CN100355733C - Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd - Google Patents
Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd Download PDFInfo
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- CN100355733C CN100355733C CNB2003101091993A CN200310109199A CN100355733C CN 100355733 C CN100355733 C CN 100355733C CN B2003101091993 A CNB2003101091993 A CN B2003101091993A CN 200310109199 A CN200310109199 A CN 200310109199A CN 100355733 C CN100355733 C CN 100355733C
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- nicotinic acid
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- 238000000034 method Methods 0.000 title abstract description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 25
- BXZSBDDOYIWMGC-UHFFFAOYSA-N 5-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(F)=C1 BXZSBDDOYIWMGC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 4
- WMADTZFXZAITIR-UHFFFAOYSA-N 2-chloro-5-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(F)=CN=C1Cl WMADTZFXZAITIR-UHFFFAOYSA-N 0.000 claims description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 230000003647 oxidation Effects 0.000 claims description 12
- 238000007254 oxidation reaction Methods 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 238000005502 peroxidation Methods 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 2
- 239000012752 auxiliary agent Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 5
- GCRNGPNGNJSZCC-UHFFFAOYSA-N tert-butyl 3-amino-3a,4,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrazole-5-carboxylate Chemical compound N1N=C(N)C2CN(C(=O)OC(C)(C)C)CC21 GCRNGPNGNJSZCC-UHFFFAOYSA-N 0.000 abstract 2
- 238000004440 column chromatography Methods 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 125000003396 thiol group Chemical class [H]S* 0.000 abstract 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- -1 radical nicotinic acid class Chemical class 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000010813 municipal solid waste Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000010025 steaming Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- MLQAVSARYWHRCN-UHFFFAOYSA-N [N].FC=1C=NC=C(C(=O)O)C1 Chemical compound [N].FC=1C=NC=C(C(=O)O)C1 MLQAVSARYWHRCN-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- ZZLGRVWAJFJQQK-UHFFFAOYSA-N 5-amino-2-chloropyridine-3-carboxylic acid Chemical compound NC1=CN=C(Cl)C(C(O)=O)=C1 ZZLGRVWAJFJQQK-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000006298 dechlorination reaction Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- UEYQJQVBUVAELZ-UHFFFAOYSA-N 2-Hydroxynicotinic acid Chemical compound OC(=O)C1=CC=CN=C1O UEYQJQVBUVAELZ-UHFFFAOYSA-N 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- WOFZRBCITDVRON-UHFFFAOYSA-N 2-chloro-5-nitronicotinic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CN=C1Cl WOFZRBCITDVRON-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The present invention relates to an industrialized preparation method for 2-chlorine-5-fluoro-nicotinic acid. Conventional and easily obtained 2, 6-dichloro-5-fluoro-nicotinic acid is used as raw materials by the present invention. Firstly, two chlorine atoms on the 2, 6-dichloro-5-fluoro-nicotinic acid are directly removed with a catalytic hydrogenation method, and are then oxidized by nitrogen so as to obtain nitrogen oxidized 5-fluoro-nicotinic acid. Finally, the 2-chlorine-5-fluoro-nicotinic acid is obtained after the nitrogen oxidized 5-fluoro-nicotinic acid is processed by a chloridizing agent. A chemical reaction formula is disclosed as following in the specification. The problems of too low yield and overlong route in the prior art are solved by the present invention. Column chromatography purification is not needed, and the use of thiol with foreign odor is avoided.
Description
Technical field:
The present invention relates to a kind of preparation method who has chlorine, fluorin radical nicotinic acid class pharmaceutical intermediate, particularly a kind of industrialized process for preparing of 2-chloro-5-fluoro-nicotinic acid.
