2-chloronicotinic acid

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Structural formula
Structural formula of 2-chloronicotinic acid
General
Surname 2-chloronicotinic acid
other names
  • 2-chloropyridine-3-carboxylic acid
  • 2-CNA
Molecular formula C 6 H 4 ClNO 2
Brief description

white to beige powdery solid

External identifiers / databases
CAS number 2942-59-8
EC number 220-937-0
ECHA InfoCard 100.019.034
PubChem 76258
ChemSpider 68737
Wikidata Q27271592
properties
Molar mass 157.55 g mol −1
Physical state

firmly

Melting point
  • 176–178 ° C (decomposition)
  • 181 ° C (decomposition)
solubility
  • hardly soluble in water (0.17 g / 100 g at 20 ° C)
  • soluble in methanol
safety instructions
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 315-319-335
P: 302 + 352-305 + 351 + 338
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

2-chloronicotinic acid is a derivative of pyridine-3-carboxylic acid ( nicotinic acid ). The chlorine atom (–Cl) - substituent in the 2-position - can easily be displaced by nucleophilic aromatic substitution of anionic or neutral nucleophiles . 2-chloronicotinic acid is an intermediate for pharmaceutical and agrochemical active ingredients , including the HIV - drug nevirapine or fungicide boscalid .

Occurrence and representation

The considerable need for 2-chloronicotinic acid has resulted in a large number of synthesis variants which, however, often only contain unsatisfactory yields of pure product, reactants which are unpleasant to handle and complicated by-product streams to be treated.

An example is the route via nicotinic acid amide-N-oxide, which is easily accessible from the nicotinic acid amide available in larger quantities by oxidation with 30% hydrogen peroxide in 73 to 82% yield, which is produced with a mixture of phosphorus pentachloride PCl 5 and phosphorus oxychloride POCl 3 in 52 % yield or (more realistic) 35 to 39% yield is converted into the 2-chloronicotinonitrile. The substituted pyridine- N -oxide is reduced to the pyridine derivative in the reaction with phosphorus trichloride (or thionyl chloride ).

This also creates u. a. 6-chloronicotinamide, which is difficult to remove, in considerable quantities. During the acid hydrolysis of the nitrile to the carboxylic acid , the undesired by-product 2-hydroxynicotinic acid is formed. [The gentle amide hydrolysis with amidases that has been developed in recent years completely avoids this by-product.] In addition, larger amounts of phosphate-containing waste water are produced during processing.

Synthesis of 2-chloronicotinic acid from nicotinamide

The route starting from nicotinic acid is more productive , which is oxidized to the N- oxide with 80% yield and, on halogenation with POCl 3 in the presence of triethylamine, gives 2-CNA in 65% yield after hydrolysis.

Synthesis of 2-chloronicotinic acid from nicotinic acid

The patent literature describes a process variant in which the product 2-CNA still containing 6-chloronicotinic acid is converted by recrystallization from methanol / water 1: 1 into pure 2-chloronicotinic acid in a total yield of 45-50%.

The synthesis starting from 3-cyano-2-pyridone, which is hydrolyzed under alkaline conditions and, after acidification, converted into 2-hydroxynicotinic acid, which is reacted with phosphorus oxychloride to form 2-chloronicotinic acid chloride and which is then hydrolyzed to the end product 2-chloronicotinic acid, is laborious and due to lack of information rather uneconomical to the yields of the process stages.

Synthesis of 2-chloronicotinic acid via 3-cyano-2-pyridone

The disadvantages of the synthesis variants based on pyridine precursors gave rise to the search for alternatives in which intermediate products formed from acyclic precursors are cyclized to 2-chloronicotinic acid derivatives.

One approach is the use of acrolein , ethyl cyanoacetate and ethyl 2-dichlorocyanoacetate, which react with potassium carbonate in 77% yield after 72 hours of reaction time to form an ethyl 2-chloro-2-cyano-5-oxo-pentanoate which reacts with POCl 3 / DMF in 65% yield is regioselectively cyclodehydrated to ethyl 2-chloronicotinate, which still has to be hydrolyzed to give 2-chloronicotinic acid.

