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WO1994021617A1 - Procede de preparation d'isothiazoles halogenes - Google Patents

Procede de preparation d'isothiazoles halogenes Download PDF

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Publication number
WO1994021617A1
WO1994021617A1 PCT/US1994/002667 US9402667W WO9421617A1 WO 1994021617 A1 WO1994021617 A1 WO 1994021617A1 US 9402667 W US9402667 W US 9402667W WO 9421617 A1 WO9421617 A1 WO 9421617A1
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WO
WIPO (PCT)
Prior art keywords
solvent
isothiazole
thioamide
phenyl
substituted
Prior art date
Application number
PCT/US1994/002667
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English (en)
Inventor
Hegde B. Vidyadhar
Original Assignee
Dowelanco
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 Dowelanco filed Critical Dowelanco
Priority to AU65186/94A priority Critical patent/AU6518694A/en
Publication of WO1994021617A1 publication Critical patent/WO1994021617A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the invention relates to method of making halogenated isothiazoles, by reacting a thioamide with a halogen in the presence of a solvent.
  • Isothiazoles are useful as intermediates in the manufacture of a wide variety of chemical products, including, for example pharmaceuticals, agricultural chemicals, such as herbicides, fungicides, insecticides, and the like.
  • the typical starting material is a thioamide.
  • Hydrogen peroxide is used to oxidize the thioamide to produce an isothiazole.
  • the isothiazole intermediate is then halogenated.
  • the reaction is the following:
  • R is ethyl or t-butyl.
  • Ada s et al. lOG-Heterocyclic Compounds 11410 discloses a method of preparing 5-amino-3-methylisothiazole by oxidative ring closure of ⁇ -iminothiobutyramide.
  • the ⁇ - iminothiobutyramide is treated with potassium persulfate in sodium hydroxide and water, or the ⁇ -iminothiobutyramide is treated with hydrogen peroxide and hydrochloric acid to give the ethylisothiazole.
  • lOG-Heterocyclic Compounds 1657 discloses preparation of 5-benz-amino-3- methylisothiazoles by oxidizing ⁇ -iminothioamides with hydrogen peroxide, ammonium chloride, potassium sulfate or chloramine.
  • Adams et al. lOG-Heterocyclic Compounds 1381 discloses a method of preparing 4 (or 5)-p- aminobenzosulfonamidoisothiazole by adding slowly 4 (or 5)- aminoisothiazole to NHC6H4SO2CI.
  • the present invention is related to a process for making halogenated isothiazoles, wherein a thioamide is converted directly to the isothiazole by reacting the thioamide with a halogen in a solvent.
  • the reaction results in the precipitation of the halogen salt.
  • the halogen salt can be easily separated from solution. Thus, the isolation of the desired isothiazole is simple and efficient.
  • the present invention concerns the process for preparation of making isothiazoles of the following formula(II) :
  • R 1 is H, C1-C10 branched or unbranched alkyl that may be substituted or unsubstituted, cyclo-alkyl or aralkyl, cyclohexylmethyl phenyl, substituted phenyl, phenoxy, substituted phenoxy, pyridyl, furyl or thienyl;
  • R 2 is H, C1-C10 branched or unbranched alkyl that may be substituted or unsubstituted, cyclo-alkyl or aralkyl, cyclohexylmethyl phenyl, substituted phenyl, phenoxy, or substituted phenoxy; and
  • X is Cl, Br, or I.
  • the isothiazoles described above are prepared by halogenating a thioamide of the formula below.
  • R1, R 2 and X are the same as described above.
  • C1-C10 alkyl is refers to straight or branched hydrocarbon groups with up to ten carbon atoms.
  • the alkyl may be substituted, provided that the all substituents are "sterically compatible" with each other.
  • sterically compatible is employed to designate substituent groups which are not affected by steric hindrance. Steric hindrance is defined in The
  • Sterically compatible may be further defined as reacting compounds having substituents whose physical bulk does not require confinement within volumes insufficient for the exercise of their normal behavior as discussed in Cramend Or g anic Chemistry 2nd Ed. p. 215 (1964) .
  • the invention is related to a process for making isothiazoles, wherein a thioamide is converted directly to the isothiazole by reacting the thioamide with a halogen in the presence of a solvent.
  • the reaction results in the precipitation of the halogen isothiazole salt.
  • the halogen salt can be easily separated from solution. Thus, the isolation of the desired isothiazole is simple and efficient.
  • the isothiazoles of the present invention encompasses compounds of the following formula:
  • R 1 is H, C1-C10 branched or unbranched alkyl that may be substituted or unsubstituted, cyclo-alkyl or aralkyl, cyclohexylmethyl phenyl, substituted phenyl, phenoxy, substituted phenoxy, pyridyl, furyl or thienyl;
  • R 2 is H, C1-C10 branched or unbranched alkyl that may be substituted or unsubstituted, cyclo-alkyl or aralkyl, cyclohexylmethyl phenyl, substituted phenyl, phenoxy, or substituted phenoxy; and
  • X is Cl, Br, or I.
  • R 1 is methyl, ethyl, t-butyl or phenyl
  • R 2 is preferably substituted phenyls
  • X is bromine.
  • the resulting compound is 5-amino (or substituted amino) 3-alkyl (or aryl) -4-halogenated isothiazole.
  • the resulting product is 5- amino-3-alkyl-4-bromo isothiazole.
  • the thioamide R 2 When the thioamide R 2 is substituted with hydrogen, then the thioamide can be made by reacting acetonitrile and ethyl propionate in the presence of a suitable base such as sodium hydride, triethylamine, potassium t-butoxide, sodium, or lithium diisopropylamide at a temperature of between about -78°C to about 100°C.
  • a suitable base such as sodium hydride, triethylamine, potassium t-butoxide, sodium, or lithium diisopropylamide
  • the resulting intermediate pivaloylacetonitrile or 3-oxoalkyl or aryl nitrile is further reacted with ammonium nitrate, where gaseous ammonia is bubbled through the reaction to give 3- aminoalkyl or aryl nitrile at a temperature of between about -20°C to about 50°C, preferably between about -5°C to about 25°C.
  • the 3-aminoalkyl or aryl nitrile can be further reacted, at a temperature of between about -20°C to about 50°C, with hydrogen sulfide to make the thioamide starting material.
  • R 2 is ethyl or phenyl, furyl or thienyl, to make 3-amino alkyl or aryl nitrile, ammonia is bubbled through the solution, but it is not necessary to use ammonium nitrate.
  • the ammonium nitrate is usually only used when the reaction is performed under atmospheric pressure.
  • R 2 is hydrogen
  • the resulting halogenated isothiazole many be further reacted with any of the other substituents defined as R 2 .
  • An example of further modifying the isothiazoles would be to react 5-amino-3- methyl isothiazole with phenyl or substituted phenyl chloroformate to form the corresponding carbamate, see U.S. Patent 4,196,126, which is incorporated herein by reference.
  • Another example would be to reflux 4-amino isothiazole with acetic anhydride to give an N-acyl compound, see Liebi ⁇ s Ann. Chem. (1979), p. 1534-46 which is incorporated herein by reference.
  • Still yet another example would be to reflux 5-amino-3-alkyl isothiazoles with acid chlorides to give the corresponding amide, which is further illustrated in PCT Application US92/10331, which is also incorporated by reference. Clearly using standard chemical techniques known in the art one could modify the resulting isothiazole.
  • the thioamide can be made by reacting a substituted enamine and a N-substituted thiocyanate.
  • the enamine and thiocyanate may be substituted with the substituents described as R 1 and R 2 .
  • the substituted enamine and a N-substituted thiocyanate is typically stirred in an aprotic solvent at a temperature between about -80°C to about 100°C.
  • Solvents that can be used include ether, THF, dioxane and the like. The reaction mixture is stirred between one and 24 hours, with a standard work-up following to obtain the desired thioamide.
  • the thioamide starting material such as pivaloylacetonitrile
  • the thioamide starting material is generally available for purchase from Aldrich Chemical Co. in Milwaukee, Wisconsin U.S.A..
  • examples of methods of preparation of the thioamide defined as Formula I can be found herein, see Example 1, Parts A through E.
  • the thioamide is converted to an isothiazole by oxidative-cyclization and halogenation. It is thought that this is accomplished by the nucleophilic attack on bromine by either the amino substituent closest to R! or tne thio substituent of the thioamide followed by the ring closure to isothiazole_
  • the halogenation can be accomplished with an elemental halogen directly or with BrCl, which can be generated in situ from HBr and Cl2, or other similar techniques.
  • Other halogenating agents such as sodium bromate/HBr and N-bromosuccinimide, N-chloro succinitride, N-itodo succinimide and the like may also be used.
  • the bromination could be conducted in the presence of an electrophilic aromatic substitution catalyst such as, FeCl3, in the presence a buffer such as NAOAc.
  • the halogenation is performed in the presence of a solvent which is resistant or inert to the reaction conditions.
  • a solvent which is resistant or inert to the reaction conditions.
  • a wide variety of solvents may be used, but preferably a protic solvent is employed.
  • the protic solvents that are the most preferred are methanol, ethanol, isopropanol, and n-butanol and the like. More preferably, the protic solvents are methanol and ethanol. Even more preferred are the halogenated solvents such as chloroform, carbon tetra chloride, dichloroethane and the like. Most preferably, the halogenated solvents are methylene chloride and chloroform.
  • the solvents may be mixed with water. If the solvents are mixed with water, generally the range of the ratio of polar solvent to water is between about 10:1 to about 10:4, preferably between about 10:2 to about 10:3.
  • buffers could be added to the reaction mixture.
  • the buffer will assist in maintaining the pH of the reaction and will assist the reaction in going to completion.
  • the amount of buffer is typically enough to maintain a pH between about 2 to about 5.
  • Halogenation is typically conducted below ambient temperature, preferably under agitation.
  • the temperature is between about 5°C and about -50°C, more preferably between about 0°C and about -50°C.
  • the halogen is slowly added to a mixture containing the solvent and the thioamide.
  • the weight ratio of the solvent to the thioamide is between about 5:1 to about 25:1, preferably between about 10:1 to about 15:1. More preferable, the halogen is combined with solvent as a first mixture and is added to a second mixture of solvent and thioamide.
  • the weight ratio of halogen to solvent in the first mixture is between about 1:25 to about 1:75, preferably between about 1:40 to about 1:60.
  • halogenated isothiazole preferably at least two equivalents of halogen are reacted with the thioamide.
  • the halogen and thioamide may be reacted in an amount of a one to one ratio, but the halogenated isothiazole yield will be typically between about 50 percent to about 70 percent.
  • the solvent and thioamide mixture is cooled prior to the halogen addition.
  • the halogenating agent is introduced to the solvent and thioamide at a rate that is commensurate in scope with the reaction and cooling.
  • additional reactants and/or solvent may be added.
  • additional solvent may be used, particularly in order to keep the slurry flowable.
  • the pH of the reaction is typically between about 1 to about 6, preferably between about 2 to about 3.
  • the resulting salt of the desired product may be isolated using standard filtration techniques.
  • the salt of the resulting product is basified and separated from solution with a halogenated or protic solvent.
  • the salt can be basified with ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and the like.
  • the salt is basified such that the pH is between about 8 to about 13.
  • the salt is basified so that the pH is between about 9 to about 10.
  • the preferred halogenated or protic solvents are described above.
  • R ⁇ is either ethyl or t-butyl and R 2 is hydrogen.
  • Ammonium nitrate (28.8 g, 0.36 mole) was added to solution of pivaloyl acetonitrile (90.0 g, 0.72 mole), which is available from Aldrich Chemical Co. at 1001 West Saint Paul Ave. Milwaukee, WI 53233, U.S.A., in absolute ethanol (500 mL) . Gaseous ammonia was bubbled through the reaction mixture (83°C) under reflux for 1 6.0 hours. After cooling to 25°C, water (100 mL) was added to the mixture and ethanol was evaporated under vacuum. The resulting aqueous solution was basified with 0.1 N NaOH (100 mL) and extracted with ether.
  • H2S was bubbled at a steady rate over a 5.0 min period through a solution of 3-amino-4, 4-dimethyl-2-pentene nitrile (8.0 g, 64.5 mmol) in THF (40 mL) , ethyl alcohol (30 mL) and triethylamine (2.0 mL) in a heavy wall tube and immediately sealed with a teflon plug. The sealed tube was then placed in an oven and heated at 120°C for 6.0 hours. Upon cooling and removal of solvent under vacuum, 3-amino- 4,4-dimethyl-2-pentene thioamide was obtained as thick yellow oil (10.1 g, 89%) which solidified on standing.