Background technology:
2-chloro-5-fluoro-nicotinic acid is the pharmaceutical intermediate of outbalance, but do not have effective synthetic method so far and prepare this product, once two kinds of preparation methods had been reported in the document, a kind of method is with 2,6-two chloro-5-fluoro-Nikithans at first react with thiomethyl alcohol, thereafter be that catalyst hydrogenation is taken off the first sulfydryl and obtained 2-chloro-5-fluoro-Nikithan with the Raney's nickel, again hydrolysis obtain 2-chloro-5-fluoro-nicotinic acid (J.Med.Chem.1993,2678-2688); Another kind method is from 2-hydroxyl-nicotinic acid, nitrated chloro again gets 2-chloro-5-nitro-nicotinic acid earlier, it obtains 2-chloro-5-amino-nicotinic acid by iron powder reducing, and 2-chloro-5-amino-nicotinic acid obtains 2-chloro-5-fluoro-nicotinic acid (EP0634413A1) after the heating of gained NITRODIAZONIUM FLUOROBORATE after the diazotization in fluoroboric acid.
Document synthetic route 1:
Document synthetic route 2:
In document synthetic route 1, the one, must replace 2 with the thiomethyl alcohol of foreign odor, 6-two chloro-5-fluoro-Nikithans, take off the first sulfydryl with Raney's nickel for the catalyst hydrogenation selectivity simultaneously, yield has only about 30%, and the model of this reaction pair Raney's nickel is had relatively high expectations, and can not get product with general Raney's nickel; And document synthetic route 2 synthesis techniques are long, and last NITRODIAZONIUM FLUOROBORATE heating fluoro-reaction yield is low excessively, and not easy to operate.
We had also once developed a kind of technology of following selectivity dechlorination, and applied for Chinese invention patent (application number: 200310108336.1):
Though this technology is effectively more than the existing technology of document, and avoid using the thiomethyl alcohol of foreign odor; Shorten the route of existing synthesis technique, improve yield, reduce cost.This technology is synthetic comparatively effective for 2-chloro-5-fluoro-nicotinate, but low excessively to 2-chloro-5-fluoro-nicotinic acid synthetic population yield, and the demand pole chromatography purification, and it is small-scale synthetic that it is suitable for the laboratory, can't suitability for industrialized production.
Summary of the invention:
The technical issues that need to address of the present invention are: solved the problem that needs chromatography purification among the existing 2-chloro-5-fluoro-nicotinic acid preparation technology; Shorten the route of existing synthesis technique, improve overall yield, reduce cost, be suitable for large-scale production; Avoid using the thiomethyl alcohol of foreign odor; A kind of industrialized process for preparing of 2-chloro-5-fluoro-nicotinic acid is provided.
Technical scheme of the present invention:
The present invention with conventional, be easy to get 2,6-two chloro-5-fluoro-nicotinic acid are raw material, slough 2 earlier by catalytic hydrogenation method, two chlorine atoms on the 6-two chloro-5-fluoro-nicotinic acid, and then the nitrogen oxidation, the nitrogen oxidation 5-fluoro-nicotinic acid that obtains obtains 2-chloro-5-fluoro-nicotinic acid after handling with chlorizating agent.
Concrete synthesis technique of the present invention is as follows:
In above-mentioned technological process, we adopt the method for direct catalytic hydrogenation to 2, and 6-two chloro-5-fluoro-nicotinic acid are sloughed two chlorine.Auxiliary addition agent is selected triethylamine for use.Catalyzer adopts conventional hydrogenation catalyst, and as Raney's nickel, palladium carbon etc., the reaction consumption is 1～10% (W/W) of reaction substrate, and solvent is an ethanol, methyl alcohol, ethyl acetate etc.; Reaction pressure is a 1-10 normal atmosphere, and optimal pressure range is between 1～5 normal atmosphere; Temperature of reaction is a normal temperature to 100 ℃, and optimum temps is 20～50 ℃.
In 5-fluoro-nicotinic acid nitrogen oxidising process, we select oxygenant commonly used, that be easy to get for use, as hydrogen peroxide, and Peracetic Acid, peroxidation m-chlorobenzoic acid etc., the nitrogen oxidation solvent is acetic acid, methylene dichloride etc., temperature is a normal temperature to 120 ℃.