Synthesis of 2-chloronicotinic acid from acrolein + cyanoacetic esters

Despite inexpensive starting materials, the reaction offers no economic advantages because of unreasonably long reaction times, the accumulation of undesired by-products and an overall yield below 50%.

A more suitable starting material is the unstable malondialdehyde in the blocked form of 3-dimethylaminoacrolein (by addition of dimethylamine to propargyl alcohol ) or preferably from the Vilsmeier salt of dimethylformamide , phosgene and vinyl isobutyl ether , which with sodium hydroxide solution gives 3-dimethylaminoacrolein in 86% yield.

In a Knoevenagel reaction , 3- (dimethylamino) acrolein reacts with ethyl cyanoacetate in the presence of glacial acetic acid and piperidine with elimination of water in 91% yield to give 1-cyano-5-dimethylamino-penta-1,3-dienoate (1-cyano-4- dimethylamino-1-ethoxycarbonyl-1,3-butadiene), which by introducing hydrogen chloride in 88% yield to 2-chloronicotinic acid ethyl ester, which can be hydrolyzed practically quantitatively to 2-chloronicotinic acid.

Synthesis of 2-chloronicotinic acid with 3-dimethylaminoacrolein

The reaction can also be carried out as a one-pot reaction with slight losses in yield.

The use of the non-polar cyanoacetic acid n-butyl ester instead of the ethyl ester is said to represent an improvement in the process. In the one-pot variant, a yield of 80% is achieved. 2-chloronicotinic acid is obtained practically quantitatively by alkaline hydrolysis of the n- butyl ester.

properties

2-chloronicotinic acid is a white to off-white crystal powder. The substance is only slightly soluble in water, but readily soluble in methanol.

Applications

The chlorine atom in position 2 is easily displaced by nucleophiles. For example, 2-chloronicotinic acid reacts with amines of different constitution in the presence of diisopropylethylamine in water under microwave irradiation in yields of 47–83% to give the corresponding 2-aminonicotinic acid derivatives.

Synthesis of 2-aminonicotinic acid derivatives

To produce the non-steroidal anti-inflammatory drug nifluminic acid , 2-chloronicotinic acid is reacted with 3-trifluoromethylaniline .

Synthesis of the anti-inflammatory drug nifluminic acid

Morniflumate as a prodrug of niflumic acid with better gastrointestinal tolerance is obtained in the reaction of 2-chloronicotinic acid methyl ester (obtained from 2-chloronicotinic acid chloride from 2-CNA) with 3-trifluoromethylaniline in the presence of zinc oxide and iodine and subsequent transesterification with 4- (2-hydroxyethyl) receive.

Synthesis of the nifluminic acid prodrug morniflumate

The nicotinic acid derivative flunixin , which is approved as a non-opioid analgesic in veterinary medicine, is formed when 2-chloronicotinic acid reacts with 2-methyl-3-trifluoromethylaniline.

Synthesis of the analgesic flunixin

The herbicide diflufenican is accessible by reacting 2-chloronicotinic acid with 3-trifluoromethylphenol to form 2- (3-trifluoromethylphenoxy) nicotinic acid, reacting it with thionyl chloride to form the acid chloride and reacting it with 2,4-difluoroaniline.

Synthesis of the herbicide diflufenican

Another herbicide derived from 2-chloronicotinic acid is nicosulfuron , which is prepared in a multi-stage synthesis via the 2-aminosulfonyl-N, N-dimethylnicotinamide.

Synthesis of the herbicide nicosulfuron

The antiviral agent nevirapine as the first approved representative of the non-nucleosidic reverse transcriptase inhibitors is based on the conversion of 2-chloronicotinic acid chloride with 2-chloro-3-amino-4-picoline, the nucleophilic substitution of the chlorine atom in the picoline part of the molecule by cyclopropylamine and subsequent ring closure with sodium hydride .

Synthesis of the anti-HIV drug nevirapine

The low overall yield of 25% prompted further process improvements, such as B. the use of 2-chloronicotinonitrile instead of 2-chloronicotinic acid.

