CN110903238B - Preparation method of kovar stat - Google Patents
Preparation method of kovar stat Download PDFInfo
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- CN110903238B CN110903238B CN201811073437.2A CN201811073437A CN110903238B CN 110903238 B CN110903238 B CN 110903238B CN 201811073437 A CN201811073437 A CN 201811073437A CN 110903238 B CN110903238 B CN 110903238B
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- chloropyridine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
The invention provides a preparation method of kovar staphylol, belonging to the field of pharmaceutical chemicals; the method comprises the steps of mixing 3, 5-dichloro-2-picolinic acid, methanol and sulfuric acid at a certain temperature for reaction to obtain 3, 5-dichloro-2-picolinic acid methyl ester; then adding 3-chlorobenzeneboronic acid, and obtaining 5- (3-chlorphenyl) -3-chloropyridine-methyl formate after the reaction is finished through catalytic reaction; and adding glycine into the 5- (3-chlorphenyl) -3-chloropyridine-methyl formate to react to obtain the 5- (3-chlorphenyl) -3-chloropyridine-methyl formate. The method has the advantages of high product purity, high yield, low cost, simple operation, and stable process.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a preparation method of valdoxat.
Background
Vadadustat (Vadadustat) is a novel titratable oral hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor that is currently being developed for the treatment of anemia. Vadadustat naturally adapts to hypoxic environments similar to those caused by increased altitude, using the same mechanisms of action used by the body. At higher altitudes, the body's response to a hypoxic environment is an increase in HIF, which coordinates the interdependent processes of iron mobilization and erythropoietin production to increase red blood cell production and, ultimately, oxygen delivery.
Currently, Vadadustat (Vadadustat) is in phase III clinical trials worldwide.
Vadadustat (Vadadustat), structural formula as follows:
US20070299086 discloses a preparation method of vatacostat (Vadadustat), which comprises the following steps:
the following disadvantages exist:
1. the route is 7 steps in total, and the total yield is 9 percent;
2. the benzyl alcohol substitution reaction in the first step is harsh, cannot be amplified (microwave reaction, 190 ℃), and in addition, a one-step hydrogenation reaction and a one-step coupling reaction are also carried out, which totally needs 5 times of column chromatography purification, and has inconvenient operation and high cost.
US20070299086 discloses a preparation method, which comprises the following steps:
the following disadvantages exist:
1. the strong acid condition exists in the route, the requirement on a reaction container is high, and the expanded production is not facilitated.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, an object of the present invention is to provide a preparation method of Vadadustat, which has the advantages of high product purity, high yield, low cost, simple operation and mild conditions.
The invention provides a method for preparing Vadadustat (shown as a formula V), which comprises the following steps:
(1) mixing 3, 5-dichloro-2-picolinic acid (compound shown in formula I) and methanol at a certain temperature, adding sulfuric acid, stirring, adding water, filtering to obtain 3, 5-dichloro-2-picolinic acid methyl ester (compound shown in formula II),
(2) adding 3, 5-dichloro-2-picolinic acid methyl ester (a compound shown in a formula II), 3-chlorobenzoic acid (a compound shown in a formula III), alkali and PdCl2 into an organic solvent, after the reaction is finished, filtering to obtain 5- (3-chlorphenyl) -3-chloropyridine-methyl formate (a compound shown in a formula IV),
(3) mixing 5- (3-chlorophenyl) -3-chloropyridine-methyl formate (compound shown in formula IV), glycine, alkali and organic solvent, stirring at a certain temperature, concentrating after the reaction is finished, adding hydrochloric acid water solution to obtain 2- (5- (3-chlorophenyl) -3-hydroxypyridinecarboxamide) acetic acid (compound shown in formula V),
according to some embodiments of the present invention, the base in step (2) may be at least one of inorganic bases such as sodium carbonate, potassium phosphate, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide, and organic bases such as diazabicyclo, triethylamine, and diisopropylethylamine.
According to some embodiments of the invention, the molar ratio of the base to methyl 3, 5-dichloro-2-pyridinecarboxylate in step (2) is from 1.0eq to 3.0 eq.
According to some embodiments of the invention, the PdCl in step (2)2The molar ratio of the compound to 3, 5-dichloro-2-pyridinecarboxylic acid methyl ester is 0.005eq-0.5 eq.
According to some embodiments of the present invention, the organic solvent in step (2) may be at least one of dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, DMF, DMSO, water, and the like.
According to some embodiments of the invention, the ratio of organic reagent to methyl 3, 5-dichloro-2-pyridinecarboxylate in step (2) is from 5ml/g to 20 ml/g.
According to some embodiments of the invention, the certain temperature in the step (2) is 30-100 ℃.
According to some embodiments of the present invention, the base in step (3) may be at least one of inorganic bases such as sodium carbonate, potassium phosphate, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide, and organic bases such as diazabicyclo, triethylamine, and diisopropylethylamine.