Then, nitrogen oxidation 5-fluoro-nicotinic acid is carried out the selectivity chlorination, chlorizating agent adopts phosphorus oxychloride, reagent such as phosphorus pentachloride, and temperature of reaction is 50-120 ℃.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally; it has adopted and has been easy to get, the raw material 1 of energy large-scale production; 6-two chloro-5-fluoro-nicotinic acid through dechlorination, nitrogen oxidation more optionally chloro get 2-chloro-5-fluoro-nicotinic acid; its overall yield reaches 50～60%; and all intermediates can be purified by recrystallization, therefore can carry out industrialized production on a large scale.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
Synthetic (the POCl of 2-chloro-5-fluoro-nicotinic acid
3, 50 ℃, 12h)
The first step: 5-fluoro-nicotinic acid synthetic
2, (100g, (101.0g, 1.0mol) and 5% palladium-carbon catalyst (4g), hydrogenation is 12 hours under 3 normal atmosphere, room temperature to add triethylamine in ethanol solution 0.476mol) (2.4L) for 6-two chloro-5-fluoro-nicotinic acid.Remove by filter catalyzer, concentrate, product (66.2g, 0.468mol), productive rate: 98%.
1H?NMR(400MHz，DMSO-d
6)：68.91(s，1H)，8.81(d，J＝2.8Hz，1H)，8.09(dd，J＝8.8&2.8Hz，1H)；Ms(M
++1，142)。
Second step: nitrogen oxidation-5-fluoro-nicotinic acid synthetic
(50g 0.36mol) is dissolved in (500mL) in the Glacial acetic acid to 5-fluoro-nicotinic acid, adds 30%H
2O
2(74mL 0.72mol), is heated to 100 ℃, and reaction is spent the night, the pressure reducing and steaming Glacial acetic acid, the washing, product (53g, 0.34mol), productive rate: 95%.
1H?NMR(400MHz，DMSO-d
6)：δ?8.75(d，J＝2.8Hz，1H)，8.37(s，1H)，7.68(dd，J＝8.4&2.8Hz，1H)；Ms(M
++1，158)。
The 3rd step: the synthetic (POCl of 2-chloro-5-fluoro-nicotinic acid
3, 50 ℃, 12h)
(10g 63.7mmol) is dissolved in POCl to nitrogen oxidation-5-fluoro-nicotinic acid
3(70mL), be heated to 50 ℃, stir 12h, pressure reducing and steaming POCl
3, add trash ice, stir, separate out light brown solid, filter, crude product (11g), the water as solvent recrystallization, pure product (6.4g, 36.5mmol), productive rate: 57%.
1H?NMR(400MHz，DMSO-d
6)：δ8.60(d，J＝2.8Hz，1H)，8.18(dd，J＝8.4?&?2.8Hz，1H)；Ms(M
++1，176,178)。
Embodiment 2
Synthesizing of 2-chloro-5-fluoro-nicotinic acid
2, (50g, (50.5g, 0.5mol) and Raney's nickel catalyst (5g), hydrogenation is 12 hours under 5 normal atmosphere, room temperature to add triethylamine in ethanol solution 0.238mol) (1.2L) for 6-two chloro-5-fluoro-nicotinic acid.Remove by filter catalyzer, concentrate, product (32.8g, 0.232mol), productive rate: 97%.
In the process of preparation 2-chloro-5-fluoro-nicotinic acid, prepare corresponding product according to second step, the 3rd described nitrogen oxidation of step and chloro processing condition and operation steps in the above-mentioned example 1, its test data is shown in above-mentioned example 1.
