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WO2012028162A1 - Procédé de fabrication d'oxindoles et d'anilines substituées en position ortho et leur utilisation en tant que produits intermédiaires pour des synthèses - Google Patents

Procédé de fabrication d'oxindoles et d'anilines substituées en position ortho et leur utilisation en tant que produits intermédiaires pour des synthèses Download PDF

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Publication number
WO2012028162A1
WO2012028162A1 PCT/EP2010/005360 EP2010005360W WO2012028162A1 WO 2012028162 A1 WO2012028162 A1 WO 2012028162A1 EP 2010005360 W EP2010005360 W EP 2010005360W WO 2012028162 A1 WO2012028162 A1 WO 2012028162A1
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Prior art keywords
alkyl
formula
compounds
substituted
aniline
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German (de)
English (en)
Inventor
Mark James Ford
Gunter Karig
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Bayer CropScience AG
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Bayer CropScience AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups

Definitions

  • the invention relates to the technical field of chemical synthesis of biologically active compounds, preferably for intermediates for the
  • a class of compounds which can be prepared in this way are e.g. optionally substituted 3-alkylthioindole-2-ones (3- (alkylsulfanyl) -1,3-dihydro-2H-indol-2-ones), which in turn are substituted into optionally substituted 2-oxindoles (1,3-dihydro-2H-indole-1-ol) 2-one) can be implemented.
  • Optionally substituted oxindoles and their precursors, such as optionally substituted 3-alkylthioindole-2-ones are versatile
  • chlorinating agent e.g., tert-butyl hypochlorite, t-BuOCl
  • C tertiary amine base (e.g., triethylamine)
  • the chlorinating agent of choice is the unstable and explosive tert-butyl hypochlorite, since the by-product of the chlorination then gives the neutral tert-butyl alcohol.
  • SO 2 Cl 2 sulfuryl chloride
  • a second non-nucleophilic base such as "proton sponge” was used (Johnson, J. Org. Chem. 1990, 55, 1374, Warpehoski, Tetrahedron Lett., 1986, 27, 4103). Since both variants are carried out at low temperatures, however, this is not a viable solution on a technical (industrial) scale.
  • chlorinating agent e.g., tert-butyl hypochlorite, t-BuOCl
  • C tertiary amine base (e.g., triethylamine)
  • Compounds (4) can be mechanistically produced only via the compounds (2). Inevitably, the use of a base (C) for rearrangement to the compounds (4) is necessary. In the literature, an additional base to aniline (compounds of formula Q) is called as "proton sponge" or triethylamine. The additional base used in these processes must inevitably be recovered in industrial (industrial) scale syntheses and separated from the unreacted compounds of the formula Q in order to be able to use the re-isolated compounds of the formula Q as starting materials.
  • the N-chloroaniline can be converted into a chlorinated ring in the aromatics, as well as other oxidation products (dimers) form.
  • the much less electron-rich and thus much less reactive for core chlorination acetanilide forms only core chlorination with tert-butyl hypochlorite at 0 ° C. (Lengyel et al., Synth., Comm., 1998, 28 (10) , 1891-1896).
  • the sulfonium intermediates (2) or (3) can be eliminated in the presence of bases to form the reactive by-product (5), which would condense, for example, with an aniline, irreversibly producing the minor component (6) (see Scheme 4). , This corresponds to the so-called Pummerer oxidation of the R2-CH-R3 radical.
