CN113603615B - Preparation method of 5-halogenated-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid - Google Patents
Preparation method of 5-halogenated-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid Download PDFInfo
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- CN113603615B CN113603615B CN202110776320.6A CN202110776320A CN113603615B CN 113603615 B CN113603615 B CN 113603615B CN 202110776320 A CN202110776320 A CN 202110776320A CN 113603615 B CN113603615 B CN 113603615B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
- C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
Abstract
The invention provides a 5-halogenated-2 [ (alkoxycarbonyl) amino group]-3-methylbenzoic acid is prepared by reacting a compound of formula (I) with a compound of formula (II) in the presence of an organic base to produce a compound of formula (III); then the compound of the formula (III) reacts with a halogenating reagent to obtain the compound of the formula (IV), namely 5-halogeno-2 [ (alkoxycarbonyl) amino group]-3-methylbenzoic acid. The reaction reagent raw materials used by the preparation method provided by the invention are cheap and easy to obtain, and the preparation method has the advantages of good selectivity, few side reactions, high product yield, high product purity, simple and economic process and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 5-halogenated-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid.
Background
5-halo-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid, is an important intermediate for synthesizing novel broad-spectrum insecticides of chlorantraniliprole and cyantraniliprole. 5-halo-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid can be synthesized by various routes, but few routes are reported, wherein patent CN 101600682B mentions that the chlorination yield is only 84%, and the lower yield results in higher production cost.
Disclosure of Invention
The invention provides a preparation method of 5-halo-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid, which is simple and economical in process and can improve the yield and quality of products, and overcomes the problems in the prior art, and the preparation method comprises the following steps:
(a) Reacting a compound shown in a formula (I) with a compound shown in a formula (II) in the presence of an organic base to generate a compound shown in a formula (III);
(b) Reacting the compound shown in the formula (III) with a halogenating reagent to obtain a compound shown in the formula (IV), namely 5-halogeno-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid;
wherein:
x is Cl or Br;
y is Cl or Br;
r is hydrogen, C 1 -C 4 Alkyl or benzyl.
The X is Cl or Br; y is Cl or Br.
The molar ratio of the aforementioned compound of formula (II) to the compound of formula (I) is 3 to 5 to 1, preferably 4 to 1.
The molar ratio of the aforementioned halogenating agent to the compound of formula (III) is from 2 to 5 to 1, preferably 2.5 to 1.
The organic base in the step (a) is organic amine or pyridine base.
In the aforementioned step (a), the molar ratio of the organic base to the compound of formula (I) is 3 to 5 to 1, preferably 4 to 1. Alternatively, the molar ratio of the organic base to the compound of formula (II) is from 0.9 to 1.1 to 1, preferably 1 to 1.
The organic base is pyridine base, and the pyridine base is pyridine or alkyl pyridine.
Further, the aforementioned alkyl pyridine is selected from 2-methylpyridine, 3-methylpyridine or 4-methylpyridine.
Still further, the aforementioned alkyl pyridine is 3-methyl pyridine.
The aforementioned step (a) is carried out in the presence of an organic solvent. The amount of solvent used is such that it dissolves the compound of formula (I).
Alternatively, in the aforementioned step (a), the mass ratio of the organic solvent to the compound of formula (I) is 3 to 10 to 1, preferably 5 to 1.
Further, in the step (a), the organic solvent is selected from acetonitrile, 1, 4-dioxane or tetrahydrofuran.
Further, in the step (a), the organic solvent is acetonitrile.
The halogenating agent in the step (b) is a halogen acid.
Further, the hydrohalic acid is selected from hydrochloric acid or hydrobromic acid.
The step (b) also comprises a step of adding hydrogen peroxide. Wherein the molar ratio of the hydrogen peroxide to the compound of the formula (III) is 1-1.5 to 1.
The aforementioned step (b) is carried out in the presence of an organic solvent.
In the step (b), the amount ratio of the organic solvent to the compound of formula (III) is 2mL to 1g, i.e., 2mL of the organic solvent is required per gram of the compound of formula (III).
Further, in the aforementioned step (b), the organic solvent is selected from acetonitrile, acetic acid or N, N-dimethylformamide.
Further, in the step (b), the organic solvent is acetic acid.
The reaction temperature in the step (a) is 0 to 50 ℃.
Further, the reaction temperature in the aforementioned step (a) is 20 to 35 ℃.
The reaction temperature in the step (b) is 0 to 50 ℃.
Further, the reaction temperature in the step (b) is 20 to 40 ℃.
Further, the reaction temperature in the aforementioned step (b) is 20 to 30 ℃.
The invention provides a preparation method of 5-halo-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid, which has the advantages of cheap and easily-obtained reaction reagent raw materials, good selectivity, few side reactions, high product yield, high product purity, simple and economical process and the like.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
C 1 -C 4 Alkyl groups are linear or branched, saturated hydrocarbon chains containing from 1 to 4 carbon atoms. It may be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.