Embodiment 3
Synthetic (the POCl of 2-chloro-5-fluoro-nicotinic acid
3+ PCl
5, 70 ℃, 12h)
According to the first step, described reaction conditions of second step and working method in the above-mentioned example 1, prepare nitrogen oxidation-5-fluoro-nicotinic acid intermediate.Then, (10g 63.7mmol) is dissolved in POCl with nitrogen oxidation-5-fluoro-nicotinic acid
3(50mL), under the ice bath, add PCl
5, (20g) be heated to 50 ℃, stir 12h, pressure reducing and steaming POCl
3, add the 50g trash ice, stir, separate out light brown solid, filter, crude product 11g, the water recrystallization, pure product (6.7g, 38.2mmol), productive rate: 60%.
Embodiment 4
Synthetic (the POCl of 2-chloro-5-fluoro-nicotinic acid
3, 110 ℃, 5h)
According to the first step, described reaction conditions of second step and working method in the above-mentioned example 1, prepare nitrogen oxidation-5-fluoro-nicotinic acid intermediate.Then, (10g 63.7mmol) is dissolved in POCl with nitrogen oxidation-5-fluoro-nicotinic acid
3(70mL), stir, be heated to backflow 5h, pressure reducing and steaming POCl
3, add trash ice, stir, separate out light brown solid, filter, crude product (10.5g), the water recrystallization, pure product (6.7g, 38.2mmol), productive rate: 60%
Embodiment 5
Synthetic (the POCl of 2-chloro-5-fluoro-nicotinic acid
3+ PCl
5, 110 ℃, 5h)
According to the first step, described reaction conditions of second step and working method in the above-mentioned example 1, prepare nitrogen oxidation-5-fluoro-nicotinic acid intermediate.Then, (10g 63.7mmol) is dissolved in POCl with nitrogen oxidation-5-fluoro-nicotinic acid
3(70mL), stirring and dissolving adds PCl in batches under the ice bath
5(15g), be heated to backflow 5h, add trash ice, stir, separate out light brown solid, filter, crude product (11g), the water as solvent recrystallization, pure product (7.5g, 42.7mmol), productive rate: 67%.
Embodiment 6
Synthetic (the POCl of 2-chloro-5-fluoro-nicotinic acid
3+ PCl
5, 110 ℃, 5h, large scale)
According to the first step, described reaction conditions of second step and working method in the above-mentioned example 1, prepare nitrogen oxidation-5-fluoro-nicotinic acid intermediate.Then, (500g 3.18mol) is dissolved in POCl with nitrogen oxidation-5-fluoro-nicotinic acid
3(2000mL), stirring and dissolving adds PCl in batches under the ice bath
5(700g), be heated to backflow 5h, pressure reducing and steaming POCl
3, add trash ice, stir, separate out light brown solid, filter, crude product (545g), the water recrystallization, pure product (362g, 2.06mol), productive rate: 65%.
Embodiment 7
Synthesizing of 2-chloro-5-fluoro-nicotinic acid
2, catalyzer is a Raney's nickel in the 6-two chloro-5-fluoro-nicotinic acid catalytic hydrogenations, and consumption is 8.0 grams, and solvent is selected ethyl acetate for use, and reaction pressure is 7 normal atmosphere, and temperature of reaction is 60 ℃; In 5-fluoro-nicotinic acid nitrogen oxidising process, oxygenant is selected Peracetic Acid for use, and reaction solvent is a methylene dichloride, and temperature of reaction is 60 ℃; Then, nitrogen oxidation 5-fluoro-nicotinic acid is carried out the selectivity chlorination, chlorizating agent adopts phosphorus pentachloride, and temperature of reaction is 80 ℃, and all the other are identical with embodiment 1.
