CN110759831B - Method for preparing halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid - Google Patents
Method for preparing halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid Download PDFInfo
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- QLUCPCIKLHKGRW-UHFFFAOYSA-N 2-amino-4-bromo-5-chlorobenzoic acid Chemical compound NC1=CC(Br)=C(Cl)C=C1C(O)=O QLUCPCIKLHKGRW-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 26
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 title claims abstract description 19
- 229950010152 halofuginone Drugs 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 8
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 52
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 27
- 239000012043 crude product Substances 0.000 claims description 22
- 238000010438 heat treatment Methods 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- PSKJIHDVFDVNBU-UHFFFAOYSA-N 4-bromo-3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C(Cl)=C1 PSKJIHDVFDVNBU-UHFFFAOYSA-N 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 17
- HEFRRYXKIYKBJK-UHFFFAOYSA-N 4-bromo-5-chloro-2-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=C(Br)C=C1[N+]([O-])=O HEFRRYXKIYKBJK-UHFFFAOYSA-N 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 6
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 6
- 229910021641 deionized water Inorganic materials 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 6
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000001165 anti-coccidial effect Effects 0.000 abstract description 2
- 238000005660 chlorination reaction Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000006396 nitration reaction Methods 0.000 abstract description 2
- 238000006722 reduction reaction Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 230000004075 alteration Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- SJUWEPZBTXEUMU-LDXVYITESA-N 7-bromo-6-chloro-3-[3-[(2s,3r)-3-hydroxypiperidin-2-yl]-2-oxopropyl]quinazolin-4-one;hydrobromide Chemical compound Br.O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 SJUWEPZBTXEUMU-LDXVYITESA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000003495 Coccidiosis Diseases 0.000 description 1
- 241001643725 Hydrangea febrifuga Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010023076 Isosporiasis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A preparation method of an anticoccidial drug halofuginone intermediate, which relates to a preparation method of a specific compound 2-amino-4-bromo-5-chlorobenzoic acid. The method sequentially comprises the following steps: the p-bromobenzoic acid is adopted as a raw material, and a product is obtained through chlorination, nitration and selective reduction reactions. The invention provides a new synthesis route and reaction conditions, the used raw materials are sufficient in market supply and wide in source, the reaction conditions in each step are mild, the process is simple, the requirements of green production are met, and the production cost is effectively reduced.
Description
Technical Field
The invention relates to a preparation method of an anticoccidial drug halofuginone intermediate, and particularly relates to a method for preparing a compound 2-amino-4-bromo-5-chlorobenzoic acid.
Background
Dichrone is a derivative of dichroine extracted from Chinese traditional medicine dichroa febrifuga. The hydrobromide salt of halofuginone was developed and manufactured by Roussel-Uelaf, France under the trade name Sudan as a 0.6% premix of halofuginone hydrobromide. The composition is mainly used for preventing and treating coccidiosis and malaria of domesticated animals such as livestock and poultry (turkey, sheep, goat, cattle and rabbit).
The asymmetric synthesis of halofuginone compounds has begun since the 90 s of the last century and various methods have been used to date to produce this type of compound. Most of these methods, however, require more severe reaction conditions such as: the commercialization of halofuginone is greatly limited by the preparation at a low temperature of-78 ℃ and rare earth metal catalysts, or parts of the method have expensive raw materials, long steps and low overall yield, wherein 2-amino-4-bromo-5-chlorobenzoic acid is used as a key intermediate of the whole route, and the process and the cost directly restrict the whole route of halofuginone.
The patent summarizes a brand-new synthesis route through a series of experiments, and the product is obtained by chlorination, nitration and selective reduction reaction by taking p-bromobenzoic acid as a raw material. The method greatly improves the selectivity of the reaction, obviously improves the yield and the product quality, and effectively controls the cost of the product.
Disclosure of Invention
The invention aims to provide a preparation method of halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid, which has the advantages of simple process, convenient operation and no environmental pollution.
In order to achieve the purpose, a series of experiments are carried out, and a brand new synthetic route is provided.
