EP3906230A1 - Composés contenant du fluor destinés à être utilisés en tant que réactifs nucléophiles pour transférer des groupes fonctionnels sur des composés organiques à valeur élevée - Google Patents

Composés contenant du fluor destinés à être utilisés en tant que réactifs nucléophiles pour transférer des groupes fonctionnels sur des composés organiques à valeur élevée

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Publication number
EP3906230A1
EP3906230A1 EP20701253.5A EP20701253A EP3906230A1 EP 3906230 A1 EP3906230 A1 EP 3906230A1 EP 20701253 A EP20701253 A EP 20701253A EP 3906230 A1 EP3906230 A1 EP 3906230A1
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European Patent Office
Prior art keywords
nmr
mhz
mmol
chloroform
alkyl
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EP20701253.5A
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German (de)
English (en)
Inventor
Matthew Hopkinson
Stefan DIX
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Freie Universitaet Berlin
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Freie Universitaet Berlin
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Publication of EP3906230A1 publication Critical patent/EP3906230A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2

Definitions

  • Fluorine-containing compounds for use as nucleophilic reagents for transferring functional groups onto high value organic compounds The present invention relates to fluorine-containing compounds for use as nucleophilic reagents for transferring functional groups onto high value organic compounds and methods for synthesizing them.
  • Fluoroalkyl groups in particular fluoroalkyl-containing thiol-groups, such as SCF 3 , are attracting increasing attention in medicinal chemistry as a substituent that when incorporated into pharmaceuticals and other biologically-active compounds, can improve their potency and bioavailability.
  • the SCF 3 group is one of the most lipophilic moieties available and can allow for an increase in the membrane permeability of drug targets.
  • Scheme 1 Selected examples of drug candidates containing SCF3 groups.
  • the synthesis of SCF3-containing molecules can be achieved using a number of different strategies.
  • a useful approach in the context of medicinal chemistry is direct trifluoromethylthiolation wherein the SCF3 moiety is attached directly as a whole intact group onto a target substrate.
  • These reactions can potentially be conducted on the same substrates used when installing other related groups (eg. CF 3 ) and thus are simple to incorporate into screening studies.
  • CF3X Cl, Br
  • F3CSSCF3 electrophilic trifluoromethylthiolation reactions.
  • R 2 , R 3 are in each case an alkyl, a cycloalkyl, an aryl, a heteroaryl, a halogen, a halogen substituted alkyl or both R 2 and R 3 are part of a cyclic system;
  • - X is S, O, Se, Te; preferably S, O, Se;
  • R 4 SO 3 - is R 4 SO 3 - with R 4 being H, C1-C10 alkyl, aryl, CaFbHc, in particular -OTf (CF 3 SO 3 - ), PhSO 3 - or p-Tos-; I-, Cl-, ClO 4 -, BF 4 -;
  • - a is 1-20, preferably 1-12, more preferably 1-8;
  • - c is 0-10, preferably 0-5, more preferably 0, 1, 2.
  • the compound of formulae (I) acts a source of nucleophilic -XC a F b H c , such as -SCF 3 . Unlike most existing species, this compound does not contain expensive metal cations and is purely organic in nature.
  • the compound of general formulae (I) is a solid that is easy to handle under ambient conditions and is bench-stable over extended periods.
  • R 1 is C1-C10 alkyl, preferably C1-C5 alkyl, more preferably C1-C3 alkyl.
  • R 1 is a methyl group (-CH3) or an ethyl group (-C2H5).
  • the moieties R 2 and R 3 are part of an aromatic system, preferably of a C6-C10 aryl ring, more preferably of a C6 aryl ring, which may be further substituted. This may comprise a non-substituted or substituted C6 aryl ring or non- substituted or substituted naphthyl ring.
  • the moieties have the following meaning: - R 1 is C1-C3 alkyl;
  • R 2 , R 3 are part of an unsubstituted or substituted C6 aryl ring or naphthyl ring, - X is S, O, Se;
  • R 4 being aryl or CaFbHc, in particular– OTf (CF3SO3-), p-Tos; Ph-SO3- ; or BF4-;
  • R 1 , X, Y, Z, a, b, c have one of the above meanings
  • R 5 is absent or a C1-C10 alkyl, a C1-C10 alkoxy, in particular C1-C5 alkoxy, or a halogen, in particular Cl or Br.
  • the present compound is of the general formulae (IIa)
  • R 1 is C1-C3 alkyl
  • R 5 is absent or C1-C5 alkoxy, or Cl.
  • X, Z, a, b, c have the above meanings.
  • the moiety is -XCaFb, as for example -XCF3, -XCF(CF3)2 or -XC8F17, in particular -SCF3, -SeCF3, -OCF3 or -SC8F17.
  • any perfluoralkyl moiety is suitable.
  • the moiety -XCaFbHc may be -XCF2H or -XCFH2, in particular - SCF2H or -SCFH2.
  • the moieties R 1 , R 2 , R 3 and R 5 can be non-substituted or further substituted.
  • substituted in particular in connection to alkyl, cycloalkyl, aryl or heteroaryl relates to the substitution of one or more atoms, usually H-atoms, by one or more of the following substituents: halogen, hydroxy, protected hydroxy, oxo, C 3 -C 10 -cycloalkyl, aryl, heteroaryl, naphthyl, imino, imido, isocyano, amino, protected amino, primary or secondary amino, heterocyclic ring, carbonate, imidazolyl, indolyl, pyrrolidinyl, C 1 -C 12 -alkoxy, C 1 -C 12 -acyl, C 1 -C 12 -acyloxy, nitro, nitroso, carboxy, ester, aldehyde, ketone,
  • R 1 , R 2 , R 3 , X, Y, Z, a, b, c have the above meanings.
  • a major advantage of the present compounds is their simple synthesis from relatively inexpensive precursor substrates.
  • G may be H, in particular in case of electrophilic or oxidative fluoroalkylation, or a leaving group such as a halogen, -XR (such as -SR, -SeR), -CN or others, in particular in case for nucleophilic fluoroalkylation.
  • a suitable starting material would be R-SH, R-S-S-R or R-Se-Se-R wherein R may be a benzothiazole or a benzoxazole.
  • the fluoroalkylating agent is selected from a group containing a compound of general formulae (VII) NaSO2CaFbHc wherein a, b and c have the above meanings.
  • a preferred variant of a fluoroalkylating agent is NaSO2CF3 (Langlois reagent). The reaction may be carried out under photoredox catalysis conditions.
  • At least one fluoroalkylating agent is selected from a group containing a compound of general formulae (VIII) Hal C a F b H c wherein Hal is I, Br, or Cl and wherein a, b, c have the above meanings.
  • a preferred variant of a fluoroalkylating agent of formulae (VIII) is IC a F b H c , such as ICF 3 or IC 8 F 17 .
  • the fluoroalkylating agent of formulae (VIII) is employed together with a suitable base (such as NaH or NaOH) under heating or irradiation with UVA light.
  • a suitable base such as NaH or NaOH
  • R-SH or R-SeH may be used as starting materials.
  • at least one alkylating agent selected from a group containing alkyl trifluoromethanesulfonate, alkyl iodide, trialkyl oxonium tetrafluoroborate, alkyl sulfate is employed for alkylating the intermediate compound of general formulae (VI).
  • the present compound can be used as a nucleophilic reagent for transferring a fluorine-containing functional group onto high value organic compounds, in particular pharmaceutical or agrochemical targets.
  • the present compound can be used as a nucleophilic reagent for transferring a fluorine-containing functional group onto alcohols, carboxylic acids or even alkyl halogenides, such as alkyl bromides.
  • alkyl bromides may react with the present compound in a silver-mediated reaction.
  • Example 1 Synthesis of 3-methyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium trifluoromethanesulfonate) (BT-SCF3, Compound 1)
  • Compound 1 can bes prepared in two steps from the cheap starting material 2,2 ⁇ - dithiobis(benzothiazole) (MBTS) which is a bulk chemical used in the industrial vulcanisation of rubber.
  • MBTS 2,2 ⁇ - dithiobis(benzothiazole)
  • the trifluoromethyl group can be installed using the relatively inexpensive reagent NaSO 2 CF 3 (Langlois’ reagent) using published procedures leading to the intermediate compound.
  • This species is a stable, non-reactive heteroaromatic compound that can be readily purified without decomposition.
  • methylation of the ring nitrogen using methyl trifluoromethanesulfonate cleanly affords the reagent 1 which is obtained as a pure compound upon simple filtration.
  • the Langlois reagent is used as the CF 3 source, the two-step synthetic strategy towards compound 1 can be modified to enable even less expensive trifluoromethylthiolating reagents to be employed.
  • compound 1 can be prepared in two steps from the inexpensive industrial compound 2-mercaptobenzothiazole (MBT) using CF 3 I as a trifluoromethylating reagent in the presence a base and UV light irradiation.
  • MBT 2-mercaptobenzothiazole
  • CF 3 I a trifluoromethylating reagent
  • the procedure for this first step is described in Example 5 and the general procedure for the methylation in described in Example 8.
  • the same general approach for the first fluoroalkylation step can be used to prepare related compounds featuring longer perfluoroalkyl chains as described in Examples 3 and 11.
  • alternative strategies for the first step could be potentially realised.
  • nucleophilic trifluoromethylation of disulfides or other sulfur compounds has been reported using the least expensive and therefore most industrially-attractive CF3 source fluoroform (HCF3).
  • Compound 1 (BT-SCF 3 ) was employed in deoxytrifluoromethylthiolation reactions of aliphatic alcohols (Hopkinson, Chem. Eur. J. 2019, 25, 7635, see scheme 4a). This reaction is very useful as hydroxy groups are widespread in organic molecules and the ability to directly convert them into SCF 3 groups avoids the preparation of alkyl halide or pseudohalide precursors, reducing the overall number of synthetic steps required to prepare SCF 3 -containing molecules.
  • Example 14 In addition to acting as a reagent for deoxytrifluoromethylthiolation, compound 1 can also serve as a more general source of -SCF 3 upon addition of a suitable metal or ammonium salt activator. This could potentially be achieved catalytically; AgSCF 3 , for example, could be generated in situ upon activation of 1 with small amounts a soluble, inexpensive silver(I) salt such as Ag 2 O or AgNO 3 (see Scheme 4b).
  • Example 19 The general procedure for deoxytrifluoromethylselenylation of alcohols is described in Example 19.
