CN111205222B - Process for preparing pyridine ring compound - Google Patents

Process for preparing pyridine ring compound Download PDF

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CN111205222B
CN111205222B CN201811391715.9A CN201811391715A CN111205222B CN 111205222 B CN111205222 B CN 111205222B CN 201811391715 A CN201811391715 A CN 201811391715A CN 111205222 B CN111205222 B CN 111205222B
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reaction
acid
hydroxy
palladium
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CN111205222A (en
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肖清波
林碧悦
王仲清
寇景平
李英龙
孙景伟
靳连芬
罗忠华
黄芳芳
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a preparation method of pyridine ring compound, belonging to the field of pharmaceutical chemical industry; the method comprises the steps of mixing 3, 5-dihydroxypicolinic acid, concentrated sulfuric acid and an alcohol solvent, and carrying out esterification reaction to obtain 3, 5-dihydroxypicolinic acid methyl ester; then sequentially carrying out upper protecting group and ammonification to obtain the { [5- (3-chlorophenyl) -3-hydroxypyridine-2-yl ] amino } acetic acid. The product produced by the method has the characteristics of high purity, high yield, low cost, simple operation and stable process.

Description

Process for preparing pyridine ring compound
Technical Field
The invention relates to the field of pharmaceutical chemical industry, in particular to a preparation method of pyridine ring compounds.
Background
Vardutaster (Vadadustat) is a novel titratable oral hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor currently developed for the treatment of anemia. Vadadurat utilizes the same mechanism of action used by the body to naturally adapt to a hypoxic environment like that caused by an increase in altitude. At higher altitudes, the body's response to the hypoxic environment is an increase in HIF, which coordinates the interdependence of iron mobilization and erythropoietin in production to increase erythrocyte production and ultimately oxygen delivery.
Vardutaster (Vadadustat), has the following structural formula:
US20070299086 discloses a process for the preparation of vardutstat (Vadadustat), which is specifically as follows:
the following drawbacks exist:
1. the route is 7 steps, and the total yield is 9%;
2. the first step of benzyl alcohol substitution reaction has harsh conditions, cannot be amplified (microwave reaction, 190 ℃), and is further provided with one step of hydrogenation reaction and one step of coupling reaction, and the total requirement of column chromatography purification is 5 times, so that the operation is inconvenient and the cost is high.
US20120309977 discloses a preparation method, specifically as follows:
the following drawbacks exist:
1. the strong acid condition exists in the route, the requirement on the reaction vessel is higher, and the expanded production is not facilitated.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. Therefore, one purpose of the invention is to provide a preparation method of Vadadurat, which has the advantages of high product purity, high yield, low cost, simple operation and mild conditions.
The invention provides a method for preparing Vadadurat (shown as a formula VI), which comprises the following steps:
(1) Mixing 3, 5-dihydroxypicolinic acid (compound shown in formula I), concentrated sulfuric acid and an alcohol solvent, heating to react, removing the solvent after the reaction is completed, adding aqueous solution of sodium hydroxide, and filtering to obtain 3, 5-dihydroxypicolinic acid methyl ester (compound shown in formula II);
(2) Adding 3, 5-dihydroxypyridine methyl formate (a compound shown in a formula II) and alkali into an organic solvent, adding N-phenyl bis (trifluoromethanesulfonyl) imine under the protection of nitrogen, reacting at room temperature, and evaporating the solvent after finishing the reaction to obtain 3-hydroxy-5- (trifluoromethanesulfonyl) -pyridine methyl formate (a compound shown in a formula III);
(3) 3-hydroxy-5- (trifluoromethanesulfonyl) -methyl picolinate (a compound shown in a formula III), 3-chlorobenzoic acid (a compound shown in a formula IV), a palladium catalyst, alkali and an organic solvent are mixed, heated for reaction, and concentrated after the reaction is finished, so as to obtain 5- (3-chlorophenyl) -3-hydroxy-methyl picolinate (a compound shown in a formula V);
(4) 5- (3-chlorophenyl) -3-hydroxy-pyridine methyl formate (formula V compound), alkali methanol solution, glycine and alcohol solvent are mixed, heated and reacted, hydrochloric acid solution is added after the reaction is finished, and the temperature is reduced, and the { [5- (3-chlorophenyl) -3-hydroxy-pyridine-2-yl ] amino } acetic acid (formula VI compound) is obtained by filtration.
According to some embodiments of the invention, the alcohol solvent in step (1) may be C 1-8 (1 carbon to 8 carbon) alcohols.
According to some embodiments of the invention, the temperature may be 30-80 ℃ during the heating in the step (1).
According to some embodiments of the invention, the base in the step (2) may be at least one of inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, etc., and organic base such as diazabicyclo, triethylamine, diisopropylethylamine, etc.
According to some embodiments of the invention, the organic solvent in the step (2) may be at least one of ethanol, acetonitrile, isopropanol, tert-butanol, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), water, and the like.
According to some embodiments of the invention, the palladium catalyst in the step (3) may be a metal palladium catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, palladium hydroxide, tetra- (triphenylphosphine) palladium, etc.
According to some embodiments of the invention, the base in step (3) may be sodium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, and the like.
According to some embodiments of the invention, the organic solvent in the step (3) may be at least one of methyl tert-butyl ether, 1, 4-dioxane, dimethyl ether, DMF, DMSO, and the like.
According to some embodiments of the invention, the alkali in the methanol solution of the alkali in the step (4) may be sodium methoxide, sodium ethoxide, or the like.
According to some embodiments of the invention, the alcohol solvent in step (4) may be C 1-8 (1 carbon to 8 carbon) alcohols.
Definition of terms
In the present specification, "eq" means equivalent weight.
In this specification "g" refers to grams.
In this specification, "ml" means milliliters.
As used herein, "room temperature" refers to 10℃to 35 ℃.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
The examples described below are given unless otherwise indicated that all temperatures are given 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 Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin good Chemies, tianjin Fuchen Chemies, wuhan Xinhua Yuan technology development Co., ltd., qingdao Teng Chemies Co., and Qingdao sea chemical Co.
The measurement conditions for Mass Spectrometry (MS) data were: electrospray ionization (ESI).
Measurement conditions of H spectrum: 400MHz/600MHz, deuterated DMSO.
Typical synthetic procedures for preparing the tetracyclic pyridone derivatives according to the examples of the invention are shown in the following synthetic schemes:
EXAMPLE 1 Synthesis of methyl 3, 5-dihydroxypicolinate (Compound of formula II)
10g of compound shown in formula I and concentrated H are added into a reaction bottle at room temperature 2 SO 4 20mL and 100mL of MeOH (methanol) are added, the temperature is raised to 65 ℃ after the completion of stirring reaction, the temperature is reduced to 50 ℃ to remove the methanol, naOH aqueous solution is added under stirring to adjust the pH to 4-5, solid is separated out, the solid is filtered by suction, 8.90g of solid is obtained, the yield is 89.88%, and the purity is 96.1%.
MS:[M+1]＝170.3，
1H NMR(600MHz,DMSO)δ7.62(d,J＝2.2Hz,1H),6.45(d,J＝1.6Hz,1H),3.82(s,3H)。
EXAMPLE 2 Synthesis of 3-hydroxy-5- (trifluoromethanesulfonyl) -picolinic acid methyl ester (Compound of formula III)
8.0g of methyl 3, 5-dihydroxypicolinate (a compound shown in a formula II), 6.92g of diisopropylethylamine and 240mL of MeOH are added into a reaction bottle at room temperature, 20.33g of N-phenyl bis (trifluoromethanesulfonyl) imine is added under the protection of nitrogen, the reaction at room temperature is finished, and after the completion of the reaction, 12.7g of a solid product is obtained by concentration, the yield is 89.5%, and the purity is 95.0%.
MS:[M+1]＝302.0，
1H NMR(600MHz,DMSO)δ8.36(d,J＝2.3Hz,1H),7.67(d,J＝2.3Hz,1H),3.89(s,3H)。
EXAMPLE 3 Synthesis of 5- (3-chlorophenyl) -3-hydroxy-picolinic acid methyl ester (Compound of formula V)
8.00g of 3-hydroxy-5- (trifluoromethanesulfonyl) -picolinic acid methyl ester (compound represented by formula III), 5.04g of 3-chlorobenzoic acid, and,[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride 2.00g, K 3 PO 4 6.81g and 160mL of 1, 4-dioxane, heating to 90 ℃ under the protection of nitrogen, stirring and reacting, and concentrating to obtain 7.59g of solid product with the yield of 93.2% and the purity of 97.1%.