Embodiment 8
Synthesizing of 2-chloro-5-fluoro-nicotinic acid
2, reaction solvent is selected methyl alcohol for use in the 6-two chloro-5-fluoro-nicotinic acid catalytic hydrogenations, and reaction pressure is 4 normal atmosphere, and temperature of reaction is 40 ℃; In 5-fluoro-nicotinic acid nitrogen oxidising process, oxygenant is selected the peroxidation m-chlorobenzoic acid for use, and reaction solvent is a methylene dichloride, and temperature of reaction is 80 ℃; Then, nitrogen oxidation 5-fluoro-nicotinic acid is carried out the selectivity chlorination, temperature of reaction is 60 ℃, and all the other are identical with embodiment 1.
Claims (3)
1, the industrialized process for preparing of 2-chloro-5-fluoro-nicotinic acid, it is characterized in that, with conventional, be easy to get 2,6-two chloro-5-fluoro-nicotinic acid are raw material, earlier directly slough 2 by catalytic hydrogenation, two chlorine atoms on the 6-two chloro-5-fluoro-nicotinic acid, in the reaction of catalytic hydrogenation, add the auxiliary agent triethylamine, catalyzer adopts a kind of in Raney's nickel, the palladium carbon, catalyst levels is 1～10% of a reaction substrate weight, solvent is a kind of in ethanol, methyl alcohol, the ethyl acetate, and reaction pressure is 1～10 normal atmosphere, and temperature of reaction is a normal temperature to 100 ℃; The nitrogen oxidation 5-fluoro-nicotinic acid that obtains through the nitrogen oxidation then, the oxygenant of the nitrogen oxidation of 5-fluoro-nicotinic acid is a kind of in hydrogen peroxide, Peracetic Acid, the peroxidation m-chlorobenzoic acid, the nitrogen oxidation solvent is a kind of in acetic acid, the methylene dichloride, and temperature is a normal temperature to 120 ℃; Obtain 2-chloro-5-fluoro-nicotinic acid after using chlorizating agent to handle at last, chlorizating agent is one or both in phosphorus oxychloride, the phosphorus pentachloride, and temperature of reaction is 50～120 ℃.
2, the industrialized process for preparing of 2-chloro-5-fluoro-nicotinic acid according to claim 1 is characterized in that pressure range is at the 1-5 normal atmosphere in catalytic hydrogenation.
3, the industrialized process for preparing of 2-chloro-5-fluoro-nicotinic acid according to claim 1 is characterized in that temperature of reaction is 20～50 ℃ in catalytic hydrogenation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101091993A CN100355733C (en) | 2003-12-09 | 2003-12-09 | Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd |
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|---|---|
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| CN100355733C true CN100355733C (en) | 2007-12-19 |
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| CN101768111B (en) * | 2009-01-07 | 2012-12-26 | 上海开拓者化学研究管理有限公司 | Method for preparing 2-chloro-5-fluoropyridine-3-benzoic acid |
| CN101768110B (en) * | 2009-01-07 | 2012-09-12 | 上海开拓者化学研究管理有限公司 | Method for preparing 2-chloro-5-fluoropyridine-3-benzoic acid |
| CN105461621A (en) * | 2015-12-24 | 2016-04-06 | 浙江埃森化学有限公司 | Method for preparing pyridine-2-formic acid by hydrogenation reduction of poly chloro pyridine-2-formic acid mixture |
| CN105777638B (en) * | 2016-01-06 | 2019-07-30 | 北京修正创新药物研究院有限公司 | The preparation method of lorcaserin impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250548A (en) * | 1990-09-10 | 1993-10-05 | Abbott Laboratories | Angiotensin II receptor antagonists |
| CN1100262A (en) * | 1993-07-13 | 1995-03-22 | 罗纳-普朗克农业有限公司 | New herbicides |
-
2003
- 2003-12-09 CN CNB2003101091993A patent/CN100355733C/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250548A (en) * | 1990-09-10 | 1993-10-05 | Abbott Laboratories | Angiotensin II receptor antagonists |
| CN1100262A (en) * | 1993-07-13 | 1995-03-22 | 罗纳-普朗克农业有限公司 | New herbicides |
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