The most important derivative of 2-chloronicotinic acid, at least in terms of quantity, is the fungicide boscalid , which is also the largest industrial application of the Suzuki coupling in the reaction of 2-nitrochlorobenzene with 4-chlorophenylboronic acid in the presence of palladium (II) acetate and triphenylphosphine (synthetic route A) represents. In the last stage, the 2- (4'-chlorophenyl) aniline obtained is reacted with the acid chloride of 2-chloronicotinic acid to form the end product.

Synthesis of the fungicide boscalid

The decarboxylative aryl coupling with the potassium salt of 2-nitrobenzoic acid and 4-bromo-chlorobenzene (synthesis route B) also provides the important intermediate 2-nitro-4'-chlorobiphenyl.

Individual evidence

  1. ↑ a b Data sheet 2-chloronicotinic acid from AlfaAesar, accessed on May 25, 2017 ( PDF )(JavaScript required) .
  2. ↑ a b c d Data sheet 2-chloronicotinic acid for synthesis (PDF) from Merck , accessed on May 25, 2017.
  3. ↑ a b Entry on 2-Chloronicotinic Acid at TCI Europe, accessed on May 25, 2017.
  4. ↑ EC Taylor, AJ Crovetti: Nicotinamide-1-oxide In: Organic Syntheses . 37, 1957, p. 63, doi : 10.15227 / orgsyn.037.0063 ; Coll. Vol. 4, 1963, p. 704 ( PDF ).
  5. ↑ EC Taylor, AJ Crovetti: Pyridine-1-oxides. I. Synthesis of some nicotinic acid derivatives . In: J. Org. Chem. Band 19 , no. 10 , 1954, pp. 1633-1640 , doi : 10.1021 / jo01375a012 .
  6. ↑ EC Taylor, AJ Crovetti: 2-Chloronicotinonitrile In: Organic Synthesis . 37, 1957, p. 12, doi : 10.15227 / orgsyn.037.0012 ; Coll. Vol. 4, 1963, p. 166 ( PDF ).
  7. ↑ H. v. Euler, H. Hasselquist, O. Heidenberger: On the knowledge of the N-oxides . In: Chem. Ber. tape 92 , no. 9 , 1959, pp. 2266-2270 , doi : 10.1002 / cber.19590920944 .
  8. ↑ L.-Q. Jin et al .: Efficient biocatalytic hydrolysis of 2-chloronicotinic amide for production of 2-chloronicotinic acid by recombinant amidase . In: Catal. Commun. tape 38 , 2013, p. 6–9 , doi : 10.1016 / j.catcom.2013.04.004 .
  9. ↑ E. Kretzschmar: About derivatives of 4-oxo-3,4-dihydropyrido [2,3-d] pyrimidine . In: Pharmacy . tape 35 , no. 5-6 , 1980, pp. 253-256 .
  10. ↑ Patent US4144238 : Process for the preparation of pure white 2-chloronicotinic acid. Applied on April 4, 1977 , published March 13, 1979 , applicant: Lonza, Ltd., inventor: A. Said. ‌
  11. ↑ Patent US4081451 : Process for preparing 2-halogeno nicotinic acids. Applied on April 4, 1977 , published March 28, 1978 , applicant: Schering Corp., inventor: J. Mayer. ‌
  12. ↑ TY Zhang, JR Stout, JG Keay, EFV Scriven, JE Toomey, GL Goe: Regioselective synthesis of 2-chloro-3-pyridinecarboxylates . In: Tetrahedron . tape 51 , no. 48 , 1995, pp. 13177-13184 , doi : 10.1016 / 0040-4020 (95) 00788-A .
  13. ↑ Patent DE944852 : Process for the preparation of derivatives of 3-amino-acrolein. Registered on June 7, 1956 , published on November 30, 1949 , applicant: Badische Anilin- & Soda-Fabrik AG, inventor: F. Wille. ‌
  14. ↑ Patent DE19825200C1 : Process for the production of 3-aminoacrolein derivatives. Registered on June 5, 1998 , published on November 18, 1999 , applicant: BASF AG, inventor: D. Grolsch, M. Keil, H. Isak. ‌
  15. ↑ Patent US4987232 : Preparation of 2-chloropyridine 3-carboxylic acid esters. Applied on December 5, 1989 , published on January 22, 1991 , applicant: Shell Internationale Research Maatschappij, BV, inventor: L. Schröder. ‌
