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US-12624006-B2 - Process for the preparation of 5-(1-cyanocyclopropyl)-pyridine-2-carboxylic acid esters amides and nitriles

US12624006B2US 12624006 B2US12624006 B2US 12624006B2US-12624006-B2

Abstract

A process for the preparation of compound of formula I is provided: Formula (I) where R 1 and R 2 are as defined in the description.

Inventors

  • Raphael Dumeunier
  • Renaud Beaudegnies
  • Martin Pouliot
  • Alexander GASPERS

Assignees

  • SYNGENTA CROP PROTECTION AG

Dates

Publication Date
20260512
Application Date
20211008
Priority Date
20201009

Claims (20)

  1. 1 . A process for the preparation of a compound of formula I: wherein R 1 is —CO 2 R 4 , —CO(NR 5 R 6 ), carboxylate or cyano; R 2 is hydrogen, halogen or —SR 3 ; R 3 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl; R 4 is hydrogen, —Si(CH 3 ) 3 or C 1 -C 6 alkyl; and R 5 and R 6 are, independently from each other, hydrogen or C 1 -C 4 alkyl, or an agrochemically acceptable salt of a compound of formula I; the process comprises: reacting a compound of formula (III) wherein R 1 and R 2 are defined as under formula I above and Hal is a halogen; with a compound of formula (IV), in the presence of a suitable base, in an appropriate solvent or a diluent; to produce a compound of formula (I) or an agrochemically acceptable salt thereof.
  2. 2 . The process according to claim 1 , wherein R 1 is —CO 2 R 4 , —CONH 2 , carboxylate or a cyano group; and R 4 is hydrogen, —Si(CH 3 ) 3 , methyl, ethyl, isopropyl, tert-butyl, or sec-butyl.
  3. 3 . The process according to claim 2 , wherein R 1 is —CO 2 H or carboxylate.
  4. 4 . The process according to claim 1 , wherein R 2 is hydrogen, chloro or —SR 3 ; wherein R 3 is ethyl.
  5. 5 . The process according to claim 4 , wherein R 2 is —S-ethyl.
  6. 6 . The process according to claim 1 , wherein Hal is chloro or bromo.
  7. 7 . The process according to claim 1 , wherein the suitable base is selected from sodium hydroxide, potassium hydroxide, sodium tertiobutanolate, and potassium tertiobutanolate.
  8. 8 . The process according to claim 1 , wherein the solvent or the diluent is selected from dimethylformamide, dimethylsulfoxide, N-methyl-pyrrolidine, dimethylacetamide, sulfolane and N,N′-dimethylpropyleneurea (DMPU).
  9. 9 . The process according to claim 1 , which is carried out in a temperature range from approximately 0° C. to approximately +100° C.
  10. 10 . The process according to claim 1 , wherein, when R 1 is a carboxylate anion, the suitable base is selected from magnesium bis(tertio-butanolate) and magnesium bis(hexamethyldisilazide).
  11. 11 . The process according to claim 1 , wherein, when R 1 is a carboxylate anion, the suitable base is selected from sodium hydroxide, potassium hydroxide, sodium tertiobutanolate, and potassium tertiobutanolate, and wherein the process further comprises addition of magnesium (II) , zinc (II) or Al (III) salts as additives following in situ formation of a compound of formula (INT I) wherein R 1 and R 2 are as defined in formula I in claim 1 .
  12. 12 . The process according to claim 11 , wherein the magnesium (II) , zinc (II) or Al (III) salts are selected from MgCl 2 , ZnCl 2 , Al(OtBu) 3 and AlCl 3 .
  13. 13 . The process according to claim 1 , wherein, when R 1 is a carboxylate anion, the suitable base is selected from sodium hydroxide, potassium hydroxide, sodium tertiobutanolate, and potassium tertiobutanolate, and wherein the process further comprises addition of trimethylsilylchloride after distillation of the water or alcohol generated during the in situ formation of a compound of formula (INT I) wherein R 1 and R 2 are as defined in formula I in claim 1 .
  14. 14 . A compound of formula (INT I) wherein R 1 is —CO 2 R 4 , —CO(NR 5 R 6 ) or cyano; R 2 is hydrogen, halogen or —SR 3 ; R 3 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl; R 4 is hydrogen, —Si(CH 3 ) 3 or C 1 -C 6 alkyl; and R 5 and R 6 are, independently from each other, hydrogen or C 1 -C 4 alkyl; or an agrochemically acceptable salt of a compound of formula INT I.
  15. 15 . A compound of formula (INT II) wherein R 1 is —CO 2 R 4 , —CO(NR 5 R 6 ) or cyano; R 2 is hydrogen, halogen or —SR 3 ; R 3 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl; R 4 is hydrogen, —Si(CH 3 ) 3 or C 1 -C 6 alkyl; and R 5 and R 6 are, independently from each other, hydrogen or C 1 -C 4 alkyl; or an agrochemically acceptable salt of a compound of formula INT II.
  16. 16 . A compound of formula (INT III) wherein R 1 is —CO 2 R 4 , —CO(NR 5 R 6 ) or cyano; R 2 is hydrogen, halogen or —SR 3 ; R 3 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl; R 4 is hydrogen, —Si(CH 3 ) 3 or C 1 -C 6 alkyl; and R 5 and R 6 are, independently from each other, hydrogen or C 1 -C 4 alkyl; or an agrochemically acceptable salt of a compound of formula INT III.
  17. 17 . A compound according to claim 14 , wherein R 1 is —CO 2 R 4 , —CONH 2 or cyano; wherein R 4 is hydrogen, —Si(CH 3 ) 3 , methyl, ethyl, isopropyl, tert-butyl, or sec-butyl; and R 2 is hydrogen, chloro or —SR 3 ; wherein R 3 is ethyl.
  18. 18 . A compound of formula INT I according to claim 14 , selected from the group consisting of: 2-[2-[(6-cyano-5-ethylsulfanyl-3-pyridyl)sulfanyl]ethyl]propanedinitrile (example 14); methyl 5-(3,3-dicyanopropylsulfanyl)-3-ethylsulfanyl-pyridine-2-carboxylate (example 15); ethyl 5-(3,3-dicyanopropylsulfanyl)-3-ethylsulfanyl-pyridine-2-carboxylate (example 16); ethyl 3-chloro-5-(3,3-dicyanopropylsulfanyl)pyridine-2-carboxylate (example 17); 5-(3,3-dicyanopropylsulfanyl)-3-ethylsulfanyl-pyridine-2-carboxylic acid (example 18); 3-chloro-5-(3,3-dicyanopropylsulfanyl)pyridine-2-carboxylic acid (example 19); and 5-(3,3-dicyanopropylsulfanyl)-3-ethylsulfanyl-pyridine-2-carboxamide (example 20).
  19. 19 . A process for the preparation of a compound of formula I: wherein R 1 is —CO 2 R 4 , —CO(NR 5 R 6 ), carboxylate or cyano; R 2 is hydrogen, halogen or —SR 3 ; R 3 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl; R 4 is hydrogen, —Si(CH 3 ) 3 or C 1 -C 6 alkyl; and R 5 and R 6 are, independently from each other, hydrogen or C 1 -C 4 alkyl, or an agrochemically acceptable salt of a compound of formula I; the process comprises: reacting a compound of formula (INT I) wherein R 1 and R 2 are defined as under formula I above; in the presence of a suitable base, in an appropriate solvent or a diluent; to produce a compound of formula (I) or an agrochemically acceptable salt thereof.
  20. 20 . The process according to claim 1 , being carried out at a temperature from approximately +20° C. to approximately +80° C.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National Stage Application, filed under 35 U.S.C. § 371, of International Application No. PCT/EP2021/077899, filed Oct. 8, 2021, which claims priority to EP 20201119.3, filed Oct. 9, 2020, the entire contents of which are incorporated by reference herein. The present invention relates to the preparation of 5-(1-cyanocyclopropyl)-pyridine-2-carboxylic acid esters amides and nitriles that are useful as intermediates for the preparation of agrochemicals. Certain 5-(1-cyanocyclopropyl)-pyridine-2-carboxylic acids with 3-alkylsulfanyl substituents (and certain corresponding esters, amides and salts thereof) are useful intermediates for the preparation of biologically active compounds in the agrochemical industries as previously described, for example, in: WO16087265, WO16121997, WO2019059244, WO2020071304, WO2020090585 and JP2020079325. Known synthesis of 5-(1-cyanocyclopropyl)-pyridine-2-carboxylic acids with 3-alkylsulfanyl substituents involve many reaction steps. For example, a route to access the 3-ethylsulfanyl derivative have been reported from methyl 5-bromo-3-ethylsulfanyl-pyridine-2-carboxylate (in WO 2018/077565) and is shown in Scheme 1 Two routes to access alkyl 5-bromo-3-ethylsulfanyl-pyridine-2-carboxylate have been reported (route A: CN105218437; route B: US2012/0165338 or J. Org. Chem. 2009, 74, 4547-4553) and are shown in Scheme 2 (R1 is H, C1-C4alkyl, or an alkali metal ion) Such long and laborious syntheses are not suitable for preparing large amount of material due to low overall yields and large amount of waste generated. Therefore, it would be advantageous to have available a more efficient and economical route to these useful intermediates. The present invention therefore provides a process for the preparation of 5-(1-cyanocyclopropyl)-pyridine-2-carboxylic acids esters amides and nitriles of formula I or agrochemically acceptable salts thereof wherein R1 is —CO2R4, —CO(NR5R6), carboxylate or cyano; R2 is hydrogen, halogen or —SR3; R3 is C1-C4alkyl or C3-C6cycloalkyl-C1-C4alkyl; R4 is hydrogen, —Si(CH3)3 or C1-C6alkyl; and R5 and R6 are, independently from each other, hydrogen or C1-C4alkyl. In accordance with a first aspect of the present invention, the direct replacement of a halogen atom in 5-position of pyridines of formula (III), using a base and a reagent of formula (IV) yields a compound of formula (I) wherein R1 and R2 are defined as previously and Hal is halogen (Scheme 3). The compound of formula (IV) is known, commercially available and its synthesis described by Yamagata, Kenji et al in Chemical & Pharmaceutical Bulletin, 30(12), 4396-401; 1982; or by Wamhoff, Heinrich and Thiemig, Heinz Albrecht in Chemische Berichte, 118(11), 4473-85; 1985; or by Caspari, Philip et al in RSC Advances, 6(100), 98059-98065; 2016. Thus, according to another aspect of the present invention, there is provided a process for the preparation of compounds of formula I (Scheme 4): wherein R1 is —CO2R4, —CO(NR5R6), carboxylate or cyano; R2 is hydrogen, halogen or —SR3; R3 is C1-C4alkyl or C3-C6cycloalkyl-C1-C4alkyl; R4 is hydrogen, —Si(CH3)3 or C1-C6alkyl; and R5 and R6 are, independently from each other, hydrogen or C1-C4alkyl, or an agrochemically acceptable salt of a compound of formula I; which process comprises: reacting a compound of formula (III) wherein R1 and R2 are defined as under formula I above and Hal is halogen with a compound of formula (IV), in the presence of a suitable base, in an appropriate solvent (or diluent);to produce a compound of formula (I) or an agrochemically acceptable salt thereof. Another aspect of the present invention provides certain compounds of formula I represented by the compounds of formula Ia wherein R1a is —CO2R4a, —CO(NR5aR6a), carboxylate or cyano; R2a is hydrogen, halogen or —SR3a; R3a is C1-C4alkyl or C3-C6cycloalkyl-C1-C4alkyl; R4a is hydrogen, —Si(CH3)3 or C1-C6alkyl; and R5a and R6a are, independently from each other, hydrogen or C1-C4alkyl, or an agrochemically acceptable salt of a compound of formula Ia;with the proviso that the compound of formula Ia is not: selected from the group consisting of a compound of the formula Ib, Ic and Id; wherein R1b is CN or —CO2Me; wherein R1c is —CO2H, —CO2Me, —CO2Et or —CONHMe; and wherein R1d is —CO2H, —CO2Me or —CONHMe. The process of the present invention is demonstrated to be of great usefulness as it allows the synthesis of key building blocks for the preparation of agrochemicals in higher yields and with more favorable conditions with respect to previously described routes. Compounds of formula I that are prepared by the inventive process, or compounds of formula III which are used in the inventive process, that have at least one basic centre can form, for example, acid addition salts, for example with strong inorganic acids such as mineral acids, for example perchloric acid, sulfuric acid, nitric acid, nitrous acid, a phosphorus acid o