  • An alternative method for the synthesis of Compound 5 uses ICF 3 as a trifluoromethylating reagent. This method is described in Example 20.
  • Example 5 General Procedure for the Trifluoromethylation of Mercaptobenzothiazoles
  • Mercaptobenzothiazole (1.0 eq) and NaOH (1.1 eq) were dissolved in MeCN/H 2 O (9:1, 0.5 M)
  • the Schlenk flask was closed and the mixture frozen by using a liquid nitrogen bath.
  • High vacuum was applied to the Schlenk flask and afterwards CF 3 I (2.0 eq) was condensed into the frozen mixture.
  • the nitrogen bath was removed, Argon was added until standard pressure was achieved and an empty balloon was attached to the Schlenk flask.
  • Example 6 General Procedure for the Trifluoromethylation of Mercaptobenzoxazoles
  • 1,2-Bis(benzo[d]thiazol-2-yl)diselane (0.8 eq, 3.2 mmol, 1.36 g) was suspended in degassed MeOH/THF (4:1, 40 mL) and NaBH4 (1.6 eq, 6.4 mmol, 0.24 g) was added portionwise under vigorous stirring at 0 °C. After 10 min degassed 1M HCl (80 mL) was added and the precipitate was washed with degassed H2O (3 x 50 mL).
  • Example 12 General Procedures for the Deoxytrifluoromethylthiolation reaction of Alcohols with BT-SCF 3 Method A: The primary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF 3 (250 mg, 0.625 mmol, 1.25 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr) 2 (174 mL,1.0 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 1-2 h at rt. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
  • Method B The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (399 mg, 1.0 mmol, 2.0 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (174 mL,1.0 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
  • Method C The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (133 mg, 0.33 mmol, one third of 2.0 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (174 mL, 1.00 mmol, 2.00 eq) was added dropwise and the reaction mixture was stirred at rt. After 20 minutes, a second portion of BT-SCF3 (133 mg, 0.33 mmol) was added followed by a third portion (133 mg, 0.33 mmol) after an additional 20 minutes. The reaction was allowed to stir at rt for a further 80 minutes (total reaction time of 2 h) before being concentrated in vacuo and purified by column chromatography over silica gel.
  • Method D The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (200 mg, 0.50 mmol, one third of 3.0 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (261 mL, 1.5 mmol, 3.0 eq) was added dropwise and the reaction mixture was stirred at rt. After 20 minutes, a second portion of BT-SCF3 (200 mg, 0.50 mmol) was added followed by a third portion (200 mg, 0.50 mmol) after an additional 20 minutes.
  • (4-(4-Methoxyphenyl)butyl)(trifluoromethyl)sulfane Prepared from 4-(4-methoxyphenyl)-1-butanol (88 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (89 mg, 0.34 mmol, 68%).
  • R f (n- pentane/CH 2 Cl 2 , 9:1): 0.29. 2-(((Trifluoromethyl)thio)methyl)isoindoline-1,3-dione
  • R f (n-pentane): 0.93. (4-Nitrobenzyl)(trifluoromethyl)sulfane
  • R f (n-pentane): 0.87. (Naphthalen-2-ylmethyl)(trifluoromethyl)sulfane
  • Example 16 Deoxydifluoroselenylation of Carboxylic Acids with BT-SeCF 2 H
  • n-Octanoic acid (1.0 eq, 0.5 mmol, 72.1 mg) and NaH (2 eq, 1.0 mmol, 24 mg) were suspended in dry THF (5.0 mL) and stirred for 15 min at 0 °C.
  • BT-SeCF2H (1.05 eq, 0.525 mmol, 225 mg) was added and the mixture was allowed to stir for another 2 h at rt. Afterwards, the mixture was quenched with sat. NH4Cl solution.
  • the organic phase was washed with H2O (1 x 5 mL), the aqueous phases were extracted with DCM (2 x 10 mL) and the combined organic phases were dried over Na2SO4 and concentrated in vacuo.
  • the crude product was purified by column chromatography (SiO2, Pentane). The product was obtained as a colourless oil (53 mg, 0.21 mmol, 42 %).
  • NEt(iPr) 2 70 mL, 0.40 mmol, 2.0 eq was then added dropwise and the reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
  • Method F The aliphatic alcohol (0.20 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT-SeCF3 (112 mg, 0.250 mmol, 1.25 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (70 mL, 0.40 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
  • Method G The aliphatic alcohol (0.20 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT-SeCF 3 (179 mg, 0.400 mmol, 2.00 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (70 mL, 0.40 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel. Characterization Data for Deoxytrifluoromethylselenylation Products (4-Nitrobenzyl)(trifluoromethyl)selane
  • Example 20 Alternative Method for the 3-Methyl-2-((trifluoromethyl)selanyl) benzo[d]thiazol-3-ium trifluoromethanesulfonate (BT-SeCF3, Compound 5) Synthesis of 2-(trifluoromethyl)selenyl)benzo[d]thiazole Bis(benzothiazole)diselenide (4.20 g, 9.85 mmol, 0.50 eq) was suspended in methanol (100 mL, degassed using the freeze-pump-thaw technique) and THF (25 mL, degassed using the freeze-pump-thaw technique) in a 3-necked round-bottomed flask under argon and the mixture was cooled to 0 °C.
  • methanol 100 mL, degassed using the freeze-pump-thaw technique
  • THF 25 mL, degassed using the freeze-pump-thaw technique

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés de formules générales (I) et leur utilisation en tant que réactifs.
EP20701253.5A 2019-01-03 2020-01-02 Composés contenant du fluor destinés à être utilisés en tant que réactifs nucléophiles pour transférer des groupes fonctionnels sur des composés organiques à valeur élevée Withdrawn EP3906230A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19150201.2A EP3677576A1 (fr) 2019-01-03 2019-01-03 Composés contenant du fluor à utiliser en tant que réactifs nucléophiles pour transférer des groupes fonctionnels sur des composés organiques à haute valeur
PCT/EP2020/050031 WO2020141195A1 (fr) 2019-01-03 2020-01-02 Composés contenant du fluor destinés à être utilisés en tant que réactifs nucléophiles pour transférer des groupes fonctionnels sur des composés organiques à valeur élevée

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EP20701253.5A Withdrawn EP3906230A1 (fr) 2019-01-03 2020-01-02 Composés contenant du fluor destinés à être utilisés en tant que réactifs nucléophiles pour transférer des groupes fonctionnels sur des composés organiques à valeur élevée

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CN112358427B (zh) * 2020-11-02 2021-08-31 山东大学 一种三氟甲硫酯类化合物的合成方法
CN112778173B (zh) * 2021-02-25 2022-08-19 山东领海生物科技有限公司 一种三氟甲烷硫醇银(i)的合成方法
CN114835646B (zh) * 2022-06-17 2024-01-30 清华大学 一种咪唑三氟甲硫基试剂及其合成应用

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CN105985266B (zh) * 2015-01-30 2018-02-16 中国科学院上海有机化学研究所 三氟甲硫基化试剂、制备方法及其应用

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