  • the compounds (4) thus prepared should preferably also have a
  • the invention relates to a process for the preparation of compounds of the formula (4):
  • R1 C1-C6 alkyl, substituted alkyl, aryl or substituted aryl,
  • R2 H, C1-C6 alkyl or substituted alkyl
  • R4 F, Cl, Br, I, CF 3, CN, N0 2, COX;
  • X OR1, SR1, NR2R2 ', wherein R2' is as R2 defined above and may be the same or different than R2, preferably F or Cl, in particular 2-F;
  • n 1 - 4, preferably 1 - 2, in particular 1;
  • R5 H, C1-C6 alkyl or substituted alkyl
  • the resulting selective and clean reaction with good yields is particularly surprising and contrary to the belief that it is reported that good yields can only be achieved when the unstable N-chloro- (1) or N-sulfonium- (2) Scheme 2) below -65 ° C, normally at -78 ° C (Gassman et al., J. Am. Chem Soc, 1974, 96 (17), 5508; Gassman et al. , J. Am. Chem. Soc., 1974, 96 (17), 5512, WO 96/41799 A1).
  • the thioether (compound of the formula W) used in the process according to the invention has the following structure:
  • R1 C1-C6 alkyl, substituted alkyl, aryl or substituted aryl, preferably
  • R2 H, C1-C6 alkyl or substituted alkyl
  • R3 electron withdrawing or activating group, such as -CO-R1; -CO-X,
  • R2 OR1, SR1, NR2R2 ', where R2 "is defined as R2 and may be the same or different than R2; R2 and R2' may form a ring;
  • the aniline (compound of the formula Q) used in the process according to the invention has the following structure:
  • R4 F, Cl, Br, I, CF3 > CN, NO2 > COX;
  • R5 H, C1-C6 alkyl or substituted alkyl
  • a hydrogen atom is in the ortho position to the nitrogen atom of the aniline.
  • the ring may be substituted with one or more substituents R4. As far as reference is made below to aniline, the above-mentioned compound is meant.
  • Suitable chlorinating agents are all those known to the person skilled in the art
  • Chlorinating agents in question such as trichloroisocyanuric acid, tert-butyl hypochlorite and sulfuryl chloride.
  • chlorinating agents such as sulfuryl chloride (SO 2 Cl 2 ), which surprisingly generate HCl against the literature, without the need for a second, non-nucleophilic base.
  • reaction in the process according to the invention can be carried out with various conditions
  • non-polar organic solvents such as chloroalkanes (for example dichloromethane and dichloroethane), aromatics (for example benzene, toluene, xylene), haloaromatics (for example chlorobenzene, dichlorobenzene),
  • chloroalkanes for example dichloromethane and dichloroethane
  • aromatics for example benzene, toluene, xylene
  • haloaromatics for example chlorobenzene, dichlorobenzene
  • substituted aromatics for example, benzotrifluoride, chlorobenzotrifluoride,
  • Chlorotoluene, chloroylol alone or as mixtures with one another or as
  • the reaction may preferably be carried out in an ester solvent such as, for example, C1-C6 alkyl acetate (for example, methyl acetate, ethyl acetate, n-propyl acetate, iso-propyl acetate, 2-methyl-prop-1-ylacetate, n-butyl acetate, But -2-ylacetat, Pentylacetate, Hexylacetate and Cyclalkylacetate, C1-C6 alkyl and Cycloalkylpropionates, C1-C6 alkyl and cycloalkyl-n-butyrates, -iso-butyrates, - pentanoates and -hexanoates and -cyclopentanoates and -cyclohexanoates) or in mixtures thereof or in admixture with other solvents.
  • Ester solvents have the advantage over other solvents, such as the dichloromethane used in the literature, that
  • chlorinating agent To use chlorinating agent.
  • the chlorinating agent is added to a mixture of one equivalent of the thioether (compound of formula W) and a technically economical excess of the aniline (compound of formula Q) of 2.0 to 5.0 equivalents, preferably 2.0 to 3.0 equivalents preferably 2.0 to 2.5 equivalents added.
  • the chlorinating agent may preferably be prediluted with a solvent or a solvent mixture and may preferably be pre-cooled.
  • a particular embodiment of the invention is that, for good product yields, a portion of the aniline (between 1 and 99% by weight, preferably between 20 and 80% by weight, particularly preferably 30 to 70% by weight of the total amount of aniline) is separated from but simultaneously or partially simultaneously with the chlorinating agent.