The technical scheme for realizing the invention is as follows:
a new method for preparing the halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid is characterized in that: the halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid represented by formula (I) is obtained as follows:
(Ⅱ) (Ⅲ) (Ⅰ)
preparation of 3-chloro-4-bromobenzoic acid (II)
Adding 1 time of p-bromobenzoic acid, 0.73-0.74 time of anhydrous aluminum trichloride (weight ratio) and 5-10 times of 1,1, 2-trichloroethane (weight ratio) into a reactor with a stirring and heating device. Cooling to 0 ℃ after uniform stirring, introducing 0.35-0.43 time (weight ratio) of chlorine, heating to 80 ℃, continuing to stir for 8-12 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, distilling under reduced pressure to remove most of solvent, adding obtained residue into petroleum ether, stirring for 30 minutes, filtering and collecting precipitated solid which is a crude product of 3-chloro-4-bromobenzoic acid (II), detecting the content by HPLC (high performance liquid chromatography) to be more than 95%, and directly using the crude product in the next reaction without further purification.
B.preparation of 2-nitro-4-bromo-5-chlorobenzoic acid (III)
Adding 1 time of 3-chloro-4-bromobenzoic acid (II) and 5-6 times of concentrated sulfuric acid (weight ratio) into a reactor, uniformly stirring, cooling to 0-5 ℃, then dropwise adding 3.23-3.52 times (weight ratio) of concentrated sulfuric acid solution of HNO3 with the mass fraction of 10%, keeping the temperature of the mixture at 0-5 ℃ in the dropwise adding process, continuously stirring for 30 minutes after the dropwise adding is finished, removing the ice bath, naturally heating to room temperature, then heating to 50 ℃, continuously stirring and reacting for 6-10 hours, after the reaction is finished, slowly pouring the mixture into a large amount of ice water, controlling the temperature within 30 ℃, stirring for 30 minutes, filtering and collecting separated solid which is a crude product of the 2-nitro-4-bromo-5-chlorobenzoic acid (III), detecting the content by HPLC to be more than 95%, and directly using the crude product in the next reaction without further purification.
Preparation of C.2-amino-4-bromo-5-chlorobenzoic acid (I)
Adding 1 time of 2-nitro-4-bromo-5-chlorobenzoic acid (III), 0.02-0.05 time of ferric chloride, 0.35-0.55 time of hydrazine hydrate solution with the mass fraction of 50% and 3-6 times of deionized water into a reactor, stirring and reacting for 6-12 hours at room temperature, adjusting the pH to 12 by using 5% sodium hydroxide solution after the reaction is finished, filtering to remove insoluble substances, adjusting the pH of filtrate to 7 by using 10% glacial acetic acid, stirring for 30 minutes, filtering and collecting precipitated solid which is 2-amino-4-bromo-5-chlorobenzoic acid (I) crude product, detecting the content to be more than 95% by HPLC, and directly using the crude product in the subsequent reaction step for preparing halofuginone without further purification. The crude product is recrystallized by a methanol-water mixed solution to obtain a refined product of the 2-amino-4-bromo-5-chlorobenzoic acid (I).
The invention has the advantages that:
1. the invention adopts a brand new synthesis route, improves the selectivity of each step of reaction, and effectively improves the utilization rate and the total yield of raw materials.
2. The raw materials adopted by the method are all sold in the market, the reactions in each step are all conventional operations, the reaction conditions are mild, the control is easy, the cost is reduced, and the product competitiveness is improved.
Detailed Description
How this invention can be carried out is further illustrated by the following specific examples:
example 1
Preparation of 3-chloro-4-bromobenzoic acid (II)
P-bromobenzoic acid (201 g, 1.0 mol), anhydrous aluminum trichloride (147g, 1.1mol) and 1,1, 2-trichloroethane (2000g) were charged to a reactor equipped with stirring and heating means. Cooling to 0 ℃ after uniform stirring, introducing chlorine (85.2 g, 1.2 mol), heating to 80 ℃, continuing to stir for 12 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, distilling under reduced pressure to remove most of solvent, adding obtained residue into petroleum ether, stirring for 30 minutes, filtering and collecting separated solid which is 214.8g of 3-chloro-4-bromobenzoic acid (II), wherein the yield is about 91.2%, the content is higher than 95% through HPLC (high performance liquid chromatography) detection, and the solid can be directly used for the next reaction without further purification.
B.preparation of 2-nitro-4-bromo-5-chlorobenzoic acid (III)
Adding 3-chloro-4-bromobenzoic acid (II) (235.5 g, 1.0 mol) and concentrated sulfuric acid (1400 g) into a reactor, uniformly stirring, cooling to 0-5 ℃, then dropwise adding concentrated sulfuric acid solution (825 g) of HNO3 with the mass fraction of 10%, keeping the temperature of the mixture at 0-5 ℃ in the dropwise adding process, continuously stirring for 30 minutes after the dropwise adding is finished, removing an ice bath, naturally heating to room temperature, then heating to 50 ℃, continuously stirring for reaction for 10 hours, slowly pouring the mixture into a large amount of ice water after the reaction is finished, controlling the temperature within 30 ℃, filtering and collecting precipitated solid after stirring for 30 minutes, wherein the precipitated solid is 231.2g of 2-nitro-4-bromo-5-chlorobenzoic acid (III), the yield is about 82.4%, the content is higher than 95% through HPLC (HPLC), and the solid can be directly used for the next reaction without further purification.
A small amount of crude product is taken to be refined by methanol and then detected, 1 HNMR（DMSO，400 MHz）：8.27（s，1H），8.74（s，1H）。FAB-MS(m/z)：:281.5 (M+H)。
preparation of C.2-amino-4-bromo-5-chlorobenzoic acid (I)
Adding 2-nitro-4-bromo-5-chlorobenzoic acid (III) (280.5 g, 1.0 mol), ferric chloride (12.5 g), 50% hydrazine hydrate solution (150 g) and deionized water (1650 g) into a reactor, stirring for reaction at room temperature for 12 hours, adjusting the pH to 12 with 5% sodium hydroxide solution after the reaction is finished, filtering to remove insoluble substances, adjusting the pH to 7 with 10% glacial acetic acid, stirring for 30 minutes, filtering to collect separated solid which is 236.8g of 2-amino-4-bromo-5-chlorobenzoic acid (I), wherein the yield is about 94.5%, the content is higher than 95% by HPLC (high performance liquid chromatography), and the solid can be directly used for the subsequent reaction step of preparing halofuginone without further purification. The crude product is recrystallized by a methanol-water mixed solution to obtain a refined product of the 2-amino-4-bromo-5-chlorobenzoic acid (I).
1 HNMR（DMSO，400 MHz）：7.07（s，1H），7.79（s，1H）。FAB-MS(m/z)：:251.5 (M+H)。
Example 2
The procedure is otherwise the same as in example 1, except that 3-chloro-4-bromobenzoic acid (II) is prepared as follows:
p-bromobenzoic acid (201 g, 1.0 mol), anhydrous aluminum trichloride (147g, 1.1mol) and 1,1, 2-trichloroethane (1050g) were charged to a reactor equipped with stirring and heating means. Cooling to 0 ℃ after uniform stirring, introducing chlorine (71 g, 1.0 mol), heating to 80 ℃, continuing to stir for 8 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, distilling under reduced pressure to remove most of solvent, adding the obtained residue into petroleum ether, stirring for 30 minutes, filtering and collecting separated solid which is 180.6g of 3-chloro-4-bromobenzoic acid (II), wherein the yield is about 76.7%, the content is higher than 95% through HPLC (high performance liquid chromatography) detection, and the solid can be directly used for the next reaction without further purification.
