skill in the art, can also be made other on the basis of the above description different
The amendment of form or improvement.The obvious amendment thus amplified out or improvement are still in the invention claim
Among protection domain.
Claims (6)
1. the synthetic method of a Vadadustat, it is characterised in that described method comprises the steps:
(1) N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester is prepared: first by 3,5-dichloro-2-pyridyl formic acid and glycine first
Ester hydrochloride carries out condensation reaction in the system that condensing agent, acid binding agent alkali, solvent form, and obtains N-(3,5-dichloropyridine-2-
Carbonyl) glycine methyl ester；
(2) N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester is prepared: by N-(3,5-dichloropyridine-2-carbonyl)
Glycine methyl ester and 3-chlorophenylboronic acid are at double (diphenylphosphino) ferrocene of 1,1'-] body that constitutes of palladium chloride, inorganic salt, solvent
System carries out catalyzed coupling reaction, obtains N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester；
(3) N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine is prepared: by N-[5-(3-chlorphenyl)-3-chloropyridine
-2-carbonyl] glycine methyl ester and Feldalat NM carry out methoxy substitution reaction in methanol, obtains N-[5-(3-chlorphenyl)-3-methoxy
Yl pyridines-2-carbonyl] glycine；
(4) Vadadustat is prepared: by N-[5-(3-chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine in mass percent
Concentration be 48% hydrobromic acid aqueous solution in be hydrolyzed reaction, obtain Vadadustat.
The synthetic method of a kind of Vadadustat the most according to claim 1, it is characterised in that the contracting described in step (1)
Mixture is N, N '-carbonyl dimidazoles (CDI), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI), 1-hydroxy benzenes
And triazole (HOBt), N, N '-dicyclohexylcarbodiimide (DCC) or N, N '-DIC (DIC)；
Described acid binding agent alkali is N, N-diisopropylethylamine, triethylamine, diethylamine, trimethylamine, pyridine, piperidines, 4-diformazan ammonia
Yl pyridines, 2,6-lutidines, aniline, N, N-dimethylaniline, N, N-diethylaniline, Tris(isopropylamine)., tri-n-butylamine,
Tetramethyl guanidine, N-methylmorpholine or two cyclohexyl amines；Described solvent is N,N-dimethylformamide (DMF) or N, N-
Dimethyl acetylamide (DMA)；Wherein, described 3,5-dichloro-2-pyridyl formic acid, glycine methyl ester hydrochloride, condensing agent,
Mol ratio between acid binding agent alkali, solvent is 1.0: (1.1～1.5): (1.1～1.8): (3.5～5.5): (10.0～25.0).
The synthetic method of a kind of Vadadustat the most according to claim 1, it is characterised in that described in step (2)
Inorganic salt is potassium carbonate or potassium phosphate；Described solvent is N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide
(DMA), 1,4-dioxane, oxolane, methyl tertiary butyl ether(MTBE) or acetonitrile；Wherein, described N-(3,5-dichloropyridine-2-
Carbonyl) glycine methyl ester, 3-chlorophenylboronic acid, double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, inorganic salt, between solvent
Mol ratio be 1.0: (1.1～1.5): (0.025～0.075): (1.15～2.25): (5.0～25.0).
The synthetic method of a kind of Vadadustat the most according to claim 1, it is characterised in that described in step (3)
The mol ratio of N-[5-(3-chlorphenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester, Feldalat NM and methanol three is 1.0: (2.2～4.0)
: (40.0～80.0).
The synthetic method of a kind of Vadadustat the most according to claim 1, it is characterised in that step (4) described N-[5-(3-
Chlorphenyl)-3-Methoxy Pyridine-2-carbonyl] glycine and hydrobromic mol ratio be 1.0: (5.0～15.0).
The synthetic method of a kind of Vadadustat the most according to claim 1, it is characterised in that the contracting described in step (1)
The temperature closing reaction is 25～60 DEG C, and the response time is 6～24 hours；The temperature of the catalyzed coupling reaction described in step (2)
Being 50～90 DEG C, the response time is 18～30 hours；The temperature of the methoxy substitution reaction described in step (3) is 60～70 DEG C,
Response time is 20～30 hours；The temperature of the hydrolysis described in step (4) is 95～105 DEG C, and the response time is 20～30
Hour.
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