  • a particular embodiment of the invention with regard to a simplified (industrial) process sequence is that in the process according to the invention for the preparation of compounds of formula (4) can be dispensed with the addition of an additional tertiary amine, whereby the reuse of unreacted, re-isolated aniline (Compound of formula Q) is simplified.
  • the invention also provides the process for the preparation of compounds of the formulas (7) and (8):
  • R1 C1-C6 alkyl, substituted alkyl, aryl or substituted aryl,
  • R2 H, C1-C6 alkyl or substituted alkyl
  • R4 F, Cl, Br, I, CF 3) CN, N0 2, COX;
  • X OR1, SR1, NR2R2 ', wherein R2' is as R2 defined above and may be the same or different than R2, preferably F or Cl, in particular 2-F;
  • n 1 - 4, preferably 1 - 2, in particular 1;
  • R5 H, C1-C6 alkyl or substituted alkyl
  • R6 C1-C6 alkyl or substituted alkyl, preferably C1-C4 alkyl or OH;
  • the intermediate 7-fluoro-3-methylthio-oxindole was synthesized by way of the synthesis of a 7-fluoroisatin (Wierenga et al., Tetrahedron Lett. 1983, 24, 2437).
  • An example of a 7-fluoro-3-methylthio-4-nitro-oxindole prepared by the Gassman process using proton sponge and triethylamine can be found in Tetrahedron Lett. 2005, 46, 4613.
  • the invention therefore also provides the compounds of the formula (4 ') which are obtainable by the process according to the invention described above and which are new, as intermediates for the preparation of fine chemicals and active ingredients from the pharmaceutical or agricultural sector:
  • R1 C2-C6 alkyl, benzyl
  • R4 2-F, 2-CI
  • R5 H, C1-C4 alkyl
  • R1 ethyl
  • R3 C0 2 methyl, C0 2 ethyl
  • R4 2-F, 2-CI
  • R5 H, methyl, ethyl
  • the invention also provides end products of the formula (7 ') which are obtainable by the process according to the invention described above and which are new: in which
  • R1 C2-C6 alkyl, benzyl
  • R4 7-F, 7-CI
  • R5 H, C1-C4 alkyl
  • R6 C1-C6 alkyl
  • R1 ethyl
  • R4 7-F, 7-CI
  • R5 H, methyl
  • R6 C1-C6 alkyl
  • the invention also provides the compounds of the formula (8 ') which are obtainable by the process according to the invention described above and which are novel, as intermediates for the preparation of fine chemicals and active ingredients from the pharmaceutical or agricultural sector:
  • R4 7-F, 7-CI
  • R5 H, C1-C4 alkyl
  • R1 ethyl
  • R4 7-F, 7-CI
  • R5 H, methyl
  • the invention also relates to the use of the new compounds of the formulas (4 '), (7') and (8 ') obtained according to the invention prepared by the process according to the invention for the preparation of
  • radicals alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino and alkylthio and the corresponding unsaturated and / or substituted radicals in the carbon skeleton are each straight-chain or branched. Unless specifically stated, these radicals are the lower carbon skeletons, e.g. with 1 to 6 C atoms or with unsaturated groups having 2 to 6 C atoms, preferred.
  • Alkyl radicals also in the composite meanings such as alkoxy, haloalkyl, etc., mean e.g. Methyl, ethyl, n- or i-propyl, n-, i-, t- or 2-butyl, pentyls, hexyls, such as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyls, such as n-heptyl, 1-methylhexyl and 1, 4-dimethylpentyl.
  • Cycloalkyl means a carbocyclic saturated ring system preferably having 3 to 8 C atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Halogen is, for example, fluorine, chlorine, bromine or iodine.
  • Haloalkyl means by halogen, preferably by fluorine, chlorine and / or bromine, in particular by fluorine and / or chlorine, partially or completely substituted alkyl, e.g.
  • Haloalkoxy is, for example, OCF 3 , OCHF 2 , OCH 2 F, CF 3 CF 2 O, OCH 2 CF 3 and OCH 2 CH 2 Cl; the same applies to other halogen-substituted radicals.
  • Aryl is a mono-, bi- or polycyclic aromatic system
  • phenyl for example, phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, pentalenyl, fluorenyl and the like, preferably phenyl.
  • a heterocyclic radical or ring may be saturated, unsaturated or heteroaromatic; it preferably contains one or more, in particular 1, 2 or 3 heteroatoms in the heterocyclic ring, preferably from the group N, O, and S; it is preferably an aliphatic heterocyclyl radical having 3 to 7 ring atoms or a heteroaromatic radical having 5 or 6 ring atoms.
  • the heterocyclic radical may be e.g. a heteroaromatic radical or ring (heteroaryl), e.g.
  • a mono, bi or polycyclic aromatic system in which at least 1 ring contains one or more heteroatoms for example pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, furyl, pyrrolyl, pyrazolyl and imidazolyl, or is a partially or fully hydrogenated radical such as oxiranyl, pyrrolidyl, piperidyl, piperazinyl, dioxolanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydrofuryl.
  • substituted heterocyclic radical are those mentioned below
  • oxo may also be attached to the hetero ring atoms, which may exist in different oxidation states, e.g. at N and S, occur.
  • Substituted radicals such as a substituted alkyl, aryl, phenyl, benzyl, Heterocyclyl and heteroaryl, mean, for example, one of
  • Substituents for example, one or more, preferably, 2 or 3 radicals from the group halogen, alkoxy, haloalkoxy, alkylthio, hydroxy, amino, nitro, carboxy, cyano, azido, alkoxycarbonyl, alkylcarbonyl, formyl, carbamoyl, mono- and dialkylaminocarbonyl, sulfamoyl, Mono and dialkylaminosulfonyl, substituted amino such as acylamino, mono and dialkylamino, and alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl and, in the case of cyclic radicals, also alkyl and
  • Haloalkyl mean; in the term "substituted radicals" such as substituted alkyl etc. are as substituents in addition to those mentioned saturated
  • hydrocarbon-containing radicals corresponding unsaturated aliphatic and aromatic radicals such as optionally substituted phenyl, phenoxy, etc.
  • radicals having C atoms those having 1 to 4 C atoms, in particular 1 or 2 C atoms, are preferred. Preferred are usually
  • Substituents from the group halogen e.g. Fluorine and chlorine, (C 1 -C 4) alkyl, preferably methyl or ethyl, (C 1 -C 4) haloalkyl, preferably trifluoromethyl, (C 1 -C 4) alkoxy, preferably methoxy or ethoxy, (C 1 -C 4) haloalkoxy, nitro and cyano.
  • Particularly preferred are the substituents methyl and fluorine.
  • the inventive method for obtaining compounds of formula (4) is for example, carried out so as to submit aniline (compound of formula Q) and thioether (compound of formula W) in the solvent and, preferably under inert gas, cooled down.
  • aniline compound of formula Q
  • thioether compound of formula W
  • To this stirred solution a mixture of chlorinating agent and solvent is added dropwise.
  • the reaction is then heated and diluted with an aqueous acid.
  • the phases are separated and the organic phase is washed with an aqueous acid.
  • the organic phase is then dried and, if the compound of formula (4) is a solid, concentrated in vacuo and possibly an anti-solvent added and stirred for several hours.
  • the solid (compound of formula (4)) is filtered off and mixed with the anti-solvent or solvent mixture
  • the process according to the invention for obtaining compounds of the formulas (7) and (8) is carried out, for example, by introducing aniline (compound of the formula Q) and thioether (compound of the formula W) in the solvent and cooling it down, preferably under protective gas.
  • aniline compound of the formula Q
  • thioether compound of the formula W
  • a mixture of chlorinating agent and solvent is added dropwise.