Example 3
The procedure is otherwise the same as in example 1, except that 3-chloro-4-bromobenzoic acid (II) is prepared as follows:
p-bromobenzoic acid (201 g, 1.0 mol), anhydrous aluminum trichloride (147g, 1.1mol) and 1,1, 2-trichloroethane (1500g) were charged to a reactor equipped with stirring and heating means. Cooling to 0 ℃ after uniform stirring, introducing chlorine (78.1 g, 1.1mol), heating to 80 ℃, continuing to stir for 10 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, distilling under reduced pressure to remove most of solvent, adding obtained residue into petroleum ether, stirring for 30 minutes, filtering and collecting separated solid which is 192.5g of 3-chloro-4-bromobenzoic acid (II), wherein the yield is about 81.7%, the content is higher than 95% through HPLC (high performance liquid chromatography) detection, and the solid can be directly used for the next reaction without further purification.
Example 4
The procedure was otherwise the same as in example 1, except that 2-nitro-4-bromo-5-chlorobenzoic acid (III) was prepared as follows:
adding 3-chloro-4-bromobenzoic acid (II) (235.5 g, 1.0 mol) and concentrated sulfuric acid (1200 g) into a reactor, uniformly stirring, cooling to 0-5 ℃, then dropwise adding a concentrated sulfuric acid solution (760 g) of HNO3 with the mass fraction of 10%, keeping the temperature of the mixture at 0-5 ℃ in the dropwise adding process, continuously stirring for 30 minutes after the dropwise adding is finished, removing the ice bath, naturally heating to room temperature, then heating to 50 ℃, continuously stirring for reaction for 6 hours, slowly pouring the mixture into a large amount of ice water after the reaction is finished, controlling the temperature within 30 ℃, filtering and collecting separated solids after stirring for 30 minutes, wherein the separated solids are 203.6g of 2-nitro-4-bromo-5-chlorobenzoic acid (III), the yield is about 72.6%, the content is higher than 95% by HPLC (high performance liquid chromatography), and the solids can be directly used for the next reaction without further purification.
A small amount of crude product is taken to be refined by methanol and then detected, 1 HNMR（DMSO，400 MHz）：8.27（s，1H），8.74（s，1H）。FAB-MS(m/z)：:281.5 (M+H)。
example 5
The procedure was otherwise the same as in example 1, except that 2-nitro-4-bromo-5-chlorobenzoic acid (III) was prepared as follows:
adding 3-chloro-4-bromobenzoic acid (II) (235.5 g, 1.0 mol) and concentrated sulfuric acid (1300 g) into a reactor, uniformly stirring, cooling to 0-5 ℃, then dropwise adding concentrated sulfuric acid solution (790 g) of HNO3 with the mass fraction of 10%, keeping the temperature of the mixture at 0-5 ℃ in the dropwise adding process, continuously stirring for 30 minutes after the dropwise adding is finished, removing the ice bath, naturally heating to room temperature, then heating to 50 ℃, continuously stirring for reaction for 8 hours, slowly pouring the mixture into a large amount of ice water after the reaction is finished, controlling the temperature within 30 ℃, filtering and collecting separated solid after stirring for 30 minutes, wherein the solid is 216.8g of 2-nitro-4-bromo-5-chlorobenzoic acid (III), the yield is about 77.3%, the content is higher than 95% by HPLC (high performance liquid chromatography), and the solid can be directly used for the next reaction without further purification.
A small amount of crude product is taken to be refined by methanol and then detected, 1 HNMR（DMSO，400 MHz）：8.27（s，1H），8.74（s，1H）。FAB-MS(m/z)：:281.5 (M+H)。
example 6
The procedure was otherwise the same as in example 1 except that 2-amino-4-bromo-5-chlorobenzoic acid (I) in step C was prepared as follows:
adding 2-nitro-4-bromo-5-chlorobenzoic acid (III) (280.5 g, 1.0 mol), ferric chloride (6 g), 50% hydrazine hydrate solution (100 g) and deionized water (850 g) into a reactor, stirring at room temperature for 6 hours, adjusting the pH to 12 with 5% sodium hydroxide solution after the reaction is finished, filtering to remove insoluble substances, adjusting the pH of filtrate to 7 with 10% glacial acetic acid, stirring for 30 minutes, filtering and collecting precipitated solid which is 211.2g of 2-amino-4-bromo-5-chlorobenzoic acid (I), wherein the yield is about 84.3%, the content is higher than 95% through HPLC (high performance liquid chromatography), and the product can be directly used for the subsequent reaction step of preparing halofuginone without further purification. The crude product is recrystallized by a methanol-water mixed solution to obtain a refined product of the 2-amino-4-bromo-5-chlorobenzoic acid (I).