Detailed Description
Example 1: synthesis of 2-ethoxy-8-methyl-4H-benzo [ d ] [1,3] oxazin-4-one
2-amino-3-methylbenzoic acid (40g, 0.264 mol) and acetonitrile (200 g) were added to a 500mL four-necked flask in this order and stirred. 3-methylpyridine (98.5g, 1.058 mol) is added into the system in one portion and stirred until the system is clear. Controlling the temperature of the system to be 20-35 ℃, dropwise adding ethyl chloroformate (114.8g, 1.058mol) into the system, preserving the temperature of the system after dropwise adding, and reacting for 2h at the temperature of 20-35 ℃. After the reaction is completed, the system is directly filtered, a filter cake is rinsed by acetonitrile water, and the obtained solid is dried to obtain 51.5g of 2-ethoxy-8-methyl-4H-benzo [ d ] [1,3] oxazine-4-one with the purity of 98.4% and the yield of 95.2%.
TABLE 1 comparison of the reaction yields in the presence of different chloroformates, organic bases and solvents
| Serial number | Cyclization reagent | Organic base | Solvent(s) | Purity of | Yield of |
| 1 | Chloroformic acid ethyl ester | Pyridine compound | Acetonitrile | 98.4％ | 97.2％ |
| 2 | Chloroformic acid ethyl ester | Pyridine compound | Dioxane (dioxane) | 96.7％ | 94.2％ |
| 3 | Chloroformic acid ethyl ester | Pyridine compound | Tetrahydrofuran (THF) | 95.8％ | 93.5％ |
| 4 | Chloroacetic acid ethyl ester | 3-methylpyridine | Acetonitrile | 98.4％ | 95.2％ |
| 5 | Chloroacetic acid ethyl ester | 3-methylpyridine | Tetrahydrofuran (THF) | 97.9％ | 93.7％ |
| 6 | Chloroacetic acid ethyl ester | Triethylamine | Tetrahydrofuran (THF) | 91.3％ | 70.5％ |
| 7 | Chloroformic acid ethyl ester | Triethylamine | Acetonitrile (ACN) | 93.2％ | 72.6％ |
| 8 | Isopropyl chloroformate | Pyridine compound | Acetonitrile | 97.8％ | 96.2％ |
| 9 | Isopropyl chloroformate | 3-methylpyridine | Tetrahydrofuran (THF) | 98.1％ | 94.6％ |
And (3) knotting: ethyl chloroformate and isopropyl chloroformate can be used as cyclization reagents, pyridine and 3-methylpyridine used for organic alkali have good effects, and acetonitrile used as a solvent has a good effect.
Example 2: synthesis of 5-chloro-2 [ (ethoxycarbonyl) amino ] -3-methylbenzoic acid
2-ethoxy-8-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (100 g, 0.487 mol), acetic acid 200ml,30% hydrochloric acid (148.2g, 1.22mol) are sequentially added into a 500mL four-mouth reaction bottle, 30% hydrogen peroxide (71.7 g, 0.633mol) is dropwise added at 20-30 ℃, and the mixture is subjected to heat preservation reaction for 2 hours. After the reaction, water was added to the reaction mixture to crystallize, filter and dry the crystals to obtain 116.7g of 5-chloro-2 [ (ethoxycarbonyl) amino ] -3-methylbenzoic acid with a purity of 98.9% and a yield of 93.4%.
TABLE 2 comparison of the reaction yields in different solvents and reaction temperatures
| Serial number | Halogenated agents | Solvent(s) | Reaction temperature | Purity of | Yield of the product |
| 1 | Hydrochloric acid/hydrogen peroxide | Acetic acid | 20-30℃ | 98.9％ | 93.4％ |
| 2 | Hydrochloric acid/hydrogen peroxide | Acetic acid | 30-40℃ | 97.1％ | 89.4％ |
| 3 | Hydrochloric acid/hydrogen peroxide | Acetonitrile | 20-30℃ | 94.6％ | 86.1％ |
| 4 | Hydrochloric acid/hydrogen peroxide | DMF | 20-30℃ | 96.1％ | 88.6％ |
And (3) knotting: the result is better when the temperature of the halogenation reaction is 20-30 ℃, and the reaction result is better when the solvent of the halogenation reaction is acetic acid.
Example 3: synthesis of 5-bromo-2 [ (ethoxycarbonyl) amino ] -3-methylbenzoic acid
2-ethoxy-8-methyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (100 g, 0.487 mol), acetic acid 200ml,48% hydrobromic acid (205.3g, 1.22mol) are sequentially added into a 500mL four-mouth reaction bottle, 30% hydrogen peroxide (60.7g, 0.536mol) is dropwise added at 20-30 ℃, the temperature is kept for 2 hours for reaction, and after the reaction is finished, water is added for crystallization, filtration and drying to obtain 116.7g of 5-bromo-2 [ (ethoxycarbonyl) amino ] -3-methylbenzoic acid with the purity of 99.1% and the yield of 95.2%.
