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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- 125000004466 alkoxycarbonylamino group Chemical group 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000007530 organic bases Chemical class 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 230000002140 halogenating effect Effects 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- -1 alkyl pyridine Chemical compound 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical group CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 5
- FVTRDWMTAVVDCU-UHFFFAOYSA-N acetic acid;hydrogen peroxide Chemical compound OO.CC(O)=O FVTRDWMTAVVDCU-UHFFFAOYSA-N 0.000 description 4
- 238000005658 halogenation reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- TZBHPYXJOJGKDT-UHFFFAOYSA-N 1,3-oxazin-4-one Chemical compound O=C1C=COC=N1 TZBHPYXJOJGKDT-UHFFFAOYSA-N 0.000 description 2
- VJOLEQQHBNGBRT-UHFFFAOYSA-N 5-bromo-2-(ethoxycarbonylamino)-3-methylbenzoic acid Chemical compound CCOC(NC(C(C)=CC(Br)=C1)=C1C(O)=O)=O VJOLEQQHBNGBRT-UHFFFAOYSA-N 0.000 description 2
- QFTBEVGRZDGICE-UHFFFAOYSA-N 5-chloro-2-(ethoxycarbonylamino)-3-methylbenzoic acid Chemical compound CCOC(=O)NC1=C(C)C=C(Cl)C=C1C(O)=O QFTBEVGRZDGICE-UHFFFAOYSA-N 0.000 description 2
- HFNDSOBLEIOGHW-UHFFFAOYSA-N acetonitrile;hydrogen peroxide Chemical compound OO.CC#N HFNDSOBLEIOGHW-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 1
- WNAJXPYVTFYEST-UHFFFAOYSA-N 2-Amino-3-methylbenzoate Chemical compound CC1=CC=CC(C(O)=O)=C1N WNAJXPYVTFYEST-UHFFFAOYSA-N 0.000 description 1
- 239000005886 Chlorantraniliprole Substances 0.000 description 1
- 239000005889 Cyantraniliprole Substances 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- PSOVNZZNOMJUBI-UHFFFAOYSA-N chlorantraniliprole Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl PSOVNZZNOMJUBI-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DVBUIBGJRQBEDP-UHFFFAOYSA-N cyantraniliprole Chemical compound CNC(=O)C1=CC(C#N)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl DVBUIBGJRQBEDP-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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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| CN101600682A (en) * | 2006-07-19 | 2009-12-09 | 杜邦公司 | Process for preparing 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 |
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