1 HNMR（DMSO，400 MHz）：7.07（s，1H），7.79（s，1H）。FAB-MS(m/z)：:251.5 (M+H)。
Example 7
The 2-amino-4-bromo-5-chlorobenzoic acid (I) was prepared by the same procedure as in example 1 except for the C step:
adding 2-nitro-4-bromo-5-chlorobenzoic acid (III) (280.5 g, 1.0 mol), ferric chloride (9 g), 50% hydrazine hydrate solution (130 g) and deionized water (1200 g) into a reactor, stirring at room temperature for reaction for 9 hours, adjusting the pH to 12 with 5% sodium hydroxide solution after the reaction is finished, filtering to remove insoluble substances, adjusting the pH of the filtrate to 7 with 10% glacial acetic acid, stirring for 30 minutes, filtering and collecting separated solid which is 218.9g of 2-amino-4-bromo-5-chlorobenzoic acid (I), wherein the yield is about 87.4%, the content is higher than 95% by HPLC (high performance liquid chromatography), and the solid can be directly used for the subsequent reaction step of preparing halofuginone without further purification. The crude product is recrystallized by a methanol-water mixed solution to obtain a refined product of the 2-amino-4-bromo-5-chlorobenzoic acid (I).
1 HNMR（DMSO，400 MHz）：7.07（s，1H），7.79（s，1H）。FAB-MS(m/z)：:251.5 (M+H)。
Example 8
The procedure was otherwise the same as in example 1 except that 2-amino-4-bromo-5-chlorobenzoic acid (I) in step C was prepared as follows:
adding 2-nitro-4-bromo-5-chlorobenzoic acid (III) (280.5 g, 1.0 mol), ferric chloride (10 g), 50% hydrazine hydrate solution (140 g) and deionized water (1250 g) into a reactor, stirring at room temperature for 10 hours, adjusting the pH to 12 with 5% sodium hydroxide solution after the reaction is finished, filtering to remove insoluble substances, adjusting the pH of the filtrate to 7 with 10% glacial acetic acid, stirring for 30 minutes, filtering to collect precipitated solid, namely 226.3g of 2-amino-4-bromo-5-chlorobenzoic acid (I), wherein the yield is about 90.3%, the content is higher than 95% by HPLC (high performance liquid chromatography), and the subsequent reaction step of preparing halofuginone can be directly carried out without further purification. The crude product is recrystallized by a methanol-water mixed solution to obtain a refined product of the 2-amino-4-bromo-5-chlorobenzoic acid (I).
1 HNMR（DMSO，400 MHz）：7.07（s，1H），7.79（s，1H）。FAB-MS(m/z)：:251.5 (M+H)。
Although the invention has been described and illustrated in some detail by the inventor, it should be understood that modifications and/or alterations to the above-described embodiments, or equivalent alterations thereto, will become apparent to those skilled in the art without departing from the spirit of the invention, and that no limitation to the invention is intended by the terms of the present invention as set forth herein is intended to be exhaustive or understood.