  16. ↑ Patent WO2000007989A1 : Process for the production of 2-halonicotinic acid derivatives and 2-chloronicotinic acid n-butyl ester as an intermediate. Registered on July 14, 1999 , published on February 17, 2000 , applicant: BASF AG, inventor: D. Grolsch, M. Keil, H. Isak, H. Mayer. ‌
  17. ↑ CE Quevedo, V. Bavetsias, E. McDonald: Microwave-assisted synthesis of 2-aminonicotinic acids by reacting 2-chloronicotinic acid with amines . In: Tetrahedron Lett. tape 50 , no. 21 , 2009, p. 2481-2483 , doi : 10.1016 / j.tetlet.2009.03.034 .
  18. ↑ Patent US3415834 : Derivatives of 2-anilino nicotinic acid and process for their preparation. Applied December 15, 1964 , published December 10, 1968 , Applicant: Laboratoire UPSA, Inventor: C. Hoffmann, A. Faure. ‌
  19. ↑ G. Cremonesi, L. Cavalieri: Efficacy and safety of morniflumate for the treatment of symptoms associated with soft tissue inflammation . In: J. Int. Med. Res. Band 43 , no. 3 , 2015, p. 290-302 , doi : 10.1177 / 030006054567212 .
  20. ↑ Patent EP0349902A2 : Processes for the preparation of morniflumate and analogous compounds. Applied on June 29, 1989 , published January 10, 1990 , Applicants: Chiesi Farmaceutici SpA, Inventors: P. Chiesi, V. Servadio, R. Pighi. ‌
  21. ↑ Patent US5484931 : Process for preparing flunixin and intermediates thereof. Filed June 15, 1994 , published January 16, 1996 , Applicant: Schering Corp., Inventor: HJ Doran, DJ Coveney. ‌
  22. ↑ Patent US4618366 : Certain N- (2,4-difluorophenyl) -2- (3-trifluoromethylphenoxy) nicotinamides having herbicidal activity. Applied June 15, 1984 , published October 21, 1986 , Applicant: May & Baker Ltd., Inventor: MC Cramp, J. Gilmour, EW Parnell. ‌
  23. ↑ Patent EP0232067B2 : Substituted pyridinesulfonamide compounds, herbicidal composition containing them, and method of preparing these compounds. Applied January 21, 1987 , published March 16, 1994 , Applicants: Ishihara Sangkyo Kaisha Ltd., Inventors: F. Kimura, T. Haga, N. Sakashita, C. Honda, S. Murai. ‌
  24. ↑ Patent US5366972 : 5,11-Dihydro-6H-dipyrido (3,2-B: 2 ', 3'-E) (1,4) diazepines and their use in the prevention or treatment of HIV infection. Filed on July 13, 1993 , published on November 22, 1994 , Applicant: Boehringer Ingelheim Pharmaceuticals, Inc., inventors KD Hargraves et al
  25. ↑ Patent US6680383B1 : Method for making nevirapine. Filed June 5, 2003 , published January 20, 2004 , Applicant: Boehringer Ingelheim Chemicals, Inc., Inventors: RF Boswell, BF Gupton, YS Lo. ‌
  26. ↑ Patent WO2016118586A1 : Low cost, high yield synthesis of nevirapine. Filed January 20, 2016 , published July 28, 2016 , Applicant: Virginia Commonwealth University, Inventor: S. Ahmad, F. Gupton, J. Vergheses, T. McQuade. ‌
  27. ↑ Patent WO199733846 : Process for the production of nitrobiphenyls. Registered on March 6, 1997 , published on September 18, 1999 , applicant: BASF AG, inventors: K. Eicken, J. Gebhardt, H. Rang, M. Rack, P. Schäfer. ‌
  28. ↑ Patent US7241896B2 : Method for producing 2-halogen-pyridine-carboxylic acid amides. Registered on October 31, 2002 , published on July 10, 2007 , applicant: BASF AG, inventor: H. Mayer, D. Golsch, H. Isak, J. Schröder. ‌
  29. ↑ LJ Goossen, N. Rodriguez: Decarboxylative Biaryl Synthesis from Carboxylic Acids and Aryl Halides . Science Forum Chemistry Ulm 2007 ( Online [PDF]).