MS:[M+1]＝264.1，
1 H NMR(400MHz,DMSO)δ10.58(s,1H),8.55(s,1H),7.88(s,1H),7.74(s,2H),7.60–7.50(m,2H),3.92(s,3H)。
EXAMPLE 4 Synthesis of { [5- (3-chlorophenyl) -3-hydroxypyridin-2-yl ] amino } acetic acid (Compound of formula VI)
The reaction flask was charged with 20.0g of methyl 5- (3-chlorophenyl) -3-hydroxy-picolinate (compound of formula V), 150mL of 30% sodium methoxide methanol solution, 2.22g of glycine and 200mL of methanol at room temperature, the temperature was raised to 75℃under nitrogen protection, 3mol/l of HCl solution was added to adjust the pH of the reaction solution to 5-6 after completion of the reaction, and the mixture was suction-filtered to give a solid, which was dried at 60℃to give 20.4g of the product in a yield of 87.9% and a purity of 98.0%.
MS:[M+1]＝307.0，
1H NMR(400MHz,DMSO)δ12.37(s,1H),9.35(t,J＝5.6Hz,1H),8.82–8.39(m,1H),7.93(d,J＝24.3Hz,1H),7.85–7.68(m,2H),7.65–7.44(m,2H),4.12–3.95(m,2H)。
EXAMPLE 5 Synthesis of methyl 3, 5-dihydroxypicolinate (Compound of formula II)
10g of compound shown in formula I and concentrated H are added into a reaction bottle at room temperature 2 SO 4 And (3) adding 20mL of methanol and 100mL of methanol, heating to 65 ℃ and stirring for reaction, stopping the reaction after the reaction is completed, cooling to 50 ℃ and removing the methanol, adding an aqueous NaOH solution under stirring to adjust the pH to 4-5, precipitating solid, and carrying out suction filtration to obtain 9.04g of solid, wherein the yield is 91.3%, and the purity is 97.2%.
EXAMPLE 6 Synthesis of 3-hydroxy-5- (trifluoromethanesulfonyl) -picolinic acid methyl ester (Compound of formula III)
8.0g of methyl 3, 5-dihydroxypicolinate (a compound shown in a formula II), 5.67g of sodium carbonate and 240mL of MeOH are added into a reaction bottle at room temperature, 20.33g of N-phenyl bis (trifluoromethanesulfonyl) imine is added under the protection of nitrogen, the reaction at room temperature is completed, and after the completion of the reaction, 12.9g of a solid product is obtained through concentration, and the yield is 91.5%, and the purity is 94.8%.
EXAMPLE 7 Synthesis of 5- (3-chlorophenyl) -3-hydroxy-picolinic acid methyl ester (Compound of formula V)
8.00g of 3-hydroxy-5- (trifluoromethanesulfonyl) -picolinic acid methyl ester (compound shown in formula III), 5.04g of 3-chlorobenzoic acid, 2.00g of palladium hydroxide and K are added into a reaction bottle at room temperature 3 PO 4 6.81g and 160mL of 1, 4-dioxane, heating to 90 ℃ under the protection of nitrogen, stirring and reacting, and concentrating to obtain 7.38g of solid product with the yield of 90.7% and the purity of 96.2%.
EXAMPLE 8 Synthesis of { [5- (3-chlorophenyl) -3-hydroxypyridin-2-yl ] amino } acetic acid (Compound of formula VI)
The reaction flask was charged with 20.0g of methyl 5- (3-chlorophenyl) -3-hydroxy-picolinate (compound of formula V), 150mL of 30% sodium ethoxide methanol solution, 2.22g of glycine and 200mL of methanol at room temperature, the temperature was raised to 75℃under nitrogen protection, 3mol/l of HCl solution was added to adjust the pH of the reaction solution to 5-6 after completion of the reaction, and the mixture was suction-filtered to give a solid, which was dried at 60℃to give 20.9g of the product in a yield of 90.2% and a purity of 97.2%.
EXAMPLE 9 Synthesis of 5- (3-chlorophenyl) -3-hydroxy-picolinic acid methyl ester (Compound of formula V)
8.00g of 3-hydroxy-5- (trifluoromethanesulfonyl) -pyridine methyl formate (compound shown as a formula III), 5.04g of 3-chlorobenzoic acid, 2.00g of palladium hydroxide, 3.60g of potassium tert-butoxide and 160mL of 1, 4-dioxane are added into a reaction bottle at room temperature, the mixture is heated to 90 ℃ under the protection of nitrogen and stirred for reaction, after the reaction, 7.23g of solid product is obtained by concentration, and the yield is 88.9% and the purity is 96.5%.
In the description of the present specification, a description referring to the terms "one embodiment," "an example," "a particular example," or "some examples," etc., means 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, schematic representations of the above terms are not necessarily directed 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, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (6)