According to some embodiments of the invention, the molar ratio of glycine to 5- (3-chlorophenyl) -3-chloropyridine-carboxylic acid methyl ester in step (3) is 0.5eq to 10.0 eq.
According to some embodiments of the present invention, the organic solvent in the step (3) may be at least one of an alcohol solvent, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, DMF, DMSO, and the like.
According to some embodiments of the invention, the ratio of organic solvent to 5- (3-chlorophenyl) -3-chloropyridine-carboxylic acid methyl ester in step (3) is from 10mL/g to 30 mL/g.
According to some embodiments of the present invention, the certain temperature in step (3) is 80 ℃ to 130 ℃.
Definition of terms
In this specification, "eq" means equivalent.
In this specification, "g" means g.
In this specification "ml" means ml.
The term "room temperature" in the present specification means 10 ℃ to 35 ℃.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The conditions for measuring Mass Spectrometry (MS) data were: electrospray ionization (ESI).
Measurement conditions of H spectrum: 400MHz, deuterated DMSO.
Typical synthetic procedures for the preparation of the fused pyridone derivatives according to the examples of the present invention are shown in the following synthetic schemes:
EXAMPLE 1 Synthesis of methyl 3, 5-dichloro-2-pyridinecarboxylate
Adding a compound 3, 5-dichloro-2-picolinic acid (1.92g), concentrated sulfuric acid (0.19mL) and methanol (19mL) into a reaction bottle at room temperature, controlling the temperature to 65 ℃, carrying out reflux reaction for 6h, completely reacting, concentrating the reaction solution at 40 ℃ under reduced pressure to dryness, adding water (19mL) for washing twice, and carrying out suction filtration and drying to obtain 1.71g of methyl 3, 5-dichloro-2-picolinate with the yield of 83.0%.
LC-MS:[M+1]＝206.05
1H NMR(400MHz,CDCl3)δ8.54(d,J＝2.0Hz,1H),7.86(d,J＝2.0Hz,1H),4.01(s,3H)。
EXAMPLE 2 Synthesis of methyl 3, 5-dichloro-2-pyridinecarboxylate
Adding a compound 3, 5-dichloro-2-picolinic acid (38.4g), concentrated sulfuric acid (3.8mL) and methanol (384mL) into a reaction bottle at room temperature, controlling the temperature to 65 ℃, carrying out reflux reaction for 6h, completely reacting, concentrating the reaction solution at 40 ℃ under reduced pressure to dryness, adding water for washing twice, and drying to obtain 38.5g of methyl 3, 5-dichloro-2-picolinate with the yield of 93.4%.
EXAMPLE 3 Synthesis of 5- (3-chlorophenyl) -3-chloropyridine-carboxylic acid methyl ester
Reaction flask at room temperatureTo the mixture were added the compound methyl 3, 5-dichloro-2-picolinate (1.03g), 3-chlorobenzoic acid (0.86g), K2CO3(0.87g), PdCl2(dppf) (0.04g), DMF (10mL) and H2O (1mL) were replaced with nitrogen, the reaction was carried out at 45 ℃ for 22H, the reaction was completed, the reaction mixture was extracted twice with water and ethyl acetate, the resulting organic phase was washed once with water and recrystallized from ethyl acetate using n-hexane to obtain 1.01g of methyl 5- (3-chlorophenyl) -3-chloropyridine-carboxylate as a white solid with a yield of 71.9%.
LC-MS:[M+1]＝282.04
1H NMR(400MHz,CDCl3)δ8.77(s,1H),7.99(d,J＝1.5Hz,1H),7.59(s,1H),7.53–7.43(m,3H),4.05(s,3H)。
EXAMPLE 4 Synthesis of methyl 5- (3-chlorophenyl) -3-chloropyridine-carboxylate
To a reaction flask, the compound methyl 3, 5-dichloro-2-pyridinecarboxylate (38.0g), 3-chlorobenzeneboronic acid (31.7g), K2CO3(31.9g)、PdCl2(1.4g), DMF (380mL) and H2O (38mL), after nitrogen replacement, controlling the temperature to 45 ℃ for reaction for 28H, completely reacting, adding water and ethyl acetate into the reaction liquid for extraction twice, washing the obtained organic phase once again with water, and recrystallizing with n-hexane and ethyl acetate to obtain 38.8g of white solid methyl 5- (3-chlorophenyl) -3-chloropyridine-carboxylate with the yield of 74.8 percent.
EXAMPLE 5 Synthesis of 2- (5- (3-chlorophenyl) -3-hydroxypyridineamido) acetic acid
Adding a compound 5- (3-chlorphenyl) -3-chloropyridine-methyl formate (0.56g), glycine (0.45g), sodium methoxide (0.54g) and methanol (5.6mL) into a reaction bottle at room temperature, controlling the temperature to be 120 ℃, reacting for 24 hours till the reaction is completed, adding water (5.6mL) and hydrochloric acid to adjust the pH value to be about 2, performing suction filtration to obtain a solid, and recrystallizing n-hexane and methanol to obtain 0.32g of white solid 2- (5- (3-chlorphenyl) -3-hydroxypyridinamido) acetic acid, wherein the yield is 52.3%.