  • the reaction is then heated and diluted with an aqueous acid.
  • the phases are separated and the organic phase is washed with an aqueous acid.
  • the organic phase is then, possibly for compounds of the formula (7) and preferably for compounds of the formula (8), admixed with an acid catalyst and stirred for several hours. 90% of the solvent is then removed in vacuo and an anti-solvent added and stirred for several hours.
  • the solid (compound of formula (7) or (8)) is filtered off and washed with the anti-solvent or solvent mixture.
  • N-butyl acetate (67 ml) was added dropwise over 30 minutes at an internal temperature of -53 to -48 ° C.
  • the reaction was warmed to 10 ° C, diluted with 0.4N hydrochloric acid (110 ml) and stirred for 5 min.
  • the phases were separated and the organic phase was washed with 0.4N hydrochloric acid (1 x 110 ml).
  • the organic phase was treated with conc. HCl (0.2 ml).
  • the reaction mixture was stirred for 24 hours, once more with conc. HCl (0.05 ml) and allowed to stand for 16 hours at 4 ° C. About 90% of the solvent was removed in vacuo, heptane (120 ml) added and stirred for 5 hours.
  • Acetic acid n-butyl ester (10ml) added directly in the reaction solution in 25 minutes, the temperature rising to -29 ° C. After 15 minutes at -30 ° C, the reaction was warmed to 10 ° C and 0.4N hydrochloric acid (110ml) was added dropwise. The phases were separated and the organic phase was washed with 0.4N hydrochloric acid (1 x 110 ml). The organic phase was treated with 10% HCl in MeOH (1, 9ml) and stirred for 16 hours. 95% of the solvent was removed in vacuo, Heptane (120ml) was added and the reaction mixture stirred for 3 hours. The solid was filtered off and washed with heptane (2 x 50 ml). 7-fluoro-3-methylthio-oxindole (8.87 g, 70.0% of theory) is obtained.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne un procédé de fabrication de composés de formule (4), suivant lequel on fait réagir un mélange d'une aniline (composé de formule Q) avec un thioéther (composé de formule W) en présence de chlorure de sulfuryle en tant qu'agent de chloration et d'un solvant organique à une température de réaction se situant dans une plage entre -60°C et -10°C. Dans un procédé ultérieur, ce composé est transformé en présence d'un catalyseur acide en l'indole de formule (7) ou en l'oxindole de formule (8).
PCT/EP2010/005360 2010-09-01 2010-09-01 Procédé de fabrication d'oxindoles et d'anilines substituées en position ortho et leur utilisation en tant que produits intermédiaires pour des synthèses Ceased WO2012028162A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014041052A1 (fr) 2012-09-17 2014-03-20 Bayer Cropscience Ag Procédé de production d'anilines orthosubstituées en continu dans un réacteur à circulation
US9850203B2 (en) 2013-09-26 2017-12-26 Pharmakea, Inc. Autotaxin inhibitor compounds

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EP0636608A1 (fr) 1993-07-30 1995-02-01 Sanofi Dérivés du 1-benzènesulfonyl-1,3-dihydro-indol-2-one, leur préparation, les compositions pharmaceutiques en contenant
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WO2014041052A1 (fr) 2012-09-17 2014-03-20 Bayer Cropscience Ag Procédé de production d'anilines orthosubstituées en continu dans un réacteur à circulation
US9527808B2 (en) 2012-09-17 2016-12-27 Bayer Cropscience Ag Continuous method for producing ortho-substituted anilines in a flow reactor
KR102057717B1 (ko) 2012-09-17 2019-12-19 바이엘 크롭사이언스 악티엔게젤샤프트 유동반응기에서 오르토 치환된 아닐린의 연속 제조방법
US9850203B2 (en) 2013-09-26 2017-12-26 Pharmakea, Inc. Autotaxin inhibitor compounds

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