1. A preparation method of pyridine ring compound comprises the following steps:
characterized by comprising the following steps:
(1) Mixing 3, 5-dihydroxypicolinic acid, concentrated sulfuric acid and an alcohol solvent, heating to react, removing the solvent after the reaction is finished, adding an aqueous solution of sodium hydroxide, and filtering to obtain 3, 5-dihydroxypicolinic acid methyl ester; wherein the alcohol is methanol;
(2) Adding 3, 5-dihydroxypyridine methyl formate and alkali into an organic solvent, adding N-phenyl bis (trifluoromethanesulfonyl) imine under the protection of nitrogen, reacting at room temperature, and evaporating the solvent to dryness after the reaction is finished to obtain 3-hydroxy-5- (trifluoromethanesulfonyl) -pyridine methyl formate;
(3) Mixing 3-hydroxy-5- (trifluoromethanesulfonyl) -picolinic acid methyl ester, 3-chlorobenzoic acid, a palladium catalyst, alkali and an organic solvent, heating for reaction, concentrating after the reaction is finished to obtain 5- (3-chlorophenyl) -3-hydroxy-picolinic acid methyl ester;
(4) Mixing 5- (3-chlorophenyl) -3-hydroxy-pyridine methyl formate, a basic methanol solution and glycine with an alcohol solvent, heating to react, adding a hydrochloric acid solution after the reaction is finished, cooling, and filtering to obtain { [5- (3-chlorophenyl) -3-hydroxypyridine-2-yl ] amino } acetic acid; and (3) the alkali in the methanol solution in the step (4) is sodium methoxide or sodium ethoxide.
2. The method of claim 1, wherein the base in step (2) is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, diazabicyclo, triethylamine, or diisopropylethylamine.
3. The method of claim 1, wherein the palladium catalyst in step (3) is [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, palladium hydroxide, or tetrakis- (triphenylphosphine) palladium.
4. The method of claim 1, wherein the base in step (3) is sodium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, or sodium tert-butoxide.
5. The method of claim 1, wherein the organic solvent in step (3) is methyl tertiary butyl ether, 1, 4-dioxane, dimethyl ether, DMF, or DMSO.
6. The method of claim 1, wherein the alcohol solvent in step (4) is C 1-8 Is an alcohol of (a) a (c).
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Citations (2)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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

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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province

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Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei

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