LC-MS:[M+1]＝307.05
1H NMR(400MHz,DMSO)δ12.37(s,1H),9.37(d,J＝6.0Hz,1H),8.55(d,J＝1.5Hz,1H),7.92(s,1H),7.78(d,J＝1.6Hz,2H),7.55(d,J＝5.5Hz,2H),4.02(d,J＝6.1Hz,2H)。
EXAMPLE 6 Synthesis of 2- (5- (3-chlorophenyl) -3-hydroxypyridinamido) acetic acid
The compound 5- (3-chlorophenyl) -3-chloropyridine-methyl formate (30.0g), glycine (24.1g), sodium methoxide (28.8g) and methanol (300mL) were added to a reaction flask at room temperature, the temperature was controlled at 120 ℃ to react for 26 hours, HPLC detects that the raw materials reacted completely, water (300mL) and hydrochloric acid were added to adjust the pH to about 2, and 20.2g of 2- (5- (3-chlorophenyl) -3-hydroxypyridinylamido) acetic acid was obtained as a white solid by suction filtration in a yield of 61.8%.
In the description herein, references to the description of the term "one embodiment," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (9)
1. A method of preparing vatacostat comprising:
(1) mixing 3, 5-dichloro-2-picolinic acid and methanol at a certain temperature, adding sulfuric acid, stirring to react, adding water, and filtering to obtain 3, 5-dichloro-2-picolinic acid methyl ester;
(2)3, 5-dichloro-2-picolinic acid methyl ester, 3-chlorobenzene boric acid, alkali and PdCl2Adding organic solvent, reacting, and filtering to obtain 5- (3-chlorphenyl) -3-chloropyridine-methyl formate；
(3) Mixing 5- (3-chlorphenyl) -3-chloropyridine-methyl formate, glycine, alkali and an organic solvent, controlling the temperature, stirring, concentrating after the reaction is finished, and adding a hydrochloric acid water solution to obtain the 2- (5- (3-chlorphenyl) -3-hydroxypyridinoamido) acetic acid.
2. The method according to claim 1, wherein the base in the step (2) is sodium carbonate, potassium phosphate, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, diazabicyclo, triethylamine or diisopropylethylamine.
3. The process according to claim 1, wherein the molar ratio of the base to the methyl 3, 5-dichloro-2-pyridinecarboxylate in the step (2) is 1.0eq to 3.0 eq.
4. The method according to claim 1, wherein the organic solvent in step (2) is dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, DMF, DMSO or water.
5. The method of claim 1, wherein the PdCl in step (2) is PdCl2The molar ratio of the compound to 3, 5-dichloro-2-pyridinecarboxylic acid methyl ester is 0.005eq-0.5 eq.
6. The process according to claim 1, wherein the molar ratio of glycine to 5- (3-chlorophenyl) -3-chloropyridine-carboxylic acid methyl ester in step (3) is 0.5eq to 10.0 eq.
7. The method according to claim 1, wherein the certain temperature in the step (3) is 80 ℃ to 130 ℃.
8. The method according to claim 1, wherein the organic solvent in step (3) is an alcoholic solvent, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, DMF or DMSO.
9. The process according to claim 1, wherein the ratio of the organic solvent to the 5- (3-chlorophenyl) -3-chloropyridine-carboxylic acid methyl ester in the step (3) is from 10ml/g to 30 ml/g.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101506149A (en) * | 2006-06-26 | 2009-08-12 | 宝洁公司 | Prolyl hydroxylase inhibitors and methods of use |
| CN103717575A (en) * | 2011-06-06 | 2014-04-09 | 阿克比治疗有限公司 | Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides |
| WO2016118858A1 (en) * | 2015-01-23 | 2016-07-28 | Akebia Therapeutics, Inc. | Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof |
| CN105837502A (en) * | 2016-04-05 | 2016-08-10 | 湖南欧亚生物有限公司 | Synthesis method of Vadadustat |
| WO2016153996A1 (en) * | 2015-03-20 | 2016-09-29 | Akebia Therapeutics, Inc. | Deuterium-enriched hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101506149A (en) * | 2006-06-26 | 2009-08-12 | 宝洁公司 | Prolyl hydroxylase inhibitors and methods of use |
| CN103717575A (en) * | 2011-06-06 | 2014-04-09 | 阿克比治疗有限公司 | Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides |
| WO2016118858A1 (en) * | 2015-01-23 | 2016-07-28 | Akebia Therapeutics, Inc. | Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof |
| WO2016153996A1 (en) * | 2015-03-20 | 2016-09-29 | Akebia Therapeutics, Inc. | Deuterium-enriched hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors |
| CN105837502A (en) * | 2016-04-05 | 2016-08-10 | 湖南欧亚生物有限公司 | Synthesis method of Vadadustat |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |