[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN100355733C - Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd - Google Patents

Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd Download PDF

Info

Publication number
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
Authority
CN
China
Prior art keywords
fluoro
nicotinic acid
chloro
reaction
temperature
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CNB2003101091993A
Other languages
Chinese (zh)
Other versions
CN1626519A (en
Inventor
施峰
施一峰
马汝建
唐苏翰
李革
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changzhou Hequan Pharmaceutical Co ltd
Original Assignee
Yaomingkangde New Medicine Development Co Ltd Wuxi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yaomingkangde New Medicine Development Co Ltd Wuxi filed Critical Yaomingkangde New Medicine Development Co Ltd Wuxi
Priority to CNB2003101091993A priority Critical patent/CN100355733C/en
Publication of CN1626519A publication Critical patent/CN1626519A/en
Application granted granted Critical
Publication of CN100355733C publication Critical patent/CN100355733C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

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

The industrialized process for preparing of 2-chloro-5-fluoro-nicotinic acid
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:
Figure C20031010919900031
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):
Figure C20031010919900041
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.
CNB2003101091993A 2003-12-09 2003-12-09 Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd Expired - Lifetime CN100355733C (en)

Priority Applications (1)

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

Applications Claiming Priority (1)

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

Publications (2)

Publication Number Publication Date
CN1626519A CN1626519A (en) 2005-06-15
CN100355733C true CN100355733C (en) 2007-12-19

Family

ID=34758872

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB2003101091993A Expired - Lifetime CN100355733C (en) 2003-12-09 2003-12-09 Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd

Country Status (1)

Country Link
CN (1) CN100355733C (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
CN1626519A (en) 2005-06-15

Similar Documents

Publication Publication Date Title
CN100355732C (en) Preparation of 2-Cl-5-F-nicotinate and nicotonic acid
EP3712130B1 (en) Method for synthesis of roxadustat and intermediate compounds thereof
CN102627573B (en) Synthesis method for 5-aminolevulinic acid hydrochloride
CN104144914B (en) For the preparation of the method for 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid methoxy-[1-methyl-2-phenyl-ethyl group]-acid amides of phenyl-replacement
CN110950765A (en) Preparation method of terbutaline sulfate
CN100355733C (en) Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd
CN111320548B (en) Synthesis method of anticancer drug intermediate 2-fluoro-3-methyl aminobenzoate
JP4872668B2 (en) Process for producing 2-amino-5-iodobenzoic acid
EP1182184B1 (en) Process for producing tetrafluoro benzenecarbaldehydes and tetrafluoro benzenemethanols
CN113024384A (en) Synthesis method of 2-fluoro-3-nitrobenzoic acid intermediate raw material
EP2079674B1 (en) Process for the preparation of trifluoroethoxytoluenes
CN108752186B (en) Preparation method of 2-benzyl-5-trifluoromethylbenzoic acid
CN112939814B (en) Preparation method of deuterated dacarbazine intermediate
CN110734368A (en) Preparation method of buparvaquone
CN114751836A (en) Method for synthesizing 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline and intermediate thereof
CN115945215B (en) Sodium lignin sulfonate quaternary ammonium salt supported phosphotungstic acid catalyst, preparation method thereof and application of oxidized oleic acid in preparation of azelaic acid
CN109678741B (en) Preparation method of 4-amino-3-fluorobenzoic acid
CN111100042A (en) Preparation method of 2-methoxy-5-sulfonamide benzoic acid
CN114702408B (en) Preparation method and application of clenbuterol impurity
CN110423211A (en) A kind of preparation method for being adapted to industrialized production of 4- oxyindole
US20040242942A1 (en) Process for producing 2,5-bis(trifluoromethyl)nitrobenzene
CN117105862A (en) Preparation method of roflumilast and intermediate thereof
CN114262293A (en) Preparation method of 2-amino-3-bromopyridine
CN110240545B (en) Preparation method of 2- (5-fluoro-2, 4-dinitrophenoxy) acetic acid
JP4956760B2 (en) Method for producing 3-bromobenzoic acid or alkyl ester thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD.

Free format text: FORMER OWNER: YAOMINGKANGDE NEW MEDICINE DEVELOPMENT CO., LTD., WUXI

Effective date: 20141114

C41 Transfer of patent application or patent right or utility model
COR Change of bibliographic data

Free format text: CORRECT: ADDRESS; FROM: 200131 PUDONG NEW AREA, SHANGHAI TO: 213034 CHANGZHOU, JIANGSU PROVINCE

TR01 Transfer of patent right

Effective date of registration: 20141114

Address after: 213034 Jiangsu province Changzhou Chunjiang town Xinbei Baizhang Street

Patentee after: CHANGZHOU HEQUAN PHARMACEUTICAL Co.,Ltd.

Address before: 200131 Shanghai Waigaoqiao Free Trade Zone No. 253 Building No. 4 Aidoulu A site

Patentee before: Wuxi AppTec Co.,Ltd.

CX01 Expiry of patent term
CX01 Expiry of patent term

Granted publication date: 20071219