TABLE 3 comparison of reaction yields in different solvents and reaction temperatures
| Serial number | Halogenated agents | Solvent(s) | Reaction temperature | Purity of | Yield of the product |
| 1 | Hydrobromic acid/hydrogen peroxide | Acetic Acid (AA) | 20-30℃ | 99.1％ | 95.2％ |
| 2 | Hydrobromic acid/hydrogen peroxide | Acetic Acid (AA) | 30-40℃ | 98.6％ | 93.8％ |
| 3 | Hydrobromic acid/hydrogen peroxide | Acetonitrile (ACN) | 20-30℃ | 95.4％ | 90.7％ |
And (4) summarizing: the result is better when the temperature of the halogenation reaction is 20-30 ℃, and the reaction result is better when the solvent of the halogenation reaction is acetic acid.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and all simple modifications and equivalent variations of the above embodiments according to the technical spirit of the present invention are included in the scope of the present invention.
Claims (13)
1. A method for producing 5-halo-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid, which comprises: the preparation method comprises the following steps:
(a) Reacting a compound shown in a formula (I) with a compound shown in a formula (II) in the presence of an organic base to generate a compound shown in a formula (III);
(b) Reacting the compound shown in the formula (III) with a halogenating reagent to obtain a compound shown in the formula (IV), namely 5-halogeno-2 [ (alkoxycarbonyl) amino ] -3-methylbenzoic acid;
wherein:
x is Cl or Br;
y is Cl or Br;
r is hydrogen, C 1 -C 4 Alkyl or benzyl;
the halogenating agent in the step (b) is hydrohalic acid selected from hydrochloric acid or hydrobromic acid;
the step (b) also comprises a step of adding hydrogen peroxide.
2. The method of claim 1, wherein: r is C 1 -C 4 An alkyl group.
3. The method according to claim 1 or 2, characterized in that: the organic base in step (a) is an organic amine.
4. The method of claim 3, wherein: the organic base is pyridine base, and the pyridine base is pyridine or alkyl pyridine.
5. The method of claim 4, wherein: the alkyl pyridine is selected from 2-methyl pyridine, 3-methyl pyridine or 4-methyl pyridine.
6. The method according to claim 1 or 2, characterized in that: the step (a) is carried out in the presence of an organic solvent selected from acetonitrile, 1, 4-dioxane or tetrahydrofuran.
7. The method of claim 6, wherein: the organic solvent is selected from acetonitrile.
8. The method according to claim 1 or 2, characterized in that: the step (b) is carried out in the presence of an organic solvent selected from acetonitrile, acetic acid or N, N-dimethylformamide.
9. The method of claim 8, wherein: the organic solvent is selected from acetic acid.
10. The method according to claim 1 or 2, characterized in that: the reaction temperature of the step (a) is 0-50 ℃; the reaction temperature of the step (b) is 0-50 ℃.
11. The method of claim 10, wherein: the reaction temperature of the step (a) is 20-35 ℃.
12. The method of claim 10, wherein: the reaction temperature of the step (b) is 20-40 ℃.
13. The method of claim 12, wherein: the reaction temperature of the step (b) is 20-30 ℃.
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Citations (5)
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|---|---|---|---|---|
| US4745116A (en) * | 1985-06-25 | 1988-05-17 | Syntex (U.S.A.) Inc. | 2-oxy-4H-3,1-benzoxazin-4-ones and related compounds and pharmaceutical use |
| CN101600682A (en) * | 2006-07-19 | 2009-12-09 | 杜邦公司 | The preparation method of 3-substituted 2-amino-5-halobenzamides |
| CN104725453A (en) * | 2015-01-21 | 2015-06-24 | 上海交通大学 | Azo linkage unit based fluorescence labeled nucleotide and applications thereof |
| CN105622539A (en) * | 2016-03-11 | 2016-06-01 | 中山万汉医药科技有限公司 | Method for preparing cetilistat |
| CN107021889A (en) * | 2017-06-08 | 2017-08-08 | 联化科技（台州）有限公司 | The preparation method and device of a kind of aromatic chlorinated thing |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4745116A (en) * | 1985-06-25 | 1988-05-17 | Syntex (U.S.A.) Inc. | 2-oxy-4H-3,1-benzoxazin-4-ones and related compounds and pharmaceutical use |
| CN101600682A (en) * | 2006-07-19 | 2009-12-09 | 杜邦公司 | The preparation method of 3-substituted 2-amino-5-halobenzamides |
| CN104725453A (en) * | 2015-01-21 | 2015-06-24 | 上海交通大学 | Azo linkage unit based fluorescence labeled nucleotide and applications thereof |
| CN105622539A (en) * | 2016-03-11 | 2016-06-01 | 中山万汉医药科技有限公司 | Method for preparing cetilistat |
| CN107021889A (en) * | 2017-06-08 | 2017-08-08 | 联化科技（台州）有限公司 | The preparation method and device of a kind of aromatic chlorinated thing |
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| "Synthesis and Antifungal Activity of Novel Quinazolin-4(3H)-one Derivatives";Maher A. El-Hashash等;《Synthetic Communications》;20150820;第45卷;第2240-2250页 * |
| 氯虫苯甲酰胺关键中间体2-氨基-5-氯-N,3-二甲基苯甲酰胺合成方法的改进;刘建华等;《农药》;20131110(第11期);第793-795页 * |
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