  • the halogenated isothiazole bromine salt was basified with ammonium hydroxide (pH of between 9 to 10) and extracted with dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated to give the halogenated isothiazole (0.315 g, 96%) as a yellow solid. The yellow solid was recrystalized from methylene chloride/hexane with a mp 68- 69°C. The analytical calculations were determined as follows:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'isothiazoles, dans lequel un thiamide est converti directement en isothiazole en faisant réagir le thioamide avec un halogène dans un solvant. La réaction provoque la précipitation du sel du dérivé halogéné. Le composé isothiazole résultant peut être représenté par la formule (II).
PCT/US1994/002667 1993-03-19 1994-03-10 Procede de preparation d'isothiazoles halogenes WO1994021617A1 (fr)

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032887A1 (fr) * 2000-10-20 2002-04-25 Syngenta Limited Procede de preparation de 5-amino-3-alkylisothiazoles et de 5-amino-4-chloro-3-alkylisothiazoles
US6403622B1 (en) 1998-10-06 2002-06-11 Bayer Aktiengesellschaft Phenylacetic acid heterocyclyl amides having an insecticidal effect
WO2003031636A1 (fr) * 2001-10-05 2003-04-17 Kaneka Corporation Procede de production de 3-hydroxy-pentanenitrile optiquement actif
US7790756B2 (en) 2006-10-11 2010-09-07 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
US8143293B2 (en) 2007-04-20 2012-03-27 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
US8163756B2 (en) 2004-12-23 2012-04-24 Deciphera Pharmaceuticals, Llc Enzyme modulators and treatments
US8188113B2 (en) 2006-09-14 2012-05-29 Deciphera Pharmaceuticals, Inc. Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US8278331B2 (en) 2008-10-29 2012-10-02 Deciphera Pharmaceuticals, Llc N-acyl ureas exhibiting anti-cancer and anti-proliferative activities
CN103889979A (zh) * 2011-09-09 2014-06-25 桑多斯股份公司 用于制备头孢洛林酯的新方法
US8940756B2 (en) 2012-06-07 2015-01-27 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11986463B2 (en) 2018-01-31 2024-05-21 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumor
US12102620B2 (en) 2018-01-31 2024-10-01 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of mastocytosis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019054A1 (fr) * 1992-03-26 1993-09-30 Dowelanco Nitro-anilines n-heterocycliques utilisees comme fongicides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019054A1 (fr) * 1992-03-26 1993-09-30 Dowelanco Nitro-anilines n-heterocycliques utilisees comme fongicides

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6403622B1 (en) 1998-10-06 2002-06-11 Bayer Aktiengesellschaft Phenylacetic acid heterocyclyl amides having an insecticidal effect
WO2002032887A1 (fr) * 2000-10-20 2002-04-25 Syngenta Limited Procede de preparation de 5-amino-3-alkylisothiazoles et de 5-amino-4-chloro-3-alkylisothiazoles
WO2003031636A1 (fr) * 2001-10-05 2003-04-17 Kaneka Corporation Procede de production de 3-hydroxy-pentanenitrile optiquement actif
US7148055B2 (en) 2001-10-05 2006-12-12 Kaneka Corporation Process for production of optically active 3-hydroxypentanenitrile
US8163756B2 (en) 2004-12-23 2012-04-24 Deciphera Pharmaceuticals, Llc Enzyme modulators and treatments
US8188113B2 (en) 2006-09-14 2012-05-29 Deciphera Pharmaceuticals, Inc. Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US7790756B2 (en) 2006-10-11 2010-09-07 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
US8143293B2 (en) 2007-04-20 2012-03-27 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
US8278331B2 (en) 2008-10-29 2012-10-02 Deciphera Pharmaceuticals, Llc N-acyl ureas exhibiting anti-cancer and anti-proliferative activities
CN103889979A (zh) * 2011-09-09 2014-06-25 桑多斯股份公司 用于制备头孢洛林酯的新方法
US8940756B2 (en) 2012-06-07 2015-01-27 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
USRE48731E1 (en) 2012-06-07 2021-09-14 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US12102620B2 (en) 2018-01-31 2024-10-01 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of mastocytosis
US11986463B2 (en) 2018-01-31 2024-05-21 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumor
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