Claims (1)
1. A method for preparing a halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid is characterized by comprising the following steps: the halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid represented by formula (I) is obtained as follows:
preparation of 3-chloro-4-bromobenzoic acid (II)
Adding 1 weight part of p-bromobenzoic acid, 0.73-0.74 weight part of anhydrous aluminum trichloride and 5-10 weight parts of 1,1, 2-trichloroethane into a reactor with a stirring and heating device, uniformly stirring, cooling to 0 ℃, introducing 0.35-0.43 weight part of chlorine, heating to 80 ℃, continuously stirring for reacting for 8-12 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, distilling under reduced pressure to remove most of solvent, adding the obtained residue into petroleum ether, stirring for 30 minutes, filtering and collecting precipitated solid which is a crude product of 3-chloro-4-bromobenzoic acid (II), detecting the content by HPLC to be more than 95%, and directly using the crude product in the next reaction without further purification;
b.preparation of 2-nitro-4-bromo-5-chlorobenzoic acid (III)
Adding 1 time of 3-chloro-4-bromobenzoic acid (II) and 5-6 parts by weight of concentrated sulfuric acid into a reactor, uniformly stirring, cooling to 0-5 ℃, and then dropwise adding 10% by mass of HNO 3 3.23-3.52 parts of concentrated sulfuric acid solution, keeping the temperature of the mixture at 0-5 ℃ in the dropwise adding process, continuously stirring for 30 minutes after the dropwise adding is finished, removing the ice bath, naturally heating to room temperature, then heating to 50 ℃, continuously stirring for reacting for 6-10 hours, slowly pouring the mixture into a large amount of ice water after the reaction is finished, controlling the temperature within 30 ℃, stirring for 30 minutes, filtering and collecting precipitated solid which is a 2-nitro-4-bromo-5-chlorobenzoic acid (III) crude product, detecting the content by HPLC (high performance liquid chromatography) to be more than 95%, and directly using the crude product for the next reaction without further purification;
preparation of C.2-amino-4-bromo-5-chlorobenzoic acid (I)
Adding 1 weight part of 2-nitro-4-bromo-5-chlorobenzoic acid (III), 0.02-0.05 weight part of ferric chloride, 0.35-0.55 weight part of hydrazine hydrate solution with the mass fraction of 50% and 3-6 weight parts of deionized water into a reactor, and then stirring and reacting for 6-12 hours at room temperature, adjusting the pH value to 12 by using a 5% sodium hydroxide solution after the reaction is finished, filtering to remove insoluble substances, adjusting the pH value of filtrate to 7 by using 10% glacial acetic acid, stirring for 30 minutes, filtering and collecting precipitated solid to obtain a crude product of the 2-amino-4-bromo-5-chlorobenzoic acid (I), detecting the content of the crude product to be more than 95% by HPLC (high performance liquid chromatography), directly using the crude product in a subsequent reaction step for preparing halofuginone without further purification, and recrystallizing the crude product by using a methanol-water mixed solution to obtain a refined product of the 2-amino-4-bromo-5-chlorobenzoic acid (I).
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| WO2017090756A1 (en) * | 2015-11-27 | 2017-06-01 | 大鵬薬品工業株式会社 | Novel biphenyl compound or salt thereof |
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| CN1651428A (en) * | 2004-02-06 | 2005-08-10 | 上海因诺生化科技有限公司 | Preparation method of hydrobromic acid antifebrile dichroanone |
| CN101835752A (en) * | 2007-08-31 | 2010-09-15 | 阿斯利康(瑞典)有限公司 | Heterocyclic amides useful for the treatment of cancer and psoriasis |
| CN101219977A (en) * | 2008-01-25 | 2008-07-16 | 延边大学 | CLT acid production method without acid waste liquid discharge |
| CN104326992A (en) * | 2014-10-15 | 2015-02-04 | 浙江省诸暨合力化学对外贸易有限公司 | Method for synthesizing difluoro methyl triazoline-ketone and sulfentrazone |
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Denomination of invention: Method for preparing the intermediate 2-amino-4-bromo-5-chlorobenzoic acid of Changshan ketone Granted publication date: 20220927 Pledgee: Zhejiang Tailong Commercial Bank Co.,Ltd. Hangzhou Fuyang sub branch Pledgor: ZHEJIANG GENEBEST PHARMACEUTICAL Co.,Ltd. Registration number: Y2024980000009 |
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